Sample records for locally-advanced non-small cell

  1. Defining local-regional control and its importance in locally advanced non-small cell lung carcinoma.

    PubMed

    Machtay, Mitchell; Paulus, Rebecca; Moughan, Jennifer; Komaki, Ritsuko; Bradley, J Effrey; Choy, Hak; Albain, Kathy; Movsas, Benjamin; Sause, William T; Curran, Walter J

    2012-04-01

    Local-regional control (LRC) rates for non-small cell lung cancer after chemoradiotherapy were studied (using two different definitions of LRC) for the association between LRC and survival. Seven legacy Radiation Therapy Ooncology Group trials of chemoradiotherapy for locally advanced non-small cell lung cancer were analyzed. Two different definitions of LRC were studied: (1) freedom from local progression (FFLP-LRC), the traditional Radiation Therapy Oncology Group methodology, in which a failure is intrathoracic tumor progression by World Health Oorganization criteria; and (2) response-mandatory (strict-LRC), in which any patient not achieving at least partial response was considered to have failure at day 0. Testing for associations between LRC and survival was performed using a Cox multivariate model that included other potential predictive factors. A total of 1390 patients were analyzed. The LRC rate at 3 years was 38% based on the FFLP-LRC definition and 14% based on the strict-LRC definition. Performance status, concurrent chemotherapy, and radiotherapy dose intensity (biologically equivalent dose) were associated with better LRC (using either definition). With the strict-LRC definition (but not FFLP-LRC), age was also important. There was a powerful association between LRC and overall survival (p, 0.0001) on univariate and multivariate analyses. Age, performance status, chemotherapy sequencing, and biologically equivalent dose were also significantly associated with survival. Histology and gender were also significant if the strict-LRC model was used. LRC is associated with survival. The definition of LRC affects the results of these analyses. A consensus definition of LRC, incorporating functional imaging and/or central review, is needed, with the possibility of using LRC as a surrogate end point in future trials.

  2. Targeted therapy for localized non-small-cell lung cancer: a review

    PubMed Central

    Paleiron, Nicolas; Bylicki, Olivier; André, Michel; Rivière, Emilie; Grassin, Frederic; Robinet, Gilles; Chouaïd, Christos

    2016-01-01

    Targeted therapies have markedly improved the management of patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy in localized NSCLC is less well established. The aim of this review is to analyze trials of targeted therapies in localized NSCLC. In patients with wild-type EGFR, tyrosine kinase inhibitors have shown no efficacy in Phase III trials. Few data are available for EGFR-mutated localized NSCLC, as routine biological profiling is not recommended. Available studies are small, often retrospectives, and/or conducted in a single-center making it difficult to draw firm conclusions. Ongoing prospective Phase III trials are comparing adjuvant tyrosine kinase inhibitor administration versus adjuvant chemotherapy. By analogy with the indication of bevacizumab in advanced NSCLC, use of antiangiogenic agents in the perioperative setting is currently restricted to nonsquamous NSCLC. Several trials of adjuvant or neoadjuvant bevacizumab are planned or ongoing, but for the moment there is no evidence of efficacy. Data on perioperative use of biomarkers in early-stage NSCLC come mainly from small, retrospective, uncontrolled studies. Assessment of customized adjuvant or neoadjuvant therapy in localized NSCLC (with or without oncogenic driver mutations) is a major challenge. PMID:27462164

  3. Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-07-01

    Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Bladder Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Transitional Cell Carcinoma of the Bladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  4. [Prognostic factors of advanced stage non-small-cell lung cancer].

    PubMed

    Kwas, H; Guermazi, E; Khattab, A; Hrizi, C; Zendah, I; Ghédira, H

    2017-09-01

    Primary lung cancer is the leading cause of cancer death in men in the world. Although the introduction of new drugs, new therapeutic strategies and despite therapeutic advances, the prognosis is relatively improved during the last years. To evaluate the prognosis of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) and to identify prognostic factors at these stages. A retrospective study, including 140 cases of locally advanced or metastatic NSCLC diagnosed in our department between 2003 and 2013. The average age was 61±10 years (35 to 90 years). Sex ratio was 18. The delays management were 80±25 days for presentation, 45±20 days for the diagnostic, while the treatment delay was 8±2.33 days. The cancer was at stage IIIA in 14%, IIIB in 27% and IV in 59%. Six months and one-year survival was between 50 and 74% and between 9 and 25%, respectively. Better survival was observed in patients with NSCLC on stage III, having better performance status, having comorbid conditions, with prolonged delays management, a short therapeutic delay and patients who received specific antitumor treatment. The prognostic factors in locally advanced and metastatic NSCLC in our patients were: stage of cancer, performance status, comorbid conditions, delay of management and specific antitumoral treatment. These factors should be considered in the management of patients with advanced NSCLC. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Clinical outcomes of black vs. non-black patients with locally advanced non-small cell lung cancer.

    PubMed

    Vyfhuis, Melissa A L; Bhooshan, Neha; Molitoris, Jason; Bentzen, Søren M; Feliciano, Josephine; Edelman, Martin; Burrows, Whitney M; Nichols, Elizabeth M; Suntharalingam, Mohan; Donahue, James; Nagib, Marc; Carr, Shamus R; Friedberg, Joseph; Badiyan, Shahed; Simone, Charles B; Feigenberg, Steven J; Mohindra, Pranshu

    2017-12-01

    The black population remains underrepresented in clinical trials despite reports suggesting greater incidence and deaths from locally advanced non-small cell lung cancer (NSCLC). We determined outcomes for black and non-black patients in a well-annotated cohort treated with either definitive chemoradiation (CRT; bimodality) or CRT followed by surgery (trimodality therapy). A retrospective analysis of 355 stage III NSCLC patients treated with curative intent at the University of Maryland, Medical Center, between January 2000-December 2013 was performed. The Kaplan-Meier approach and the Cox proportional hazards models were used to analyze overall survival (OS) and freedom-from-recurrence (FFR) in black and non-black patients. The chi-square test was used to compare categorical variables. Black patients comprised 42% of the cohort and were more likely to be younger (p<0.0001), male (p=0.030), single (p<0.0001), reside in lower household income zipcodes (p<0.0001), have an Eastern Cooperative Oncology Group (ECOG) performance status >0 (p<0.001), and less likely to undergo surgery (p<0.0001). With a median follow-up of 15 months for all patients and 89 months for surviving patients (range:1-186 months), median OS times for black and non-black patients were 22 and 24 months, respectively (p=0.698). FFR rates were also comparable between the two groups (p=0.468). Surgery improved OS in both cohorts. Race was not a significant predictor for OS or FFR even when adjusted for other factors. We found similar oncologic outcomes in black and non-black NSCLC patients when treated with curative intent in a comprehensive cancer center setting, despite epidemiologic differences in presentation and receipt of care. Future efforts to improve outcomes in black patients could focus on addressing modifiable social disparities. Copyright © 2017. Published by Elsevier B.V.

  6. Phase II study. Concurrent chemotherapy and radiotherapy with nitroglycerin in locally advanced non-small cell lung cancer.

    PubMed

    Arrieta, Oscar; Blake, Mónika; de la Mata-Moya, María Dolores; Corona, Francisco; Turcott, Jenny; Orta, David; Alexander-Alatorre, Jorge; Gallardo-Rincón, Dolores

    2014-05-01

    Nitroglycerin, a nitric oxide donor agent, reduces the expression of hypoxia-inducible factor-1α (HIF-1α) and could be a normalizer of the tumor microenvironment. Both factors are associated with chemo-radio-resistance. The aim of this study was to determine the safety profile and efficacy of nitroglycerin administration with chemo-radiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). This is a phase II trial of locally advanced NSCLC patients treated with cisplatin and vinorelbine plus concurrent nitroglycerin with radiotherapy. A 25-mg NTG patch was administered to the patients for 5 days (1 day before and 4 days after chemotherapy induction and consolidation) and all day during chemo-radiotherapy. VEGF plasmatic level was determined before and after two cycles of chemotherapy. Thirty-five patients were enrolled in this trial. Sixty-three percent of patients achieved an overall response after induction of chemotherapy, and 75% achieved an overall response after chemo-radiotherapy. The median progression-free survival was 13.5 months (95% CI, 8.8-18.2), and the median overall survival was 26.9 months (95% CI, 15.3-38.5). Reduction of VEGF level was associated with better OS. The toxicity profile related to nitroglycerin included headache (20%) and hypotension (2.9%). The addition of nitroglycerin to induction chemotherapy and concurrent chemoradiotherapy in patients with locally advanced NSCLC has an acceptable toxicity profile and supports the possibility to add nitroglycerin to chemotherapy and radiotherapy. A randomized trial is warranted to confirm these findings. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung cancer.

    PubMed

    Nestle, Ursula; De Ruysscher, Dirk; Ricardi, Umberto; Geets, Xavier; Belderbos, Jose; Pöttgen, Christoph; Dziadiuszko, Rafal; Peeters, Stephanie; Lievens, Yolande; Hurkmans, Coen; Slotman, Ben; Ramella, Sara; Faivre-Finn, Corinne; McDonald, Fiona; Manapov, Farkhad; Putora, Paul Martin; LePéchoux, Cécile; Van Houtte, Paul

    2018-04-01

    Radiotherapy (RT) plays a major role in the curative treatment of locally advanced non-small cell lung cancer (NSCLC). Therefore, the ACROP committee was asked by the ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)radiotherapy (RT) and adjuvant RT for locally advanced NSCLC. The guidelines given here are a result of the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing procedure within the committee. Hence, we provide advice for methods and time-points of diagnostics and imaging before the start of treatment planning and for the mandatory and optional imaging to be used for planning itself. Concerning target volumes, recommendations are given for GTV delineation of primary tumour and lymph nodes followed by issues related to the delineation of CTVs for definitive and adjuvant radiotherapy. In the context of PTV delineation, recommendations about the management of geometric uncertainties and target motion are given. We further provide our opinions on normal tissue delineation and organisational and responsibility questions in the process of target volume delineation. This guideline intends to contribute to the standardisation and optimisation of the process of RT treatment planning for clinical practice and prospective studies. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Pulmonary Rehabilitation in Improving Lung Function in Patients With Locally Advanced Non-Small Cell Lung Cancer Undergoing Chemoradiation

    ClinicalTrials.gov

    2017-04-12

    Cachexia; Fatigue; Pulmonary Complications; Radiation Toxicity; Recurrent Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  9. Effectiveness of local therapy for stage I non-small-cell lung cancer in nonagenarians.

    PubMed

    Arnold, Brian N; Thomas, Daniel C; Rosen, Joshua E; Salazar, Michelle C; Detterbeck, Frank C; Blasberg, Justin D; Boffa, Daniel J; Kim, Anthony W

    2017-09-01

    Stage I non-small-cell lung cancer is potentially curable, yet older patients undergo treatment at lower rates than younger patients. This analysis sought to describe the treatment outcomes of nonagenarians with stage I non-small-cell lung cancer to better guide treatment decisions in this population. The National Cancer DataBase was queried for patients age ≥90 years old with stage I non-small-cell lung cancer (tumors ≤4 cm). Patients were divided into 3 groups: local therapy, other therapy, or no treatment. The primary outcomes were 5-year overall and relative survival. Of the 616 patients identified, 33% (202) were treated with local therapy, 34% (207) were treated with other therapy, and 34% (207) underwent no treatment. Compared with local therapy, overall mortality was significantly higher with no treatment (hazard ratio 2.50, 95% confidence interval, 1.95-3.21) and other therapy (hazard ratio 1.43, 95% confidence interval, 1.11-1.83). The 5-year relative survival was 81% for local therapy, 49% for other therapy, and 32% for no treatment (P < .0001). Nonagenarians managed with local therapy for stage I non-small-cell lung cancer (tumors ≤4 cm) have better overall survival than those receiving other therapy or no treatment and should be considered for treatment with either operation or stereotactic body radiation therapy if able to tolerate treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    PubMed Central

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2012-01-01

    Purpose Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of KrasG12D-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radio-sensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer. PMID:23182391

  11. Hedgehog pathway inhibition radiosensitizes non-small cell lung cancers.

    PubMed

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T; Aftab, Blake T; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M; Wong, John; Rudin, Charles M; Tran, Phuoc T; Hales, Russell K

    2013-05-01

    Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras(G12D)-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntagmore » and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.« less

  13. Present and future treatment of advanced non-small cell lung cancer.

    PubMed

    Crinò, Lucio; Cappuzzo, Federico

    2002-06-01

    Platinum-based chemotherapy is considered the standard treatment for advanced non-small cell lung cancer (NSCLC). Several phase II trials using cisplatin in combination with new chemotherapeutic agents, such as gemcitabine, the taxanes, vinorelbine, and irinotecan, showed impressive response rates and suggested an improvement in overall survival. Large phase III trials comparing these second-generation cisplatin regimens indicated a substantial equivalence of new combinations, marginally improving the outcome of patients over the first-generation platinum-based regimens. Phase III trials have not yet shown dramatic advantages for either multiple-drug regimens, with nonoverlapping mechanisms of action and toxicity, or nonplatinum doublets, with efficacy and/or toxicity profiles superior to those of platinum-based chemotherapy. Chemotherapy in advanced non-small cell lung cancer has reached a plateau, and it is clear that new approaches are required. These should include prevention, screening, and early detection, and the use of novel treatments based on our understanding of the biology and molecular biology of this disease. Copyright 2002, Elsevier Science (USA). All rights reserved.

  14. Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced non-small cell lung cancer.

    PubMed

    Wu, Chen-Ta; Motegi, Atsushi; Motegi, Kana; Hotta, Kenji; Kohno, Ryosuke; Tachibana, Hidenobu; Kumagai, Motoki; Nakamura, Naoki; Hojo, Hidehiro; Niho, Seiji; Goto, Koichi; Akimoto, Tetsuo

    2016-08-10

    To assess the feasibility of proton beam therapy for the patients with locally advanced non-small lung cancer. The dosimetry was analyzed retrospectively to calculate the doses to organs at risk, such as the lung, heart, esophagus and spinal cord. A dosimetric comparison between proton beam therapy and dummy photon radiotherapy (three-dimensional conformal radiotherapy) plans was performed. Dummy intensity-modulated radiotherapy plans were also generated for the patients for whom curative three-dimensional conformal radiotherapy plans could not be generated. Overall, 33 patients with stage III non-small cell lung cancer were treated with proton beam therapy between December 2011 and August 2014. The median age of the eligible patients was 67 years (range: 44-87 years). All the patients were treated with chemotherapy consisting of cisplatin/vinorelbine or carboplatin. The median prescribed dose was 60 GyE (range: 60-66 GyE). The mean normal lung V20 GyE was 23.6% (range: 14.9-32%), and the mean normal lung dose was 11.9 GyE (range: 6.0-19 GyE). The mean esophageal V50 GyE was 25.5% (range: 0.01-63.6%), the mean heart V40 GyE was 13.4% (range: 1.4-29.3%) and the mean maximum spinal cord dose was 40.7 GyE (range: 22.9-48 GyE). Based on dummy three-dimensional conformal radiotherapy planning, 12 patients were regarded as not being suitable for radical thoracic three-dimensional conformal radiotherapy. All the dose parameters of proton beam therapy, except for the esophageal dose, were lower than those for the dummy three-dimensional conformal radiotherapy plans. In comparison to the intensity-modulated radiotherapy plan, proton beam therapy also achieved dose reduction in the normal lung. None of the patients experienced grade 4 or worse non-hematological toxicities. Proton beam therapy for patients with stage III non-small cell lung cancer was feasible and was superior to three-dimensional conformal radiotherapy for several dosimetric parameters. © The Author 2016

  15. Treatment Recommendations for Locally Advanced, Non-Small-Cell Lung Cancer: The Influence of Physician and Patient Factors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, Irwin H.; Hayman, James A.; Landrum, Mary Beth

    2009-08-01

    Purpose: To determine the impact of patient age, comorbidity, and physician factors on treatment recommendations for locally advanced, unresectable non-small-cell lung cancer (NSCLC). Methods and Materials: We surveyed radiation oncologists regarding their recommendations for treatment (chemoradiation, radiation alone, chemotherapy alone, or no therapy) for hypothetical patients with Stage IIIB NSCLC who varied by age (55 vs. 80 years) and comorbid illness (none, moderate, or severe chronic obstructive pulmonary disease [COPD]). Multinomial logistic regression was used to assess the impact of physician and practice characteristics on radiation oncologists' treatment recommendations for three scenarios with the least agreement. Results: Of 214 radiationmore » oncologists, nearly all (99%) recommended chemoradiation for a healthy 55 year old. However, there was substantial variability in recommendations for a 55 year old with severe COPD, an 80-year-old with moderate COPD, and an 80-year-old with severe COPD. Physicians seeing a lower volume of lung cancer patients were statistically less likely to recommend radiotherapy for younger or older patients with severe COPD (both p < 0.05), but the impact was modest. Conclusions: Nearly all radiation oncologists report following the evidence-based recommendation of chemoradiation for young, otherwise healthy patients with locally advanced, unresectable NSCLC, but there is substantial variability in treatment recommendations for older or sicker patients, probably related to the lack of clinical trial data for such patients. The physician and practice characteristics we examined only weakly affected treatment recommendations. Additional clinical trial data are necessary to guide recommendations for treatment of elderly patients and patients with poor pulmonary function to optimize their management.« less

  16. Involved-Field Radiotherapy versus Elective Nodal Irradiation in Combination with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Study

    PubMed Central

    Chen, Ming; Bao, Yong; Ma, Hong-Lian; Wang, Jin; Wang, Yan; Peng, Fang; Zhou, Qi-Chao; Xie, Cong-Hua

    2013-01-01

    This prospective randomized study is to evaluate the locoregional failure and its impact on survival by comparing involved field radiotherapy (IFRT) with elective nodal irradiation (ENI) in combination with concurrent chemotherapy for locally advanced non-small cell lung cancer. It appears that higher dose could be delivered in IFRT arm than that in ENI arm, and IFRT did not increase the risk of initially uninvolved or isolated nodal failures. Both a tendency of improved locoregional progression-free survival and a significant increased overall survival rate are in favor of IFRT arm in this study. PMID:23762840

  17. Radiological response and survival in locally advanced non-small-cell lung cancer patients treated with three-drug induction chemotherapy followed by radical local treatment.

    PubMed

    Bonanno, Laura; Zago, Giulia; Marulli, Giuseppe; Del Bianco, Paola; Schiavon, Marco; Pasello, Giulia; Polo, Valentina; Canova, Fabio; Tonetto, Fabrizio; Loreggian, Lucio; Rea, Federico; Conte, PierFranco; Favaretto, Adolfo

    2016-01-01

    If concurrent chemoradiotherapy cannot be performed, induction chemotherapy followed by radical-intent surgical treatment is an acceptable option for non primarily resectable non-small-cell lung cancers (NSCLCs). No markers are available to predict which patients may benefit from local treatment after induction. This exploratory study aims to assess the feasibility and the activity of multimodality treatment, including triple-agent chemotherapy followed by radical surgery and/or radiotherapy in locally advanced NSCLCs. We retrospectively collected data from locally advanced NSCLCs treated with induction chemotherapy with carboplatin (area under the curve 6, d [day]1), paclitaxel (200 mg/m(2), d1), and gemcitabine (1,000 mg/m(2) d1, 8) for three to four courses, followed by radical surgery and/or radiotherapy. We analyzed radiological response and toxicity. Estimated progression-free survival (PFS) and overall survival (OS) were correlated to response, surgery, and clinical features. In all, 58 NSCLCs were included in the study: 40 staged as IIIA, 18 as IIIB (according to TNM Classification of Malignant Tumors-7th edition staging system). A total of 36 (62%) patients achieved partial response (PR), and six (10%) progressions were recorded. Grade 3-4 hematological toxicity was observed in 36 (62%) cases. After chemotherapy, 37 (64%) patients underwent surgery followed by adjuvant radiotherapy, and two patients received radical-intent radiotherapy. The median PFS and OS were 11 months and 23 months, respectively. Both PFS and OS were significantly correlated to objective response (P<0.0001) and surgery (P<0.0001 and P=0.002). Patients obtaining PR and receiving local treatment achieved a median PFS and OS of 35 and 48 months, respectively. Median PFS and OS of patients not achieving PR or not receiving local treatment were 5-7 and 11-15 months, respectively. The extension of surgery did not affect the outcome. The multimodality treatment was feasible, and triple

  18. Advances in immunotherapy for non-small cell lung cancer.

    PubMed

    Reckamp, Karen L

    2015-12-01

    In most patients, lung cancer presents as advanced disease with metastases to lymph nodes and/or distant organs, and survival is poor. Lung cancer is also a highly immune-suppressing malignancy with numerous methods to evade antitumor immune responses, including deficiencies in antigen processing and presentation, release of immunomodulatory cytokines, and inhibition of T-cell activation. Advances in understanding the complex interactions of the immune system and cancer have led to novel therapies that promote T-cell activation at the tumor site, resulting in prolonged clinical benefit. Immune checkpoint inhibitors, specifically programmed death receptor 1 pathway antibodies, have demonstrated impressively durable responses and improved survival in patients with non-small cell lung cancer. This article will review the recent progress made in immunotherapy for lung cancer with data from trials evaluating programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 monoclonal antibodies in addition to cancer vaccines. The review will focus on studies that have been published and the latest randomized trials exploring immune therapy in lung cancer. These results form the framework for a new direction in the treatment of lung cancer toward immunotherapy.

  19. Sirolimus and Auranofin in Treating Patients With Advanced or Recurrent Non-Small Cell Lung Cancer or Small Cell Lung Cancer

    ClinicalTrials.gov

    2017-08-28

    Extensive Stage Small Cell Lung Carcinoma; Lung Adenocarcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Small Cell Lung Carcinoma; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  20. EF5 and Motexafin Lutetium in Detecting Tumor Cells in Patients With Abdominal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-15

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Fallopian Tube Cancer; Gastrointestinal Stromal Tumor; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Gastrointestinal Carcinoid Tumor; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Primary Peritoneal Cavity Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Adult Soft Tissue Sarcoma; Recurrent Colon Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Small Intestine Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage 0 Non-small Cell Lung Cancer; Stage I Adult Soft Tissue Sarcoma; Stage I Colon Cancer; Stage I Gastric Cancer; Stage I Non-small Cell Lung Cancer; Stage I Ovarian Epithelial Cancer; Stage I Ovarian Germ Cell Tumor; Stage I Pancreatic Cancer; Stage I Rectal Cancer; Stage I Uterine Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage II Colon Cancer; Stage II Gastric Cancer; Stage II Non-small Cell Lung Cancer; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; Stage II Pancreatic Cancer; Stage II Rectal Cancer; Stage II Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Colon Cancer; Stage III Gastric Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Uterine Sarcoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Colon Cancer; Stage

  1. Radiological response and survival in locally advanced non-small-cell lung cancer patients treated with three-drug induction chemotherapy followed by radical local treatment

    PubMed Central

    Bonanno, Laura; Zago, Giulia; Marulli, Giuseppe; Del Bianco, Paola; Schiavon, Marco; Pasello, Giulia; Polo, Valentina; Canova, Fabio; Tonetto, Fabrizio; Loreggian, Lucio; Rea, Federico; Conte, PierFranco; Favaretto, Adolfo

    2016-01-01

    Objectives If concurrent chemoradiotherapy cannot be performed, induction chemotherapy followed by radical-intent surgical treatment is an acceptable option for non primarily resectable non-small-cell lung cancers (NSCLCs). No markers are available to predict which patients may benefit from local treatment after induction. This exploratory study aims to assess the feasibility and the activity of multimodality treatment, including triple-agent chemotherapy followed by radical surgery and/or radiotherapy in locally advanced NSCLCs. Methods We retrospectively collected data from locally advanced NSCLCs treated with induction chemotherapy with carboplatin (area under the curve 6, d [day]1), paclitaxel (200 mg/m2, d1), and gemcitabine (1,000 mg/m2 d1, 8) for three to four courses, followed by radical surgery and/or radiotherapy. We analyzed radiological response and toxicity. Estimated progression-free survival (PFS) and overall survival (OS) were correlated to response, surgery, and clinical features. Results In all, 58 NSCLCs were included in the study: 40 staged as IIIA, 18 as IIIB (according to TNM Classification of Malignant Tumors–7th edition staging system). A total of 36 (62%) patients achieved partial response (PR), and six (10%) progressions were recorded. Grade 3–4 hematological toxicity was observed in 36 (62%) cases. After chemotherapy, 37 (64%) patients underwent surgery followed by adjuvant radiotherapy, and two patients received radical-intent radiotherapy. The median PFS and OS were 11 months and 23 months, respectively. Both PFS and OS were significantly correlated to objective response (P<0.0001) and surgery (P<0.0001 and P=0.002). Patients obtaining PR and receiving local treatment achieved a median PFS and OS of 35 and 48 months, respectively. Median PFS and OS of patients not achieving PR or not receiving local treatment were 5–7 and 11–15 months, respectively. The extension of surgery did not affect the outcome. Conclusion The

  2. Effects of icotinib on advanced non-small cell lung cancer with different EGFR phenotypes.

    PubMed

    Pan, Huiyun; Liu, Rong; Li, Shengjie; Fang, Hui; Wang, Ziwei; Huang, Sheng; Zhou, Jianying

    2014-09-01

    Icotinib is the first oral epidermal growth factor receptor (EGFR) tyrosine kinase receptor inhibitor, which has been proven to exert significant inhibitory effects on non-small cell lung cancer in vitro. Clinical evidence has showed that the efficacy of Icotinib on retreating advanced non-small cell lung cancer is comparable to Gefitinib. However, different phenotypes of EGFR can affect the therapeutic outcomes of EGFR tyrosine kinase receptor inhibitor. Therefore, our study focused on efficacy and safety of Icotinib in patients with advanced non-small cell lung cancer of different EGPR phenotypes. Clinical data of patients with advanced non-small cell lung cancer who received Icotinib treatment from August, 2011 to May, 2013 were retrospectively analyzed. Kaplan-Meier analysis was used for survival analysis and comparison. 18 wild-type EGFR and 51 mutant type were found in a total of 69 patients. Objective response rate of patients with mutant type EGFR was 54.9 % and disease control rate was 86.3 %. Objective response rate of wild-type patients was 11.1 % (P = 0.0013 vs mutant type), disease control rate was 50.0 % (P = 0.0017). Median progression-free survival (PFS) of mutant type and wild-type patients were 9.7 and 2.6 months, respectively (P < 0.001). Median PFS of exon 19 mutated mutant patients was 11.3 months, mean PFS of exon 21 L858R mutated mutant patients was 8.7 months (P = 0.3145). Median overall survival (OS) of EGFR mutated patients had not reached. OS time of 13 wild-type patients was 12.9 months (P < 0.001). The common adverse reactions of Icotinib included rash, diarrhea, itching skin with occurrence rates of 24.6 % (17/69), 13.0 % (9/69), and 11.6 % (8/69), respectively. Most adverse reactions were grade I-II. Icotinib has great efficacy in EGFR mutated patients, making it an optimal regimen to treat EGFR mutated patients. Furthermore, most of adverse reactions associated with Icotinib treatment were tolerable.

  3. Implementation of immunotherapy in the treatment of advanced non-small cell lung cancer (NSCLC).

    PubMed

    Tsiara, Anna; Liontos, Michalis; Kaparelou, Maria; Zakopoulou, Roubini; Bamias, Aristotelis; Dimopoulos, Meletios-Athanasios

    2018-04-01

    Mechanisms of tumor immune surveillance and immune escape have been recently elucidated and led to the development of a new therapeutic field in oncology, that of immunotherapy. Immunotherapy aims to reactivate the immune system against cancer. Neoplasias like non-small cell lung cancer (NSCLC) are of particular interest and clinical studies with immunotherapeutic agents have shown significant survival benefit. Several agents have gained corresponding regulatory approvals. In particular, nivolumab, pembrolizumab and atezolizumab have been approved for second-line treatment of NSCLC, pembrolizumab is the only immune checkpoint inhibitor that has been approved in the first-line treatment and durvalumab is approved in the locally advanced disease. In this review, we aim to present the implementation of immunotherapy in the treatment of advanced NSCLC. We will discuss not only the approved regimens but also the future perspectives, the serious adverse events such as hyperprogression and the possible predictive markers that will aid the selection of the patients that will benefit from immunotherapy.

  4. Implementation of immunotherapy in the treatment of advanced non-small cell lung cancer (NSCLC)

    PubMed Central

    Liontos, Michalis; Kaparelou, Maria; Zakopoulou, Roubini; Bamias, Aristotelis; Dimopoulos, Meletios-Athanasios

    2018-01-01

    Mechanisms of tumor immune surveillance and immune escape have been recently elucidated and led to the development of a new therapeutic field in oncology, that of immunotherapy. Immunotherapy aims to reactivate the immune system against cancer. Neoplasias like non-small cell lung cancer (NSCLC) are of particular interest and clinical studies with immunotherapeutic agents have shown significant survival benefit. Several agents have gained corresponding regulatory approvals. In particular, nivolumab, pembrolizumab and atezolizumab have been approved for second-line treatment of NSCLC, pembrolizumab is the only immune checkpoint inhibitor that has been approved in the first-line treatment and durvalumab is approved in the locally advanced disease. In this review, we aim to present the implementation of immunotherapy in the treatment of advanced NSCLC. We will discuss not only the approved regimens but also the future perspectives, the serious adverse events such as hyperprogression and the possible predictive markers that will aid the selection of the patients that will benefit from immunotherapy. PMID:29862233

  5. {sup 18}F-Fluorodeoxyglucose/Positron Emission Tomography Predicts Patterns of Failure After Definitive Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ohri, Nitin, E-mail: ohri.nitin@gmail.com; Bodner, William R.; Halmos, Balazs

    Background: We previously reported that pretreatment positron emission tomography (PET) identifies lesions at high risk for progression after concurrent chemoradiation therapy (CRT) for locally advanced non-small cell lung cancer (NSCLC). Here we validate those findings and generate tumor control probability (TCP) models. Methods: We identified patients treated with definitive, concurrent CRT for locally advanced NSCLC who underwent staging {sup 18}F-fluorodeoxyglucose/PET/computed tomography. Visible hypermetabolic lesions (primary tumors and lymph nodes) were delineated on each patient's pretreatment PET scan. Posttreatment imaging was reviewed to identify locations of disease progression. Competing risks analyses were performed to examine metabolic tumor volume (MTV) and radiation therapymore » dose as predictors of local disease progression. TCP modeling was performed to describe the likelihood of local disease control as a function of lesion size. Results: Eighty-nine patients with 259 hypermetabolic lesions (83 primary tumors and 176 regional lymph nodes) met the inclusion criteria. Twenty-eight patients were included in our previous report, and the remaining 61 constituted our validation cohort. The median follow-up time was 22.7 months for living patients. In 20 patients, the first site of progression was a primary tumor or lymph node treated with radiation therapy. The median time to progression for those patients was 11.5 months. Data from our validation cohort confirmed that lesion MTV predicts local progression, with a 30-month cumulative incidence rate of 23% for lesions above 25 cc compared with 4% for lesions below 25 cc (P=.008). We found no evidence that radiation therapy dose was associated with local progression risk. TCP modeling yielded predicted 30-month local control rates of 98% for a 1-cc lesion, 94% for a 10-cc lesion, and 74% for a 50-cc lesion. Conclusion: Pretreatment FDG-PET identifies lesions at risk for progression after CRT

  6. Meta-analysis Exploring the Effectiveness of S-1-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer.

    PubMed

    Sun, Xin; Sun, Li; Zhang, Shu-Ling; Xiong, Zhi-Cheng; Ma, Jie-Tao; Han, Cheng-Bo

    2017-01-01

    S-1 is a new oral fluoropyrimidine formulation that comprises tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. S-1 is designed to enhance antitumor activity and to reduce gastrointestinal toxicity. Several studies have demonstrated that both S-1 monotherapy and S-1 combination regimens showed encouraging efficacies and mild toxicities in the treatment of lung squamous cell carcinoma and adenocarcinoma. However, it is unclear whether S-1 can be used as standard care in advanced non-small cell lung cancer (NSCLC). The purpose of this meta-analysis was to assess the efficacy and safety of S-1-based chemotherapy, compared with standard chemotherapy, in patients with locally advanced or metastatic NSCLC. Thirteen randomized controlled trials (RCTs) involving 2,134 patients with a similar ratio of different pathological types were included. In first-line or second-line chemotherapy, compared with standard chemotherapy, S-1-based chemotherapy showed similar efficacy in terms of median overall survival (mOS), median progression free survival (mPFS), and objective response rate (ORR) (all P > 0.1), and significantly reduced the incidence of grade ≥ 3 hematological toxicities. In patients with locally advanced NSCLC receiving concurrent chemoradiotherapy, compared with standard chemoradiotherapy, significantly improved survival in the S-1-based chemotherapy was noted in terms of mOS and mPFS (risk radio [RR] = 1.289, P = 0.009; RR = 1.289, P = 0.000, respectively) with lower incidence of grade ≥ 3 neutropenia (RR = 0.453, P = 0.000). The present meta-analysis demonstrates that S-1-based chemotherapy shows similar benefits in advanced NSCLC and improves survival in locally advanced NSCLC, compared with standard treatment.

  7. [Recent Advances in Immunotherapy for Non-Small Cell Lung Cancer].

    PubMed

    Muto, Satoshi; Suzuki, Hiroyuki

    2018-02-01

    Cancer immunotherapy for non-small cell lung cancer began around 1970 with nonspecific immunomodulators and cytokine therapies. This has since developed into cell therapy including lymphokine-activated killer cells(LAK)and tumor infiltrating lymphocytes(TIL), as well as cancer vaccine therapy. However, no clear indication of effectiveness has been reported. Despite the high expectation over the effectiveness of cancer vaccine therapy, the treatment strategy was deemed unsuccessful, and focus turned to the study of immune escape mechanism, which is now regarded as standard treatment for non-small cell lung cancer. With the advent of immune checkpoint inhibitors, cancer immunotherapy has finally become a standard treatment for non-small cell lung cancer. There are still several obstacles to overcome including the identification of a predictive biomarker for improved efficacy, as well as the establishment of multidrug or multimodality combination therapy. PD-L1 expression is currently used as a predictive biomarker for anti-PD-1 therapy, but does not meet the expectations of the aimed results. Although tumor mutation burden is considered another promising biomarker, there remain clinical problems, for example the need of next generation sequencer. It was reported that combination therapy of immune checkpoint inhibitor after chemoradiation therapy was also effective. However, it remains unclear of what is required to further improve the clinical effects. In this article, we will review the history of cancer immunotherapy for non-small cell lung cancer and discuss the future prospects.

  8. The potential predictive value of circulating immune cell ratio and tumor marker in atezolizumab treated advanced non-small cell lung cancer patients.

    PubMed

    Zhuo, Minglei; Chen, Hanxiao; Zhang, Tianzhuo; Yang, Xue; Zhong, Jia; Wang, Yuyan; An, Tongtong; Wu, Meina; Wang, Ziping; Huang, Jing; Zhao, Jun

    2018-05-04

    The PD-L1 antibody atezolizumab has shown promising efficacy in patients with advanced non-small cell lung cancer. But the predictive marker of clinical benefit has not been identified. This study aimed to search for potential predictive factors in circulating blood of patients receiving atezolizumab. Ten patients diagnosed with advanced non-small cell lung cancer were enrolled in this open-label observing study. Circulating immune cells and plasma tumor markers were examined in peripheral blood from these patients before and after atezolizumab treatment respectively. Relation between changes in circulating factors and anti-tumor efficacy were analyzed. Blood routine test showed that atezolizumab therapy induced slightly elevation of white blood cells count generally. The lymphocyte ratio was increased slightly in disease controlled patients but decreased prominently in disease progressed patients in response to atezolizumab therapy. Flow cytometric analysis revealed changes in percentage of various immune cell types, including CD4+ T cell, CD8+ T cell, myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also altered after anti-PD-L1 therapy. In comparison with baseline, the disease progressed patients showed sharp increase in tumor marker levels, while those disease controlled patients were seen with decreased regulatory T cell and myeloid-derived suppressor cell ratios. The circulating immune cell ratios and plasma tumor marker levels were related with clinical efficacy of atezolizumab therapy. These factors could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.

  9. Anetumab Ravtansine and Atezolizumab in Treating Participants With Advanced Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2018-06-12

    Mesothelin Positive; Stage III Non-Small Cell Lung Cancer AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IV Non-Small Cell Lung Cancer AJCC v7

  10. Treating advanced non-small-cell lung cancer in Chinese patients: focus on icotinib

    PubMed Central

    Liang, Jun-Li; Ren, Xiao-Cang; Lin, Qiang

    2014-01-01

    Icotinib hydrochloride is an orally administered small-molecule reversible tyrosine kinase inhibitor that has been independently researched and developed and has independent intellectual property rights in the People’s Republic of China. Clinical trials have demonstrated that the response to icotinib among advanced non-small-cell lung cancer (NSCLC) patients who received at least one platinum-based chemotherapy regimen was not inferior to gefitinib. Since being launched August 2011 in the People’s Republic of China, icotinib has been widely used in clinics, and has become an important treatment option for Chinese patients with advanced NSCLC. The present study presents the Phase I, II, and III clinical trials of icotinib and discusses current clinical applications in the People’s Republic of China and future research directions. PMID:24876785

  11. [Clinical Advanced in Early-stage ALK-positive Non-small Cell Lung Cancer Patients].

    PubMed

    Gao, Qiongqiong; Jiang, Xiangli; Huang, Chun

    2017-02-20

    Lung cancer is the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, with the majority of the cases diagnosed at the advanced stage. Molecular targeted therapy is becoming the focus attention for advanced NSCLC. Echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene (EML4-ALK) is among the most common molecular targets of NSCLC; its specific small-molecule tyrosine kinase inhibitors (TKIs) are approved for use in advanced NSCLC cases of ALK-positive. However, the influence of EML4-ALK fusion gene on the outcome of early-stage NSCLC cases and the necessity of application of TKIs for early-stage ALK-positive NSCLC patients are still uncertain. In this paper, we summarized the progression of testing methods for ALK-positive NSCLC patients as well as clinicopathological implication, outcome, and necessity of application of TKIs for early-stage ALK-positive NSCLC patients.

  12. [Recent Advances and Prospect of Advanced Non-small Cell Lung Cancer Targeted 
Therapy: Focus on Small Molecular Tyrosine Kinase Inhibitors].

    PubMed

    Zhang, Guowei; Wang, Huijuan; Ma, Zhiyong

    2017-04-20

    At present the treatment of advanced non-small cell lung cancer enters a targeted era and develops rapidly. New drugs appear constantly. Small molecular tyrosine kinase inhibitors have occupied the biggest piece of the territory, which commonly have a clear biomarker as predictor, and show remarkable effect in specific molecular classification of patients. The epidermal growth factor tyrosine kinase inhibitors such as gefitinib, erlotinib, icotinib and anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib have brought a milestone advance. In recent years new generations of tyrosine kinase inhibitors have achieved a great success in patients with acquired resistance to the above two kinds of drugs. At the same time new therapeutic targets are constantly emerging. So in this paper, we reviewed and summarized the important drugs and clinical trails on this topic, and made a prospect of the future development.

  13. Intensity-modulated radiotherapy for locally advanced non-small-cell lung cancer: a dose-escalation planning study.

    PubMed

    Lievens, Yolande; Nulens, An; Gaber, Mousa Amr; Defraene, Gilles; De Wever, Walter; Stroobants, Sigrid; Van den Heuvel, Frank

    2011-05-01

    To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Predicting Radiation Esophagitis Using 18F-FDG PET During Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer.

    PubMed

    Mehmood, Qurrat; Sun, Alexander; Becker, Nathan; Higgins, Jane; Marshall, Andrea; Le, Lisa W; Vines, Douglass C; McCloskey, Paula; Ford, Victoria; Clarke, Katy; Yap, Mei; Bezjak, Andrea; Bissonnette, Jean-Pierre

    2016-02-01

    Treatment of locally advanced non-small cell lung cancer with chemoradiotherapy (CRT) is limited by development of toxicity in normal tissue, including radiation esophagitis (RE). Increasingly, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is being used for adaptive planning. Our aim was to assess changes in esophageal FDG uptake during CRT and relate the changes to the onset and severity of RE. This prospective study in patients with stage II-III non-small cell lung cancer involved serial four-dimensional computed tomography and PET scans during CRT (60-74Gy). RE was recorded weekly using the Common Terminology Criteria for Adverse Events (v4.0), and imaging was performed at weeks 0, 2, 4, and 7. Changes in the esophagus's peak standard uptake value (SUVpeak) were analyzed for each time point and correlated with grade of RE using the Wilcoxon rank-sum test. The volume of esophagus receiving 50 Gy (V50) and volume of esophagus receiving 60 Gy (V60) were correlated with the development of RE, and the C-statistic (area under the curve [AUC]) was calculated to measure predictivity of grade 3 RE. RE developed in 20 of 27 patients (74%), with grade 3 reached in 6 (22%). A significant percentage increase in SUVpeak in the patients with RE was noted at week 4 (p = 0.01) and week 7 (p = 0.03). For grade 3 RE, a significant percentage increase in SUVpeak was noted at week 2 (p = 0.01) and week 7 (p = 0.03) compared with that for less than grade 3 RE. Median V50 (46.3%) and V60 (33.4%) were significantly higher in patients with RE (p = 0.04). The AUC measurements suggested that the percentage change in SUVpeak at week 2 (AUC = 0.69) and V50 (AUC = 0.67) and V60 (AUC = 0.66) were similarly predictive of grade 3 RE. Serial FDG-PET images during CRT show significant increases in SUVpeak for patients in whom RE develops. The changes at week 2 may predict those at risk for the development of grade 3 RE and may be informative for adaptive planning and

  15. [Clinical effects for patients with recurrent advanced non-small cell lung cancer treated with icotinib hydrochloride].

    PubMed

    Nong, Jingying; Qin, Na; Wang, Jinghui; Yang, Xinjie; Zhang, Hui; Wu, Yuhua; Lv, Jialin; Zhang, Quan; Zhang, Shucai

    2013-05-01

    Icotinib hydrochloride is the third single target EGFR-TKI used in clinical treatment of advanced non-small cell lung cancer (NSCLC). Clinical research reports on its efficacy and survival in patients with Recurrent Advanced NSCLC are still little.The aim of this study is to evaluate the efficacy and survival of Icotinib hydrochloride for patients with advanced non-small cell lung cancer who failed to previous chemotherapy and explore the association of clinical features with the efficacy and survival. The clinical data of 60 NSCLC patients referred to the Beijing Chest Hospital, Capital Medical University from March 2009 to July 2012 were retrospectively analyzed. The overall response rate (ORR) was 45.0% and the disease control rate (DCR) was 80.0%. The median progression-free survival (PFS) time was 6.7 months. RR and PFS in female were superior to male (P=0.014, 0.013, respectively). RR, DCR in 2nd-line subgroup were superior to ≥3rd-line subgroup (P=0.020, 0.024, respectively). RR, DCR and PFS in EGFR mutation carriers were significantly superior to wild-type patients (P=0.006, <0.001, 0.002, respectively). There was no statistical difference in RR and PFS between those age<65 and ≥65 or PS<2 and PS≥2. There was no statistical difference in RR and DCR between exon 19 deletion and exon 21 mutations, while the former had much longer PFS (P=0.020). EGFR mutation and exon 19 deletion are the independent prognostic factors to significantly improve the PFS (P=0.009, 0.012, respectively). The side effects were generally mild and consisted of rash and diarrhea. Icotinib hydrochloride is effective especially in EGFR mutation carriers and well tolerated in patients with recurrent advanced non-small-cell lung cancer.

  16. Pulmonary atelectasis and survival in advanced non-small cell lung carcinoma.

    PubMed

    Bulbul, Yilmaz; Eris, Bulent; Orem, Asim; Gulsoy, Ayhan; Oztuna, Funda; Ozlu, Tevfik; Ozsu, Savas

    2010-08-01

    Atelectasis was reported as a favorable prognostic sign of pulmonary carcinoma; however, the underlying mechanism in those patients is not known. In this study, we aimed to investigate prospectively the potential impact of atelectasis and/or obstructive pneumonitis (AO) on survival and the relation between atelectasis and some laboratory blood parameters. The study was conducted on 87 advanced stage non-small cell lung cancer (NSCLC) patients. Clinical and laboratory parameters of patients at first presentation were recorded, and patients were divided into two groups according to the presence of AO in thorax computed tomography (CT). Survival was calculated using Kaplan-Meier and univariate Cox's regression analyses. Laboratory parameters that might be related with prolonged survival in atelectasis were compared using chi-square, Student's t, and Mann-Whitney U tests. Of the patients, 54% had stage IV disease, and AO was detected in 48.3% of all cases. Overall median survival was 13.2 months for all cases, 10.9 months for patients without AO, and 13.9 months for patients with AO (P=0.067). Survival was significantly longer in stage III patients with AO (14.5 months versus 9.2 months, P=0.032), but not in stage IV patients. Patients with AO in stage III had significantly lower platelet counts (P=0.032) and blood sedimentation rates than did those with no AO (P=0.045). We concluded that atelectasis and/or obstructive pneumonitis was associated with prolonged survival in locally advanced NSCLC. There was also a clear association between atelectasis and/or obstructive pneumonitis and platelets and blood sedimentation rate.

  17. Pretreatment 18F-FDG PET Textural Features in Locally Advanced Non-Small Cell Lung Cancer: Secondary Analysis of ACRIN 6668/RTOG 0235.

    PubMed

    Ohri, Nitin; Duan, Fenghai; Snyder, Bradley S; Wei, Bo; Machtay, Mitchell; Alavi, Abass; Siegel, Barry A; Johnson, Douglas W; Bradley, Jeffrey D; DeNittis, Albert; Werner-Wasik, Maria; El Naqa, Issam

    2016-06-01

    In a secondary analysis of American College of Radiology Imaging Network (ACRIN) 6668/RTOG 0235, high pretreatment metabolic tumor volume (MTV) on (18)F-FDG PET was found to be a poor prognostic factor for patients treated with chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). Here we utilize the same dataset to explore whether heterogeneity metrics based on PET textural features can provide additional prognostic information. Patients with locally advanced NSCLC underwent (18)F-FDG PET prior to treatment. A gradient-based segmentation tool was used to contour each patient's primary tumor. MTV, maximum SUV, and 43 textural features were extracted for each tumor. To address overfitting and high collinearity among PET features, the least absolute shrinkage and selection operator (LASSO) method was applied to identify features that were independent predictors of overall survival (OS) after adjusting for MTV. Recursive binary partitioning in a conditional inference framework was utilized to identify optimal thresholds. Kaplan-Meier curves and log-rank testing were used to compare outcomes among patient groups. Two hundred one patients met inclusion criteria. The LASSO procedure identified 1 textural feature (SumMean) as an independent predictor of OS. The optimal cutpoint for MTV was 93.3 cm(3), and the optimal SumMean cutpoint for tumors above 93.3 cm(3) was 0.018. This grouped patients into three categories: low tumor MTV (n = 155; median OS, 22.6 mo), high tumor MTV and high SumMean (n = 23; median OS, 20.0 mo), and high tumor MTV and low SumMean (n = 23; median OS, 6.2 mo; log-rank P < 0.001). We have described an appropriate methodology to evaluate the prognostic value of textural PET features in the context of established prognostic factors. We have also identified a promising feature that may have prognostic value in locally advanced NSCLC patients with large tumors who are treated with chemoradiotherapy. Validation studies are warranted

  18. Fluorine 18 fluorodeoxyglucose PET/CT volume-based indices in locally advanced non-small cell lung cancer: prediction of residual viable tumor after induction chemotherapy.

    PubMed

    Soussan, Michael; Cyrta, Joanna; Pouliquen, Christelle; Chouahnia, Kader; Orlhac, Fanny; Martinod, Emmanuel; Eder, Véronique; Morère, Jean-François; Buvat, Irène

    2014-09-01

    To study whether volume-based indices of fluorine 18 fluorodeoxyglucose positron emission tomographic (PET)/computed tomographic (CT) imaging is an accurate tool to predict the amount of residual viable tumor after induction chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). This study was approved by institutional review board with waivers of informed consent. Twenty-two patients with locally advanced NSCLC underwent surgery after induction chemotherapy. All had pre- and posttreatment FDG PET/CT scans. CT largest diameter, CT volume, maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (TV), and total lesion glycolysis of primary tumor were calculated. Changes in tumor measurements were determined by dividing follow-up by baseline measurement (ratio index). Amounts of residual viable tumor, necrosis, fibrous tissue, inflammatory infiltrate, and Ki-67 proliferative index were estimated on resected tumor. Correlations between imaging indices and histologic parameters were estimated by using Spearman correlation coefficients or Mann-Whitney tests. No baseline or posttreatment indices correlated with percentage of residual viable tumor. TV ratio was the only index that correlated with percentage of residual viable tumor (r = 0.61 [95% confidence interval: 0.24, 0.81]; P = .003). Conversely, SUVmax and SUVmean ratios were only indices correlated with Ki-67 (r = 0.62 [95% confidence interval: 0.24, 0.82]; P = .003; and r = 0.60 [95% confidence interval: 0.21, 0.81]; P = .004, respectively). Total lesion glycolysis ratio was moderately correlated with residual viable tumor (r = 0.53 [95% confidence interval: 0.13, 0.78]; P = .01) and with Ki-67 (r = 0.57 [95% confidence interval: 0.18, 0.80]; P = .006). No ratios were correlated with presence of inflammatory infiltrate or foamy macrophages. TV and total lesion glycolysis ratios were the only indices correlated with residual viable tumor after induction

  19. GTI-2040 and Docetaxel in Treating Patients With Recurrent, Metastatic, or Unresectable Locally Advanced Non-Small Cell Lung Cancer, Prostate Cancer, or Other Solid Tumors

    ClinicalTrials.gov

    2013-01-23

    Recurrent Non-small Cell Lung Cancer; Recurrent Prostate Cancer; Stage III Prostate Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  20. Non-small cell lung cancer: current treatment and future advances

    PubMed Central

    Zappa, Cecilia

    2016-01-01

    Lung cancer has a poor prognosis; over half of people diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is less than 18%. Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Risk factors for developing NSCLC have been identified, with cigarette smoking being a major factor along with other environmental and genetic risk factors. Depending on the staging of lung cancer, patients are eligible for certain treatments ranging from surgery to radiation to chemotherapy as well as targeted therapy. With the advancement of genetics and biomarkers testing, specific mutations have been identified to better target treatment for individual patients. This review discusses current treatments including surgery, chemotherapy, radiotherapy, and immunotherapy as well as how biomarker testing has helped improve survival in patients with NSCLC. PMID:27413711

  1. Health-related quality of life in long-term survivors of unresectable locally advanced non-small cell lung cancer.

    PubMed

    Ran, Juntao; Wang, Jingbo; Bi, Nan; Jiang, Wei; Zhou, Zongmei; Hui, Zhouguang; Liang, Jun; Feng, Qinfu; Wang, Luhua

    2017-12-02

    Heath-related quality of life (HRQoL) among survivors with unresectable locally-advanced non-small cell lung cancer (LA-NSCLC) treated with radiotherapy and chemotherapy still is not clear. The current study were performed to determine HRQoL for long-term survivors with unresectable LA-NSCLC and to identify risk factors for poor HRQoL. Among patients with LA-NSCLC receiving radiotherapy and chemotherapy between January 2006 and December 2010, 82 long-term survivors beyond 5 years were identified in this cross-sectional study. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the lung cancer-specific questionnaire QLQ-LC13 were employed to gather information on HRQoL. HRQoL scores were compared between different subgroups to analyze factors related to HRQoL. Fifty-five out of 82 (67%) long-term survivors completed the HRQoL survey. They reported a mild reduction in global health status and physical and emotional functioning. Fatigue, dyspnea, coughing, and financial difficulties ranked the highest scores in the symptom scales. Analysis of risk factors for HRQoL showed age, exercise, smoking status, and treatment regimen were associated with global health status and functional scores, while age, gender, radiation pneumonitis, weight loss, and exercise were associated with symptom scores. This study provides the first description of the HRQoL of long-term LA-NSCLC survivors receiving radiotherapy and chemotherapy who may experience a relatively high HRQoL. Factors related to poorer HRQoL are potential targets for intervention.

  2. Pulmonary atelectasis and survival in advanced non-small cell lung carcinoma

    PubMed Central

    2010-01-01

    Atelectasis was reported as a favorable prognostic sign of pulmonary carcinoma; however, the underlying mechanism in those patients is not known. In this study, we aimed to investigate prospectively the potential impact of atelectasis and/or obstructive pneumonitis (AO) on survival and the relation between atelectasis and some laboratory blood parameters. The study was conducted on 87 advanced stage non-small cell lung cancer (NSCLC) patients. Clinical and laboratory parameters of patients at first presentation were recorded, and patients were divided into two groups according to the presence of AO in thorax computed tomography (CT). Survival was calculated using Kaplan-Meier and univariate Cox's regression analyses. Laboratory parameters that might be related with prolonged survival in atelectasis were compared using chi-square, Student's t, and Mann-Whitney U tests. Of the patients, 54% had stage IV disease, and AO was detected in 48.3% of all cases. Overall median survival was 13.2 months for all cases, 10.9 months for patients without AO, and 13.9 months for patients with AO (P = 0.067). Survival was significantly longer in stage III patients with AO (14.5 months versus 9.2 months, P = 0.032), but not in stage IV patients. Patients with AO in stage III had significantly lower platelet counts (P = 0.032) and blood sedimentation rates than did those with no AO (P = 0.045). We concluded that atelectasis and/or obstructive pneumonitis was associated with prolonged survival in locally advanced NSCLC. There was also a clear association between atelectasis and/or obstructive pneumonitis and platelets and blood sedimentation rate. PMID:20636252

  3. Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma

    ClinicalTrials.gov

    2018-06-07

    Advanced Pleural Malignant Mesothelioma; HLA-A*0201 Positive Cells Present; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Pleural Malignant Mesothelioma; Stage III Non-Small Cell Lung Cancer AJCC v7; Stage III Pleural Malignant Mesothelioma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IV Non-Small Cell Lung Cancer AJCC v7; Stage IV Pleural Malignant Mesothelioma AJCC v7; WT1 Positive

  4. Comparison of Toxicity Between Intensity-Modulated Radiotherapy and 3-Dimensional Conformal Radiotherapy for Locally Advanced Non-small-cell Lung Cancer.

    PubMed

    Ling, Diane C; Hess, Clayton B; Chen, Allen M; Daly, Megan E

    2016-01-01

    The role of intensity-modulated radiotherapy (IMRT) in reducing treatment-related toxicity for locally advanced non-small-cell lung cancer (NSCLC) remains incompletely defined. We compared acute toxicity and oncologic outcomes in a large cohort of patients treated with IMRT or 3-dimensional conformal radiotherapy (3-DCRT), with or without elective nodal irradiation (ENI). A single-institution retrospective review was performed evaluating 145 consecutive patients with histologically confirmed stage III NSCLC treated with definitive chemoradiotherapy. Sixty-five (44.8%) were treated with 3-DCRT using ENI, 43 (30.0%) with 3-DCRT using involved-field radiotherapy (IFRT), and 37 (25.5%) with IMRT using IFRT. All patients received concurrent chemotherapy. Comparison of acute toxicities by treatment technique (IMRT vs. 3-DCRT) and extent of nodal irradiation (3-DCRT-IFRT vs. 3-DCRT-ENI) was performed for grade 2 or higher esophagitis or pneumonitis, number of acute hospitalizations, incidence of opioid requirement, percutaneous endoscopic gastrostomy utilization, and percentage weight loss during treatment. Local control and overall survival were analyzed by the Kaplan-Meier method. We identified no significant differences in any measures of acute toxicity by treatment technique or extent of nodal irradiation. There was a trend toward lower rates of grade 2 or higher pneumonitis among IMRT patients compared to 3-DCRT patients (5.4% vs. 23.0%; P = .065). Local control and overall survival were similar between cohorts. Acute and subacute toxicities were similar for patients treated with IMRT and with 3-DCRT with or without ENI, with a nonsignificant trend toward a reduction in pneumonitis with IMRT. Larger studies are needed to better define which patients will benefit from IMRT. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Sirolimus and Gold Sodium Thiomalate in Treating Patients With Advanced Squamous Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2012-12-13

    Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  6. Economic outcomes of maintenance gefitinib for locally advanced/metastatic non-small-cell lung cancer with unknown EGFR mutations: a semi-Markov model analysis.

    PubMed

    Zeng, Xiaohui; Li, Jianhe; Peng, Liubao; Wang, Yunhua; Tan, Chongqing; Chen, Gannong; Wan, Xiaomin; Lu, Qiong; Yi, Lidan

    2014-01-01

    Maintenance gefitinib significantly prolonged progression-free survival (PFS) compared with placebo in patients from eastern Asian with locally advanced/metastatic non-small-cell lung cancer (NSCLC) after four chemotherapeutic cycles (21 days per cycle) of first-line platinum-based combination chemotherapy without disease progression. The objective of the current study was to evaluate the cost-effectiveness of maintenance gefitinib therapy after four chemotherapeutic cycle's stand first-line platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC with unknown EGFR mutations, from a Chinese health care system perspective. A semi-Markov model was designed to evaluate cost-effectiveness of the maintenance gefitinib treatment. Two-parametric Weibull and Log-logistic distribution were fitted to PFS and overall survival curves independently. One-way and probabilistic sensitivity analyses were conducted to assess the stability of the model designed. The model base-case analysis suggested that maintenance gefitinib would increase benefits in a 1, 3, 6 or 10-year time horizon, with incremental $184,829, $19,214, $19,328, and $21,308 per quality-adjusted life-year (QALY) gained, respectively. The most sensitive influential variable in the cost-effectiveness analysis was utility of PFS plus rash, followed by utility of PFS plus diarrhoea, utility of progressed disease, price of gefitinib, cost of follow-up treatment in progressed survival state, and utility of PFS on oral therapy. The price of gefitinib is the most significant parameter that could reduce the incremental cost per QALY. Probabilistic sensitivity analysis indicated that the cost-effective probability of maintenance gefitinib was zero under the willingness-to-pay (WTP) threshold of $16,349 (3 × per-capita gross domestic product of China). The sensitivity analyses all suggested that the model was robust. Maintenance gefitinib following first-line platinum-based chemotherapy for patients

  7. Adaptive/nonadaptive proton radiation planning and outcomes in a phase II trial for locally advanced non-small cell lung cancer.

    PubMed

    Koay, Eugene J; Lege, David; Mohan, Radhe; Komaki, Ritsuko; Cox, James D; Chang, Joe Y

    2012-12-01

    To analyze dosimetric variables and outcomes after adaptive replanning of radiation therapy during concurrent high-dose protons and chemotherapy for locally advanced non-small cell lung cancer (NSCLC). Nine of 44 patients with stage III NSCLC in a prospective phase II trial of concurrent paclitaxel/carboplatin with proton radiation [74 Gy(RBE) in 37 fractions] had modifications to their original treatment plans after re-evaluation revealed changes that would compromise coverage of the target volume or violate dose constraints; plans for the other 35 patients were not changed. We compared patients with adaptive plans with those with nonadaptive plans in terms of dosimetry and outcomes. At a median follow-up of 21.2 months (median overall survival, 29.6 months), no differences were found in local, regional, or distant failure or overall survival between groups. Adaptive planning was used more often for large tumors that shrank to a greater extent (median, 107.1 cm(3) adaptive and 86.4 cm(3) nonadaptive; median changes in volume, 25.3% adaptive and 1.2% nonadaptive; P<.01). The median number of fractions delivered using adaptive planning was 13 (range, 4-22). Adaptive planning generally improved sparing of the esophagus (median absolute decrease in V(70), 1.8%; range, 0%-22.9%) and spinal cord (median absolute change in maximum dose, 3.7 Gy; range, 0-13.8 Gy). Without adaptive replanning, target coverage would have been compromised in 2 cases (57% and 82% coverage without adaptation vs 100% for both with adaptation); neither patient experienced local failure. Radiation-related grade 3 toxicity rates were similar between groups. Adaptive planning can reduce normal tissue doses and prevent target misses, particularly for patients with large tumors that shrink substantially during therapy. Adaptive plans seem to have acceptable toxicity and achieve similar local, regional, and distant control and overall survival, even in patients with larger tumors, vs nonadaptive plans

  8. Maintenance or non-maintenance therapy in the treatment of advanced non-small cell lung cancer: that is the question.

    PubMed

    Galetta, D; Rossi, A; Pisconti, S; Millaku, A; Colucci, G

    2010-11-01

    Lung cancer is the most common cancer worldwide with non-small cell lung cancer (NSCLC), including squamous carcinoma, adenocarcinoma and large cell carcinoma, accounting for about 85% of all lung cancer types with most of the patients presenting with advanced disease at the time of diagnosis. In this setting first-line platinum-based chemotherapy for no more than 4-6 cycles are recommended. After these cycles of treatment, non-progressing patients enter in the so called "watch and wait" period in which no further therapy is administered until there is disease progression. In order to improve the advanced NSCLC outcomes, the efficacy of further treatment in the "watch and wait" period was investigated. This is the "maintenance therapy". Recently, the results coming from randomized phase III trials investigating two new agents, pemetrexed and erlotinib, in this setting led to their registration for maintenance therapy. Here, we report and discuss these results. Copyright © 2010 Elsevier Ltd. All rights reserved.

  9. Outcome and toxicity of intensity modulated radiotherapy with simultaneous integrated boost in locally advanced non-small cell lung cancer patients.

    PubMed

    Fondevilla Soler, A; López-Guerra, J L; Dzugashvili, M; Sempere Rincón, P; Sautbaet, A; Castañeda, P; Díaz, J M; Praena-Fernandez, J M; Rivin Del Campo, E; Azinovic, I

    2017-12-01

    The aim of this study was to assess the feasibility and treatment outcome of intensity modulated radiation therapy with simultaneous integrated boost (SIB-IMRT) in locally advanced non-small cell lung cancer (NSCLC) patients. A total of 64 NSCLC patients with stage IIB (3%), IIIA (36%), and IIIB (61%) were treated with concomitant (N = 47; 73%) or sequential (N = 9; 14%) chemotherapy between February 2009 and January 2014. Eight patients (13%) received RT alone. All patients received the same irradiation scheme using IMRT: prophylactic dose for mediastinum was 56 Gy at 1.65 Gy/fraction and SIB to macroscopic disease up to 68 Gy at 2 Gy/fraction. The median follow-up was 16 months (range, 1-70 months). The overall survival rate for all patients was 79% after 1 year and 46% after 2 years. Disease-free survival (DFS) was 81 and 45% after 1 and 2 years, respectively, resulting in a median DFS of 16 months. Multivariate analysis showed a statistically significant association between stage IIIB patients and a higher risk of mortality (HR 2.11; P = 0.019). In addition, T4 stage associated with higher risk of recurrence (HR 2.23; P = 0.024) while concomitant chemoradiation was associated with lower risk of any recurrence (HR 0.34; P = 0.004) No patient experienced grade ≥3 esophagitis and only 6 cases (9%) had grade 3 pneumonitis. Only having a higher lung volume was associated with higher risk of pneumonitis in the multivariate analysis (HR 16.21; P = 0.022). This study in advanced NSCLC patients shows that SIB-IMRT is an effective technique with acceptable toxicity, also when combined with chemotherapy.

  10. The resistance mechanisms and treatment strategies for EGFR-mutant advanced non-small-cell lung cancer

    PubMed Central

    Zhong, Wen-Zhao; Zhou, Qing; Wu, Yi-Long

    2017-01-01

    Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been established as the standard therapy for EGFR-sensitizing mutant advanced non-small-cell lung cancer (NSCLC). However, patients ultimately develop resistance to these drugs. There are several mechanisms of both primary and secondary resistance to EGFR-TKIs. The primary resistance mechanisms include point mutations in exon 18, deletions or insertions in exon 19, insertions, duplications and point mutations in exon 20 and point mutation in exon 21 of EGFR gene. Secondary resistance to EGFR-TKIs is due to emergence of T790M mutation, activation of alternative signaling pathways, bypassing downstream signaling pathways and histological transformation. Strategies to overcome these intrinsic and acquired resistance mechanisms are complex. With the development of the precision medicine for advanced NSCLC, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account resistance mechanism. Though combination therapy is emerging as the standard of to overcome resistance mechanisms. Personalized treatment modalities based on molecular diagnosis and monitoring is essential for disease management. Emerging data from the ongoing clinical trials on combination therapy of third generation TKIs and antibodies in EGFR mutant NSCLC are promising for better survival outcomes. PMID:29050366

  11. Treatment decision-making for advanced non-small cell lung cancer and differences among European countries: 1st AIOT-ETOP meeting.

    PubMed

    Gridelli, Cesare; Stahel, Rolf; Besse, Benjamin; Ciardiello, Fortunato; Felip, Enriqueta; Gasparini, Stefano; Graziano, Paolo; Rossi, Antonio; de Marinis, Filippo

    2011-12-01

    The Italian Association of Thoracic Oncology (AIOT) and the European Thoracic Oncology Platform (ETOP) realized the first conjunct educational meeting, open to European oncologists involved in the treatment of thoracic malignancies, entitled "Advanced non-small cell lung cancer: new perspectives in first-line setting". The educational meeting included 8 interactive talks, held by European key opinion leaders, and 5 related clinical cases in which the attendees, divided in working tables based on their country origin, were involved for interactive discussion. The aim of this course was to elucidate the differences or similarities among the European countries in the first-line treatment of patients affected by advanced non-small cell lung cancer (NSCLC). Twenty-two attendees of the following countries participated: Austria, France, Italy, Spain, Swiss, and UK. As expected, some discrepancies between the groups were identified concerning the approach to the diagnostic phase, the choice of first-line regimen, the duration of treatment and the use of maintenance therapy. These discrepancies were mainly due to familiarity with specific therapies and lack of access to certain therapies due to local regulatory issues. The European Medicine Agency grants marketing of drugs in all Europe, regulatory agency of each country can register the drug, but can also deny public reimbursement thus restricting the options of the oncologist. The European Oncology Associations should join to their effort to achieve a uniform access to the cancer therapy for all patients in Europe. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  12. Ceritinib for treatment of ALK-rearranged advanced non-small-cell lung cancer.

    PubMed

    Vansteenkiste, Johan F

    2014-10-01

    The anaplastic lymphoma kinase (ALK) gene plays a key role in the pathogenesis of selected tumors, including non-small-cell lung cancer (NSCLC). Patients with ALK-rearranged NSCLC are initially sensitive to the ALK inhibitor crizotinib but eventually become resistant, limiting its therapeutic potential. Ceritinib is an oral second-generation ALK inhibitor with greater preclinical antitumor potency than crizotinib in ALK-positive NSCLC. A Phase I trial of ceritinib in ALK-positive tumors demonstrated good activity in patients with advanced NSCLC, including those who had progressed on crizotinib. Adverse events are similar to those seen with other ALK tyrosine kinase inhibitors and are generally manageable. Ongoing trials are evaluating ceritinib in patients with ALK-rearranged NSCLC treated with prior chemotherapy and/or crizotinib.

  13. Dosimetric feasibility of 4DCT-ventilation imaging guided proton therapy for locally advanced non-small-cell lung cancer.

    PubMed

    Huang, Qijie; Jabbour, Salma K; Xiao, Zhiyan; Yue, Ning; Wang, Xiao; Cao, Hongbin; Kuang, Yu; Zhang, Yin; Nie, Ke

    2018-04-25

    The principle aim of this study is to incorporate 4DCT ventilation imaging into functional treatment planning that preserves high-functioning lung with both double scattering and scanning beam techniques in proton therapy. Eight patients with locally advanced non-small-cell lung cancer were included in this study. Deformable image registration was performed for each patient on their planning 4DCTs and the resultant displacement vector field with Jacobian analysis was used to identify the high-, medium- and low-functional lung regions. Five plans were designed for each patient: a regular photon IMRT vs. anatomic proton plans without consideration of functional ventilation information using double scattering proton therapy (DSPT) and intensity modulated proton therapy (IMPT) vs. functional proton plans with avoidance of high-functional lung using both DSPT and IMPT. Dosimetric parameters were compared in terms of tumor coverage, plan heterogeneity, and avoidance of normal tissues. Our results showed that both DSPT and IMPT plans gave superior dose advantage to photon IMRTs in sparing low dose regions of the total lung in terms of V5 (volume receiving 5Gy). The functional DSPT only showed marginal benefit in sparing high-functioning lung in terms of V5 or V20 (volume receiving 20Gy) compared to anatomical plans. Yet, the functional planning in IMPT delivery, can further reduce the low dose in high-functioning lung without degrading the PTV dosimetric coverages, compared to anatomical proton planning. Although the doses to some critical organs might increase during functional planning, the necessary constraints were all met. Incorporating 4DCT ventilation imaging into functional proton therapy is feasible. The functional proton plans, in intensity modulated proton delivery, are effective to further preserve high-functioning lung regions without degrading the PTV coverage.

  14. Bavituximab plus paclitaxel and carboplatin for the treatment of advanced non-small-cell lung cancer.

    PubMed

    Digumarti, Raghunadharao; Bapsy, P P; Suresh, Attili V; Bhattacharyya, G S; Dasappa, Lokanatha; Shan, Joseph S; Gerber, David E

    2014-11-01

    Bavituximab is a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating and tumor-specific vascular targeting properties. Preclinical studies have shown activity against numerous solid tumors and at least an additive effect in combination with chemotherapy. This study evaluated bavituximab in combination with paclitaxel and carboplatin in patients with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC). This phase II, open-label study (NCT00687817) was conducted in 49 patients with stage IIIB/IV NSCLC utilizing a Simon two-stage design. Patients were treated with up to six cycles of carboplatin area under the concentration-time curve (AUC) 5 plus paclitaxel 175 mg/m2 every 21 days with weekly bavituximab 3 mg/kg followed by bavituximab monotherapy until progression or unacceptable toxicity. The primary efficacy endpoint of overall response rate (ORR) was 40.8% (complete response [CR] 2.0%, partial response [PR] was 38.8%). Median progression-free survival (PFS) and overall survival (OS) were 6.0 and 12.4 months, respectively. Treatment-related adverse events (AEs) occurred in 40.8% of patients. The most common treatment-related AEs were anemia (10.2%), asthenia, vomiting, paresthesia, anorexia, and fatigue (6.1% each). One patient with a central, cavitating squamous tumor developed fatal hemoptysis and aspiration. Bavituximab in combination with paclitaxel-carboplatin as first-line therapy demonstrated a tolerable safety profile and potential efficacy in this single-arm phase II trial in patients with advanced local or metastatic NSCLC. Randomized trials with this regimen are in progress. NCT00687817. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Implications of Pathologic Complete Response Beyond Mediastinal Nodal Clearance With High-Dose Neoadjuvant Chemoradiation Therapy in Locally Advanced, Non-Small Cell Lung Cancer.

    PubMed

    Vyfhuis, Melissa A L; Burrows, Whitney M; Bhooshan, Neha; Suntharalingam, Mohan; Donahue, James M; Feliciano, Josephine; Badiyan, Shahed; Nichols, Elizabeth M; Edelman, Martin J; Carr, Shamus R; Friedberg, Joseph; Henry, Gavin; Stewart, Shelby; Sachdeva, Ashutosh; Pickering, Edward M; Simone, Charles B; Feigenberg, Steven J; Mohindra, Pranshu

    2018-06-01

    To determine, in a retrospective analysis of a large cohort of stage III non-small cell lung cancer patients treated with curative intent at our institution, whether having a pathologic complete response (pCR) influenced overall survival (OS) or freedom from recurrence (FFR) in patients who underwent definitive (≥60 Gy) neoadjuvant doses of chemoradiation (CRT). At our institution, 355 patients with locally advanced non-small cell lung cancer were treated with curative intent with definitive CRT (January 2000-December 2013), of whom 111 underwent mediastinal reassessment for possible surgical resection. Ultimately 88 patients received trimodality therapy. Chi-squared analysis was used to compare categorical variables. The Kaplan-Meier analysis was performed to estimate OS and FFR, with Cox regression used to determine the absolute hazards. Using high-dose neoadjuvant CRT, we observed a mediastinal nodal clearance (MNC) rate of 74% (82 of 111 patients) and pCR rate of 48% (37 of 77 patients). With a median follow-up of 34.2 months (range, 3-177 months), MNC resulted in improved OS and FFR on both univariate (OS: hazard ratio [HR] 0.455, 95% confidence interval [CI] 0.272-0.763, P = .004; FFR: HR 0.426, 95% CI 0.250-0.726, P = .002) and multivariate analysis (OS: HR 0.460, 95% CI 0.239-0.699, P = .001; FFR: HR 0.455, 95% CI 0.266-0.778, P = .004). However, pCR did not independently impact OS (P = .918) or FFR (P = .474). Mediastinal nodal clearance after CRT continues to be predictive of improved survival for patients undergoing trimodality therapy. However, a pCR at both the primary and mediastinum did not further improve survival outcomes. Future therapies should focus on improving MNC to encourage more frequent use of surgery and might justify use of preoperative CRT over chemotherapy alone. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. S0536: Cetuximab, Paclitaxel, Carboplatin, and Bevacizumab in Treating Patients With Advanced Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2015-08-11

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  17. Role of long non-coding RNA in drug resistance in non-small cell lung cancer.

    PubMed

    Wang, Leirong; Ma, Leina; Xu, Fei; Zhai, Wenxin; Dong, Shenghua; Yin, Ling; Liu, Jia; Yu, Zhuang

    2018-05-03

    Lung cancer is the leading cause of cancer-associated death, and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Many drugs have been used to treat NSCLC in order to improve patient prognosis. Platinum-based chemotherapy is the first-line treatment for locally advanced or metastatic patients. For patients with activating EGFR mutations, tyrosine kinase inhibitors are the best treatment choice. NSCLC initially exhibits an excellent response to treatment; however, acquired resistance has been observed in many patients, leading to ineffective treatment. Clinical resistance is an impediment in the treatment of patients with advanced NSCLC. Many sequencing technologies have shown that long non-coding RNA (lncRNA) is expressed differently between drug-resistant and drug-sensitive lung cancer cells. We review the literature on lncRNA in drug resistance of NSCLC. The aim of this review is to gain insight into the molecular mechanisms of drug resistance, mainly focusing on the role of lncRNA in NSCLC. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  18. Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial.

    PubMed

    Chun, Stephen G; Hu, Chen; Choy, Hak; Komaki, Ritsuko U; Timmerman, Robert D; Schild, Steven E; Bogart, Jeffrey A; Dobelbower, Michael C; Bosch, Walter; Galvin, James M; Kavadi, Vivek S; Narayan, Samir; Iyengar, Puneeth; Robinson, Clifford G; Wynn, Raymond B; Raben, Adam; Augspurger, Mark E; MacRae, Robert M; Paulus, Rebecca; Bradley, Jeffrey D

    2017-01-01

    Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports

  19. Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): A comparative analysis of toxicities and clinical outcomes.

    PubMed

    Fernandes, Annemarie T; Shen, Jason; Finlay, Jarod; Mitra, Nandita; Evans, Tracey; Stevenson, James; Langer, Corey; Lin, Lilie; Hahn, Stephen; Glatstein, Eli; Rengan, Ramesh

    2010-05-01

    Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT. We assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy. Of the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT. Nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  20. Evaluation of a prognostic scoring system based on the systemic inflammatory and nutritional status of patients with locally advanced non-small-cell lung cancer treated with chemoradiotherapy.

    PubMed

    Mitsuyoshi, Takamasa; Matsuo, Yukinori; Itou, Hitoshi; Shintani, Takashi; Iizuka, Yusuke; Kim, Young Hak; Mizowaki, Takashi

    2018-01-01

    Systemic inflammation and poor nutritional status have a negative effect on the outcomes of cancer. Here, we analyzed the effects of the pretreatment inflammatory and nutritional status on clinical outcomes of locally advanced non-small-cell lung cancer (NSCLC) patients treated with chemoradiotherapy. We retrospectively reviewed 89 patients with locally advanced NSCLC treated with chemoradiotherapy between July 2006 and June 2013. Serum C-reactive protein (CRP) was assessed as an inflammatory marker, and serum albumin, body mass index (BMI) and skeletal mass index were assessed as nutritional status markers. The relationships between these markers and overall survival (OS) were assessed. The median OS was 24.6 months [95% confidence interval (CI): 19.4-39.3 months]. During follow-up, 58 patients (65%) had disease recurrence and 52 patients (58%) died. In multivariate Cox hazard analysis, CRP levels and BMI approached but did not achieve a significant association with OS (P = 0.062 and 0.094, respectively). Recursive partitioning analysis identified three prognostic groups based on hazard similarity (CRP-BMI scores): 0 = CRP < 0.3 mg/dl, 1 = CRP ≥ 0.3 mg/dl and BMI ≥ 18.5 kg/m2, and 2 = CRP ≥ 0.3 mg/dl and BMI < 18.5 kg/m2. The CRP-BMI score was significantly associated with OS (P = 0.023). Patients with scores of 0, 1 and 2 had median OS of 39.3, 24.5 and 14.5 months, respectively, and the scores also predicted the probability of receiving salvage treatment after recurrence. The CRP-BMI score is thus a simple and useful prognostic marker of clinical outcome for patients with locally advanced NSCLC treated with chemoradiotherapy. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  1. Predictive factors for survival and correlation to toxicity in advanced Stage III non-small cell lung cancer patients with concurrent chemoradiation.

    PubMed

    Kim, Yong-Hyub; Ahn, Sung-Ja; Kim, Young-Chul; Kim, Kyu-Sik; Oh, In-Jae; Ban, Hee-Jung; Chung, Woong-Ki; Nam, Taek-Keun; Yoon, Mee Sun; Jeong, Jae-Uk; Song, Ju-Young

    2016-02-01

    Concurrent chemoradiotherapy is the standard treatment for locally advanced Stage III non-small cell lung cancer in patients with a good performance status and minimal weight loss. This study aimed to define subgroups with different survival outcomes and identify correlations with the radiation-related toxicities. We retrospectively reviewed 381 locally advanced Stage III non-small cell lung cancer patients with a good performance status or weight loss of <10% who received concurrent chemoradiotherapy between 2004 and 2011. Three-dimensional conformal radiotherapy was administered once daily, combined with weekly chemotherapy. The Kaplan-Meier method was used for survival comparison and Cox regression for multivariate analysis. Multivariate analysis was performed using all variables with P values <0.1 from the univariate analysis. Median survival of all patients was 24 months. Age > 75 years, the diffusion lung capacity for carbon monoxide ≤80%, gross tumor volume ≥100 cm(3) and subcarinal nodal involvement were the statistically significant predictive factors for poor overall survival both in univariate and multivariate analyses. Patients were classified into four groups according to these four predictive factors. The median survival times were 36, 29, 18 and 14 months in Groups I, II, III and IV, respectively (P < 0.001). Rates of esophageal or lung toxicity ≥Grade 3 were 5.9, 14.1, 12.5 and 22.2%, respectively. The radiotherapy interruption rate differed significantly between the prognostic subgroups; 8.8, 15.4, 22.7 and 30.6%, respectively (P = 0.017). Severe toxicity and interruption of radiotherapy were more frequent in patients with multiple adverse predictive factors. To maintain the survival benefit in patients with concurrent chemoradiotherapy, strategies to reduce treatment-related toxicities need to be deeply considered. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Gefitinib in advanced non-small cell lung cancer: does it deserve a second chance?

    PubMed

    Stinchcombe, Thomas E; Socinski, Mark A

    2008-09-01

    There has been intense investigation into the epidermal growth factor receptor (EGFR) as a therapeutic target in the treatment of non-small cell lung cancer (NSCLC). Currently there are two EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, approved for the treatment of advanced NSCLC. In a phase III trial (BR.21), treatment with erlotinib resulted in a statistically significant improvement in overall survival in patients who had experienced progression after one or two previous chemotherapy treatments in comparison with best supportive care (BSC). In contrast, in the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, treatment with gefitinib did not result in a statistically significant improvement in overall survival time in comparison with BSC in patients who had received one or two previous chemotherapy treatments and were refractory to or intolerant of the previous chemotherapy. After the results of the ISEL trial, the U.S. Food and Drug Administration restricted the use of gefitinib, and gefitinib was effectively removed from routine clinical practice within the U.S. However, gefitinib was approved in other countries and clinical trials investigating gefitinib continued. Recently the Iressa Non-small cell lung cancer Trial Evaluating REsponse and Survival against Taxotere (INTEREST) trial met the primary endpoint of demonstrating noninferiority in terms of overall survival for gefitinib (250 mg daily) in comparison with docetaxel (75 mg/m(2) every 3 weeks). Patients treated with gefitinib experienced a lower rate of treatment-related toxicity and higher rate of improvement in quality of life. Results of recent gefitinib trials have been provocative, and suggest a role for gefitinib in the treatment of advanced NSCLC.

  3. [Neoadjuvant Radiochemotherapy Followed by Curative Resection in Patients with Advanced Non-Small Cell Lung Cancer in Stage IIIA/IIIB: Prognostic Factors and Results].

    PubMed

    Schreiner, W; Dudek, W; Lettmaier, S; Gavrychenkova, S; Rieker, R; Fietkau, R; Sirbu, H

    2016-06-01

    The role of surgical lung resection following neo-adjuvant radio-chemotherapy (RCT) in patients with locally advanced non-small cell lung cancer (NSCLC) is yet not clearly defined. The aim of our study was to analyze the postoperative survival and to identify relevant prognostic factors. 46 patients underwent curative resections after neo-adjuvant RCT for locally advanced NSCLC (IIIA/IIIB) between February 2008 and February 2015. A retrospective data analysis regarding preoperative regression status, perioperative mortality, postoperative survival, patho-histological remission, relapse pattern and other prognostic factors was performed. A neo-adjuvant RCT with a median radiation dose of 50.4 [range, 45-60] Gy was performed in 44 (96 %) patients. Partial and/or complete regression was observed in 32 (70 %) patients. R0-resection was achieved in 44 (96 %) patients. The 30-day mortality was 4 % and the perioperative morbidity was 37 %. The overall and progression free 5-year survival rate was 47 % and respectively 45 % [in median 58 months]. The 5-year survival rate of 64 % in the "responder"-group was significantly better when compared with 24 % in the "non-responder"-group (p = 0.038). The tri-modality therapy improved the prognosis in patients with locally advanced NSCLC (stage IIIA/IIIB). The complete patho-histological remission is an important prognostic factor for better long term survival. Dividing the patients in "responder" and "non-responder" after neo-adjuvant RCT may have large therapeutically consequences in the future. Georg Thieme Verlag KG Stuttgart · New York.

  4. SU-E-T-572: Normal Lung Tissue Sparing in Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hong, C; Ju, S; Ahn, Y

    2015-06-15

    Purpose: To compare normal lung-sparing capabilities of three advanced radiation therapy techniques for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Four-dimensional computed tomography (4DCT) was performed in 10 patients with stage IIIb LA-NSCLC. The internal target volume (ITV); planning target volume (PTV); and organs at risks (OARs) such as spinal cord, total normal lung, heart, and esophagus were delineated for each CT data set. Intensity-modulated radiation therapy (IMRT), Tomohelical-IMRT (TH-IMRT), and TomoDirect-IMRT (TD-IMRT) plans were generated (total prescribed dose, 66 Gy in 33 fractions to the PTV) for each patient. To reduce the normal lung dose, complete and directionalmore » block function was applied outside the normal lung far from the target for both TH-IMRT and TD-IMRT, while pseudo- OAR was set in the same region for IMRT. Dosimetric characteristics of the three plans were compared in terms of target coverage, the sparing capability for the OAR, and the normal tissue complication probability (NTCP). Beam delivery efficiency was also compared. Results: TH-IMRT and TD-IMRT provided better target coverage than IMRT plans. Lung volume receiving ≥–30 Gy, mean dose, and NTCP were significant with TH-IMRT than with IMRT (p=0.006), and volume receiving ≥20–30 Gy was lower in TD-IMRT than in IMRT (p<0.05). Compared with IMRT, TH-IMRT had better sparing effect on the spinal cord (Dmax, NTCP) and heart (V45) (p<0.05). NTCP for the spinal cord, V45 and V60 for the heart, and Dmax for the esophagus were significantly lower in TD-IMRT than in IMRT. The monitor units per fraction were clearly smaller for IMRT than for TH-IMRT and TD-IMRT (p=0.006). Conclusion: In LA-NSCLC, TH-IMRT gave superior PTV coverage and OAR sparing compared to IMRT. TH-IMRT provided better control of the lung volume receiving ≥5–30 Gy. The delivery time and monitor units were lower in TD-IMRT than in TH-IMRT.« less

  5. Phase I study of carboplatin combined with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer.

    PubMed

    Takeoka, Hiroaki; Yamada, Kazuhiko; Azuma, Koichi; Zaizen, Yoshiaki; Yamashita, Fumie; Yoshida, Tsukasa; Naito, Yoshiko; Okayama, Yusuke; Miyamoto, Maki; Hoshino, Tomoaki

    2014-05-01

    The primary objective of this study was to evaluate the safety and tolerability of carboplatin plus pemetrexed for elderly patients (≥75 years) with chemotherapy-naïve advanced non-squamous non-small cell lung cancer. Patients received escalated doses of carboplatin at an area under the concentration-time curve of 4 (Level 1) or 5 (Level 2) plus pemetrexed (500 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation was decided according to whether dose-limiting toxicity occurred in the first cycle of chemotherapy. A total of 20 patients (6 at Level 1, 14 at Level 2) were enrolled. No dose-limiting toxicities were observed in patients at Level 1 or the first six patients at Level 2, and therefore the combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was considered to be the recommended dose. Among a total of 14 patients in Level 2, only 1 patient experienced dose-limiting toxicity: Grade 3 febrile neutropenia and urticaria. The major toxicities were neutropenia, thrombocytopenia and anemia. Liver dysfunction, fatigue and anorexia were also common, but generally manageable. Six patients showed partial responses, giving the overall response rate of 30%. The median progression-free survival period was 4.8 months (95% confidence interval 2.9-6.7 months). The combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was determined as the recommended dose in chemotherapy-naïve elderly patients (≥75 years) with advanced non-squamous non-small cell lung cancer, in view of overall safety and tolerability.

  6. Atezolizumab: A Review in Previously Treated Advanced Non-Small Cell Lung Cancer.

    PubMed

    Blair, Hannah A

    2018-05-21

    Atezolizumab (TECENTRIQ™), an immune checkpoint inhibitor, is an immunoglobulin G1 monoclonal antibody that binds to programmed death ligand 1 (PD-L1) and blocks its interactions with programmed death 1 and B7.1 receptors. Atezolizumab is approved as monotherapy in several countries worldwide for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have previously received chemotherapy. Approval was based on its clinical benefit in this setting in the phase II POPLAR and phase III OAK trials. In these studies, atezolizumab significantly prolonged overall survival (OS) relative to docetaxel, regardless of PD-L1 status. Increasing PD-L1 expression was associated with OS improvements. Atezolizumab also demonstrated efficacy in the phase II FIR and BIRCH trials, as assessed by objective response rates (ORRs) in patients with tumours expressing PD-L1. Higher ORRs were seen in patients with high PD-L1 expression. Atezolizumab had an acceptable, manageable tolerability profile, with a low incidence of immune-related adverse events. Therefore, atezolizumab is a valuable treatment option for patients with advanced NSCLC that has progressed during or after chemotherapy.

  7. Efficacy and influence factors of icotinib hydrochloride in treating advanced non-small cell lung cancer.

    PubMed

    Ma, X-H; Tian, T-D; Liu, H-M; Li, Q-J; Gao, Q-L; Li, L; Shi, B

    2017-01-01

    To evaluate the efficacy and safety of icotinib hydrochloride in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and discuss the influence factors on efficacy. 120 treatment-experienced patients confirmed by pathology or cytology with stage III B-IV non-small cell lung cancer took icotinib hydrochloride and erlotinib orally until the occurrence of disease progression or serious adverse reactions. Then, the efficacy of icotinib hydrochloride and the related influence factors were analyzed. In icotinib hydrochloride group, the response rate and the disease control rate were 30.00% and 65.00%, and the median progression-free survival time was 179 days (95% CI: 103.21-254.78); in erlotinib group, the response rate and the disease control rate were 25.00% and 56.70%, and the median progression-free survival time was 121 days (95% CI: 95.05-146.94). Moreover, the objective response rate and the disease control rate of second-line therapy were both superior to the third-line and above therapy. The objective response rate of patients with complete response/partial response/stable disease after the first-line therapy was higher than that of patients without response after the first-line therapy (p<0.05), and the significant differences existed in the objective response rate and the disease control rate among mutant group, wild-type group, and unknown group (p<0.05). The response rate and the disease control rate of erythra group were higher than those of non-erythra group (p<0.05). It was showed in the univariate analysis that the progression-free survival was correlated with the smoking status and the epidermal growth factor receptor gene mutations. The icotinib hydrochloride is effective and safe in treating the treatment-experienced patients with advanced NSCLC, especially for patients with sensitive mutations.

  8. Prospective Study of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Concurrent With Individualized Radiotherapy for Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang Jing; Xia Tingyi, E-mail: xiatingyi1959@21cn.com; Wang Yingjie

    Purpose: To establish the safety profile and efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) concurrent with individualized radiotherapy (RT) in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Patients and Methods: Between June 2007 and January 2010, 26 patients with Stage III/IV NSCLC were enrolled in this prospective study. These patients were treated with EGFR-TKIs (gefitinib 250 mg or erlotinib 150 mg, oral daily) concurrent with individualized RT with curative intent. The thoracic RT plans were individually designed on the basis of tumor size and normal tissue volume constraints. All patients were assessed for toxicity,more » and 25 patients were available for efficacy. The primary endpoints were acute toxicity, overall survival, and median survival time. The secondary endpoints included local control rate, time to tumor progression, and progression-free survival (PFS). Results: Median gross tumor volume, mean lung dose, and lung V20 were 56 cm{sup 3}, 8.6 Gy, and 14%, respectively. Median thoracic radiation dose was 70 Gy at a margin of gross tumor volume (range, 42-82 Gy), and median biological equivalent dose was 105 Gy (range, 60-119 Gy). Acute skin, hematologic, esophageal, and pulmonary toxicities were acceptable and manageable. Severe adverse events included neutropenia (Grade 4, 4%) and thrombocytopenia (Grade 4, 8%), esophagitis (Grade 3, 4%), and pneumonitis (Grade 3, 4%). With a median follow-up of 10.2 months, a local control rate of 96% was achieved for thoracic tumor. Median time to progression, median PFS, and median survival time were 6.3, 10.2, and 21.8 months, respectively. The 1- and 2-year PFS rates were both 42%, and 1-, 2-, and 3-year overall survival rates were 57%, 45%, and 30%, respectively. Conclusion: Concurrent EGFR-TKIs with individualized RT shows a favorable safety profile and promising outcome, therefore serving as a therapeutic option for patients with

  9. Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer.

    PubMed

    Gu, Aiqin; Shi, Chunlei; Xiong, Liwen; Chu, Tianqing; Pei, Jun; Han, Baohui

    2013-02-01

    To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (P<0.05). The symptom improvement rate was 57.3% (51/89), and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 (33.7%)] and diarrhea [15/89 (16.9%)]. The level of toxicity was typically low. The use of icotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

  10. Coriolus versicolor polysaccharide peptide slows progression of advanced non-small cell lung cancer.

    PubMed

    Tsang, K W; Lam, C L; Yan, C; Mak, J C; Ooi, G C; Ho, J C; Lam, B; Man, R; Sham, J S; Lam, W K

    2003-06-01

    Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths, and over 60% of patients present with advanced stages. Although polysaccharide peptides (PSP), isolated from the fungus Coriolus versicolor, have been reported to have anti-tumor effects, its clinical efficacy has not been properly evaluated. Double-blind placebo-controlled randomized study to evaluate the effects of 28-day administration of PSP (Windsor Pharmaceutical, Hong Kong) on patients, who had completed conventional treatment for advanced NSCLC. Thirty-four patients, with no significant difference in their baseline demographic, clinical or tumor characteristics, or previous treatment regimes (P>0.05) were recruited into each of the PSP and control arms. After 28-day treatment, there was a significant improvement in blood leukocyte and neutrophil counts, serum IgG and IgM, and percent of body fat among the PSP, but not the control, patients (P<0.05). Although the evaluable PSP patients did not improve in NSCLC-related symptoms, there were significantly less PSP patients withdrawn due to disease progression, than their control counterparts (5.9 and 23.5%, respectively; P=0.04; OR 4.00). There was no reported adverse reaction attributable to the trial medications. PSP treatment appears to be associated with slower deterioration in patients with advanced NSCLC.

  11. [Gemcitabine and non small-cell lung cancer].

    PubMed

    Vignot, Stéphane; Besse, Benjamin

    2007-01-01

    Questions raised during gemcitabine development reflect non small-cell lung cancer (NSCLC) history during last 10 years. Third generation therapies (gemcitabine, vinorelbine and taxanes) combined with platinium compounds are now to be prescribed in almost all clinical situations, from surgically removed tumors to metastatic diseases. The 30% response rate usually reported in advanced disease (with a median survival of 10 months) has to be improved and a more global approach is nowadays mandatory, including targeted agents. This review sum-up the clinical situations in which gemcitabine can be prescribed (advanced disease), or shall be prescribed (adjuvant setting, combination with anti-angiogenic agent or EGFR inhibitors), and highlight opening questions.

  12. Osimertinib and Navitoclax in Treating Patients With EGFR-Positive Previously Treated Advanced or Metastatic Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2018-05-23

    EGFR Activating Mutation; EGFR NP_005219.2:p.T790M; Stage III Non-Small Cell Lung Cancer AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IV Non-Small Cell Lung Cancer AJCC v7

  13. Liquid biopsy: A potential and promising diagnostic tool for advanced stage non-small cell lung cancer patients.

    PubMed

    Doval, D C; Deshpande, R; Dhabhar, B; Babu, K G; Prabhash, K; Chopra, R; Sripada, P V; Deshmukh, C; Suryavanshi, M

    2017-12-01

    More than 50% of non-small cell lung cancer (NSCLC) cases harbor an actionable mutation, and molecular testing at different intervals can help in personalized and targeted treatment. Core tissue biopsy and needle biopsy done at the time of diagnosis/disease progression are interventional, time-consuming and can affect the patients adversely. Noninterventional biomarker testing by liquid biopsy promises to revolutionize advanced stage cancer screening. The present report was formulated based on an expert panel meeting of renowned oncologists who gave their opinions for minimally invasive liquid biopsy to detect targetable molecular biomarkers in advanced NSCLC cases. An exhaustive literature search was done to support their recommendations. Clinical utility of minimally invasive liquid biopsy, for detection of molecular biomarkers in advanced stage NSCLC patients, was broadly discussed by the key opinion leaders.

  14. Regional Lymph Node Uptake of [{sup 18}F]Fluorodeoxyglucose After Definitive Chemoradiation Therapy Predicts Local-Regional Failure of Locally Advanced Non-Small Cell Lung Cancer: Results of ACRIN 6668/RTOG 0235

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Markovina, Stephanie; Duan, Fenghai; Snyder, Bradley S.

    2015-11-01

    Purpose: The American College of Radiology Imaging Network (ACRIN) 6668/Radiation Therapy Oncology Group (RTOG) 0235 study demonstrated that standardized uptake values (SUV) on post-treatment [{sup 18}F]fluorodeoxyglucose-positron emission tomography (FDG-PET) correlated with survival in locally advanced non-small cell lung cancer (NSCLC). This secondary analysis determined whether SUV of regional lymph nodes (RLNs) on post-treatment FDG-PET correlated with patient outcomes. Methods and Materials: Included for analysis were patients treated with concurrent chemoradiation therapy, using radiation doses ≥60 Gy, with identifiable FDG-avid RLNs (distinct from primary tumor) on pretreatment FDG-PET, and post-treatment FDG-PET data. ACRIN core laboratory SUV measurements were used. Event time was calculatedmore » from the date of post-treatment FDG-PET. Local-regional failure was defined as failure within the treated RT volume and reported by the treating institution. Statistical analyses included Wilcoxon signed rank test, Kaplan-Meier curves (log rank test), and Cox proportional hazards regression modeling. Results: Of 234 trial-eligible patients, 139 (59%) had uptake in both primary tumor and RLNs on pretreatment FDG-PET and had SUV data from post-treatment FDG-PET. Maximum SUV was greater for primary tumor than for RLNs before treatment (P<.001) but not different post-treatment (P=.320). Post-treatment SUV of RLNs was not associated with overall survival. However, elevated post-treatment SUV of RLNs, both the absolute value and the percentage of residual activity compared to the pretreatment SUV were associated with inferior local-regional control (P<.001). Conclusions: High residual metabolic activity in RLNs on post-treatment FDG-PET is associated with worse local-regional control. Based on these data, future trials evaluating a radiation therapy boost should consider inclusion of both primary tumor and FDG-avid RLNs in the boost volume to maximize local

  15. CCDC106 promotes non-small cell lung cancer cell proliferation.

    PubMed

    Zhang, Xiupeng; Zheng, Qin; Wang, Chen; Zhou, Haijing; Jiang, Guiyang; Miao, Yuan; Zhang, Yong; Liu, Yang; Li, Qingchang; Qiu, Xueshan; Wang, Enhua

    2017-04-18

    Coiled-coil domain containing (CCDC) family members enhance tumor cell proliferation, and high CCDC protein levels correlate with unfavorable prognoses. Limited research demonstrated that CCDC106 may promote the degradation of p53/TP53 protein and inhibit its transactivity. The present study demonstrated that CCDC106 expression correlates with advanced TNM stage (P = 0.008), positive regional lymph node metastasis (P < 0.001), and poor overall survival (P < 0.001) in 183 non-small cell lung cancer cases. A549 and H1299 cells were selected as representative of CCDC106-low and CCDC106-high expressing cell lines, respectively. CCDC106 overexpression promoted A549 cell proliferation and xenograft tumor growth in nude mice, while siRNA-mediated CCDC106 knockdown inhibited H1299 cell proliferation. CCDC106 promoted AKT phosphorylation and upregulated the cell cycle-regulating proteins Cyclin A2 and Cyclin B1. Cell proliferation promoted by CCDC106 via Cyclin A2 and Cyclin B1 was rescued by treatment with the AKT inhibitor, LY294002. Our studies revealed that CCDC106 is associated with non-small cell lung cancer progression and unfavorable prognosis. CCDC106 enhanced Cyclin A2 and Cyclin B1 expression and promoted A549 and H1299 cell proliferation, which depended on AKT signaling. These results suggest that CCDC106 may be a novel target for lung cancer treatment.

  16. Combination therapy for advanced or metastatic non-small cell lung cancer will be tested in new clinical trial | Center for Cancer Research

    Cancer.gov

    Non-small cell lung cancer (NSCLC) develops when abnormal lung cells begin to grow out of control. These cells can form into a tumor and spread to other areas of the body. David Schrump, M.D., of the Thoracic and Gastrointestinal Oncology Branch is leading a clinical trial of a new combination treatment for patients with advanced or metastatic NSCLC that cannot be treated

  17. The continuing role of chemotherapy for advanced non-small cell lung cancer in the targeted therapy era.

    PubMed

    Lwin, Zarnie; Riess, Jonathan W; Gandara, David

    2013-10-01

    There have been remarkable advances in the targeted treatment of advanced non-small cell lung cancer (NSCLC) over the past several years. Survival outcomes are steadily improving as management paradigms shift in the diagnosis and treatment of advanced NSCLC. Customizing treatment based on histology and molecular typing has become a standard of care in this era of targeted therapy. While new chemotherapeutic agents have proven effective, the pivotal role of platinum-based chemotherapy doublets has been confirmed. Maintenance chemotherapy has become an option, but who to employ it in remains unclear in the real-world setting. Efforts to overcome resistance to targeted agents are ongoing utilizing combination regimens of chemotherapy plus targeted agents, but optimizing combination strategies needs further exploration. This review highlights recent developments in novel chemotherapeutics and in chemotherapy strategies over the past two years. Despite advances in molecular medicine, there remains an essential role for chemotherapy in advanced NSCLC, even in the recent targeted therapy era.

  18. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial.

    PubMed

    Shi, Yuankai; Zhang, Li; Liu, Xiaoqing; Zhou, Caicun; Zhang, Li; Zhang, Shucai; Wang, Dong; Li, Qiang; Qin, Shukui; Hu, Chunhong; Zhang, Yiping; Chen, Jianhua; Cheng, Ying; Feng, Jifeng; Zhang, Helong; Song, Yong; Wu, Yi-Long; Xu, Nong; Zhou, Jianying; Luo, Rongcheng; Bai, Chunxue; Jin, Yening; Liu, Wenchao; Wei, Zhaohui; Tan, Fenlai; Wang, Yinxiang; Ding, Lieming; Dai, Hong; Jiao, Shunchang; Wang, Jie; Liang, Li; Zhang, Weimin; Sun, Yan

    2013-09-01

    Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer. In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18-75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67-1·05; median progression-free survival 4·6 months [95% CI 3·5-6·3] vs 3·4 months [2·3-3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug

  19. Supportive care in the era of immunotherapies for advanced non-small-cell lung cancer.

    PubMed

    Awada, Gil; Klastersky, Jean

    2018-03-01

    The therapeutic armamentarium for advanced non-small-cell lung cancer has evolved considerably over the past years. Immune checkpoint inhibitors targeting programmed cell death-1 such as pembrolizumab and nivolumab or programmed cell death ligand 1 such as atezolizumab, durvalumab and avelumab have shown favorable efficacy results in this patient population in the first-line and second-line setting. These immunotherapies are associated with a distinct toxicity profile based on autoimmune organ toxicity which is a new challenge for supportive care during treatment with these drugs. The differential diagnosis of events occurring during immune checkpoint inhibitor treatment is broad: they can be due to immune-related or nonimmune-related adverse events, atypical tumor responses (pseudoprogression or hyperprogression) or events related to comorbidities or other treatments. The management of these patients includes a thorough baseline clinical, biological and radiologic evaluation, patient education, correct follow-up and management by a multidisciplinary team with a central role for the medical oncologist. Immune-related toxicities should be managed according to available guidelines.

  20. [Advances in Liquid Biopsy and its Clinical Application in the Diagnosis 
and Treatment of Non-small Cell Lung Cancer].

    PubMed

    Zheng, Difan; Chen, Haiquan

    2016-06-20

    With the advances of technology, great progresses have been made in liquid biopsy in recent years. Liquid biopsy is currently playing a more and more important role in early diagnosis and treatment of cancer. Compared with traditional tissue biopsy, liquid biopsy is more popular in clinical practice due to its non-invasiveness, convenience and high repeatability. It has huge potential in the future. This review introduces circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) as the most important objects in liquid biopsy, mainly focusing on their history, biological characteristics, detection technologies, limitations and applications in non-small cell lung cancer.

  1. Advances in radiotherapy techniques and delivery for non-small cell lung cancer: benefits of intensity-modulated radiation therapy, proton therapy, and stereotactic body radiation therapy

    PubMed Central

    Diwanji, Tejan P.; Mohindra, Pranshu; Vyfhuis, Melissa; Snider, James W.; Kalavagunta, Chaitanya; Mossahebi, Sina; Yu, Jen; Feigenberg, Steven

    2017-01-01

    The 21st century has seen several paradigm shifts in the treatment of non-small cell lung cancer (NSCLC) in early-stage inoperable disease, definitive locally advanced disease, and the postoperative setting. A key driver in improvement of local disease control has been the significant evolution of radiation therapy techniques in the last three decades, allowing for delivery of definitive radiation doses while limiting exposure of normal tissues. For patients with locally-advanced NSCLC, the advent of volumetric imaging techniques has allowed a shift from 2-dimensional approaches to 3-dimensional conformal radiation therapy (3DCRT). The next generation of 3DCRT, intensity-modulated radiation therapy and volumetric-modulated arc therapy (VMAT), have enabled even more conformal radiation delivery. Clinical evidence has shown that this can improve the quality of life for patients undergoing definitive management of lung cancer. In the early-stage setting, conventional fractionation led to poor outcomes. Evaluation of altered dose fractionation with the previously noted technology advances led to advent of stereotactic body radiation therapy (SBRT). This technique has dramatically improved local control and expanded treatment options for inoperable, early-stage patients. The recent development of proton therapy has opened new avenues for improving conformity and the therapeutic ratio. Evolution of newer proton therapy techniques, such as pencil-beam scanning (PBS), could improve tolerability and possibly allow reexamination of dose escalation. These new progresses, along with significant advances in systemic therapies, have improved survival for lung cancer patients across the spectrum of non-metastatic disease. They have also brought to light new challenges and avenues for further research and improvement. PMID:28529896

  2. Bevacizumab-induced chronic interstitial pneumonia during maintenance therapy in non-small cell lung cancer.

    PubMed

    Sekimoto, Yasuhito; Kato, Motoyasu; Shukuya, Takehiko; Koyama, Ryo; Nagaoka, Tetsutaro; Takahashi, Kazuhisa

    2016-04-01

    Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor and a key drug for advanced non-small cell lung cancer. There are few reports describing bevacizumab-induced chronic interstitial pneumonia. A 62-year-old man with advanced non-small cell lung cancer was admitted to our hospital with dyspnea. He previously received four courses of carboplatin plus paclitaxel with bevacizumab combination therapy and thereafter received four courses of maintenance bevacizumab monotherapy. A chest-computed tomography scan on admission revealed diffuse ground glass opacity. He had not received any other drugs and did not have pneumonia. Thus, he was diagnosed with bevacizumab-induced chronic interstitial pneumonia and was treated with a high dose of corticosteroids. After steroid treatment, his dyspnea and radiological findings improved. This case report is the first description of bevacizumab-induced chronic interstitial pneumonia during maintenance therapy in a patient with non-small cell lung cancer.

  3. Serum peptide expression and treatment responses in patients with advanced non-small-cell lung cancer

    PubMed Central

    An, Juan; Tang, Chuan-Hao; Wang, Na; Liu, Yi; Lv, Jin; Xu, Bin; Li, Xiao-Yan; Guo, Wan-Feng; Gao, Hong-Jun; He, Kun; Liu, Xiao-Qing

    2018-01-01

    Epidermal growth factor receptor (EGFR) mutation is an important predictor for response to personalized treatments of patients with advanced non-small-cell lung cancer (NSCLC). However its usage is limited due to the difficult of obtaining tissue specimens. A novel prediction system using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has been reported to be a perspective tool in European countries to identify patients who are likely to benefit from EGFR tyrosine kinase inhibitor (TKI) treatment. In the present study, MALDI-TOF MS was used on pretreatment serum samples of patients with advanced non-small-cell lung cancer to discriminate the spectra between disease control and disease progression groups in one cohort of Chinese patients. The candidate features for classification were subsequently validated in a blinded fashion in another set of patients. The correlation between plasma EGFR mutation status and the intensities of representative spectra for classification was evaluated. A total of 103 patients that were treated with EGFR-TKIs were included. It was determined that 8 polypeptides peaks were significant different between the disease control and disease progression group. A total of 6 polypeptides were established in the classification algorithm. The sensitivity of the algorithm to predict treatment responses was 76.2% (16/21) and the specificity was 81.8% (18/22). The accuracy rate of the algorithm was 79.1% (34/43). A total of 3 polypeptides were significantly correlated with EGFR mutations (P=0.04, P=0.03 and P=0.04, respectively). The present study confirmed that MALDI-TOF MS analysis can be used to predict responses to EGFR-TKI treatment of the Asian population where the EGFR mutation status differs from the European population. Furthermore, the expression intensities of the three polypeptides in the classification model were associated with EGFR mutation. PMID:29844828

  4. Combination therapy for advanced or metastatic non-small cell lung cancer will be tested in new clinical trial | Center for Cancer Research

    Cancer.gov

    Non-small cell lung cancer (NSCLC) develops when abnormal lung cells begin to grow out of control. These cells can form into a tumor and spread to other areas of the body. David Schrump, M.D., of the Thoracic and Gastrointestinal Oncology Branch is leading a clinical trial of a new combination treatment for patients with advanced or metastatic NSCLC that cannot be treated surgically. Read more... 

  5. Clinical and Cost Implications of Universal Versus Locally Advanced-Stage and Advanced-Stage-Only Molecular Testing for Epidermal Growth Factor Receptor Mutations and Anaplastic Lymphoma Kinase Rearrangements in Non-Small Cell Lung Carcinoma: A Tertiary Academic Institution Experience.

    PubMed

    Sauter, Jennifer L; Butnor, Kelly J

    2016-04-01

    Although epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-directed therapies are not approved for patients with early-stage non-small cell lung carcinoma (NSCLC), many institutions perform EGFR and ALK testing for all patients with NSCLC at the time of initial diagnosis. Current consensus guidelines recommend EGFR testing and suggest ALK testing at the time of initial diagnosis for patients with advanced disease. To examine the cost and clinical impact of EGFR and ALK testing of patients with early-stage NSCLC. Records from all patients with a diagnosis of NSCLC made on a nonresection specimen at our institution during a single calendar year (2012) were reviewed, and a cost analysis was performed. Of 133 total patients, 47 (35%) had early-stage (stage I or II) disease and 86 (65%) had locally advanced (stage III) or advanced (stage IV) disease at presentation. Eight of 47 patients with early-stage disease (17%) had progression/recurrence during 18 to 30 months of follow-up, 6 of 8 (75%) of whom had pathologic confirmation of progression/recurrence. The estimated additional cost of EGFR and ALK testing for all newly diagnosed patients with NSCLC at our institution is $75,200 per year, compared to testing only patients with locally advanced and advanced-stage disease. The cost of universal molecular testing of NSCLC is substantial. EGFR and ALK testing of patients with early-stage disease appears to have negligible clinical impact, as most patients do not have disease recurrence/progression. Those whose disease recurs/progresses typically undergo rebiopsy. Our findings do not support the practice of universal EGFR and ALK testing in NSCLC at the time of initial diagnosis.

  6. First-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer : analysis of the Italian patients enrolled in the SAiL study.

    PubMed

    Bearz, Alessandra; Passalacqua, Rodolfo; Alabiso, Oscar; Cinieri, Saverio; Gridelli, Cesare; Cravesana, Claudia; Crinò, Lucio

    2012-11-01

    First-line bevacizumab-based therapy has been shown to improve outcomes in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The recent international phase IV SAiL study (a Study of Avastin [bevacizumab] in combination with platinum-containing chemotherapy in patients with advanced or recurrent non-squamous cell Lung cancer) evaluated the safety and efficacy of bevacizumab combined with standard chemotherapy regimens in routine clinical practice. Here we report the results of a subanalysis of baseline characteristics and efficacy data for Italian patients enrolled in SAiL. In the SAiL study, patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC received bevacizumab (7.5 or 15 mg/kg) every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Efficacy was assessed in terms of time to disease progression (TTP) and overall survival (OS). The Italian intent-to-treat population comprised 215 patients from a SAiL population of 2212 patients. At baseline, Italian patients tended to have less advanced disease than the overall population. Thus, the proportion of patients at enrollment with tumour stage IIIb and IV was 23.7 and 76.3 %, respectively, for the Italian population versus 19.7 and 80.3 % for the whole SAiL population. In addition, a higher proportion of Italian patients had an Eastern Cooperative Oncology Group performance status of 0 (72.6 vs. 37.2 %) and the prevalence of co-morbid conditions was lower in Italian patients (59.5 % of Italian patients reported a co-morbid condition and 60.0 % were receiving non-oncological treatment compared with 73.3 and 73.4 %, respectively, of SAiL patients overall). The mean exposures to bevacizumab and to chemotherapy were comparable between the Italian patient group and overall patient population, although cisplatin doublets were more commonly employed in Italian patients whereas carboplatin doublets were more

  7. Immunohistochemistry reliably detects ALK rearrangements in patients with advanced non-small-cell lung cancer.

    PubMed

    Han, Xiao-Hong; Zhang, Ning-Ning; Ma, Li; Lin, Dong-Mei; Hao, Xue-Zhi; Liu, Yu-Tao; Wang, Lin; Liu, Peng; Yuan, Zheng; Li, Dan; Lin, Hua; Sun, Yan; Shi, Yuan-Kai

    2013-10-01

    Accurate determination of anaplastic lymphoma kinase (ALK) rearrangements is critical in identifying ALK-positive patients for targeted therapy in non-small-cell lung cancer (NSCLC). Fluorescence in situ hybridization (FISH) is the current standard method to detect ALK rearrangements but is technically challenging and costly. We compared optimised immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization techniques in this study of 139 samples of advanced NSCLC with non-squamous histology. ALK alteration was found in 32.6 % (43/132) of patients by FISH, 32.9 % (45/137) of patients by IHC and 27.9 % (34/122) of samples by qRT-PCR (concordance rate of 96.9 % between FISH and IHC, 95.7 % between FISH and qRT-PCR, P < 0.001). IHC sensitivity and specificity were 97.7 % and 96.6 %, respectively, while the sensitivity and specificity of qRT-PCR were 89.2 % and 98.7 %, respectively. ALK rearrangements were more common in young patients (P = 0.007), non-smokers or light smokers (P = 0.008) and adenocarcinoma histology, especially with signet ring cell features (P < 0.001). Optimised IHC could be a useful method in screening ALK rearrangements in clinical practice with qRT-PCR as an alternative diagnostic tool to clarify specific ALK variants.

  8. Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-small Cell Lung Cancer, or Squamous Cell Head and Neck Cancer

    ClinicalTrials.gov

    2017-09-14

    Head and Neck Squamous Cell Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Non-Small Cell Lung Cancer AJCC v7; Stage IV Renal Cell Cancer

  9. Erlotinib as a single agent in select subsets of patients with advanced non-small-cell lung cancer.

    PubMed

    Carrión, Ramón Pérez; Gracián, Antonio Cubillo; Hernandez, Pedro Salinas

    2007-07-01

    Erlotinib is an orally active inhibitor of the epidermal growth factor receptor that is effective for the treatment of non-small-cell lung cancer (NSCLC). Patients with a poor performance status (PS) of 2 constitute up to 40% of advanced NSCLC. This group of patients have a lower life expectancy and are thought to have a greater degree of treatment-related toxicity. The clinical benefit on 238 patients with poor PS included in an open-label, nonrandomized, phase II trial of erlotinib in advanced/metastatic NSCLC was 57.58% defined as complete response plus partial response plus stable disease. Median time to progression was 2.9 months. This review will summarize available data about erlotinib on patients with a PS of 2.

  10. Stages of Non-Small Cell Lung Cancer

    MedlinePlus

    ... Cancer Prevention Lung Cancer Screening Research Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Non-Small Cell Lung Cancer Go to Health Professional Version Key ...

  11. [Clinical efficacy and adverse effects of taxol plus carboplatin or gemcitabine plus carboplatin in patients with advanced non-small-cell lung carcinoma].

    PubMed

    Wang, Xiao-Yun; Zhao, Yu-Liang

    2010-12-21

    To observe the clinical efficacy and adverse effects of taxol plus carboplatin (TP) or gemcitabine plus carboplatin (GP) in patients with advanced non-small-cell lung carcinoma. A total of 86 patients with advanced non-small-cell lung carcinoma with a histologically confirmed diagnosis at our department were treated with at least two cycles of drug therapy according to the WHO standard. There were 43 cases in TP group and 43 cases in GP group. TP group: taxol 150 mg/m(2), d1, carboplatin 300 mg/m(2) in d1; GP group: gemcitabine 1000 mg/m(2), 30 min, d1, 8, carboplatin 300 mg/m(2) in d1, 3 weeks a cycle. The efficacy and side effects were analyzed after two cycles of chemotherapy. When TP and GP groups were compared, the effective rate was 44.2% vs 39.5%; disease control rate (CR + PR + SD): 81.4% vs 74.4%; median time to progress (TTP): 4.6 vs 4.5 months; medium survivals: 8.6 vs 8.8 months; 1-year survival rates: 17.2% vs 18.1%; 2-year survival rates: 8% vs 10%. The statistic analysis showed that the two groups had no significant difference. The main cytotoxicities of GP and TP groups were predominantly thrombocytopenia and leucopenia respectively. The two groups had no significant statistical difference. The incidences of allergen, alopecia and peripheral neurotoxicity were higher in the TP group. The two groups had statistical difference. Tolerance was excellent in both groups. The therapeutic effect and tolerance are excellent for advanced non-small cell lung carcinoma. The efficacy and survival rate of two groups show no statistical difference.

  12. [Prospect and Current Situation of Immune Checkpoint Inhibitors 
in First-line Treatment in Advanced Non-small Cell Lung Cancer Patients].

    PubMed

    Wang, Haiyang; Yu, Xiaoqing; Fan, Yun

    2017-06-20

    With the breakthroughs achieved of programmed death-1 (PD-1)/PD-L1 inhibitors monotherapy as first-line and second-line treatment in advanced non-small cell lung cancer (NSCLC), the treatment strategy is gradually evolving and optimizing. Immune combination therapy expands the benefit population and improves the curative effect. A series of randomized phase III trials are ongoing. In this review, we discuss the prospect and current situation of immune checkpoint inhibitors in first-line treatment in advanced NSCLC patients.

  13. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study.

    PubMed

    Crinò, Lucio; Dansin, Eric; Garrido, Pilar; Griesinger, Frank; Laskin, Janessa; Pavlakis, Nick; Stroiakovski, Daniel; Thatcher, Nick; Tsai, Chun-Ming; Wu, Yi-long; Zhou, Caicun

    2010-08-01

    Results of two phase 3 trials have shown first-line bevacizumab in combination with chemotherapy improves clinical outcomes in patients with advanced or recurrent non-squamous non-small-cell lung cancer (NSCLC). The SAiL (MO19390) study was undertaken to assess the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice. Between August, 2006, and June, 2008, patients with untreated locally advanced, metastatic, or recurrent non-squamous NSCLC were recruited to this open-label, single group, phase 4 study from centres in 40 countries. Eligible patients had histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent disease (stage IIIB-IV); an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, hepatic, and renal function. Patients received bevacizumab (7.5 or 15 mg/kg every 3 weeks) plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety; analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00451906. At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. The incidence of clinically significant (grade > or = 3) adverse events of special interest was generally low; thromboembolism occurred in 172 (8%) patients, hypertension in 125 (6%), bleeding in 80 (4%), proteinuria in 67 (3%), and pulmonary haemorrhage in 15 (1%). 57 (3%) patients died because of these adverse events, with thromboembolism (26 patients, 1%) and bleeding (17, 1%) as the most common causes. The most common grade 3 or higher serious adverse events deemed by investigators to be associated with bevacizumab were pulmonary embolism (28 patients; 1%) and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis (all of which occurred in 13 patients [1%]). Bevacizumab was temporarily

  14. An overview of mortality & predictors of small-cell and non-small cell lung cancer among Saudi patients.

    PubMed

    Alghamdi, Hatim I; Alshehri, Ali F; Farhat, Ghada N

    2018-03-01

    Lung cancer ranks as the top cancer worldwide in terms of incidence and constitutes a major health problem. About 90% of lung cancer cases are diagnosed at advance stage where treatment is not available. Despite evidence that lung cancer screening improves survival, guidelines for lung cancer screening are still a subject for debate. In Saudi Arabia, only 14% of lung cancers are diagnosed at early stage and researches on survival and its predictors are lacking. This overview analysis was conducted on predictors of lung cancer mortality according to the two major cancer types, small-cell lung cancers (SCLCs) and non-small cell lung cancers (NSCLCs) in Saudi Arabia. A secondary data analysis was performed on small-cell lung cancers (SCLCs) and Non-small cell lung cancers (NSCLCs) registered in the Saudi Cancer Registry (SCR) for the period 2009-2013 to estimate predictors of mortality for both lung cancer types. A total of 404 cases (197 SCLC and 207 NSCLC) were included in the analysis, all Saudi nationals. A total of 213 (52.75%) deaths occurred among lung cancer patients, 108 (54.82%) among SCLCs and 105 (50.72%) among NCSLCs. Three quarter of patients are diagnosis with advance stage for both SCLC & NSCLC. Univariate analysis revealed higher mean age at diagnosis in dead patients compared to alive patients for SCLCs (p=0.04); but not NSCLCs, a lower mortality for NSCLCs diagnosed in 2013 (p=0.025) and a significant difference in stage of tumor (p=0.006) and (p=0.035) for both SCLC and NSCLC respectively. In multiple logistic regression, stage of tumor was a strong predictor of mortality, where distant metastasis increased morality by 6-fold (OR=5.87, 95% CI: 2.01 - 17.19) in SCLC and by 3-fold (OR=3.29, 95% CI: 1.22 - 8.85) in NSCLC, compared to localized tumors. Those with NSCLC who were diagnosed in 2013 were less likely to die by 64% compared to NSCLC diagnosed in 2009 (OR=0.36, 95% CI: 0.14 - 0.93). Age, sex, topography and laterality were not associated with

  15. A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang

    2016-01-01

    Lessons Learned This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity. These findings provide clinicians with evidence for application of higher-dose icotinib. Background. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100–200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Methods. Twenty-six patients with advanced NSCLC were treated at doses of 250–625 mg three times daily The EGFR mutation test was not mandatory in this study. Results. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5–4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease

  16. A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

    PubMed

    Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang; Shentu, Jianzhong

    2016-11-01

    This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T max ) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t 1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. This study demonstrated that higher

  17. [Lung Resection after Definitive and Neo-Adjuvant Chemoradiation for Stage IIIA/B Locally Advanced Non-Small Cell Lung Cancer: a Retrospective Analysis].

    PubMed

    Schreiner, Waldemar; Gavrychenkova, Sofiia; Dudek, Wojciech; Lettmaier, Sebastian; Rieker, Ralf; Fietkau, Rainer; Sirbu, Horia

    2018-06-01

    The outcomes of so called "salvage" resections after definitive chemoradiation vs. curative resections after neoadjuvant chemoradiation therapy (IT-resection) in patients with stage IIIA/B locally advanced non-small cell lung cancer have rarely been compared. The aim of our study was to compare perioperative results, postoperative and recurrence-free survival and to identify relevant prognostic survival factors for both therapy strategies. Between June 2008 and May 2017, 43 patients underwent pulmonary resection following induction therapy (group 1) and 14 patients underwent salvage resection after definitive chemoradiation (group 2). Retrospective analysis was performed of demographic factors, tumour stage and location, initial therapy, preoperative regression status, perioperative morbidity and mortality, postoperative and recurrence-free survival. In group 2, significantly higher radiation dose was applied (p < 0.001) and the interval between chemoradiation and lung resection was significantly longer (p = 0.02). In addition, significantly higher perioperative blood loss and more frequent blood transfusions were noted (p = 0.003 and 0.005, respectively). Perioperative morbidity and mortality were statistically comparable in the two groups (p = 0.72 and 0.395, respectively). Postoperative 5 year survival in group 1 was 55%, in group 2 48% (log-rank p = 0.353). Five year recurrence-free survival in group 1 was 53%, in group 2 42% (log-rank p = 0.180). Diffuse metastasis occurred mostly in group 2, whereas in group 1 oligometastasis was more frequently noted. Postoperative outcome after salvage resection seems statistically comparable to results following curative resection after induction therapy. Diffuse distant metastasis is frequently noted. Careful patient selection is required. Georg Thieme Verlag KG Stuttgart · New York.

  18. Microwave Ablation in Combination with Chemotherapy for the Treatment of Advanced Non-Small Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wei, Zhigang, E-mail: weizhigang321321@163.com; Ye, Xin, E-mail: yexintaian@aliyun.com; Yang, Xia, E-mail: yangxjinan@163.com

    2015-02-15

    PurposeTo verify whether microwave ablation (MWA) used as a local control treatment had an improved outcome regarding advanced non-small cell lung cancer (NSCLC) when combined with chemotherapy.MethodsThirty-nine patients with histologically verified advanced NSCLC and at least one measurable site other than the ablative sites were enrolled. Primary tumors underwent MWA followed by platinum-based doublet chemotherapy. Modified response evaluation criteria in solid tumors (mRECIST) and RECIST were used to evaluate therapeutic response. Complications were assessed using the National Cancer Institute Common Toxicity Criteria (version 3.0).ResultsMWA was administered to 39 tumors in 39 patients. The mean and median diameters of the primarymore » tumor were 3.84 cm and 3.30 cm, respectively, with a range of 1.00–9.00 cm. Thirty-three (84.6 %) patients achieved a partial response. No correlation was found between MWA efficacy and clinicopathologic characteristics. For chemotherapy, 11 patients (28.2 %) achieved a partial response, 18 (46.2 %) showed stable disease, and 10 (25.6 %) had progressive disease. The overall objective response rate and disease control rate were 28.2 and 74.4 %, respectively. The median progression-free survival time was 8.7 months (95 % CI 5.5–11.9). The median overall survival time was 21.3 months (95 % CI 17.0–25.4). Complications were observed in 22 (56.4 %) patients, and grade 3 adverse events were observed in 3 (7.9 %) patients.ConclusionsPatients with advanced NSCLC could benefit from MWA in combination with chemotherapy. Complications associated with MWA were common but tolerable.« less

  19. Small bowel perforation secondary to metastatic non-small cell lung cancer. A rare entity with a dismal prognosis.

    PubMed

    Salemis, Nikolaos S; Nikou, Efstathios; Liatsos, Christos; Gakis, Christos; Karagkiouzis, Grigorios; Gourgiotis, Stavros

    2012-09-01

    The incidence of gastrointestinal metastases from lung cancer is higher than previously thought as they have been reported in 2-14% of the cases in autopsy studies. However, clinically significant metastases are rare. Small bowel perforation secondary to metastatic non-small cell lung cancer is a very rare clinical entity. The aim of this study is to describe a case of ileal perforation in a patient with intestinal metastases of a non-small cell lung cancer, along with a review of the literature. A 57-year-old male with a history of non-small cell lung cancer was referred to our emergency department with signs and symptoms of acute surgical abdomen. A computed tomography scan demonstrated dilated small bowel loops, liver deposits, and signs of perforation of an intra-abdominal hollow viscus. Emergency exploratory laparotomy revealed diffuse purulent peritonitis and a perforated ileal tumor. A segmental small bowel resection and primary anastomosis were performed. Histological and immunohistochemical findings were consistent with a metastatic non-small cell lung carcinoma. Additional evaluation revealed widespread metastatic disease. Unfortunately, despite adjuvant treatment, the patient died of progressive disease 2 months after surgery. Small bowel perforation due to metastatic non-small cell lung cancer is a very rare clinical entity. The possibility of small bowel metastases should be kept in mind in patients with lung cancer presenting with an acute abdomen. Intestinal perforation occurs in advanced stages and is usually a sign of widespread disease. Aggressive surgery can provide effective palliation and may improve short-term survival. The prognosis is however dismal.

  20. First-line treatment of advanced ALK-positive non-small-cell lung cancer

    PubMed Central

    Gandhi, Shipra; Chen, Hongbin; Zhao, Yujie; Dy, Grace K

    2015-01-01

    Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer deaths, both within the US and worldwide. There have been major treatment advances in NSCLC over the past decade with the discovery of molecular drivers of NSCLC, which has ushered in an era of personalized medicine. There are several actionable genetic aberrations in NSCLC, such as epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). In 3%–7% of NSCLC, a chromosomal inversion event in chromosome 2 leads to fusion of a portion of the ALK gene with the echinoderm microtubule–associated protein-like 4 (EML4) gene. The constitutive activation of the ALK fusion oncogene renders it vulnerable to therapeutic intervention. This review focuses on the first-line treatment of advanced ALK-positive NSCLC using ALK inhibitors. Crizotinib was the first agent proven to be efficacious as first-line treatment for ALK-positive NSCLC. However, acquired resistance inevitably develops. The central nervous system is a sanctuary site that represents a common site for disease progression as well. Hence, more potent, selective next-generation ALK inhibitors that are able to cross the blood–brain barrier have been developed for treatment against crizotinib-resistant ALK-positive NSCLC and are also currently being evaluated for first-line therapy as well. In this review, we provide summary of the clinical experience with these drugs in the treatment of ALK-positive NSCLC. PMID:28210152

  1. [Clinical observation of icotinib hydrochloride for patients with advanced non-small cell lung cancer].

    PubMed

    Li, Xi; Yang, Xin-jie; Sun, Yi-fen; Qin, Na; Lü, Jia-lin; Wu, Yu-hua; Zhang, Hui; Zhang, Quan; Zhang, Shu-cai

    2012-08-01

    To explore the efficacy and side effects of icotinib hydrochloride in the treatment of patients with advanced non-small cell lung cancer (NSCLC). The efficacy and side effects of icotinib hydrochloride in treatment of 59 cases with stage IV NSCIC and followed-up from March 2009 to January 2012 were retrospectively analyzed. Twenty seven patients (45.8%) showed partial response (PR), 17 patients (28.8%) achieved SD, and 15 (25.4%) had progressive disease. The objective response rate (ORR) was 45.8% (27/59), and disease control rate (DCR) was 74.6% (44/59). Among the 23 patients with EGFR mutation, ORR was 73.9% (17/23), and DCR was 95.7% (22/23). Thirty six patients (61.0%) achieved remission of symptoms to varying degrees. The main symptoms relieved were cough, asthmatic suffocating, pain and hoarseness. The major adverse events were mild skin rash (35.6%) and diarrhea (15.3%). Others were dry skin, nausea and stomach problems. The efficacy of icotinib hydrochloride were related to the ECOG performance status, smoking history, EGFR mutation and rash significantly (P < 0.05). Monotherapy with icotinib hydrochloride is effective and tolerable for patients with advanced NSCLC, especially with EGFR mutation.

  2. [Clinical Observation of Icotinib Hydrochloride for Advanced Non-small Cell Lung Cancer Patients with EGFR Status Identified].

    PubMed

    Li, Xi; Qin, Na; Wang, Jinghui; Yang, Xinjie; Zhang, Xinyong; Lv, Jialin; Wu, Yuhua; Zhang, Hui; Nong, Jingying; Zhang, Quan; Zhang, Shucai

    2015-12-01

    Icotinib is the first self-developed small molecular drug in China for targeted therapy of lung cancer. Compared to the other two commercially available epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, icotinib is similar to them in chemical structure, mechanism of activity and therapeutic effects. To explore the efficacy and side effects of icotinib hydrochloride in the treatment of the advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation and wild-type. Patients with advanced NSCLC who were treated with icotinib hydrochloride in Beijing Chest Hospital were retrospective analyzed from March 2009 to December 2014. The clinical data of 124 patients (99 with EGFR mutation and 25 with wild type) with advanced NSCLC were enrolled in this study. The patients' overall objective response rate (ORR) was 51.6 % and the disease control rate (DCR) was 79.8%; The patients with EGFR mutation, ORR was 63.6%, DCR was 93.9%. The ORR was 4.0% and the DCR was 24.0% in the wild-type patients. Median progression-free survival (PFS) with icotinib treatment in EGFR mutation patients was 10.5 months and 1.0 month in wild-type patients. The major adverse events were mild skin rash (30.6%) and diarrhea (16.1%). Monotherapy with icotinib hydrochloride is effective and tolerable for the advanced NSCLC EGFR mutation patients.


  3. [The role of meta-analysis in assessing the treatment of advanced non-small cell lung cancer].

    PubMed

    Pérol, M; Pérol, D

    2004-02-01

    Meta-analysis is a statistical method allowing an evaluation of the direction and quantitative importance of a treatment effect observed in randomized trials which have tested the treatment but have not provided a definitive conclusion. In the present review, we discuss the methodology and the contribution of meta-analyses to the treatment of advanced-stage or metastatic non-small-cell lung cancer. In this area of cancerology, meta-analyses have provided determining information demonstrating the impact of chemotherapy on patient survival. They have also helped define a two-drug regimen based on cisplatin as the gold standard treatment for patients with a satisfactory general status. Recently, the meta-analysis method was used to measure the influence of gemcitabin in combination with platinium salts and demonstrated a small but significant benefit in survival, confirming that gemcitabin remains the gold standard treatment in combination with cisplatin.

  4. Feasibility of home delivery of pemetrexed in patients with advanced non-squamous non-small cell lung cancer.

    PubMed

    Lal, R; Hillerdal, G N; Shah, R N H; Crosse, B; Thompson, J; Nicolson, M; Vikström, A; Potter, V A; Visseren-Grul, C; Lorenzo, M; D'yachkova, Y; Bourayou, N; Summers, Y J

    2015-08-01

    To evaluate the feasibility and adherence to home delivery (HD) of pemetrexed maintenance treatment in patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC). Exploratory, prospective, single-arm, Phase II study in advanced nsqNSCLC patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 that did not progress after 4 first-line induction cycles of a platinum doublet. The first cycle of pemetrexed (500mg/m(2)) was hospital administered, further cycles were HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or treatment discontinuation due to HD) as primary endpoint, and by health-related quality-of-life (HRQoL: EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, overall survival (OS), and safety. 52 patients (UK & Sweden) received a median of 4 (range 1-19) pemetrexed maintenance cycles. Adherence rate up to Cycle 6 was 98.0% (95% confidence interval [CI]: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (patient decision), and 1 after Cycle 6 (non-compliance with oral dexamethasone). 87% (33/38) of the patients preferred home to hospital treatment and in 90% (28/31) of cases, physicians were satisfied with distant management of patients. During HD Cycles 2-4 mean change from baseline ranged from 3.0 to 7.7 for EQ-5D visual analog scale. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD-related adverse event (device-related infection, Grade 2) and 1 patient died after Cycle 1, before HD, due to a possibly drug-related atypical pneumonia. HD of pemetrexed maintenance treatment in patients with advanced nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer.

    PubMed

    Ramalingam, Suresh S; Yang, James C-H; Lee, Chee Khoon; Kurata, Takayasu; Kim, Dong-Wan; John, Thomas; Nogami, Naoyuki; Ohe, Yuichiro; Mann, Helen; Rukazenkov, Yuri; Ghiorghiu, Serban; Stetson, Daniel; Markovets, Aleksandra; Barrett, J Carl; Thress, Kenneth S; Jänne, Pasi A

    2018-03-20

    Purpose The AURA study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] -tyrosine kinase inhibitor selective for EGFR-tyrosine kinase inhibitor sensitizing [ EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort). End points included investigator-assessed objective response rate (ORR), progression-free survival (PFS), and safety evaluation. Plasma samples were collected at or after patients experienced disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), to investigate osimertinib resistance mechanisms. Results At data cutoff (November 1, 2016), median follow-up was 19.1 months. Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median PFS time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including amplification of MET (n = 1); amplification of EGFR and KRAS (n = 1); MEK1, KRAS, or PIK3CA mutation (n = 1 each); EGFR C797S mutation (n = 2); JAK2 mutation (n = 1); and HER2 exon 20 insertion (n = 1). Acquired EGFR T790M was not detected. Conclusion Osimertinib demonstrated a robust ORR and prolonged PFS in treatment-naïve patients with EGFRm advanced NSCLC. There was no evidence of acquired EGFR T790M mutation in postprogression plasma samples.

  6. Expression of CD147 in advanced non-small cell lung cancer correlated with cisplatin-based chemotherapy resistance.

    PubMed

    Zeng, H Z; Qu, Y Q; Liang, A B; Deng, A M; Zhang, W J; Xiu, B; Wang, H; Wang, H

    2011-01-01

    CD147, a widely expressed cell surface glycoprotein in cancer, is associated with tumor invasiveness and chemotherapy resistance. Recently, CD147 is also regarded as a potential therapeutic target for cancer therapy. The aim of the study was to investigate CD147 expression in non-small cell lung cancer (NSCLC), and evaluate its correlation with cisplatin-based chemotherapy resistance. In this study, we examined immunohistochemically the expression of CD147 in 118 advanced NSCLC cases treated with cisplatin-based chemotherapy, and then the association of CD147 expression with clinicopathological characteristics was analyzed. Furthermore, RNA interference approach was used to silence CD147 expression in a cisplatin-resistant human lung cancer cell line A549/DDP, and the inhibition effect of cisplatin on tumor cells was assayed by MTT. In the overall series, positive CD147 expression was observed in 101/118 (85.6%) cases. A membranous CD147 pattern was identified in 76/101 (75.2%) of CD147 positive tumors. CD147 membranous expression,but not the overall CD147 expression, was associated with poor response to cisplatin-based chemotherapies and a poor prognosis in advanced NSCLC patients. In vitro results showed that silencing CD147 increased the proliferation inhibitory effect of cisplatin to A549/DDP cells. In conclusion, our study indicated that membranous CD147 expression is a predictive factor of the response to cisplatin-based chemotherapies, and the use of CD147-targeted therapeutic adjuvants might be considered in the treatment of advanced NSCLC patients.

  7. Endobronchial ultrasound-guided transbronchial needle injection for local control of recurrent non-small cell lung cancer.

    PubMed

    Khan, Farrah; Anker, Christopher J; Garrison, Garth; Kinsey, C Matthew

    2015-01-01

    Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an established technique for the diagnosis of thoracic malignancies. Non-ultrasound-guided transbronchial needle injection has been used previously to deliver chemotherapeutic agents. To use endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) to achieve local control of recurrent early-stage lung cancer. A 63-year-old man presented with recurrent early stage non-small cell lung carcinoma after chemotherapy and external beam radiation. We used EBUS-TBNI to deliver cisplatin into the tumor located outside the airway. This procedure was performed on three separate occasions without complication. EBUS-TBNI resulted in resolution of fluorodeoxyglucose avidity, measured by positron emission tomography-computed tomography, in the region at 4 weeks. However, at 5 months, there was evidence of distal recurrence. This is the first description of EBUS-TBNI to treat local recurrence of lung cancer and one of the first reports of the use of EBUS for intratumoral therapy. Additional research is warranted to determine the clinical usefulness and safety of this therapeutic approach.

  8. Changes in cross-sectional area of pulmonary vessels on chest computed tomography after chemotherapy in patients with advanced non-squamous non-small-cell lung cancer.

    PubMed

    Karayama, Masato; Inui, Naoki; Kusagaya, Hideki; Suzuki, Seiichiro; Inoue, Yusuke; Enomoto, Noriyuki; Fujisawa, Tomoyuki; Nakamura, Yutaro; Suda, Takafumi

    2016-05-01

    Chemotherapy is associated with a risk of vascular damage. Novel anti-angiogenic agents, which can directly affect tumor angiogenesis, are increasingly being used. However, the effects of these agents on normal vasculature are not well understood. Here, we evaluated the effects of chemotherapy in general, and the anti-angiogenic agent bevacizumab, more specifically, on the pulmonary vasculature in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). For this, we used the cross-sectional area of pulmonary vessels (CSA), which is an easily measurable indicator of small pulmonary vasculature on non-contrast chest computed tomography (CT). We retrospectively reviewed CT scans of the lungs of 75 chemo-naïve patients with advanced non-squamous NSCLC, for measurement of CSA, before and after first-line platinum-based chemotherapy, using a semi-automatic image-processing program. Measured vessels were classified in two groups: small vessels with CSA <5 mm(2) and large vessels with CSA between 5 and 10 mm(2). The CSAs for each group of vessels were calculated and summed separately, and expressed as a percentage of the total lung area (%CSA<5 and %CSA5-10). Chemotherapy was associated with a selective decrease in small-diameter vessels, with a significant decrease in %CSA<5, but not %CSA5-10. When comparing chemotherapy with bevacizumab (n = 38) and without bevacizumab (n = 37), there was no significant difference in the reduction of %CSA<5. Platinum-based chemotherapy might induce small pulmonary vascular damage. Use of bevacizumab does not enhance the reduction in area of pulmonary vessels.

  9. Erlotinib in Treating Patients With Advanced Non-Small Cell Lung Cancer, Ovarian Cancer, or Squamous Cell Carcinoma of the Head and Neck

    ClinicalTrials.gov

    2013-01-08

    Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx

  10. Improving chemotherapy for patients with advanced non-small cell lung cancer.

    PubMed

    von Plessen, Christian

    2011-01-01

    Lung cancer is the third most common mortal disease in industrialised countries and the prognosis has been slow to improve. The largest subgroup has locally advanced or metastatic non-small cell lung cancer (NSCLC). Unfortunately, these patients can usually not be cured and the main treatment option is palliative chemotherapy. Given the palliative intention of the chemotherapy, it is clinically highly relevant to establish the optimal treatment duration. While chemotherapy prolongs survival and improves quality of life (QoL), it also has side effects and only a minority of patients achieve an objective treatment response. Clinicians need guidance on treatment duration from controlled trials to balance these aspects. Improvements of the conditions under which chemotherapy is given can increase patient and staff satisfaction and increase system performance. This is especially relevant to incurable patients who spend a lot of their limited time at oncology outpatient clinics. Staffing, infrastructure and organisation of these units are often suboptimal to serve patients with palliative needs and reports of improvement projects can inspire and guide clinicians in improving their microsystems of care. Clinicians, health care administrators and the public need knowledge about the outcomes of palliative chemotherapy in unselected patient populations. The efficacy of palliative chemotherapy for advanced NSCLC has been amply documented in controlled clinical trials. Meanwhile, the elderly and patients with higher performance status have usually been under-represented in these trials and population studies of the effectiveness of chemotherapy are needed. (i) To establish the optimal duration of platinum-based first line chemotherapy for advanced NSCLC; (ii) To improve the care processes at an oncology outpatient clinical microsystem; (iii) To describe the use of chemotherapy in a national population and investigate associations between chemotherapy use and survival; and (iv

  11. Stereotactic Body Radiation Therapy Boost After Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Dose Escalation Study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hepel, Jaroslaw T., E-mail: jhepel@lifespan.org; Department of Radiation Oncology, Tufts Medical Center, Tufts University, Boston, Massachusetts; Leonard, Kara Lynne

    Purpose: Stereotactic body radiation therapy (SBRT) boost to primary and nodal disease after chemoradiation has potential to improve outcomes for advanced non-small cell lung cancer (NSCLC). A dose escalation study was initiated to evaluate the maximum tolerated dose (MTD). Methods and Materials: Eligible patients received chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (<120 cc and <60 cc, respectively). SBRT was delivered in 2 fractions after chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fraction increments, resulting in 4 dose cohorts. MTD was defined when ≥2 of 6 patients permore » cohort experienced any treatment-related grade 3 to 5 toxicity within 4 weeks of treatment or the maximum dose was reached. Late toxicity, disease control, and survival were also evaluated. Results: Twelve patients (3 per dose level) underwent treatment. All treatment plans met predetermined dose-volume constraints. The mean age was 64 years. Most patients had stage III disease (92%) and were medically inoperable (92%). The maximum dose level was reached with no grade 3 to 5 acute toxicities. At a median follow-up time of 16 months, 1-year local-regional control (LRC) was 78%. LRC was 50% at <24 Gy and 100% at ≥24 Gy (P=.02). Overall survival at 1 year was 67%. Late toxicity (grade 3-5) was seen in only 1 patient who experienced fatal bronchopulmonary hemorrhage (grade 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient's 4-cc PBV dose was substantially higher than that received by other patients in all 4 cohorts and was associated with the toxicity observed: 20.3 Gy (P<.05) and 73.5 Gy (P=.07) for SBRT boost and total treatment, respectively. Conclusions: SBRT boost to both primary and nodal disease after chemoradiation is feasible and well tolerated. Local control rates are encouraging, especially at doses ≥24

  12. Does Response to Induction Chemotherapy Predict Survival for Locally Advanced Non-Small-Cell Lung Cancer? Secondary Analysis of RTOG 8804/8808

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    McAleer, Mary Frances, E-mail: mfmcalee@mdanderson.or; Moughan, Jennifer M.S.; Byhardt, Roger W.

    2010-03-01

    Purpose: Induction chemotherapy (ICT) improves survival compared with radiotherapy (RT) alone in locally advanced non-small-cell lung cancer (LANSCLC) patients with good prognostic factors. Concurrent chemoradiotherapy (CCRT) is superior to ICT followed by RT. The question arises whether ICT response predicts the outcome of patients subsequently treated with CCRT or RT. Methods and Materials: Between 1988 and 1992, 194 LANSCLC patients were treated prospectively with ICT (two cycles of vinblastine and cisplatin) and then CCRT (cisplatin plus 63 Gy for 7 weeks) in the Radiation Therapy Oncology Group 8804 trial (n = 30) or ICT and then RT (60 Gy/6 wk)more » on Radiation Therapy Oncology Group 8808 trial (n = 164). Of the 194 patients, 183 were evaluable and 141 had undergone a postinduction assessment. The overall survival (OS) of those with complete remission (CR) or partial remission (PR) was compared with that of patients with stable disease (SD) or progressive disease (PD) after ICT. Results: Of the 141 patients, 6, 30, 99, and 6 had CR, PR, SD, and PD, respectively. The log-rank test showed a significant difference (p <0.0001) in OS when the response groups were compared (CR/PR vs. SD/PD). On univariate and multivariate analyses, a trend was seen toward a response to ICT with OS (p = 0.097 and p = 0.06, respectively). A squamous histologic type was associated with worse OS on univariate and multivariate analyses (p = 0.031 and p = 0.018, respectively). SD/PD plus a squamous histologic type had a hazard ratio of 2.25 vs. CR/PR plus a nonsquamous histologic type (p = 0.007) on covariate analysis. Conclusion: The response to ICT was associated with a significant survival difference when the response groups were compared. A response to ICT showed a trend toward, but was not predictive of, improved OS in LANSCLC patients. Patients with SD/PD after ICT and a squamous histologic type had the poorest OS. These data suggest that patients with squamous LANSCLC might

  13. A Model to Predict the Use of Surgical Resection for Advanced-Stage Non-Small Cell Lung Cancer Patients.

    PubMed

    David, Elizabeth A; Andersen, Stina W; Beckett, Laurel A; Melnikow, Joy; Kelly, Karen; Cooke, David T; Brown, Lisa M; Canter, Robert J

    2017-11-01

    For advanced-stage non-small cell lung cancer, chemotherapy and chemoradiotherapy are the primary treatments. Although surgical intervention in these patients is associated with improved survival, the effect of selection bias is poorly defined. Our objective was to characterize selection bias and identify potential surgical candidates by constructing a Surgical Selection Score (SSS). Patients with clinical stage IIIA, IIIB, or IV non-small cell lung cancer were identified in the National Cancer Data Base from 1998 to 2012. Logistic regression was used to develop the SSS based on clinical characteristics. Estimated area under the receiver operating characteristic curve was used to assess discrimination performance of the SSS. Kaplan-Meier analysis was used to compare patients with similar SSSs. We identified 300,572 patients with stage IIIA, IIIB, or IV non-small cell lung cancer without missing data; 6% (18,701) underwent surgical intervention. The surgical cohort was 57% stage IIIA (n = 10,650), 19% stage IIIB (n = 3,483), and 24% stage IV (n = 4,568). The areas under the receiver operating characteristic curve from the best-fit logistic regression model in the training and validation sets were not significantly different, at 0.83 (95% confidence interval, 0.82 to 0.83) and 0.83 (95% confidence interval, 0.82 to 0.83). The range of SSS is 43 to 1,141. As expected, SSS was a good predictor of survival. Within each quartile of SSS, patients in the surgical group had significantly longer survival than nonsurgical patients (p < 0.001). A prediction model for selection of patients for surgical intervention was created. Once validated and prospectively tested, this model may be used to identify patients who may benefit from surgical intervention. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  14. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.

    PubMed

    Soria, Jean-Charles; Ohe, Yuichiro; Vansteenkiste, Johan; Reungwetwattana, Thanyanan; Chewaskulyong, Busyamas; Lee, Ki Hyeong; Dechaphunkul, Arunee; Imamura, Fumio; Nogami, Naoyuki; Kurata, Takayasu; Okamoto, Isamu; Zhou, Caicun; Cho, Byoung Chul; Cheng, Ying; Cho, Eun Kyung; Voon, Pei Jye; Planchard, David; Su, Wu-Chou; Gray, Jhanelle E; Lee, Siow-Ming; Hodge, Rachel; Marotti, Marcelo; Rukazenkov, Yuri; Ramalingam, Suresh S

    2018-01-11

    Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded

  15. Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion

    PubMed Central

    Preusser, Matthias; Winkler, Frank; Valiente, Manuel; Manegold, Christian; Moyal, Elizabeth; Widhalm, Georg; Tonn, Jörg-Christian; Zielinski, Christoph

    2018-01-01

    This article is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose is to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context. PMID:29387475

  16. Predictive models for customizing chemotherapy in advanced non-small cell lung cancer (NSCLC).

    PubMed

    Bonanno, Laura

    2013-06-01

    The backbone of first-line treatment for Epidermal Growth Factor (EGFR) wild-type (wt) advanced Non-small cell lung cancer (NSCLC) patients is the use of a platinum-based chemotherapy combination. The treatment is characterized by great inter-individual variability in outcome. Molecular predictive markers are extremely needed in order to identify patients most likely to benefit from platinum-based treatment and resistant ones, thus optimizing chemotherapy approach in NSCLC. Several components of DNA repair response (DRR) have been investigated as potential predictive markers. Among them, high levels of expression of ERCC1, both at protein and mRNA levels, have been associated with resistance to cisplatin in NSCLC. In addition, low levels of expression of RRM1, a target for gemcitabine, have been associated with improved OS in advanced NSCLC patients treated with cisplatin and gemcitabine. Preclinical data and retrospective analyses showed that BRCA1 is able to induce resistance to cisplatin and sensitivity to antimicrotubule agents. In addition, the mRNA levels of expression of RAP80, encoding for a protein cooperating with BRCA1 in homologous recombination (HR), have demonstrated to further sub-classify low BRCA1 NSCLC tumors, improving the predictive model. On the basis of biological knowledge on DNA repair pathway and recent controversial results from clinical validation of potential molecular markers, integrated analysis of multiple DNA repair components could improve predictive information and pave the way to a new approach to customized chemotherapy clinical trials.

  17. Economic analysis: randomized placebo-controlled clinical trial of erlotinib in advanced non-small cell lung cancer.

    PubMed

    Bradbury, Penelope A; Tu, Dongsheng; Seymour, Lesley; Isogai, Pierre K; Zhu, Liting; Ng, Raymond; Mittmann, Nicole; Tsao, Ming-Sound; Evans, William K; Shepherd, Frances A; Leighl, Natasha B

    2010-03-03

    The NCIC Clinical Trials Group conducted the BR.21 trial, a randomized placebo-controlled trial of erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) in patients with previously treated advanced non-small cell lung cancer. This trial accrued patients between August 14, 2001, and January 31, 2003, and found that overall survival and quality of life were improved in the erlotinib arm than in the placebo arm. However, funding restrictions limit access to erlotinib in many countries. We undertook an economic analysis of erlotinib treatment in this trial and explored different molecular and clinical predictors of outcome to determine the cost-effectiveness of treating various populations with erlotinib. Resource utilization was determined from individual patient data in the BR.21 trial database. The trial recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm). Costs arising from erlotinib treatment, diagnostic tests, outpatient visits, acute hospitalization, adverse events, lung cancer-related concomitant medications, transfusions, and radiation therapy were captured. The incremental cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007 Canadian dollars) to incremental effectiveness (life-years gained). In exploratory analyses, we evaluated the benefits of treatment in selected subgroups to determine the impact on the incremental cost-effectiveness ratio. The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was $94,638 per life-year gained (95% confidence interval = $52,359 to $429,148). The major drivers of cost-effectiveness included the magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that erlotinib may be more cost-effective in never-smokers or patients with high EGFR gene copy number. With an incremental cost-effectiveness ratio of $94 638 per life-year gained, erlotinib treatment for patients with previously treated

  18. Clinical response to apatinib monotherapy in advanced non-small cell lung cancer.

    PubMed

    Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

    2018-06-01

    Apatinib, an oral tyrosine kinase inhibitor mainly targeting VEGFR-2, exerts both antiangiogenesis and antiproliferation effects. Apatinib shows clinical benefit in advanced non-small cell lung cancer (NSCLC) at an initial dose of 750 mg qd. We further assessed the efficacy and safety of apatinib at a more frequently used dose of 500 mg qd. The preliminary clinical outcome of apatinib in patients with brain metastases was also reported. We retrospectively reviewed the clinical data of 25 patients who received apatinib between August 2015 and May 2016. Progression-free survival (PFS) was calculated by using the Kaplan-Meier method. The objective response rate and disease control rate were 8.0% and 68.0%, respectively. The median PFS was 5.17 (95% confidence interval [CI]: 0.76-9.57) months. In the second-line setting (n = 13), the median PFS was 7.37 (95% CI: 0.01-14.72) months, whereas the median PFS for the 12 patients treated with apatinib as third line or beyond therapy was 5.17 (95% CI: 1.78-8.55) months. Of the seven patients with brain metastases, four patients had stable disease. All patients were well tolerant to apatinib without any grade 3 or 4 adverse events. The most common grade 1 or 2 adverse events included hypertension (72.0%), hand-foot-skin reaction (24.0%), fatigue (24.0%) and abnormal liver function (20.0%). Apatinib is effective and well tolerated in patients with advanced NSCLC, even at a dosage of 500 mg qd, and might offer a new option for the treatment of such patients with brain metastases. © 2017 John Wiley & Sons Australia, Ltd.

  19. Characteristics and outcomes of ALK+ non-small cell lung cancer patients in Korea.

    PubMed

    Lim, Sung Hee; Yoh, Kyung Ah; Lee, Jong Seok; Ahn, Myung-Ju; Kim, Yu Jung; Kim, Se Hyun; Zhang, Jie; Patel, Dony; Swallow, Elyse; Kageleiry, Andrew; Galebach, Philip; Lee, Dongyeol; Stein, Karen; Degun, Ravi; Park, Keunchil

    2017-10-01

    This study aimed to describe characteristics, treatment patterns and survival among Korean patients diagnosed with locally advanced or metastatic anaplastic lymphoma kinase (ALK)+ non-small cell lung cancer (NSCLC). A retrospective patient chart review was conducted in major cancer centers in Korea in 2014-2015. Participating physicians reviewed patient charts and reported characteristics, treatment patterns, clinician-defined progression-free survival (PFS) and overall survival (OS) of ALK+ locally advanced or metastatic NSCLC patients. PFS and OS were estimated using Kaplan-Meier analysis. Physicians reported on 55 ALK+ NSCLC patients. Median age at locally advanced or metastatic NSCLC diagnosis was 60 years. Most patients (82%) received initial chemotherapy; 13% received an ALK inhibitor in the first line; 62% received an ALK inhibitor by the end of follow-up. Of the 30 patients who received crizotinib, 83% discontinued and 13% died during crizotinib therapy. Median PFS on crizotinib was 6.7 months. Of those who discontinued, 32% switched to chemotherapy, 16% switched to a different ALK inhibitor and 52% received no further therapy. After discontinuing crizotinib, median OS was 6.0 months overall, and 3.4 months among patients who did not receive a second-generation ALK inhibitor. In this study of locally advanced or metastatic ALK+ NSCLC patients in Korea, roughly one-third did not receive an ALK inhibitor. Among patients who discontinued crizotinib, over half received no further antineoplastic therapy and OS was poor, particularly among patients without second-generation ALK inhibitor use. These findings suggest a need for greater access to effective treatments following crizotinib discontinuation for ALK+ NSCLC patients in Korea. © 2017 John Wiley & Sons Australia, Ltd.

  20. Real-world Efficacy and Safety of Nivolumab for Advanced Non-Small-cell Lung Cancer: A Retrospective Multicenter Analysis.

    PubMed

    Kobayashi, Keigo; Nakachi, Ichiro; Naoki, Katsuhiko; Satomi, Ryosuke; Nakamura, Morio; Inoue, Takashi; Tateno, Hiroki; Sakamaki, Fumio; Sayama, Koichi; Terashima, Takeshi; Koh, Hidefumi; Abe, Takayuki; Nishino, Makoto; Arai, Daisuke; Yasuda, Hiroyuki; Kawada, Ichiro; Soejima, Kenzo; Betsuyaku, Tomoko

    2018-05-01

    Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated advanced non-small-cell lung cancer based on the results from phase III clinical trials. We evaluated the real-world efficacy and safety of nivolumab in a nonselected population and identified the clinical characteristics that influence efficacy. A total of 142 patients with advanced non-small-cell lung cancer who were administered nivolumab at Keio University and affiliated hospitals in Japan from January to July 2016 were enrolled. The treatment efficacy and adverse events were retrospectively reviewed, and the clinical characteristics associated with the nivolumab response were evaluated using univariate and stratified analyses and the Cochran-Mantel-Haenszel test. The objective response rate was 17.0% (95% confidence interval [CI], 12.0%-24.0%), the median progression-free survival (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with adverse events of any grade was 45.0%. EGFR/ALK mutation status was inversely associated with the treatment response (P < .05), and the difference in PFS for the mutation-positive versus mutation-negative patients was statistically significant (49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2; P = .029). Previous radiotherapy also had a positive association with the treatment response (P = .012). The objective response rate, PFS, and adverse event profiles were comparable to those observed in previous clinical trials. EGFR/ALK mutation-negative status and previous radiotherapy might be key clinical characteristics associated with a positive treatment response. Our findings could aid in the efficient immunotherapeutic management of lung cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Economic analysis of ALK testing and crizotinib therapy for advanced non-small-cell lung cancer.

    PubMed

    Lu, Shun; Zhang, Jie; Ye, Ming; Wang, Baoai; Wu, Bin

    2016-06-01

    The economic outcome of crizotinib in advanced non-small-cell lung cancer harboring anaplastic lymphoma kinase rearrangement would be investigated. Based on a mathematical model, the economic outcome of three techniques for testing ALK gene rearrangement combing with crizotinib would be evaluated and compared with traditional regimen. The impact of the crizotinib patient assistance program (PAP) was assessed. Ventana immunohistochemistry, quantitative real-time reverse transcription-polymerase chain reaction and IHC testing plus fluorescent in situ hybridization confirmation for anaplastic lymphoma kinase testing following crizotinib treatment leaded to the incremental cost-effectiveness ratios of US$16,820 and US$223,242, US$24,424 and US$223,271, and US$16,850 and US$254,668 per quality-adjusted life-year gained with and without PAP, respectively. Gene-guided crizotinib therapy might be a cost-effective alternative comparing with the traditional regimen in the PAP setting.

  2. Involved field radiotherapy (IFRT) versus elective nodal irradiation (ENI) for locally advanced non-small cell lung cancer: a meta-analysis of incidence of elective nodal failure (ENF).

    PubMed

    Li, Ruijian; Yu, Liang; Lin, Sixiang; Wang, Lina; Dong, Xin; Yu, Lingxia; Li, Weiyi; Li, Baosheng

    2016-09-21

    The use of involved field radiotherapy (IFRT) has generated concern about the increasing incidence of elective nodal failure (ENF) in contrast to elective nodal irradiation (ENI). This meta-analysis aimed to provide more reliable and up-to-date evidence on the incidence of ENF between IFRT and ENI. We searched three databases for eligible studies where locally advanced non-small cell lung cancer (NSCLC) patients received IFRT or ENI. Outcome of interest was the incidence of ENF. The fixed-effects model was used to pool outcomes across the studies. There were 3 RCTs and 3 cohort studies included with low risk of bias. There was no significant difference in incidence of ENF between IFRT and ENI either among RCTs (RR = 1.38, 95 % CI: 0.59-3.25, p = 0.46) or among cohort studies (RR = 0.99, 95 % CI: 0.46-2.10, p = 0.97). There was also no significant difference in incidence of ENF between IFRT and ENI when RCTs and cohort studies were combined (RR = 1.15, 95 % CI: 0.65-2.01, p = 0.64). I 2 of test for heterogeneity was 0 %. This meta-analysis provides more reliable and stable evidence that there is no significant difference in incidence of ENF between IFRT and ENI.

  3. A treatment trade‐off based decision aid for patients with locally advanced non‐small cell lung cancer

    PubMed Central

    Brundage, Michael D.; Feldman‐Stewart, Deb; Dixon, Peter; Gregg, Richard; Youssef, Youssef; Davies, Diane; Mackillop, William J.

    2008-01-01

    Purpose To describe the structure and use of a decision aid for patients with locally advanced non‐small cell lung cancer (LA‐NSCLC) who are eligible for combined‐modality treatment (CMT) or for radiotherapy alone (RT). Methods The aid included a structured description of the treatment options and trade‐off exercises designed to help clarify the patient’s values for the relevant outcomes by determining the patient’s survival advantage threshold (the increase in survival conferred by CMT over RT that the patient deemed necessary for choosing CMT). Additional outcome measures included each patient’s strength of treatment preference, decisional conflict, objective understanding of survival information, decisional role preference, and evaluation of the aid itself. Results Twenty‐five patients met the eligibility criteria for study. Of these, seven declined the decision aid because they had a clear treatment preference (four chose CMT and three chose RT). The remaining 18 participants completed the decision aid; 16 chose CMT and two chose RT. All 18 patients wished to participate in the decision to some extent. All patients reported that using the decision support was useful to them and recommended its use for others. No patient or physician reported that the aid interfered with the physician‐patient relationship. Patients’ 3‐year survival advantage thresholds, and their median survival advantage thresholds, were each strongly correlated with their strengths of treatment preference (ρ=0.80, P < 0.001 and ρ=0.77, P < 0.001, respectively). For all but one patient, either their 3‐year or median survival threshold was consistent with their final treatment choice. Eight patients reported a stronger treatment preference after using the decision aid. Conclusions We conclude that a treatment trade‐off based decision aid for patients with locally advanced non‐small cell lung cancer is feasible, that it demonstrates internal

  4. Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non-small-cell lung cancer (LA-NSCLC): identification of five groups with different survival.

    PubMed

    Werner-Wasik, M; Scott, C; Cox, J D; Sause, W T; Byhardt, R W; Asbell, S; Russell, A; Komaki, R; Lee, J S

    2000-12-01

    Survival of patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) is predicted by the stage of the disease and other characteristics. This analysis was undertaken to identify these characteristics in a large cooperative group patient population, as well as to define subgroups of the population with differing outcomes. Analysis included 1,999 patients treated in 9 RTOG trials between 1983 and 1994 with thoracic irradiation (RT) with (n = 355) or without chemotherapy (CT). In univariate analysis, the following characteristics were significantly associated with an improved survival: use of CT, CT delivered without major deviation, abnormal pulmonary function tests, normal hemoglobin, protein, LDH and BUN, presence of dyspnea, hemoptysis, cough or hoarseness, uninvolved lymph nodes, T1 or T2 stage, no malignant pleural effusion (PE), weight loss of < 8%, Karnofsky performance status (KPS) of at least 90, adenocarcinoma histology, female gender, and age less than 70 years. Recursive partitioning analysis (RPA) was subsequently applied to identify 5 patient subgroups with significantly different median survival times (MST): Group I, KPS of > or = 90, who received chemotherapy (MST 16.2 months); Group II, KPS of > or = 90, who received no CT, but had no PE (MST 11.9 months); Group III, KPS < 90, younger than 70 years, with non-large cell histology (MST 9.6 months); Group IV, KPS > or = 90, but with PE, or KPS < 90, younger than 70 years, and with large cell histology, or older than 70 years, but without PE (MST 5.6-6.4 months); Group V, older than 70, with PE (MST 2.9 months). Cisplatinum-based CT improves survival, for excellent prognosis of LA-NSCLC patients, over RT alone. The presence of a malignant pleural effusion is a major negative prognostic factor for survival. The identification of RPA prognostic groups among patients with LA-NSCLC provides prognostic information and may serve as a basis of stratification in future trials.

  5. Treatment Options by Stage (Non-Small Cell Lung Cancer)

    MedlinePlus

    ... Cancer Prevention Lung Cancer Screening Research Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Non-Small Cell Lung Cancer Go to Health Professional Version Key ...

  6. Efficacy and safety of iodine-125 radioactive seeds brachytherapy for advanced non-small cell lung cancer-A meta-analysis.

    PubMed

    Zhang, Wenchao; Li, Jiawei; Li, Ran; Zhang, Ying; Han, Mingyong; Ma, Wei

    This meta-analysis was conducted to investigate the efficacy and safety of 125 I brachytherapy for locally advanced non-small cell lung cancer (NSCLC). Trials comparing 125 I brachytherapy with chemotherapy in NSCLC were identified. Meta-analysis was performed to obtain pooled risk ratios for an overall response rate (ORR), disease control rate (DCR) and complications, and pooled hazard ratio for overall survival (OS). Fifteen studies including 1188 cases were included. The pooled result indicated that there were significant differences in ORR, DCR, and OS between 125 I brachytherapy combined with chemotherapy and chemotherapy alone, but no statistic differences in gastrointestinal symptoms, leukopenia, myelosuppression, and hemoglobin reduction. Patients treated with 125 I brachytherapy combined with chemotherapy have a higher relative risk of pneumothorax, bloody sputum, and pneumorrhagia compared with chemotherapy alone. Seeds migration only occurred in the group treated with 125 I brachytherapy. There were significant differences in ORR, DCR, and myelosuppression between 125 I brachytherapy alone and chemotherapy. 125 I brachytherapy combined with chemotherapy can significantly enhance the clinical efficacy and improve the OS of patients with advanced NSCLC without increasing the incidence of complications of chemotherapy. 125 I brachytherapy alone can significantly enhance the clinical efficacy and reduce the incidence of myelosuppression compared with chemotherapy. However, 125 I brachytherapy may cause lung injury. Large sample and higher-quality randomized controlled trials are needed to confirm the pooled results of complications. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  7. Phase 0 Trial of Itraconazole for Early-Stage Non-Small Cell Lung Cancer

    DTIC Science & Technology

    2015-10-01

    63 Male Caucasian T1bN0M0 Stage IA Undifferentiated carcinoma , favor Large cell 63 Female Caucasian T1aN0N0 Stage IA squamous cell carcinoma ... carcinoma ; and possibly prolongs survival in advanced non-small cell lung cancer (NSCLC). Insight into itraconazole mechanism and biomarkers will...study team members in which itraconazole resulted in tumor regression and Hh pathway antagonism in basal cell carcinoma ; and (3) a clinical trial in

  8. Treatment patterns and cost-effectiveness of first line treatment of advanced non-squamous non-small cell lung cancer in Medicare patients.

    PubMed

    Gilden, Daniel M; Kubisiak, Joanna M; Pohl, Gerhardt M; Ball, Daniel E; Gilden, David E; John, William J; Wetmore, Stewart; Winfree, Katherine B

    2017-02-01

    To assess the cost-effectiveness of first-line pemetrexed/platinum and other commonly administered regimens in a representative US elderly population with advanced non-squamous non-small cell lung cancer (NSCLC). This study utilized the Surveillance Epidemiology and End Results (SEER) cancer registry linked to Medicare claims records. The study population included all SEER-Medicare patients diagnosed in 2008-2009 with advanced non-squamous NSCLC (stages IIIB-IV) as their only primary cancer and who started chemotherapy within 90 days of diagnosis. The study evaluated the four most commonly observed first-line regimens: paclitaxel/carboplatin, platinum monotherapy, pemetrexed/platinum, and paclitaxel/carboplatin/bevacizumab. Overall survival and total healthcare cost comparisons as well as incremental cost-effectiveness ratios (ICERs) were calculated for pemetrexed/platinum vs each of the other three. Unstratified analyses and analyses stratified by initial disease stage were conducted. The final study population consisted of 2,461 patients. Greater administrative censorship of pemetrexed recipients at the end of the study period disproportionately reduced the observed mean survival for pemetrexed/platinum recipients. The disease stage-stratified ICER analysis found that the pemetrexed/platinum incurred total Medicare costs of $536,424 and $283,560 per observed additional year of life relative to platinum monotherapy and paclitaxel/carboplatin, respectively. The pemetrexed/platinum vs triplet comparator analysis indicated that pemetrexed/platinum was associated with considerably lower total Medicare costs, with no appreciable survival difference. Limitations included differential censorship of the study regimen recipients and differential administration of radiotherapy. Pemetrexed/platinum yielded either improved survival at increased cost or similar survival at reduced cost relative to comparator regimens in the treatment of advanced non-squamous NSCLC. Limitations

  9. Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy.

    PubMed

    Kumar, Sameera S; Higgins, Kristin A; McGarry, Ronald C

    2017-01-01

    The current standard of care for locally advanced non-small cell lung cancer (NSCLC) includes radiation, chemotherapy, and surgery in certain individualized cases. In unresectable NSCLC, chemoradiation has been the standard of care for the past three decades. Local and distant failure remains high in this group of patients, so dose escalation has been studied in both single institution and national clinical trials. Though initial studies showed a benefit to dose escalation, phase III studies examining dose escalation using standard fractionation or hyperfractionation have failed to show a benefit. Over the last 17 years, stereotactic body radiation therapy (SBRT) has shown a high degree of safety and local control for stage I lung cancers and other localized malignancies. More recently, phase I/II studies using SBRT for dose escalation after conventional chemoradiation in locally advanced NSCLC have been promising with good apparent safety. Immunotherapy also offers opportunities to address distant disease and preclinical data suggest immunotherapy in tandem with SBRT may be a rational way to induce an "abscopal effect" although there are little clinical data as yet. By building on the proven concept of conventional chemoradiation for patients with locally advanced NSCLC with a subsequent radiation dose intensification to residual disease with SBRT concurrent with immunotherapy, we hope address the issues of metastatic and local failures. This "quadmodality" approach is still in its infancy but appears to be a safe and rational approach to the improving the outcome of NSCLC therapy.

  10. Endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma: Is it a significant prognostic factor?

    PubMed

    Shin, Hae Jin; Moon, Hee Seok; Kang, Sun Hyung; Sung, Jae Kyu; Jeong, Hyun Yong; Kim, Seok Hyun; Lee, Byung Seok; Kim, Ju Seok; Yun, Gee Young

    2017-12-01

    The purpose of this study was to evaluate the prognostic impact of endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma.This retrospective study was based on medical records from a single tertiary medical center. The records of 317 patients with esophageal squamous cell carcinoma treated with surgery or definitive chemoradiotherapy (CRT) between January 2009 and March 2016 were reviewed. Finally, we retrieved the data on 168 consecutive patients. These 168 patients were divided into 2 groups based on their endoscopic traversability findings: Group A (the endoscope traversable group), and Group B (the endoscope non-traversable group). We then retrospectively compared the clinical characteristics of these 2 groups.The endoscope non-traversable group (Group B) revealed an advanced clinical stage, a poor Eastern Cooperative Oncology Group (ECOG) score, a lower serum albumin level, a higher rate of requirement for esophageal stent insertion and definitive CRT as initial treatment than the endoscope traversable group (Group A). Patients with endoscope traversable cancer showed a significantly higher 3-year overall survival and 3-year relapse-free survival than patients who were endoscope non-traversable (53.8% vs 17.3%, P < .001 and 71.1% vs 45.3%, P = .003, respectively). Upon multivariate analysis of patients with locally advanced esophageal squamous cell carcinoma treated with definitive CRT, the serum albumin level <3.5 g/dL and endoscopic non-traversability were significant negative factors of survival.Endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma treated with definitive CRT is a significant prognostic factor. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

  11. Safety profile of platinum-based chemotherapy in the treatment of advanced non-small cell lung cancer in elderly patients.

    PubMed

    Rossi, Antonio; Maione, Paolo; Gridelli, Cesare

    2005-11-01

    Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. More than 50% of NSCLC patients are diagnosed at > 65 years of age and approximately one-third of all patients are > 70 years of age. Elderly patients tolerate chemotherapy poorly compared with their younger counterpart because of the progressive reduction of organ function and comorbidities related to age. For this reason, these patients are often not considered eligible for aggressive platinum-based chemotherapy, the standard medical treatment for advanced NSCLC. In clinical practice, single-agent chemotherapy should remain the standard treatment. Feasibility of platinum-based chemotherapy remains an open issue and has to be proven prospectively. Moreover, a multidimensional geriatric assessment for individualised treatment choice in NSCLC elderly patients is mandatory. This review focuses on the currently-available evidences for the treatment of elderly patients affected by advanced NSCLC with regards to the role and safety of platinum-based chemotherapy.

  12. Immune Checkpoint Inhibitors for Patients With Advanced Non-Small-Cell Lung Cancer: A Systematic Review.

    PubMed

    Ellis, Peter M; Vella, Emily T; Ung, Yee C

    2017-09-01

    Second-line treatment options are limited for patients with advanced non-small-cell lung cancer (NSCLC). Standard therapy includes the cytotoxic agents docetaxel and pemetrexed, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib. Immune checkpoint inhibitors are a new class of treatment that have shown durable overall radiologic response rates and have been well tolerated. The objective of this systematic review was to investigate the efficacy of immune checkpoint inhibitors compared with other chemotherapies in patients with advanced NSCLC. Medline, Embase, and PubMed were searched for randomized controlled trials comparing treatment with immune checkpoint inhibitors against treatment with chemotherapy in patients with stage IIIB or IV NSCLC. Nine randomized controlled trials with 15 publications were included. A significant overall survival benefit of second-line nivolumab (nonsquamous: hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.60-0.77; P < .001; squamous: HR = 0.59, 95% CI, 0.44-0.79; P < .001) or second-line atezolizumab (HR = 0.73, 95% CI, 0.62-0.87; P = .0003) or second-line pembrolizumab (in patients with programmed cell death ligand 1 [PD-L1]-positive tumors) (pembrolizumab 2 mg/kg HR = 0.71, 95% CI, 0.58-0.88; P = .0008; pembrolizumab 10 mg/kg HR = 0.61, 95% CI, 0.49-0.75; P < .0001) or first-line pembrolizumab (HR = 0.60, 95% CI, 0.41-0.89; P = .005) compared with chemotherapy was found. The adverse effects were mainly higher in the chemotherapy arms. For patients with advanced stage IIIB/IV NSCLC, the improvement in overall survival outweighed the harms and supported the use of first-line pembrolizumab (in patients with ≥ 50% PD-L1-positive tumors) or second-line nivolumab, atezolizumab, or pembrolizumab (in patients with PD-L1-positive tumors). Copyright © 2017 Elsevier Inc. All rights reserved.

  13. The small length scale effect for a non-local cantilever beam: a paradox solved.

    PubMed

    Challamel, N; Wang, C M

    2008-08-27

    Non-local continuum mechanics allows one to account for the small length scale effect that becomes significant when dealing with microstructures or nanostructures. This paper presents some simplified non-local elastic beam models, for the bending analyses of small scale rods. Integral-type or gradient non-local models abandon the classical assumption of locality, and admit that stress depends not only on the strain value at that point but also on the strain values of all points on the body. There is a paradox still unresolved at this stage: some bending solutions of integral-based non-local elastic beams have been found to be identical to the classical (local) solution, i.e. the small scale effect is not present at all. One example is the Euler-Bernoulli cantilever nanobeam model with a point load which has application in microelectromechanical systems and nanoelectromechanical systems as an actuator. In this paper, it will be shown that this paradox may be overcome with a gradient elastic model as well as an integral non-local elastic model that is based on combining the local and the non-local curvatures in the constitutive elastic relation. The latter model comprises the classical gradient model and Eringen's integral model, and its application produces small length scale terms in the non-local elastic cantilever beam solution.

  14. Factors Associated With Early Mortality in Patients Treated With Concurrent Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Warner, Andrew; Dahele, Max; Hu, Bo

    Purpose: Concurrent chemoradiation therapy (con-CRT) is recommended for fit patients with locally advanced non-small cell lung cancer (LA-NSCLC) but is associated with toxicity, and observed survival continues to be limited. Identifying factors associated with early mortality could improve patient selection and identify strategies to improve prognosis. Methods and Materials: Analysis of a multi-institutional LA-NSCLC database consisting of 1245 patients treated with con-CRT in 13 institutions was performed to identify factors predictive of 180-day survival. Recursive partitioning analysis (RPA) was performed to identify prognostic groups for 180-day survival. Multivariate logistic regression analysis was used to create a clinical nomogram predicting 180-daymore » survival based on important predictors from RPA. Results: Median follow-up was 43.5 months (95% confidence interval [CI]: 40.3-48.8) and 127 patients (10%) died within 180 days of treatment. Median, 180-day, and 1- to 5-year (by yearly increments) actuarial survival rates were 20.9 months, 90%, 71%, 45%, 32%, 27%, and 22% respectively. Multivariate analysis adjusted by region identified gross tumor volume (GTV) (odds ratio [OR] ≥100 cm{sup 3}: 2.61; 95% CI: 1.10-6.20; P=.029) and pulmonary function (forced expiratory volume in 1 second [FEV{sub 1}], defined as the ratio of FEV{sub 1} to forced vital capacity [FVC]) (OR <80%: 2.53; 95% CI: 1.09-5.88; P=.030) as significant predictors of 180-day survival. RPA resulted in a 2-class risk stratification system: low-risk (GTV <100 cm{sup 3} or GTV ≥100 cm{sup 3} and FEV{sub 1} ≥80%) and high-risk (GTV ≥100 cm{sup 3} and FEV{sub 1} <80%). The 180-day survival rates were 93% for low risk and 79% for high risk, with an OR of 4.43 (95% CI: 2.07-9.51; P<.001), adjusted by region. A clinical nomogram predictive of 180-day survival, incorporating FEV{sub 1}, GTV, N stage, and maximum esophagus dose yielded favorable calibration (R{sup 2} = 0

  15. A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non-small-cell lung cancer.

    PubMed

    Hasegawa, Takaaki; Futamura, Yohei; Horiba, Akane; Yoshida, Tsutomu; Suzuki, Toshitaka; Kato, Tatsuo; Kaito, Daizo; Ohno, Yasuhi; Iida, Takayoshi; Hayashi, Shinya; Sawa, Toshiyuki

    2016-01-01

    We investigated the efficacy and safety of albumin-bound paclitaxel (nab-PTX) and carboplatin (CBDCA) with concurrent radiotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Concurrent chemoradiotherapy consisted of weekly administration of nab-PTX (40 mg/m(2)) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m(2) on Days 1, 8 and 15)/CBDCA (AUC 5 mg/ml/min on Day 1). Response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival were estimated using the Kaplan-Meier method. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. A total of 10 patients were enrolled in this trial between September 2013 and January 2014 from three institutes. The overall response rate was 40.0% and the median progression-free survival was 6.7 months. Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. The results of this study indicate that no further investigation is warranted into nab-PTX and CBDCA with concurrent thoracic radiation for Stage III NSCLC with V20 > 30% due to severe toxicity. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  16. Intensity-Modulated Proton Therapy for Elective Nodal Irradiation and Involved-Field Radiation in the Definitive Treatment of Locally Advanced Non-Small Cell Lung Cancer: A Dosimetric Study

    PubMed Central

    Kesarwala, Aparna H.; Ko, Christine J.; Ning, Holly; Xanthopoulos, Eric; Haglund, Karl E.; O’Meara, William P.; Simone, Charles B.; Rengan, Ramesh

    2015-01-01

    Background Photon involved-field radiation therapy (IFRT), the standard for locally advanced non-small cell lung cancer (LA-NSCLC), results in favorable outcomes without increased isolated nodal failures, perhaps from scattered dose to elective nodal stations. Given the high conformality of intensity-modulated proton therapy (IMPT), proton IFRT could increase nodal failures. We investigated the feasibility of IMPT for elective nodal irradiation (ENI) in LA-NSCLC. Materials and Methods IMPT IFRT plans were generated to the same total dose of 66.6–72 Gy received by 20 LA-NSCLC patients treated with photon IFRT. IMPT ENI plans were generated to 46 CGE to elective nodal (EN) planning treatment volumes (PTV) plus 24 CGE to involved field (IF)-PTVs. Results Proton IFRT and ENI both improved D95 involved field (IF)-PTV coverage by 4% (p<0.01) compared to photon IFRT. All evaluated dosimetric parameters improved significantly with both proton plans. Lung V20 and mean lung dose decreased 18% (p<0.01) and 36% (p<0.01), respectively, with proton IFRT and 11% (p=0.03) and 26% (p<0.01) with ENI. Mean esophagus dose decreased 16% with IFRT and 12% with ENI; heart V25 decreased 63% with both (all p<0.01). Conclusions This study demonstrates the feasibility of IMPT for LA-NSCLC ENI. Potential decreased toxicity indicates IMPT could allow ENI while maintaining a favorable therapeutic ratio compared to photon IFRT. PMID:25604729

  17. Intensity-modulated proton therapy for elective nodal irradiation and involved-field radiation in the definitive treatment of locally advanced non-small-cell lung cancer: a dosimetric study.

    PubMed

    Kesarwala, Aparna H; Ko, Christine J; Ning, Holly; Xanthopoulos, Eric; Haglund, Karl E; O'Meara, William P; Simone, Charles B; Rengan, Ramesh

    2015-05-01

    Photon involved-field (IF) radiation therapy (IFRT), the standard for locally advanced (LA) non-small cell lung cancer (NSCLC), results in favorable outcomes without increased isolated nodal failures, perhaps from scattered dose to elective nodal stations. Because of the high conformality of intensity-modulated proton therapy (IMPT), proton IFRT could increase nodal failures. We investigated the feasibility of IMPT for elective nodal irradiation (ENI) in LA-NSCLC. IMPT IFRT plans were generated to the same total dose of 66.6-72 Gy received by 20 LA-NSCLC patients treated with photon IFRT. IMPT ENI plans were generated to 46 cobalt Gray equivalent (CGE) to elective nodal planning treatment volumes (PTV) plus 24 CGE to IF-PTVs. Proton IFRT and ENI improved the IF-PTV percentage of volume receiving 95% of the prescribed dose (D95) by 4% (P < .01) compared with photon IFRT. All evaluated dosimetric parameters improved significantly with both proton plans. The lung percentage of volume receiving 20 Gy/CGE (V20) and mean lung dose decreased 18% (P < .01) and 36% (P < .01), respectively, with proton IFRT, and 11% (P = .03) and 26% (P < .01) with ENI. The mean esophagus dose decreased 16% with IFRT and 12% with ENI; heart V25 decreased 63% with both (all P < .01). This study demonstrates the feasibility of IMPT for LA-NSCLC ENI. Potential decreased toxicity indicates that IMPT could allow ENI while maintaining a favorable therapeutic ratio compared with photon IFRT. Published by Elsevier Inc.

  18. Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: A case report and literature review.

    PubMed

    Wu, Fengying; Zhang, Shijia; Gao, Guanghui; Zhao, Jing; Ren, Shengxiang; Zhou, Caicun

    2018-03-04

    Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.

  19. IASLC Statement Paper: Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC).

    PubMed

    Rolfo, Christian; Mack, Philip C; Scagliotti, Giorgio V; Baas, Paul; Barlesi, Fabrice; Bivona, Trever G; Herbst, Roy S; Mok, Tony S; Peled, Nir; Pirker, Robert; Raez, Luis E; Reck, Martin; Riess, Jonathan W; Sequist, Lecia V; Shepherd, Frances A; Sholl, Lynette M; Tan, Daniel Sw; Wakelee, Heather A; Wistuba, Ignacio I; Wynes, Murry W; Carbone, David P; Hirsch, Fred R; Gandara, David R

    2018-06-06

    The isolation of circulating cell-free tumoral DNA (ctDNA) in plasma and its subsequent molecular analysis is a powerful tool that can help improve clinical outcomes across multiple cancer types, including non-small cell lung cancer (NSCLC). Assays of this nature that utilize blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of new platforms have been recently developed that improve not only the fidelity of the molecular analysis of the liquid biopsy but also the number of tests performed on a single specimen. ctDNA assays for detection of both epidermal growth factor receptor (EGFR) sensitizing and resistance mutations have already entered clinical practice and many other molecular tests - such as resistance mutations for ALK rearrangements - are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology, was convened by the International Association for the Study of Lung Cancer (IASLC) to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs. Copyright © 2018. Published by Elsevier Inc.

  20. Vinorelbine and paclitaxel for locoregional advanced or metastatic non-small-cell lung cancer.

    PubMed

    Pérez, Juan E; Machiavelli, Mario R; Romero, Alberto O; Romero Acuña, Luis A; Domínguez, María E; Fasce, Hebe; Flores Acosta, Luis; Marrone, Nora; Romero Acuña, Juan M; Langhi, Mario J; Amato, Sonia; Bologna, Fabrina; Ortiz, Eduardo H; Leone, Bernardo A; Lacava, Juan A; Vallejo, Carlos T

    2002-08-01

    A phase II trial was performed to evaluate the efficacy and toxicity of the novel combination of vinorelbine and paclitaxel as first-line chemotherapy in patients with stages IIIB and IV non-small-cell lung cancer. From January 1997 to September 1999, 34 patients (9 stage IIIB and 25 stage IV) received a regimen consisting of the following: vinorelbine 30 mg/m2 20 minutes intravenous (i.v.) infusion, days 1 and 8; and paclitaxel 135 mg/m2 3-hour i.v. (starting 1 hour after vinorelbine) on day 1. Cycles were repeated every 28 days until progression of disease or unacceptable toxicity development. The median age was 57 years (range 41-70 years); median performance status was 1. Histology was as follows: squamous cell in 24 (71%), large cell in 1 (3%), and adenocarcinoma in 9 (26%). All patients are evaluable for toxicity, whereas 30 are evaluable for response (4 patients refused treatment). Objective response was recorded in 4 of 30 patients (13%, 95% CI 1-25%). No complete response was observed. Partial response was recorded in 4 patients (13%), no change in 10 patients (34%), and progressive disease in 16 patients (53%). The median time to treatment failure was 4 months and median survival was 9 months. The limiting toxicity was myelosuppression: leukopenia in 23 patients (68%), whereas neutropenia was observed in 25 patients (78%). Peripheral neurotoxicity developed in 14 patients (41%) (without G3 or G4 episodes), and constipation (G1-G2: 10 patients), myalgia (G1-G2: 11 patients), diarrhea (G1-G2: 7 patients), and stomatitis were observed in 7 patients. Vinorelbine-paclitaxel combination showed only modest activity against locoregionally advanced or metastatic NSCLC.

  1. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial.

    PubMed

    Ramalingam, Suresh S; Jänne, Pasi A; Mok, Tony; O'Byrne, Kenneth; Boyer, Michael J; Von Pawel, Joachim; Pluzanski, Adam; Shtivelband, Mikhail; Docampo, Lara Iglesias; Bennouna, Jaafar; Zhang, Hui; Liang, Jane Q; Doherty, Jim P; Taylor, Ian; Mather, Cecile B; Goldberg, Zelanna; O'Connell, Joseph; Paz-Ares, Luis

    2014-11-01

    Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade

  2. Socioeconomic factors related to surgical treatment for localized, non-small cell lung cancer.

    PubMed

    Jiang, Xiaqing; Lin, Ge; Islam, K M Monirul

    2017-02-01

    Various socioeconomic factors were reported to be associated with receiving surgical treatment in localized, non-small cell lung cancer (NSCLC) patients in previous studies. We wanted to assess the impact of residential poverty on receiving surgical treatment in a state-wide population of localized NSCLC, adjusting for demographic, clinical, residence and tumor factors. Data on 970 patients with primary localized NSCLC were collected from the Nebraska Cancer Registry (NCR), and linked with the Nebraska Hospital Discharge Data (NHDD) between 2005 and 2009, as well as the 2010 Census data. Characteristics of patients with and without surgery were compared using Chi-square tests. Unadjusted and adjusted odds ratios (ORs) of receiving surgery for low versus high poverty were generated based on the series of logistic regression models controlling for demographics, comorbidity, residence and tumor histology. Patients who were 65 year old or younger, without comorbidities, single or married, and with adenocarcinoma histologic type were more likely to receive surgery. Without adjustment, poverty was negatively associated with receiving surgery. Patients who resided in low poverty neighborhoods (less than 5% of the households under poverty line) were twice more likely to receive surgery than those who lived in high poverty neighborhoods (more than 15% of the households under poverty line) (OR 2.13, 95% CI 1.33-3.40). After adjustment, poverty was independently and negatively associated with receiving surgery treatment. Residents in low poverty neighborhoods were still about twice more likely to receive surgery than those in high poverty neighborhoods when the other demographic, urban/rural residency and clinical factors were adjusted (ORs 2.01-2.18, all p < 0.05). The mechanism of how living in poverty interacts with other factors and its impact on patient's choice and their chance of getting surgical treatment invites future studies. Copyright © 2017 Elsevier Ltd. All

  3. Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer.

    PubMed

    Gettinger, Scott; Rizvi, Naiyer A; Chow, Laura Q; Borghaei, Hossein; Brahmer, Julie; Ready, Neal; Gerber, David E; Shepherd, Frances A; Antonia, Scott; Goldman, Jonathan W; Juergens, Rosalyn A; Laurie, Scott A; Nathan, Faith E; Shen, Yun; Harbison, Christopher T; Hellmann, Matthew D

    2016-09-01

    Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved survival over docetaxel in previously treated advanced non-small-cell lung cancer (NSCLC). First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I, multicohort, Checkmate 012 trial. Fifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity; postprogression treatment was permitted per protocol. The primary objective was to assess safety; secondary objectives included objective response rate (ORR) and 24-week progression-free survival (PFS) rate; overall survival (OS) was an exploratory end point. Any-grade treatment-related adverse events (AEs) occurred in 71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3 to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued because of a treatment-related AE. The confirmed ORR was 23% (12 of 52), including four ongoing complete responses. Nine of 12 responses (75%) occurred by first tumor assessment (week 11); eight (67%) were ongoing (range, 5.3+ to 25.8+ months) at the time of data lock. ORR was 28% (nine of 32) in patients with any degree of tumor PD-ligand 1 expression and 14% (two of 14) in patients with no PD-ligand 1 expression. Median PFS was 3.6 months, and the 24-week PFS rate was 41% (95% CI, 27 to 54). Median OS was 19.4 months, and the 1-year and 18-month OS rates were 73% (95% CI, 59 to 83) and 57% (95% CI, 42 to 70), respectively. First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC. © 2016 by American Society of Clinical Oncology.

  4. MOLECULARLY TARGETED THERAPIES IN NON-SMALL CELL LUNG CANCER ANNUAL UPDATE 2014

    PubMed Central

    Morgensztern, Daniel; Campo, Meghan J.; Dahlberg, Suzanne E.; Doebele, Robert C.; Garon, Edward; Gerber, David E.; Goldberg, Sarah B.; Hammerman, Peter S.; Heist, Rebecca; Hensing, Thomas; Horn, Leora; Ramalingam, Suresh S.; Rudin, Charles M.; Salgia, Ravi; Sequist, Lecia; Shaw, Alice T.; Simon, George R.; Somaiah, Neeta; Spigel, David R.; Wrangle, John; Johnson, David; Herbst, Roy S.; Bunn, Paul; Govindan, Ramaswamy

    2015-01-01

    There have been significant advances in the understanding of the biology and treatment of non-small cell lung cancer (NSCLC) over the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC (Table 1). We are beginning to understand the mechanisms of acquired resistance following exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies and immunotherapy. PMID:25535693

  5. Targeting the VEGF pathway: antiangiogenic strategies in the treatment of non-small cell lung cancer.

    PubMed

    Aita, Marianna; Fasola, Gianpiero; Defferrari, Carlotta; Brianti, Annalisa; Bello, Maria Giovanna Dal; Follador, Alessandro; Sinaccio, Graziella; Pronzato, Paolo; Grossi, Francesco

    2008-12-01

    The management of advanced non-small cell lung cancer (NSCLC) has evolved considerably in recent years, due to a progressive understanding of tumour biology and the identification of promising molecular targets. Several agents have been developed so far inhibiting vascular endothelial growth factor (VEGF) - a key protein in tumour neoangiogenesis, growth and dissemination - or its receptor signalling system. The finding in study E4599 of a survival benefit for carboplatin-paclitaxel plus bevacizumab - a humanised anti-VEGF monoclonal antibody - over chemotherapy (CT) alone led the U.S. Food and Drug Administration (FDA) to approve the novel combination for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. In a randomised phase III trial presented at the American Society of Clinical Oncology (ASCO) 2007 Annual Meeting, patients receiving cisplatin-gemcitabine plus bevacizumab experienced a significantly longer progression-free survival (PFS) compared to the standard arm. Based on these data, the European Medicines Agency (EMEA) has granted marketing authorisation for bevacizumab in addition to any platinum-based CT for first-line treatment of advanced NSCLC other than predominantly squamous histology. Aim of this report is to provide an overview on bevacizumab in NSCLC, with special emphasis on clinical results presented at ASCO last meeting. Multitargeted tyrosine kinase inhibitors (TKIs), sharing a focus on both the angiogenesis process and additional cell-surface receptors, and VEGF Trap, a novel fusion protein with markedly higher affinity for VEGF than bevacizumab, will be briefly discussed as well.

  6. Hypofractionated Image-guided Radiation Therapy (3Gy/fraction) in Patients Affected by Inoperable Advanced-stage Non-small Cell Lung Cancer After Long-term Follow-up.

    PubMed

    Agolli, Linda; Valeriani, Maurizio; Bracci, Stefano; Nicosia, Luca; DE Sanctis, Vitaliana; Enrici, Riccardo Maurizi; Osti, Mattia Falchetto

    2015-10-01

    We conducted long-term follow-up analysis of the outcomes for patients affected by advanced-stage non-small cell lung cancer (NSCLC) treated with hypofractionated radiotherapy (RT). Sixty patients with advanced-stage NSCLC (IIIA-IV) treated with hypofractionated radiotherapy (60Gy/20 fractions) were analyzed. Radiation was delivered using an image-guided RT technique to verify the correct position. Toxicities were graded according to the Common Toxicity Criteria for Adverse Effects v4.0 scale. Overall, six patients achieved a complete response and 46 patients had a partial response (tumor response rate 86%). After a median follow-up of 30 months, locoregional progression occurred in 23 patients and distant progression occurred in 38. The 1-year and 2-years overall survival were 57% and 40%, respectively. The 1-year and 2-years progression-free survival (PFS) were 47.1% and 33.5%, respectively. The median duration of OS and PFS was 13 months and 12 months, respectively. The 2-year local PFS and metastases-free survival (MFS) were 53% and 40.3%, respectively. On univariate analysis, the T-size (≥5 cm), and type of response to RT (non-response/progressive disease) were significantly associated with worse OS. Type of response was identified as significant prognostic factors for PFS (p<0.01) local PFS (p=0.015) and MFS (p<0.01). Acute grade 3 esophagitis and pneumonitis occurred in three patients (5%) and four patients (6%), respectively. Late grade 3 esophagitis and pneumonitis occurred in 2% (one patient) and 3% (two patients), respectively. No patient experienced grade 4 acute or late RT-related toxicities. Hypofractionated RT offers good disease control for patients with advanced-stage NSCLC with acceptable toxicity rates. Phase III randomized trials are necessary to compare hypofractionated RT with conventional RT. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  7. Phase II trial of cytarabine, cisplatin and vindesine for advanced non-small cell lung cancer.

    PubMed

    Bianco, A; Perez, J E; Machiavelli, M; Leone, B A; Romero, A; Rabinovich, M G; Vallejo, C T; Rodriguez, R; Cuevas, M A; Alvarez, L A

    1990-02-28

    Thirty-two patients with advanced non-small cell lung cancer (NSCLC) were entered in this study to evaluate the efficacy and toxicity of a chemotherapy schedule including cisplatin (C) 40 mg/m2 intravenously (i.v.) on days 1-3; vindesine (V) 3 mg/m2 i.v. on day 1, and cytarabine (ara-C) 15 mg/m2 subcutaneously every 12 hours on days 1-3 (total dose: 90 mg/m2). Cisplatin was administered simultaneously with one dose of ara-C. Cycles were repeated every 28 days. Five patients out of 28 (18%) fully evaluable for response presented partial remissions. No complete response was observed. Median survival was 8 months and median duration of response was 4 months. Hematologic toxicity was severe in 3 patients. There were no toxicity-related deaths. Other adverse reactions included nausea and vomiting, alopecia and peripheral neuropathy. We conclude that this chemotherapy combination is marginally effective against NSCLC showing in this group of patients a low number of responses of short duration without a significant impact on survival.

  8. [Efficacy of icotinib for advanced non-small cell lung cancer patients with EGFR status identified].

    PubMed

    Song, Zhengbo; Yu, Xinmin; Cai, Jufen; Shao, Lan; Lin, Baochai; He, Chunxiao; Zhang, Beibei; Zhang, Yiping

    2013-03-01

    As the first epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in China, icotinib shows promising anticancer activity in vitro and vivo. The phase III clinical study (ICOGEN) showed that icotinib has a good efficacy and tolerability in Chinese patients with advanced non-small cell lung cancer (NSCLC) compared with gefitinib. This retrospective study aims to evaluate the efficacy and tolerability of icotinib monotherapy for advanced NSCLC patients with EGFR mutation and wild-type patients in our hospital. Patients with advanced NSCLC who were treated with icotinib in Zhejiang Cancer Hospital were retrospectively analyzed from August, 2011 to August, 2012. Survival was estimated using Kaplan-Meier analysis and Log-rank tests. The clinical data of 49 patients (13 with wild-type and 36 with EGFR mutation) with NSCLC were enrolled in the current study. The patients' overall objective response rate (ORR) was 58.3% and the disease control rate (DCR) in 36 EGFR mutation patients was 88.9%. The ORR was 7.7% and DCR was 53.8% in the wild-type patients. Median progression-free survival (PFS) with icotinib treatment in EGFR mutation patients was 9.5 months and 2.2 months in wild-type patients (P<0.001). Nineteen patients with EGFR mutation received icotinib as first-line and 17 in further-line treatment. The PFS was 9.5 months in the first-line and 8.5 months for second-line or further-line patients (P=0.41). Median overall survival (OS) in EGFR mutation patients was not reached, but was 12.6 months in wild-type patients. Most of the drug-related adverse events were mild (grade I or II) and reversible with no grade IV toxicity. Icotinib monotherapy showed significant antitumor activity in advanced NSCLC EGFR mutation patients. The toxicity was well tolerated and acceptable.

  9. Clinical potential of nintedanib for the second-line treatment of advanced non-small-cell lung cancer: current evidence.

    PubMed

    Rothschild, Sacha I

    2014-01-01

    The therapeutic landscape in non-small-cell lung cancer (NSCLC) is changing. The description of molecular alterations leading to NSCLC carcinogenesis and progression (so-called oncogenic driver mutations) and the development of targeted agents interfering with the tumor-promoting intracellular signaling pathways have improved the outcome for many patients with advanced/metastatic NSCLC. However, many patients with stage IV NSCLC do not have one of the targetable predictive biomarkers, and are therefore in need of classical chemotherapy. This especially applies to squamous cell cancer. A platinum-based doublet chemotherapy is the standard of care for patients with stage IV NSCLC. As second-line therapies, docetaxel, pemetrexed, and the EGFR tyrosine-kinase inhibitor erlotinib have demonstrated benefit in Phase III randomized trials. Recently, the addition of the angiokinase inhibitor nintedanib to docetaxel has proven efficacious, and is a new treatment option in the second-line setting. Preclinical and clinical data of nintedanib for the treatment of lung cancer patients are reviewed here.

  10. Clinical potential of nintedanib for the second-line treatment of advanced non-small-cell lung cancer: current evidence

    PubMed Central

    Rothschild, Sacha I

    2014-01-01

    The therapeutic landscape in non-small-cell lung cancer (NSCLC) is changing. The description of molecular alterations leading to NSCLC carcinogenesis and progression (so-called oncogenic driver mutations) and the development of targeted agents interfering with the tumor-promoting intracellular signaling pathways have improved the outcome for many patients with advanced/metastatic NSCLC. However, many patients with stage IV NSCLC do not have one of the targetable predictive biomarkers, and are therefore in need of classical chemotherapy. This especially applies to squamous cell cancer. A platinum-based doublet chemotherapy is the standard of care for patients with stage IV NSCLC. As second-line therapies, docetaxel, pemetrexed, and the EGFR tyrosine-kinase inhibitor erlotinib have demonstrated benefit in Phase III randomized trials. Recently, the addition of the angiokinase inhibitor nintedanib to docetaxel has proven efficacious, and is a new treatment option in the second-line setting. Preclinical and clinical data of nintedanib for the treatment of lung cancer patients are reviewed here. PMID:28210142

  11. Treatment modalities for advanced ALK-rearranged non-small-cell lung cancer.

    PubMed

    Sullivan, Ivana; Planchard, David

    2016-04-01

    The ALK gene plays a key role in the pathogenesis of non-small-cell lung cancer (NSCLC). Patients with NSCLC harboring an ALK-rearrangement represent the second oncogene addiction to be identified in this disease. Crizotinib was the first ALK inhibitor showing pronounced clinical activity, and is now a reference treatment for ALK-positive NSCLC disease. However, despite initial impressive responses to crizotinib, acquired resistance almost invariably develops within 12 months. The pressing need for effective second-line agents has prompted the rapid development of next-generation ALK inhibitors. These agents, notably ceritinib and alectinib as the most developed, have a higher potency against ALK than crizotinib, along with activity against tumors harboring crizotinib-resistant mutations and potentially improved CNS penetration.

  12. Targeted erlotinib for first-line treatment of advanced non-small cell lung cancer: a budget impact analysis.

    PubMed

    Bajaj, Preeti S; Veenstra, David L; Goertz, Hans-Peter; Carlson, Josh J

    2014-08-01

    A recent phase III trial showed that patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor specific EGFR mutations significantly benefit from first-line treatment with erlotinib compared to chemotherapy. This study sought to estimate the budget impact if coverage for EGFR testing and erlotinib as first-line therapy were provided in a hypothetical 500,000-member managed care plan. The budget impact model was developed from a US health plan perspective to evaluate administration of the EGFR test and treatment with erlotinib for EGFR-positive patients, compared to non-targeted treatment with chemotherapy. The eligible patient population was estimated from age-stratified SEER incidence data. Clinical data were derived from key randomized controlled trials. Costs related to drug, administration, and adverse events were included. Sensitivity analyses were conducted to assess uncertainty. In a plan of 500,000 members, it was estimated there would be 91 newly diagnosed advanced NSCLC patients annually; 11 are expected to be EGFR-positive. Based on the testing and treatment assumptions, it was estimated that 3 patients in Scenario 1 and 6 patients in Scenario 2 receive erlotinib. Overall health plan expenditures would increase by $0.013 per member per month (PMPM). This increase is largely attributable to erlotinib drug costs, in part due to lengthened progression-free survival and treatment periods experienced in erlotinib-treated patients. EGFR testing contributes slightly, whereas adverse event costs mitigate the budget impact. The budget impact did not exceed $0.019 PMPM in sensitivity analyses. Coverage for targeted first-line erlotinib therapy in NSCLC likely results in a small budget impact for US health plans. The estimated impact may vary by plan, or if second-line or maintenance therapy, dose changes/interruptions, or impact on patients' quality-of-life were included.

  13. Robot-assisted Extracranial Stereotactic Radiotherapy of Adrenal Metastases in Oligometastatic Non-small Cell Lung Cancer.

    PubMed

    Celik, Eren; Semrau, Robert; Baues, Christian; Trommer-Nestler, Maike; Baus, Wolfgang; Marnitz, Simone

    2017-09-01

    The aim of this study was to evaluate the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in the treatment of patients with adrenal metastases in oligometastatic non-small-cell lung cancer (NSCLC). Between November 2012 and May 2015, fifteen patients with oligometastatic non-small cell lung cancer and adrenal metastases were treated with the Cyberknife® system. The primary endpoint was local control. The 1-year and 2-year local control rates were 60% and 46.6%, respectively. The differences in local control for patients with metachronous and synchronous metastases reached statistical significance (p=0.00028). Two-year overall survival of 91.2% for patients with metachronous metastases was also more favourable compared to patients with synchronous adrenal metastases with 42.8%. Extracranial stereotactic radiotherapy with the Cyberknife® is a safe and non-invasive technique that extends the therapeutic spectrum in the treatment of patients with adrenal metastases in oligometastatic NSCLC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  14. Continued EGFR-TKI with concurrent radiotherapy to improve time to progression (TTP) in patients with locally progressive non-small cell lung cancer (NSCLC) after front-line EGFR-TKI treatment.

    PubMed

    Wang, Y; Li, Y; Xia, L; Niu, K; Chen, X; Lu, D; Kong, R; Chen, Z; Sun, J

    2018-03-01

    Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the optimal treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, most patients developed systemic or local progression due to acquired EGFR-TKI resistance. This retrospective study aimed to evaluate the feasibility of continued EGFR-TKI with concurrent radiotherapy (CTCRT) in patients with local progression after front-line EGFR-TKI treatment. Advanced NSCLC patients with active EGFR mutation who received EGFR-TKI were treated with CTCRT after local progression. Medical data were analyzed for time to progression (TTP), progression-free survival (PFS), tumor response rate, overall survival (OS) and adverse events. A total of 50 irradiated lesions from 44 patients were included. Median TTP and PFS of measurable lesions (n = 31) were both significantly prolonged after local radiotherapy (TTP1 + TTP2 vs. TTP1: 21.7 vs. 16.0 months, P = 0.010; PFS1 + PFS2 vs. PFS1: 21.3 vs. 16.0 months, P = 0.027). For all lesions (n = 50), objective response rate (ORR) and local tumor control rate (LCR) were 54.0 and 84.0%, respectively. Median OS was 26.6 months. There were no serious adverse events before or after radiotherapy. The treatment modality of CTCRT is considerable and effective for EGFR-mutant NSCLC patients even with local failure from front-line EGFR-TKI treatment.

  15. Survivorship Care Planning in Patients With Colorectal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-12-16

    Stage I Colon Cancer; Stage I Rectal Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Colon Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIA Rectal Cancer; Stage IIB Colon Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIB Rectal Cancer; Stage IIC Colon Cancer; Stage IIC Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer

  16. Recent Management of Patients with Advanced Epidermal Growth Factor Receptor Mutation Non-small Cell Lung Cancer: Role of Afatinib and Lesson Learned for Developing Countries.

    PubMed

    Amin, Zulkifli; Jayalie, Vito Filbert; Rajabto, Wulyo

    2017-01-01

    Lung cancer is a devastating disease with a high incidence, mortality and morbidity rate, especially in developing countries. Conventional treatment with cytotoxic chemotherapy has some limitations attributed to chemoresistance and toxicity. Recent advances have shown that first generation Tyrosine Kinase Inhibitor (TKI), Gefitinib and Erlotinib, and the newest available second generation Tyrosine Kinase Inhibitor (TKI), Afatinib, have the potential to be an option in the management of patients with epidermal growth factor receptor/ EGFR mutation positive advanced/ metastatic non-small cell lung cancer. Afatinib works by binding to EGFR irreversibly, thus inactivating the tyrosine kinase receptor. Some studies demostrated that Afatinib first-line may result in longer progression free survival (PFS) and better disease control, and as an alternative for patients who intolerance to Gefitinib or Erlotinib. In Indonesia, the era of National Health Insurance has been implemented and National Health Insurance has covered treatment for cancer, including first generation TKIs, Gefitinib dan erlotinib, for patients with EGFR mutation positive advanced/ metastatic non-small cell lung cancer at Cipto Mangunkusumo National Hospital. Afatinib, as one of the newest available second generation TKI, may be given free of charge too as an alternative if the National Health Insurance will be covered in the future. Further research is needed to know the efficacy and adverse effects that may occur in patients from developing countries.

  17. Driver genes in non-small cell lung cancer: Characteristics, detection methods, and targeted therapies

    PubMed Central

    He, Bing; Zhang, Hu-Qin

    2017-01-01

    Lung cancer is one of the most common causes of cancer-related death in the world. The large number of lung cancer cases is non-small cell lung cancer (NSCLC), which approximately accounting for 75% of lung cancer. Over the past years, our comprehensive knowledge about the molecular biology of NSCLC has been rapidly enriching, which has promoted the discovery of driver genes in NSCLC and directed FDA-approved targeted therapies. Of course, the targeted therapies based on driver genes provide a more exact option for advanced non-small cell lung cancer, improving the survival rate of patients. Now, we will review the landscape of driver genes in NSCLC including the characteristics, detection methods, the application of target therapy and challenges. PMID:28915704

  18. Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer.

    PubMed

    McKeage, Kate

    2015-01-01

    Alectinib (Alecensa(®)) is a second-generation, orally active, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK). Alectinib is approved for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) in Japan, where it has been given orphan drug designation. Approval was based on a phase 1-2 study in ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC who received twice-daily alectinib 300 mg. In the phase 2 portion, 93.5 % of patients achieved an objective response. Treatment response was rapid, with a partial response achieved in two-thirds of patients within 3 weeks (cycle 1). Patient follow-up is ongoing, and after approximately 2 years, 19.6 % of patients had achieved a complete response, and the 2-year progression-free survival rate is 76 %. During treatment with alectinib (median follow-up approximately 8 months), there was no progression of CNS lesions among patients with known CNS metastases at baseline (although prior radiation therapy may have confounded results). In preclinical models, alectinib was active against most ALK fusion-gene mutations related to crizotinib resistance, and preliminary results from clinical trials indicate efficacy in crizotinib-refractory NSCLC. Alectinib was generally well tolerated in clinical trials, and there were no treatment-related grade 4 adverse events or deaths. The most common grade 3 treatment-related adverse events were decreased neutrophil counts and increased creatinine phosphokinase. While more data are needed to confirm the efficacy of alectinib and to evaluate its activity in crizotinib-resistant disease, the drug provides a very promising option for the treatment of ALK-rearranged advanced NSCLC.

  19. Efficacy and safety of icotinib as first-line therapy in patients with advanced non-small-cell lung cancer.

    PubMed

    Shen, Yan-Wei; Zhang, Xiao-Man; Li, Shu-Ting; Lv, Meng; Yang, Jiao; Wang, Fan; Chen, Zhe-Ling; Wang, Bi-Yuan; Li, Pan; Chen, Ling; Yang, Jin

    2016-01-01

    Several clinical trials have proven that icotinib hydrochloride, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, exhibits encouraging efficacy and tolerability in patients with advanced non-small-cell lung cancer (NSCLC) who failed previous chemotherapy. This study was performed to assess the efficacy and toxicity of icotinib as first-line therapy for patients with advanced pulmonary adenocarcinoma with EGFR-sensitive mutation. Thirty-five patients with advanced NSCLC with EGFR-sensitive mutation who were sequentially admitted to the First Affiliated Hospital of Xi'an Jiaotong University from March 2012 to March 2014 were enrolled into our retrospective research. All patients were administered icotinib as first-line treatment. The tumor responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Among the 35 patients, the tumor objective response rate (ORR) and disease control rate were 62.9% (22/35) and 88.6% (31/35), respectively. The median progression-free survival was 11.0 months (95% confidence interval [CI]: 10.2-11.8 months), and median overall survival was 21.0 months (95% CI: 20.1-21.9 months). The most common drug-related toxicities were rashes (eleven patients) and diarrhea (nine patients), but these were generally manageable and reversible. Icotinib monotherapy is effective and tolerable as first-line treatment for patients with advanced lung adenocarcinoma with EGFR-sensitive mutation.

  20. Home administration of maintenance pemetrexed for patients with advanced non-squamous non-small cell lung cancer: rationale, practicalities and phase II feasibility study design.

    PubMed

    Lal, Rohit; Bourayou, Nawel; Hillerdal, Gunnar; Nicolson, Marianne; Vikstrom, Anders; Lorenzo, Maria; D'yachkova, Yulia; Barriga, Susana; Visseren-Grul, Carla

    2013-10-03

    Home-based care in oncology is mainly reserved for patients at the end of life. Regulations regarding home delivery of cytotoxics differ across Europe, with a notable lack of practice guidelines in most countries. This has led to a lack of data addressing the feasibility of home-based administration of cytotoxic chemotherapy. In advanced non-squamous non-small cell lung cancer, pemetrexed is approved as maintenance therapy after first-line chemotherapy. In this setting, patients have the potential to be treated long-term with maintenance therapy, which, in the absence of unacceptable toxicity, is continued until disease progression. The favourable safety profile of pemetrexed and the ease of its administration by 10-minute intravenous infusion every 3 weeks make this drug a suitable candidate for administration in a home setting. Literature and regulations relevant to the home-based delivery of cytotoxic therapy were reviewed, and a phase II feasibility study of home administration of pemetrexed maintenance therapy was designed. At least 50 patients with advanced non-squamous non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0-1 and no progressive disease after four cycles of platinum-based first-line therapy are required to allow investigation of the feasibility of home-based administration of pemetrexed maintenance therapy (500 mg/m(2) every 3 weeks until progressive disease or unacceptable toxicity). Feasibility is being assessed as adherence to the home-based administration process (primary endpoint), patient safety, impact on patients' quality of life, patient and physician satisfaction with home care, and healthcare resource use and costs. Enrolment of patients from the UK and Sweden, where home-based care is relatively well developed, commenced in December 2011. This feasibility study addresses an important aspect of maintenance therapy, that is, patient comfort during protracted home-based chemotherapy. The study design

  1. Home administration of maintenance pemetrexed for patients with advanced non-squamous non-small cell lung cancer: rationale, practicalities and phase II feasibility study design

    PubMed Central

    2013-01-01

    Background Home-based care in oncology is mainly reserved for patients at the end of life. Regulations regarding home delivery of cytotoxics differ across Europe, with a notable lack of practice guidelines in most countries. This has led to a lack of data addressing the feasibility of home-based administration of cytotoxic chemotherapy. In advanced non-squamous non-small cell lung cancer, pemetrexed is approved as maintenance therapy after first-line chemotherapy. In this setting, patients have the potential to be treated long-term with maintenance therapy, which, in the absence of unacceptable toxicity, is continued until disease progression. The favourable safety profile of pemetrexed and the ease of its administration by 10-minute intravenous infusion every 3 weeks make this drug a suitable candidate for administration in a home setting. Methods Literature and regulations relevant to the home-based delivery of cytotoxic therapy were reviewed, and a phase II feasibility study of home administration of pemetrexed maintenance therapy was designed. At least 50 patients with advanced non-squamous non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0–1 and no progressive disease after four cycles of platinum-based first-line therapy are required to allow investigation of the feasibility of home-based administration of pemetrexed maintenance therapy (500 mg/m2 every 3 weeks until progressive disease or unacceptable toxicity). Feasibility is being assessed as adherence to the home-based administration process (primary endpoint), patient safety, impact on patients’ quality of life, patient and physician satisfaction with home care, and healthcare resource use and costs. Enrolment of patients from the UK and Sweden, where home-based care is relatively well developed, commenced in December 2011. Discussion This feasibility study addresses an important aspect of maintenance therapy, that is, patient comfort during protracted home

  2. Comparison of EGFR signaling pathway somatic DNA mutations derived from peripheral blood and corresponding tumor tissue of patients with advanced non-small-cell lung cancer using liquidchip technology.

    PubMed

    Zhang, Hui; Liu, Deruo; Li, Shanqing; Zheng, Yongqing; Yang, Xinjie; Li, Xi; Zhang, Quan; Qin, Na; Lu, Jialin; Ren-Heidenreich, Lifen; Yang, Huiyi; Wu, Yuhua; Zhang, Xinyong; Nong, Jingying; Sun, Yifen; Zhang, Shucai

    2013-11-01

    Somatic DNA mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway are known to predict responsiveness to EGFR-tyrosine kinase inhibitor drugs in patients with advanced non-small-cell lung cancers. We evaluated a sensitive liquidchip platform for detecting EGFR, KRAS (alias Ki-ras), proto-oncogene B-Raf, and phosphatidylinositol 3-kinase CA mutations in plasma samples, which were highly correlated with matched tumor tissues from 86 patients with advanced non-small-cell lung cancers. Either EGFR exon 19 or 21 mutations were detected in 36 patients: 23 of whom had identical mutations in both their blood and tissue samples; whereas mutations in the remaining 13 were found only in their tumor samples. These EGFR mutations occurred at a significantly higher frequency in females, never-smokers, and in patients with adenocarcinomas (P ≤ 0.001). The EGFR exon 20 T790M mutation was detected in only one of the paired samples [100% (95% CI, 96% to 100%) agreement]. For KRAS, proto-oncogene B-Raf, and phosphatidylinositol 3-kinase CA mutations, the overall agreements were 97% (95% CI, 90% to 99%), 98% (95% CI, 92% to 99%), and 97% (95% CI, 90% to 99%), respectively, and these were not associated with age, sex, smoking history, or histopathologic type. In conclusion, mutations detected in plasma correlated strongly with mutation profiles in each respective tumor sample, suggesting that this liquidchip platform may offer a rapid and noninvasive method for predicting tumor responsiveness to EGFR-tyrosine kinase inhibitor drugs in patients with advanced non-small-cell lung cancers. Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  3. Erlotinib Hydrochloride and Cetuximab in Treating Patients With Advanced Gastrointestinal Cancer, Head and Neck Cancer, Non-Small Cell Lung Cancer, or Colorectal Cancer

    ClinicalTrials.gov

    2015-09-28

    Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Gastrointestinal Stromal Tumor; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer

  4. Current and future molecular diagnostics in non-small-cell lung cancer.

    PubMed

    Li, Chun Man; Chu, Wing Ying; Wong, Di Lun; Tsang, Hin Fung; Tsui, Nancy Bo Yin; Chan, Charles Ming Lok; Xue, Vivian Wei Wen; Siu, Parco Ming Fai; Yung, Benjamin Yat Ming; Chan, Lawrence Wing Chi; Wong, Sze Chuen Cesar

    2015-01-01

    The molecular investigation of lung cancer has opened up an advanced area for the diagnosis and therapeutic management of lung cancer patients. Gene alterations in cancer initiation and progression provide not only information on molecular changes in lung cancer but also opportunities in advanced therapeutic regime by personalized targeted therapy. EGFR mutations and ALK rearrangement are important predictive biomarkers for the efficiency of tyrosine kinase inhibitor treatment in lung cancer patients. Moreover, epigenetic aberration and microRNA dysregulation are recent advances in the early detection and monitoring of lung cancer. Although a wide range of molecular tests are available, standardization and validation of assay protocols are essential for the quality of the test outcome. In this review, current and new advancements of molecular biomarkers for non-small-cell lung cancer will be discussed. Recommendations on future development of molecular diagnostic services will also be explored.

  5. Real world study of regimen containing bevacizumab as first-line therapy in Chinese patients with advanced non-small cell lung cancer.

    PubMed

    Xing, Puyuan; Mu, Yuxin; Wang, Yan; Hao, Xuezhi; Zhu, Yixiang; Hu, Xingsheng; Wang, Hongyu; Liu, Peng; Lin, Lin; Wang, Zhijie; Li, Junling

    2018-05-16

    Large scale randomized controlled trials have demonstrated that the use of bevacizumab in addition to chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) conveys significant survival benefits. We explored the clinical impact of a first-line regimen containing bevacizumab (B+) versus a non-bevacizumab regimen (non-B) in advanced non-squamous NSCLC (NS-NSCLC) patients in a real world setting. The medical records of patients with advanced NS-NSCLC who received first-line therapy with or without bevacizumab were retrospectively collected. The primary outcome was progression-free survival (PFS), with secondary objectives of objective response rate (ORR), disease control rate (DCR), and safety. Exploratory analysis of EGFR and ALK status was conducted in subgroup. One hundred and forty-nine patients met the selection criteria: 62 in the B+ and 87 in the non-B group. The baseline characteristics were well balanced. In the overall population, the median PFS was significantly longer in the B+ than in the non-B group (9.7 vs. 7.0 months, hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.30-0.91; P = 0.0184). Improved trends in both ORR and DCR were observed in the B+ group. In wild-type patients, the median PFS of the B+ was 11.3 compared to 5.5 months in the non-B group (HR 0.43, 95% CI 0.20-0.91; P = 0.0234). In wild type and unknown populations, the median PFS was 11.3 (B+) compared to 6.0 months (non-B) (HR 0.53; 95% CI 0.28-1.02; P = 0.0520). The safety profile was acceptable in both groups and no unexpected findings were observed. Our analysis confirmed that a first-line regimen containing bevacizumab showed superior clinical benefits over a non-bevacizumab regimen in Chinese patients with advanced NS-NSCLC in a real world setting. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  6. Behavioral and Psychological Predictors of Chemotherapy Adherence in Patients with Advanced Non-Small-Cell Lung Cancer

    PubMed Central

    Greer, Joseph A.; Pirl, William F.; Park, Elyse R.; Lynch, Thomas J.; Temel, Jennifer S.

    2013-01-01

    Objective Dose delays and reductions in chemotherapy due to hematologic toxicities are common among patients with advanced non-small-cell lung cancer (NSCLC). However, limited data exist on behavioral or psychological predictors of chemotherapy adherence. The goal of this study was to explore the frequency and clinical predictors of infusion dose delays and reductions in this patient population. Methods Fifty patients newly diagnosed with advanced NSCLC of high performance status (ECOG PS=0-1) completed baseline assessments on quality of life (FACT-L) and mood (HADS) within eight weeks of diagnosis. Participants were followed prospectively for six months. Chemotherapy dosing data came from medical chart review. Results All patients received chemotherapy during the course of the study, beginning with either a platinum-based doublet (74%), an oral epidermal growth factor receptor-tyrosine kinase inhibitor (14%), or a parenteral single agent (12%). Forty percent (N=20) of patients had either a dose delay (38%) and/or reduction (16%) in their scheduled infusions. Fisher’s exact tests showed that patients who experienced neutropenia, smoked at the time of diagnosis, or reported heightened baseline anxiety were significantly more likely to experience dose delays or reductions. There were no associations between chemotherapy adherence and patient demographics, performance status, or quality of life. Conclusion In this sample, over one-third of patients with advanced NSCLC experienced either a dose delay or reduction in prescribed chemotherapy regimens. Behavioral and psychological factors, such as tobacco use and anxiety symptoms, appear to play an important role in chemotherapy adherence, though further study is required to confirm these findings. PMID:19027443

  7. Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer: a randomized phase II clinical trial

    PubMed Central

    Vrankar, Martina; Zwitter, Matjaz; Bavcar, Tanja; Milic, Ana; Kovac, Viljem

    2014-01-01

    Background The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid. Patients and methods. Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m2 in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m2 in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m2 on day 2 was administered. All patients continued treatment with radiation therapy with 60–66 Gy concurrent with cisplatin 50 mg/m2 on days 1, 8, 29 and 36 and etoposid 50 mg/m2 on days 1–5 and 29–33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were

  8. Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer.

    PubMed

    Liu, Hui; Zhang, Tiantuo; Ye, Jin; Li, Hongtao; Huang, Jing; Li, Xiaodong; Wu, Benquan; Huang, Xubing; Hou, Jinghui

    2012-10-01

    Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. The predictive significance of tumor-infiltrating lymphocytes (TILs) for response to neoadjuvant chemotherapy in non-small cell lung cancer (NSCLC) remains unknown. The aim of this study was to investigate the prognostic and predictive value of TIL subtypes in patients with advanced NSCLC treated with platinum-based chemotherapy. In total, 159 patients with stage III and IV NSCLC were retrospectively enrolled. The prevalence of CD3(+), CD4(+), CD8(+) and Foxp3(+) TILs was assessed by immunohistochemistry in tumor tissue obtained before chemotherapy. The density of TILs subgroups was treated as dichotomous variables using the median values as cutoff. Survival curves were estimated by the Kaplan-Meier method, and differences in overall survival between groups were determined using the Log-rank test. Prognostic effects of TIL subsets density were evaluated by Cox regression analysis. The presence of CD3(+), CD4(+), CD8(+), and FOXP3(+) TILs was not correlated with any clinicopathological features. Neither the prevalence of TILs nor combined analysis displayed obvious prognostic performances for overall survival in Cox regression model. Instead, higher FOXP3(+)/CD8(+) ratio in tumor sites was an independent factor for poor response to platinum-based chemotherapy in overall cohort. These findings suggest that immunological CD8(+) and FOXP3(+)Tregs cell infiltrate within tumor environment is predictive of response to platinum-based neoadjuvant chemotherapy in advanced NSCLC patients. The understanding of the clinical relevance of the microenvironmental immunological milieu might provide an important clue for the design of novel strategies in cancer immunotherapy.

  9. Usefulness of circulating free DNA for monitoring epidermal growth factor receptor mutations in advanced non-small cell lung cancer patients: a case report

    PubMed Central

    Gonzalez-Cao, Maria; Ramirez, Santiago Viteri; Ariza, Nuria Jordana; Balada, Ariadna; Garzón, Mónica; Teixidó, Cristina; Karachaliou, Niki; Morales-Espinosa, Daniela; Molina-Vila, Miguel Ángel; Rosell, Rafael

    2016-01-01

    Genomic analysis of circulating tumor DNA (ctDNA) released from cancer cells into the bloodstream has been proposed as a useful method to capture dynamic changes during the course of the disease. In particular, the ability to monitor epidermal growth factor receptor (EGFR) mutation status in cell-free circulating DNA (cfDNA) isolated from advanced non-small cell lung cancer (NSCLC) patients EGFR can help to the correct management of the disease and overcome the challenges associated with tumor heterogeneity and insufficient biopsied material to perform key molecular diagnosis. Here, we report a case of long term monitorization of EGFR mutation status in cfDNA from peripheral blood in an NSCLC patient in, with excellent correlation with clinical evolution. PMID:27826535

  10. A phase II trial of Cremorphor EL-free paclitaxel (Genexol-PM) and gemcitabine in patients with advanced non-small cell lung cancer.

    PubMed

    Ahn, Hee Kyung; Jung, Minkyu; Sym, Sun Jin; Shin, Dong Bok; Kang, Shin Myung; Kyung, Sun Young; Park, Jeong-Woong; Jeong, Sung Hwan; Cho, Eun Kyung

    2014-08-01

    Genexol-PM is a Cremorphor EL (CrEL)-free polymeric micelle formulation of paclitaxel that allows higher-dose administration with less hypersensitivity. This study was designed to evaluate the efficacy and safety of Genexol-PM and gemcitabine combination in advanced non-small cell lung cancer patients as a first-line treatment. This is a prospective, single-arm, single-center phase II study. Patients with advanced NSCLC received Genexol-PM at 230 mg/m(2) on day 1 and gemcitabine 1,000 mg/m(2) on day 1 and day 8 of a 3-week cycle. Six cycles of chemotherapy were planned unless there was disease progression. The primary endpoint was overall response rate. Forty-three patients received the study drugs with a median of 4 cycles per patient (range 1-6). The overall response rate was 46.5%. The median progression-free survival was 4.0 months (95% CI 2.0-6.0 months), and median overall survival was 14.8 months (95% CI 9.1-20.5 months). The most common toxicities were anemia (n = 29, 67%), asthenia (n = 17, 40%), myalgia (n = 16, 37%), peripheral neuropathy (n = 15, 35 %), and diarrhea (n = 12, 30%). The most common grade 3/4 adverse events were neutropenia (n = 7, 16%) and pneumonia (n = 5, 12%). Two patients died of pneumonia and dyspnea. CrEL-free paclitaxel in combination with gemcitabine demonstrated favorable antitumor activity with little emetogenicities in non-small cell lung cancer patients. However, frequent grade 3/4 toxicities were observed, and safety should be evaluated thoroughly in future studies.

  11. Low-Dose Acetylsalicylic Acid in Treating Patients With Stage I-III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2017-06-29

    Adenocarcinoma of the Lung; Recurrent Non-small Cell Lung Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  12. Clinical benefit of continuing crizotinib therapy after initial disease progression in Chinese patients with advanced ALK-rearranged non-small-cell lung cancer

    PubMed Central

    Hong, Xiangchan; Chen, Qi; Ding, Lingyu; Liang, Ying; Zhou, Ningning; Fang, Wenfeng; Chen, Xinru; Wu, Haiying

    2017-01-01

    Purpose Although most patients with ALK-positive non?small-cell lung cancer (NSCLC) who benefit from treatment with crizotinib ultimately develop progressive disease (PD), continuing crizotinb beyond the initial PD (CBPD) in these patients may be beneficial. In this study, we investigated whether Chinese patients with advanced ALK-positive NSCLC benefit from CBPD, and whether any factors are predictive of a longer post-initial progression-free survival time (PFS2). Materials and Methods Data on 33 patients with ALK-positive NSCLC who achieved disease control with crizotinib were analyzed retrospectively. The impact of continued crizotinib therapy on the patients’ PFS2 time was assessed after adjusting for potential confounding factors. Results With initial crizotinib therapy, the objective response rate (ORR) and median PFS time (PFS1) in the 33 patients were 63.6% and 8.6 months, respectively. With continued crizotinib therapy after documentation of PD, the median PFS2 for all 33 patients was 16 weeks, and in those with CNS progression but systemic disease control it was 30 weeks. Patients who received local therapy after disease progression had a significantly longer PFS2 compared with those who did not (P = 0.039). Multivariable Cox regression analysis showed that the PFS1 with initial crizotinib treatment and local therapy were independent predictors of PFS2. Discussion This study provides further evidence of the benefit of continuing crizotinib therapy in Chinese patients with progressive ALK-positive NSCLC. Patients with a longer PFS1 and those who received local brain therapy would have a longer period of continuing crizotinib. PMID:28427213

  13. Clinical benefit of continuing crizotinib therapy after initial disease progression in Chinese patients with advanced ALK-rearranged non-small-cell lung cancer.

    PubMed

    Hong, Xiangchan; Chen, Qi; Ding, Lingyu; Liang, Ying; Zhou, Ningning; Fang, Wenfeng; Chen, Xinru; Wu, Haiying

    2017-06-20

    Although most patients with ALK-positive non-small-cell lung cancer (NSCLC) who benefit from treatment with crizotinib ultimately develop progressive disease (PD), continuing crizotinb beyond the initial PD (CBPD) in these patients may be beneficial. In this study, we investigated whether Chinese patients with advanced ALK-positive NSCLC benefit from CBPD, and whether any factors are predictive of a longer post-initial progression-free survival time (PFS2). Data on 33 patients with ALK-positive NSCLC who achieved disease control with crizotinib were analyzed retrospectively. The impact of continued crizotinib therapy on the patients' PFS2 time was assessed after adjusting for potential confounding factors. With initial crizotinib therapy, the objective response rate (ORR) and median PFS time (PFS1) in the 33 patients were 63.6% and 8.6 months, respectively. With continued crizotinib therapy after documentation of PD, the median PFS2 for all 33 patients was 16 weeks, and in those with CNS progression but systemic disease control it was 30 weeks. Patients who received local therapy after disease progression had a significantly longer PFS2 compared with those who did not (P = 0.039). Multivariable Cox regression analysis showed that the PFS1 with initial crizotinib treatment and local therapy were independent predictors of PFS2. This study provides further evidence of the benefit of continuing crizotinib therapy in Chinese patients with progressive ALK-positive NSCLC. Patients with a longer PFS1 and those who received local brain therapy would have a longer period of continuing crizotinib.

  14. [Modalities of use of ceritinib (Zykadia™), a 2nd generation ALK inhibitor, in advanced stage non-small cell lung cancer].

    PubMed

    Giroux Leprieur, Etienne; Fallet, Vincent; Wislez, Marie

    2015-12-01

    Around 4% of advanced non-small cell lung cancers (NSCLC) harbor a ALK rearrangement, with high sensitivity to ALK inhibitor as crizotinib. However, the vast majority of these tumors end with a tumor progression after several months of treatment with crizotinib. Ceritinib is a 2nd generation ALK inhibitor, which showed high efficiency in NSCLC with ALK rearrangement. Results from phase I trial showed a response rate at 58% in these tumors, with a similar rate for previously crizotinib-treated patients or crizotinib-naïve patients. Moreover, cerebral responses were observed with ceritinib. Preliminary date from a phase 2 trial confirmed these results. These promising results allowed a European marketing authorization (autorisation de mise sur le marché [AMM]) since May 2015 for the treatment of advanced NSCLC with ALK rearrangement and resistance or intolerance to crizotinib. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  15. Efficacy and safety of icotinib as first-line therapy in patients with advanced non-small-cell lung cancer

    PubMed Central

    Shen, Yan-Wei; Zhang, Xiao-Man; Li, Shu-Ting; Lv, Meng; Yang, Jiao; Wang, Fan; Chen, Zhe-Ling; Wang, Bi-Yuan; Li, Pan; Chen, Ling; Yang, Jin

    2016-01-01

    Background and objective Several clinical trials have proven that icotinib hydrochloride, a novel epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor, exhibits encouraging efficacy and tolerability in patients with advanced non-small-cell lung cancer (NSCLC) who failed previous chemotherapy. This study was performed to assess the efficacy and toxicity of icotinib as first-line therapy for patients with advanced pulmonary adenocarcinoma with EGFR-sensitive mutation. Patients and methods Thirty-five patients with advanced NSCLC with EGFR-sensitive mutation who were sequentially admitted to the First Affiliated Hospital of Xi’an Jiaotong University from March 2012 to March 2014 were enrolled into our retrospective research. All patients were administered icotinib as first-line treatment. The tumor responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Results Among the 35 patients, the tumor objective response rate (ORR) and disease control rate were 62.9% (22/35) and 88.6% (31/35), respectively. The median progression-free survival was 11.0 months (95% confidence interval [CI]: 10.2–11.8 months), and median overall survival was 21.0 months (95% CI: 20.1–21.9 months). The most common drug-related toxicities were rashes (eleven patients) and diarrhea (nine patients), but these were generally manageable and reversible. Conclusion Icotinib monotherapy is effective and tolerable as first-line treatment for patients with advanced lung adenocarcinoma with EGFR-sensitive mutation. PMID:26966381

  16. Does advanced lung inflammation index (ALI) have prognostic significance in metastatic non-small cell lung cancer?

    PubMed

    Ozyurek, Berna Akinci; Ozdemirel, Tugce Sahin; Ozden, Sertac Buyukyaylaci; Erdoğan, Yurdanur; Ozmen, Ozlem; Kaplan, Bekir; Kaplan, Tugba

    2018-01-22

    Lung cancer is the most commonly diagnosed and death-related cancer type and is more frequent in males. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all case. In this study, it was aimed to research the relationship between advanced lung inflammation index (ALI) and the primary mass maximum standardized uptake value (SUVmax) and C-reactive protein (CRP) at initial diagnosis and the prognostic value of ALI in determining the survival in metastatic NSCLC. A total of 112 patients diagnosed as stage 4 non-small-lung cancer in our hospital between January 2006 and December 2013 were included in this study. ALI was calculated as body mass index (BMI) × serum albumin/neutrophil-to-lymphocyte ratio (NLR). The patients were divided into two groups as ALI < 18 (high inflammation) and ALI ≥ 18 (low inflammation). The log-rank test and Cox proportional hazard model were used to identify predictors of mortality. Evaluation was made of 94 male and 18 female patients with a mean age of 59.7 ± 9.9 years. A statistically significant negative relationship was determined between ALI and CRP values (P < .001), but no relationship was found between ALI and SUVmax values (P = .436). The median survival time in patients with ALI < 18 was 12 months and, in those with ALI ≥ 18, it was 16 months (P = .095). ALI is an easily calculated indicator of inflammation in lung cancer patients. Values <18 can be considered to predict a poor prognosis. © 2018 John Wiley & Sons Ltd.

  17. Non-small cell lung cancer in never smokers: a clinical entity to be identified.

    PubMed

    Santoro, Ilka Lopes; Ramos, Roberta Pulcheri; Franceschini, Juliana; Jamnik, Sergio; Fernandes, Ana Luisa Godoy

    2011-01-01

    It has been recognized that patients with non-small cell lung cancer who are lifelong never-smokers constitute a distinct clinical entity. The aim of this study was to assess clinical risk factors for survival among never-smokers with non-small cell lung cancer. All consecutive non-small cell lung cancer patients diagnosed (n = 285) between May 2005 and May 2009 were included. The clinical characteristics of never-smokers and ever-smokers (former and current) were compared using chi-squared or Student's t tests. Survival curves were calculated using the Kaplan-Meier method, and log-rank tests were used for survival comparisons. A Cox proportional hazards regression analysis was evaluated by adjusting for age (continuous variable), gender (female vs. male), smoking status (never- vs. ever-smoker), the Karnofsky Performance Status Scale (continuous variable), histological type (adenocarcinoma vs. non-adenocarcinoma), AJCC staging (early vs. advanced staging), and treatment (chemotherapy and/or radiotherapy vs. the best treatment support). Of the 285 non-small cell lung cancer patients, 56 patients were never-smokers. Univariate analyses indicated that the never-smoker patients were more likely to be female (68% vs. 32%) and have adenocarcinoma (70% vs. 51%). Overall median survival was 15.7 months (95% CI: 13.2 to 18.2). The never-smoker patients had a better survival rate than their counterpart, the ever-smokers. Never-smoker status, higher Karnofsky Performance Status, early staging, and treatment were independent and favorable prognostic factors for survival after adjusting for age, gender, and adenocarcinoma in multivariate analysis. Epidemiological differences exist between never- and ever-smokers with lung cancer. Overall survival among never-smokers was found to be higher and independent of gender and histological type.

  18. Bevacizumab Plus Radiosurgery for Nonsquamous Non-Small Cell Lung Cancer Patients with Brain Metastases: Safe Combination?

    PubMed

    Guinde, Julien; Carron, Romain; Tomasini, Pascale; Greillier, Laurent; Régis, Jean; Barlesi, Fabrice

    2017-11-01

    In the context of bronchial cancers, the brain is one of the most frequent sites for metastases. Local treatments of these metastases have evolved and are often combined to obtain greater efficiency, while the main objective remains to reduce the symptoms. Radiosurgery is currently used as a primary option for patients harboring few numbers of small to middle-sized brain metastases. In nonsquamous non-small cell lung cancer (NSCLC), chemotherapy is often associated with bevacizumab. Our goal was to assess the safety of this early combination. Six patients with advanced nonsquamous NSCLC were treated with radiosurgery for the management of their brain metastases (n = 40), followed within <4 weeks by a treatment with bevacizumab. No systemic or cerebral adverse event of grade 3 (intratumoral or parenchymal hemorrhage) or unexpected toxicity secondary to bevacizumab has been indexed. Radiosurgery may be safely combined with bevacizumab quite early on for patients with nonsquamous NSCLC with brain metastases. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. The potential role of bortezomib in combination with chemotherapy and radiation in non-small-cell lung cancer.

    PubMed

    Edelman, Martin J

    2005-10-01

    The combination of chemotherapy and radiation has been validated for the treatment of locally advanced non-small-cell lung cancer (NSCLC). However, the results are still unsatisfactory, and there is a need to improve current treatment. One approach is to use new agents that have the potential to enhance the efficacy of chemotherapy, radiation therapy (RT), or both. One potential target is the ubiquitin-proteasome pathway. This pathway plays an essential role in the degradation of most short- and long-lived intracellular proteins in eukaryotic cells and therefore regulating the cell cycle, neoplastic growth, and metastasis. Bortezomib is a selective 26S proteasome inhibitor that has been approved for the treatment of multiple myeloma. Bortezomib has demonstrated in vitro chemotherapy- and RT-sensitizing properties as well as single-agent activity in lung cancer. This article will review the rationale for the use of bortezomib as part of the chemotherapy/RT strategy for the treatment of NSCLC.

  20. General Information about Non-Small Cell Lung Cancer

    MedlinePlus

    ... Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Non-Small Cell Lung Cancer Go to ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  1. Exploring hope and healing in patients living with advanced non-small cell lung cancer.

    PubMed

    Eustache, Chloe; Jibb, Emily; Grossman, Mary

    2014-09-01

    To explore the experience and meaning of hope in relation to the healing process of patients living with stage IIIb or IV non-small cell lung cancer. Interpretative qualitative study design. Peter Brojde Lung Cancer Centre in the Jewish General Hospital in Montreal, Quebec, Canada. 12 English- and French-speaking patients, aged 36-78 years. One 60-90-minute semistructured interview per participant was conducted. An inductive approach to data analysis was taken, involving immersion in the data, coding, classifying, and creating linkages. Four main themes emerged: (a) the morass of shattered hope, (b) tentative steps toward a new hope paradigm, (c) reframing hope within the context of a life-threatening illness, and (d) strengthening the link between hope and wellness. Patients described a process where hope was diminished or lost entirely, regained, and reshaped as they learned to live and grow following their diagnosis. This study adds to the literature by describing the dynamic nature of hope as well as factors facilitating or hindering the hope process. It demonstrates how finding meaning, a structural component of healing, can be used to envision a new hopeful future. This study suggests hope and healing cannot exist in isolation, and highlights the importance of understanding the fluctuating nature of hope in patients with advanced lung cancer to foster it, therefore promoting healing.

  2. Assessment of quality of life in patients with advanced non-small cell lung carcinoma treated with a combination of carboplatin and paclitaxel*

    PubMed Central

    Avelino, Camila Uanne Resende; Cardoso, Rafael Marques; de Aguiar, Suzana Sales; da Silva, Mário Jorge Sobreira

    2015-01-01

    OBJECTIVE: Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. Most patients are diagnosed at an advanced stage, palliative chemotherapy therefore being the only treatment option. This study was aimed at evaluating the health-related quality of life (HRQoL) of advanced-stage NSCLC patients receiving palliative chemotherapy with carboplatin and paclitaxel. METHODS: This was a multiple case study of advanced-stage NSCLC outpatients receiving chemotherapy at a public hospital in Rio de Janeiro, Brazil. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire was used in conjunction with its supplemental lung cancer-specific module in order to assess HRQoL. RESULTS: Physical and cognitive functioning scale scores differed significantly among chemotherapy cycles, indicating improved and worsened HRQoL, respectively. The differences regarding the scores for pain, loss of appetite, chest pain, and arm/shoulder pain indicated improved HRQoL. CONCLUSIONS: Chemotherapy was found to improve certain aspects of HRQoL in patients with advanced-stage NSCLC. PMID:25972967

  3. Customizing systemic therapy in patients with advanced non-small cell lung cancer

    PubMed Central

    Sadowska, A. M.; Nowé, V.; Janssens, A.; Boeykens, E.; De Backer, W. A.; Germonpré, P. R.

    2011-01-01

    Lung cancer is the leading cause of cancer deaths worldwide. Standard chemotherapy has been shown to improve quality of life and has a modest influence on overall survival. This modest improvement in survival is partly due to the choice of chemotherapy regimens that have been based on prognostic factors such as age, performance status and comorbidities of the patient. This underlines the importance of developing a more personalized therapy for patients with non-small cell lung cancer. Such an approach may reduce the variation in how individual patients respond to medications by tailoring therapies to their genetic profile. In this review we focus on several aspects of customized therapy, looking not only at patient characteristics but also to tumor histology and specific tumor biomarkers. PMID:21904581

  4. Customizing systemic therapy in patients with advanced non-small cell lung cancer.

    PubMed

    Sadowska, A M; Nowé, V; Janssens, A; Boeykens, E; De Backer, W A; Germonpré, P R

    2011-07-01

    Lung cancer is the leading cause of cancer deaths worldwide. Standard chemotherapy has been shown to improve quality of life and has a modest influence on overall survival. This modest improvement in survival is partly due to the choice of chemotherapy regimens that have been based on prognostic factors such as age, performance status and comorbidities of the patient. This underlines the importance of developing a more personalized therapy for patients with non-small cell lung cancer. Such an approach may reduce the variation in how individual patients respond to medications by tailoring therapies to their genetic profile. In this review we focus on several aspects of customized therapy, looking not only at patient characteristics but also to tumor histology and specific tumor biomarkers.

  5. Antiangiogenic therapy for patients with aggressive or refractory advanced non-small cell lung cancer in the second-line setting.

    PubMed

    Reck, Martin; Garassino, Marina Chiara; Imbimbo, Martina; Shepherd, Frances A; Socinski, Mark A; Shih, Jin-Yuan; Tsao, Anne; Lee, Pablo; Winfree, Katherine B; Sashegyi, Andreas; Cheng, Rebecca; Varea, Rocio; Levy, Benjamin; Garon, Edward

    2018-06-01

    A majority of patients with advanced or metastatic non-small cell lung cancer (NSCLC) will experience disease progression after first-line therapy. Patients who have advanced NSCLC that is especially aggressive, which is defined as disease that rapidly progresses on first-line treatment or disease that is refractory to first-line treatment, have a critical unmet medical need. These patients have a poor prognosis in the second-line setting. Several studies have recently shown that treatment with an antiangiogenic therapy may benefit these patients. This review summarizes the approved antiangiogenic therapies for the treatment of patients with advanced NSCLC in the second-line setting, specifically focusing on the outcomes from subgroups of patients with rapidly progressing or refractory disease. Several antiangiogenic agents, as monotherapy or in combination with other treatments, have been or are currently being studied in patients with advanced NSCLC. Antiangiogenics that are approved for use in patients with advanced NSCLC are limited to bevacizumab in combination with chemotherapy (nonsquamous NSCLC), ramucirumab in combination with docetaxel (all histologies), and nintedanib in combination with docetaxel (adenocarcinoma histology). This review focuses on the efficacy, safety, and quality of life outcomes in the subpopulation of patients with rapidly progressing or refractory NSCLC treated with approved antiangiogenic therapies in the second-line setting. We also discuss the impact of newly approved immunotherapy agents on the outcomes of patients with aggressive or refractory disease. Studies in progress and planned future research will determine if combination treatment with antiangiogenics and immunotherapies will benefit patients with aggressive, advanced NSCLC. Copyright © 2018. Published by Elsevier B.V.

  6. Intensified High-Dose Chemoradiotherapy With Induction Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer-Safety and Toxicity Results Within a Prospective Trial

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Poettgen, Christoph, E-mail: christoph.poettgen@uk-essen.d; Eberhardt, Wilfried E.; Gauler, Thomas

    2010-03-01

    Purpose: To analyze the toxicity profile of an intensified definitive chemoradiotherapy (CRT) schedule in patients with locally advanced non-small-cell lung cancer (Stage IIIA N2/selected IIIB) treated within a prospective multicenter trial. Patients and Methods: After mediastinoscopy and routine staging procedures, three cycles of induction chemotherapy (cisplatin 50 mg/m{sup 2}, Days 1 and 8; paclitaxel 175 mg/m{sup 2} Day 1, every 21 days) were planned, followed by concurrent CRT (accelerated-hyperfractionated regimen, 45 Gy, 2 x 1.5 Gy/d, cisplatin 50 mg/m{sup 2}, Days 64 and 71, vinorelbine 20 mg/m{sup 2}, Days 64 and 71). At 45 Gy, a multidisciplinary panel decision wasmore » made regarding operability. Inoperable patients received definitive radiotherapy (total dose 65 or 71 Gy, depending on the mean lung dose) with additional concurrent chemotherapy (cisplatin 40 mg/m{sup 2}, Day 85; vinorelbine 15 mg/m{sup 2}, Days 85 and 92). Results: A total of 28 patients (23 men and 5 women; median age, 58 years; range 41-73; Stage IIIA in 3 and Stage IIIB in 25) were judged ineligible for surgery by the multidisciplinary panel and underwent definitive CRT (75% of the patients received 71 Gy). The maximum toxicity (Grade 3 or greater) during induction chemotherapy included leukopenia (11%) and anemia (4%). During concurrent CRT, leukopenia (Grade 3 or greater) was observed in 39% of the patients. The maximal nonhematologic toxicity during concurrent CRT included esophagitis (Grade 3 or greater) in 18% and pneumonitis (Grade 3 or greater) in 4% of the patients. At 3 years, the locoregional control rate was 52% (95% confidence interval, 29-75%) and the overall survival rate was 31% (95% confidence interval, 12-50%). Conclusion: This intensified treatment protocol with induction chemotherapy and concurrent CRT, including hyperfractionated-accelerated RT, showed only moderate toxicity and proved feasible. This treatment represents the definitive CRT arm of our ongoing

  7. Clinical Application of Genomic Profiling With Circulating Tumor DNA for Management of Advanced Non-Small-cell Lung Cancer in Asia.

    PubMed

    Loong, Herbert H; Raymond, Victoria M; Shiotsu, Yukimasa; Chua, Daniel T T; Teo, Peter M L; Yung, Tony; Skrzypczak, Stan; Lanman, Richard B; Mok, Tony S K

    2018-05-07

    Genomic profiling of cell-free circulating tumor DNA (ctDNA) is a potential alternative to repeat invasive biopsy in patients with advanced cancer. We report the first real-world cohort of comprehensive genomic assessments of patients with non-small-cell lung cancer (NSCLC) in a Chinese population. We performed a retrospective analysis of patients with advanced or metastatic NSCLC whose physician requested ctDNA-based genomic profiling using the Guardant360 platform from January 2016 to June 2017. Guardant360 includes all 4 major types of genomic alterations (point mutations, insertion-deletion alterations, fusions, and amplifications) in 73 genes. Genomic profiling was performed in 76 patients from Hong Kong during the 18-month study period (median age, 59.5 years; 41 men and 35 women). The histologic types included adenocarcinoma (n = 10), NSCLC, not otherwise specified (n = 58), and squamous cell carcinoma (n = 8). In the adenocarcinoma and NSCLC, not otherwise specified, combined group, 62 of the 68 patients (91%) had variants identified (range, 1-12; median, 3), of whom, 26 (42%) had ≥ 1 of the 7 National Comprehensive Cancer Network-recommended lung adenocarcinoma genomic targets. Concurrent detection of driver and resistance mutations were identified in 6 of 13 patients with EGFR driver mutations and in 3 of 5 patients with EML4-ALK fusions. All 8 patients with squamous cell carcinoma had multiple variants identified (range, 1-20; median, 6), including FGFR1 amplification and ERBB2 (HER2) amplification. PIK3CA amplification occurred in combination with either FGFR1 or ERBB2 (HER2) amplification or alone. Genomic profiling using ctDNA analysis detected alterations in most patients with advanced-stage NSCLC, with targetable aberrations and resistance mechanisms identified. This approach has demonstrated its feasibility in Asia. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Msi2 Regulates the Aggressiveness of Non Small Cell Lung Cancer (NSCLC)

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-15-1-0192 TITLE: Msi2 Regulates the Aggressiveness of Non -Small Cell Lung Cancer (NSCLC) PRINCIPAL INVESTIGATOR: Yanis...Annual 3. DATES COVERED (From - To) 15 Sep 2015 - 14 Sep 2016 4. TITLE AND SUBTITLE Msi2 Regulates the Aggressiveness of Non -Small Cell Lung Cancer...in vitro and in vivo are ongoing, while immunohistochemistry studies are starting Fall 2016. 15. SUBJECT TERMS Non -small cell lung cancer

  9. Predictors of Individual Tumor Local Control After Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Garsa, Adam A.; Badiyan, Shahed N.; DeWees, Todd

    2014-10-01

    Purpose: To evaluate local control rates and predictors of individual tumor local control for brain metastases from non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS). Methods and Materials: Between June 1998 and May 2011, 401 brain metastases in 228 patients were treated with Gamma Knife single-fraction SRS. Local failure was defined as an increase in lesion size after SRS. Local control was estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analysis. Receiver operating characteristic analysis was used to identify an optimal cutpoint for conformality index relative to local control. Amore » P value <.05 was considered statistically significant. Results: Median age was 60 years (range, 27-84 years). There were 66 cerebellar metastases (16%) and 335 supratentorial metastases (84%). The median prescription dose was 20 Gy (range, 14-24 Gy). Median overall survival from time of SRS was 12.1 months. The estimated local control at 12 months was 74%. On multivariate analysis, cerebellar location (hazard ratio [HR] 1.94, P=.009), larger tumor volume (HR 1.09, P<.001), and lower conformality (HR 0.700, P=.044) were significant independent predictors of local failure. Conformality index cutpoints of 1.4-1.9 were predictive of local control, whereas a cutpoint of 1.75 was the most predictive (P=.001). The adjusted Kaplan-Meier 1-year local control for conformality index ≥1.75 was 84% versus 69% for conformality index <1.75, controlling for tumor volume and location. The 1-year adjusted local control for cerebellar lesions was 60%, compared with 77% for supratentorial lesions, controlling for tumor volume and conformality index. Conclusions: Cerebellar tumor location, lower conformality index, and larger tumor volume were significant independent predictors of local failure after SRS for brain metastases from NSCLC. These results warrant further investigation in a

  10. Spotlight on necitumumab in the treatment of non-small-cell lung carcinoma

    PubMed Central

    Thakur, Manish K; Wozniak, Antoinette J

    2017-01-01

    The treatment options for metastatic non-small-cell lung cancer (NSCLC) have expanded dramatically in the last 10 years with the discovery of newer drugs and targeted therapy. Epidermal growth factor receptor (EGFR), when aberrantly activated, promotes cell growth and contributes in various ways to the malignant process. EGFR has become an important therapeutic target in a variety of malignancies. Small-molecule tyrosine kinase inhibitors (TKIs) of EGFR are being used to treat advanced NSCLC and are particularly effective in the presence of EGFR mutations. Monoclonal antibodies have also been developed that block the EGFR at the cell surface and work in conjunction with chemotherapy. Necitumumab is a second-generation fully human IgG1 monoclonal antibody that has shown promise in metastatic NSCLC. The benefit has mostly been restricted to squamous cell lung cancer in the frontline setting. Considering that the survival advantage for these patients was modest, there is a need to discover biomarkers that will predict which patients will likely have the best outcomes. This review focuses on the development and clinical trial experience with necitumumab in NSCLC. PMID:28293124

  11. Oncogenic drivers, targeted therapies, and acquired resistance in non-small-cell lung cancer.

    PubMed

    Gower, Arjan; Wang, Yisong; Giaccone, Giuseppe

    2014-07-01

    In the past decade, a shift toward targeted therapies in non-small-cell lung cancer following molecular profiling has dramatically changed the way advanced adenocarcinoma is treated. However, tumor cells inevitably acquire resistance to such therapies, circumventing any sustained clinical benefit. As the genomic classification of lung cancer continues to evolve and as the mechanisms of acquired resistance to targeted therapies become elucidated and more improved target-specific drugs come into sight, the future will see more promising results from the clinic through the development of new therapeutic strategies to overcome, or prevent the development of, resistance for lung cancer patients.

  12. Atezolizumab in Japanese Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer: A Subgroup Analysis of the Phase 3 OAK Study.

    PubMed

    Hida, Toyoaki; Kaji, Reiko; Satouchi, Miyako; Ikeda, Norihiko; Horiike, Atsushi; Nokihara, Hiroshi; Seto, Takashi; Kawakami, Tomohisa; Nakagawa, Shintaro; Kubo, Toshio

    2018-02-01

    Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) agent, is effective and well tolerated in patients with pretreated advanced non-small-cell lung cancer (NSCLC). We assessed its efficacy and safety in Japanese patients through subgroup analyses of the phase 3 OAK study (NCT02008227). Key eligibility criteria of this randomized, controlled, open-label, international study include locally advanced/metastatic NSCLC, ≥ 1 prior platinum-based chemotherapy, age ≥ 18 years, measurable disease (Response Evaluation Criteria in Solid Tumors v1.1), and Eastern Cooperative Oncology Group performance status 0 or 1. Atezolizumab 1200 mg or docetaxel 75 mg/m 2 was provided intravenously every 3 weeks. Co-primary end points were overall survival (OS) in the intention-to-treat (ITT) population and those with ≥ 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC; TC1/2/3 or IC1/2/3). Sixty-four ITT patients were Japanese; 19 had TC1/2/3 or IC1/2/3 status. In Japanese ITT patients, median OS in the atezolizumab arm (n = 36) was longer than the docetaxel arm (n = 28; 21.3 months [95% confidence interval (CI), 11.0-not estimable (NE)] versus 17.0 months [95% CI, 12.5-NE], respectively; hazard ratio 0.80 [95% CI, 0.41-1.57]). In the TC1/2/3 or IC1/2/3 population, median OS was 21.3 months (95% CI, 15.0-NE) and NE in the atezolizumab (n = 11) and docetaxel (n = 8) groups, respectively (hazard ratio, 0.81 [95% CI, 0.22-3.05]). Atezolizumab was generally well tolerated, with no treatment-related deaths. Atezolizumab was effective and well tolerated in pretreated Japanese patients with NSCLC. Results are consistent with the primary analysis of OAK. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  13. EF5 in Measuring Tumor Hypoxia in Patients With Stage I-III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2015-04-10

    Stage IA Non-Small Cell Lung Carcinoma; Stage IB Non-Small Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer

  14. Erlotinib: a pharmacoeconomic review of its use in advanced non-small cell lung cancer.

    PubMed

    Lyseng-Williamson, Katherine A

    2010-01-01

    Erlotinib (Tarceva), an oral epidermal growth factor receptor tyrosine kinase inhibitor, is associated with modest improvements in survival in patients with advanced non-small cell lung cancer (NSCLC) who have previously received one or more prior chemotherapy regimens. In a well designed clinical trial in this patient population, median overall survival and progression-free survival were significantly longer in patients receiving erlotinib 150 mg/day than in those receiving placebo. Erlotinib is generally well tolerated, with most adverse events being of mild to moderate severity. A large body of modelled pharmacoeconomic data suggests that second- or third-line erlotinib 150 mg/day is a cost-saving option relative to treatment with the approved second-line intravenous chemotherapies of docetaxel and pemetrexed in patients with advanced NSCLC. In patients who had received at least one prior chemotherapy regimen, erlotinib was predicted to be dominant (i.e. more effective and less costly) or cost saving (i.e. equally effective and less costly) relative to docetaxel or pemetrexed with regard to the cost per QALY or life-year gained in cost-effectiveness analyses. Although the effect of erlotinib on overall survival was generally assumed to be equivalent to that of the chemotherapies, the estimated amount of QALYs gained was slightly greater with erlotinib than with docetaxel. In cost-minimization and national budgetary impact analyses, estimated total direct costs with erlotinib were lower than those with docetaxel and pemetrexed, because of the generally lower drug acquisition, administration and adverse event management costs associated with erlotinib. Cost advantages with erlotinib were predicted across analyses, regardless of the type of model developed, specific costs that were included, country that the study was conducted in and year of costing. Sensitivity analyses consistently showed that these results were robust to plausible changes in the key model

  15. Mechanism and non-mechanism based imaging biomarkers for assessing biological response to treatment in non-small cell lung cancer.

    PubMed

    Weller, A; O'Brien, M E R; Ahmed, M; Popat, S; Bhosle, J; McDonald, F; Yap, T A; Du, Y; Vlahos, I; deSouza, N M

    2016-05-01

    Therapeutic options in locally advanced non-small cell lung cancer (NSCLC) have expanded in the past decade to include a palate of targeted interventions such as high dose targeted thermal ablations, radiotherapy and growing platform of antibody and small molecule therapies and immunotherapies. Although these therapies have varied mechanisms of action, they often induce changes in tumour architecture and microenvironment such that response is not always accompanied by early reduction in tumour mass, and evaluation by criteria other than size is needed to report more effectively on response. Functional imaging techniques, which probe the tumour and its microenvironment through novel positron emission tomography and magnetic resonance imaging techniques, offer more detailed insights into and quantitation of tumour response than is available on anatomical imaging alone. Use of these biomarkers, or other rational combinations as readouts of pathological response in NSCLC have potential to provide more accurate predictors of treatment outcomes. In this article, the robustness of the more commonly available positron emission tomography and magnetic resonance imaging biomarker indices is examined and the evidence for their application in NSCLC is reviewed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations

    PubMed Central

    Wang, Jun; Wang, Baocheng; Chu, Huili; Yao, Yunfeng

    2016-01-01

    Identifying activating EGFR mutations is a useful predictive strategy that helps select a population of advanced non-small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors (TKIs). Patients with sensitizing EGFR mutations (predominantly an in-frame deletion in exon 19 and an L858R substitution) are highly responsive to first-generation EGFR TKIs, such as gefitinib and erlotinib, and show improved progression-free survival without serious side effects. However, all patients with activating EGFR mutations who are initially responsive to EGFR TKIs eventually develop acquired resistance after a median progression-free survival of 10–16 months, followed by disease progression. Moreover, ~20%–30% of NSCLC patients have no objective tumor regression on initial EGFR TKI treatment, although they harbor an activating EGFR mutation. These patients represent an NSCLC subgroup that is defined as having intrinsic or primary resistance to EGFR TKIs. Different mechanisms of acquired EGFR TKI resistance have been identified, and several novel compounds have been developed to reverse acquired resistance, but little is known about EGFR TKI intrinsic resistance. In this review, we summarize the latest findings involving mechanisms of intrinsic resistance to EGFR TKIs in advanced NSCLC with activating EGFR mutations and present possible therapeutic strategies to overcome this resistance. PMID:27382309

  17. Treatment algorithm in 2014 for advanced non-small cell lung cancer: therapy selection by tumour histology and molecular biology.

    PubMed

    Manegold, Christian

    2014-09-01

    The availability of antineoplastic monoclonal antibodies, small molecules and newer cytotoxics such as pemetrexed, the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib, afatinib as well as the anti-angiogenic bevacizumab and the ALK-inhibitor crizotinib has recently changes the treatment algorithm of advanced non-small cell lung cancer. Decision making in 2014 is characterized by customizing therapy, by selecting a specific therapeutic regimen based on the histotype and the genotype of the tumour. This refers to first-line induction therapy and maintenance therapy as well, but also to subsequent lines of therapy since anti-neoplastic drugs and regimens used upfront clinically influence the selection of agents/regimes considered for second-/third-line treatment. Consequently, therapy customization through tumour histology and molecular markers has significantly influenced the work of pathologists around the globe and the process of obtaining an extended therapeutically relevant tumour diagnosis. Not only histological sub-typing became standard but molecular information is also considered of increasing importance for treatment selection. Routine molecular testing in certified laboratories must be established, and the diagnostic process should ideally be performed under the guidance of evidence based recommendation. The process of investigating and implementing medical targeting in lung cancer therefore, requires advanced diagnostic techniques and expertise and because of its large dimension is costly and influenced by the limitation of financial and clinical resources. Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.

  18. Is uniportal thoracoscopic surgery a feasible approach for advanced stages of non-small cell lung cancer?

    PubMed Central

    Fieira, Eva; Delgado, Maria; Mendez, Lucía; Fernandez, Ricardo; de la Torre, Mercedes

    2014-01-01

    Objectives Conventional video-assisted thoracoscopic (VATS) lobectomy for advanced lung cancer is a feasible and safe surgery in experienced centers. The aim of this study is to assess the feasibility of uniportal VATS approach in the treatment of advanced non-small cell lung cancer (NSCLC) and compare the perioperative outcomes and survival with those in early-stage tumors operated through the uniportal approach. Methods From June 2010 to December 2012, we performed 163 uniportal VATS major pulmonary resections. Only NSCLC cases were included in this study (130 cases). Patients were divided into two groups: (A) early stage and (B) advanced cases (>5 cm, T3 or T4, or tumors requiring neoadjuvant treatment). A descriptive and retrospective study was performed, comparing perioperative outcomes and survival obtained in both groups. A survival analysis was performed with Kaplan-Meier curves and the log-rank test was used to compare survival between patients with early and advanced stages. Results A total of 130 cases were included in the study: 87 (A) vs. 43 (B) patients (conversion rate 1.1 vs. 6.5%, P=0.119). Mean global age was 64.9 years and 73.8% were men. The patient demographic data was similar in both groups. Upper lobectomies (A, 52 vs. B, 21 patients) and anatomic segmentectomies (A, 4 vs. B, 0) were more frequent in group A while pneumonectomy was more frequent in B (A, 1 vs. B, 6 patients). Surgical time was longer (144.9±41.3 vs. 183.2±48.9, P<0.001), and median number of lymph nodes (14 vs. 16, P=0.004) were statistically higher in advanced cases. Median number of nodal stations (5 vs. 5, P=0.165), days of chest tube (2 vs. 2, P=0.098), HOS (3 vs. 3, P=0.072), and rate of complications (17.2% vs. 14%, P=0.075) were similar in both groups. One patient died on the 58th postoperative day. The 30-month survival rate was 90% for the early stage group and 74% for advanced cases Conclusions Uniportal VATS lobectomy for advanced cases of NSCLC is a safe and

  19. Antitumor activity of EGFR-specific CAR T cells against non-small-cell lung cancer cells in vitro and in mice.

    PubMed

    Li, He; Huang, Yao; Jiang, Du-Qing; Cui, Lian-Zhen; He, Zhou; Wang, Chao; Zhang, Zhi-Wei; Zhu, Hai-Li; Ding, Yong-Mei; Li, Lin-Fang; Li, Qiang; Jin, Hua-Jun; Qian, Qi-Jun

    2018-02-07

    Effective control of non-small-cell lung cancer (NSCLC) remains clinically challenging, especially during advanced stages of the disease. This study developed an adoptive T-cell treatment through expression of a chimeric antigen receptor (CAR) to target human epidermal growth factor receptor (EGFR) in NSCLC. We optimized the non-viral piggyBac transposon system to engineer human T cells for the expression of EGFR-CAR, consisting of EGFR scFv, transmembrane domain, and intracellular 4-1BB-CD3ζ signaling domains. The modified CAR T cells exhibited expansion capability and anticancer efficacy in a time- and antigen-dependent manner in vitro as well as regression of EGFR-positive human lung cancer xenografts in vivo. EGFR-CAR T therapy is a promising strategy to improve the efficacy and potency of the adoptive immunotherapy in NSCLC. Moreover, EGFR-CAR T therapy could become a clinical application for NSCLC patients in the future.

  20. Erlotinib or best supportive care for third-line treatment of advanced non-small-cell lung cancer: a real-world cost-effectiveness analysis.

    PubMed

    Cromwell, Ian; van der Hoek, Kimberly; Malfair Taylor, Suzanne C; Melosky, Barbara; Peacock, Stuart

    2012-06-01

    Erlotinib has been approved as a third-line treatment for advanced non-small-cell lung cancer (NSCLC) in British Columbia (BC). A cost-effectiveness analysis was conducted to compare costs and effectiveness in patients who received third-line erlotinib to those in a historical patient cohort that would have been eligible had erlotinib been available. In a population of patients who have been treated with drugs for advanced NSCLC, overall survival (OS), progression-to-death survival (PTD) and probability of survival one year after end of second-line (1YS) were determined using a Kaplan-Meier survival analysis. Costs were collected retrospectively from the perspective of the BC health care system. Incremental mean OS was 90 days (0.25 LYG), and incremental mean cost was $11,102 (CDN 2009), resulting in a mean ICER of $36,838/LYG. Univariate sensitivity analysis yielded ICERs ranging from $21,300 to $51,700/LYG. Our analysis suggests that erlotinib may be an effective and cost-effective third-line treatment for advanced NSCLC compared to best supportive care. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  1. Cell block samples from malignant pleural effusion might be valid alternative samples for anaplastic lymphoma kinase detection in patients with advanced non-small-cell lung cancer.

    PubMed

    Zhou, Jianya; Yao, Hongtian; Zhao, Jing; Zhang, Shumeng; You, Qihan; Sun, Ke; Zou, Yinying; Zhou, Caicun; Zhou, Jianying

    2015-06-01

    To evaluate the clinical value of cell block samples from malignant pleural effusion (MPE) as alternative samples to tumour tissue for anaplastic lymphoma kinase (ALK) detection in patients with advanced non-small-cell lung cancer (NSCLC). Fifty-two matched samples were eligible for analysis. ALK status was detected by Ventana immunohistochemistry (IHC) (with the D5F3 clone), reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridization (FISH) in MPE cell block samples, and by FISH in tumour tissue block samples. In total, ALK FISH results were obtained for 52 tumour tissue samples and 41 MPE cell block samples. Eight cases (15.4%) were ALK-positive in tumour tissue samples by FISH, and among matched MPE cell block samples, five were ALK-positive by FISH, seven were ALK-positive by RT-PCR, and eight were ALK-positive by Ventana IHC. The ALK status concordance rates between tumour tissue and MPE cell block samples were 78.9% by FISH, 98.1% by RT-PCR, and 100% by Ventana IHC. In MPE cell block samples, the sensitivity and specificity of Ventana IHC (100% and 100%) and RT-PCR (87.5% and 100%) were higher than those of FISH (62.5% and 100%). Malignant pleural effusion cell block samples had a diagnostic performance for ALK detection in advanced NSCLC that was comparable to that of tumour tissue samples. MPE cell block samples might be valid alternative samples for ALK detection when tissue is not available. Ventana IHC could be the most suitable method for ALK detection in MPE cell block samples. © 2014 John Wiley & Sons Ltd.

  2. Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer-data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002).

    PubMed

    Miyauchi, Eisaku; Inoue, Akira; Kobayashi, Kunihiko; Maemondo, Makoto; Sugawara, Shunichi; Oizumi, Satoshi; Isobe, Hiroshi; Gemma, Akihiko; Saijo, Yasuo; Yoshizawa, Hirohisa; Hagiwara, Koichi; Nukiwa, Toshihiro

    2015-07-01

    Epidermal growth factor receptor tyrosine kinase inhibitors are effective as first-line therapy for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations. However, it is unknown whether second-line platinum-based chemotherapy after epidermal growth factor receptor tyrosine kinase inhibitor therapy could lead to better outcomes. We evaluated the efficacy of second-line platinum-based chemotherapy after gefitinib for advanced non-small cell lung cancers harboring epidermal growth factor receptor mutations (the NEJ002 study). Seventy-one non-small cell lung cancers, treated with gefitinib as first-line therapy and then receiving platinum-based chemotherapy as second-line therapy were evaluated in NEJ002. Patients were evaluated for antitumor response to second-line chemotherapy by computed tomography according to the criteria of the Response Evaluation Criteria in Solid Tumors group (version 1.0). Of the 71 patients receiving platinum-based chemotherapy after first-line gefitinib, a partial response was documented in 25.4% (18/71), stable disease in 43.7% (31/71) and progression of disease in 21.1% (15/71). The objective response and disease control rates were 25.4% (18/71) and 69% (49/71), respectively. There was no significant difference between first- and second-line chemotherapy in objective response and disease control rates for advanced non-small cell lung cancer harboring activating epidermal growth factor receptor mutations. In the analysis of epidermal growth factor receptor mutation types, the objective responses of deletions in exon 19 and a point mutation in exon 21 (L858R) were 27.3% (9/33) and 28.1% (9/32), respectively, but these differences between objective response rates were not significant. The efficacy of second-line platinum-based chemotherapy followed at progression by gefitinib was similar to first-line platinum-based chemotherapy, and epidermal growth factor receptor mutation types did not influence

  3. SU-E-J-244: Development and Validation of a Knowledge Based Planning Model for External Beam Radiation Therapy of Locally Advanced Non-Small Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liu, Z; Kennedy, A; Larsen, E

    2015-06-15

    Purpose: The study aims to develop and validate a knowledge based planning (KBP) model for external beam radiation therapy of locally advanced non-small cell lung cancer (LA-NSCLC). Methods: RapidPlan™ technology was used to develop a lung KBP model. Plans from 65 patients with LA-NSCLC were used to train the model. 25 patients were treated with VMAT, and the other patients were treated with IMRT. Organs-at-risk (OARs) included right lung, left lung, heart, esophagus, and spinal cord. DVH and geometric distribution DVH were extracted from the treated plans. The model was trained using principal component analysis and step-wise multiple regression. Boxmore » plot and regression plot tools were used to identify geometric outliers and dosimetry outliers and help fine-tune the model. The validation was performed by (a) comparing predicted DVH boundaries to actual DVHs of 63 patients and (b) using an independent set of treatment planning data. Results: 63 out of 65 plans were included in the final KBP model with PTV volume ranging from 102.5cc to 1450.2cc. Total treatment dose prescription varied from 50Gy to 70Gy based on institutional guidelines. One patient was excluded due to geometric outlier where 2.18cc of spinal cord was included in PTV. The other patient was excluded due to dosimetric outlier where the dose sparing to spinal cord was heavily enforced in the clinical plan. Target volume, OAR volume, OAR overlap volume percentage to target, and OAR out-of-field volume were included in the trained model. Lungs and heart had two principal component scores of GEDVH, whereas spinal cord and esophagus had three in the final model. Predicted DVH band (mean ±1 standard deviation) represented 66.2±3.6% of all DVHs. Conclusion: A KBP model was developed and validated for radiotherapy of LA-NSCLC in a commercial treatment planning system. The clinical implementation may improve the consistency of IMRT/VMAT planning.« less

  4. Assessment of cytology based molecular analysis to guide targeted therapy in advanced non-small-cell lung cancer.

    PubMed

    Li, Wenbin; Zhang, Zhihui; Guo, Lei; Qiu, Tian; Ling, Yun; Cao, Jian; Guo, Huiqin; Zhao, Huan; Li, Lin; Ying, Jianming

    2016-02-16

    To investigate the use of molecular testing on cytological specimens in selecting advanced non-small cell lung cancer (NSCLC) patients who are adequate for targeted treatment, a total of 137 NSCLC cases were analyzed by fluorescence in situ hybridization (FISH) for anaplastic lymphoma kinase (ALK) rearrangements, and Epidermal growth factor receptor (EGFR), kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were evaluated by quantitative real-time PCR (qRT-PCR) platform combining amplification refractory mutation system (ARMS) primers and TaqMan probes. Cytological specimens included 91 fine-needle aspirates, 5 fibreoptic bronchoscopic derived samples and 41 pleural effusions. Among 137 NSCLCs analyzed for ALK FISH, 16 (11.7%, of 137) were detected to harbor ALK rearrangement. FISH positive cases were all defined as adenocarcinoma (ADC) histologic subtype and the FNA samples showed the highest ALK positive rate (13.2%, 12/91). Of the 9 ALK FISH positive patients who received crizotinib treatment, 8 (88.9%) patients exhibited tumor regression. In addition, 60 (44.8%, of 134) cases were found to harbor EGFR mutations and 22 patients with EGFR sensitive mutations who received gefitinib or erlotinib treatment showed a median PFS of 16.0 months. Mutations of KRAS occurred in 8 (6.0%, of 134) cases and this was mutually exclusive from EGFR mutation. Our results demonstrated that ALK FISH and EGFR, KRAS mutational analysis on cytological specimens are sensitive methods for screening advanced stage NSCLC patients who are adequate for targeted treatment.

  5. Failure Rates and Patterns of Recurrence in Patients With Resected N1 Non-Small-Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Varlotto, John M., E-mail: jvarlotto@hmc.psu.edu; Medford-Davis, Laura Nyshel; Recht, Abram

    2011-10-01

    Purpose: To examine the local and distant recurrence rates and patterns of failure in patients undergoing potentially curative resection of N1 non-small-cell lung cancer. Methods and Materials: The study included 60 consecutive unirradiated patients treated from 2000 to 2006. Median follow-up was 30 months. Failure rates were calculated by the Kaplan-Meier method. A univariate Cox proportional hazard model was used to assess factors associated with recurrence. Results: Local and distant failure rates (as the first site of failure) at 2, 3, and 5 years were 33%, 33%, and 46%; and 26%, 26%, and 32%, respectively. The most common site ofmore » local failure was in the mediastinum; 12 of 18 local recurrences would have been included within proposed postoperative radiotherapy fields. Patients who received chemotherapy were found to be at increased risk of local failure, whereas those who underwent pneumonectomy or who had more positive nodes had significantly increased risks of distant failure. Conclusions: Patients with resected non-small-cell lung cancer who have N1 disease are at substantial risk of local recurrence as the first site of relapse, which is greater than the risk of distant failure. The role of postoperative radiotherapy in such patients should be revisited in the era of adjuvant chemotherapy.« less

  6. Phase I Results of Vinorelbine With Concurrent Radiotherapy in Elderly Patients With Unresectable, Locally Advanced Non-Small-Cell Lung Cancer: West Japan Thoracic Oncology Group (WJTOG3005-DI)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Harada, Hideyuki, E-mail: h.harada@scchr.jp; Seto, Takashi; Igawa, Satoshi

    Purpose: To investigate the safety and efficacy of concurrent vinorelbine and thoracic radiotherapy in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). Methods and Materials: Eligible patients were 71 years of age or older with unresectable Stage III NSCLC. Patients were treated with thoracic radiotherapy (60 Gy) and concurrent vinorelbine (20 mg/m{sup 2} in Level 1 and 25 mg/m{sup 2} in Level 2) on Days 1 and 8 every 3 weeks for two cycles, followed by adjuvant vinorelbine (25 mg/m{sup 2}) on Days 1 and 8 every 3 weeks for two cycles. Results: Four patients were enrolled at Levelmore » 1. One patient experienced Grade 3 febrile neutropenia at Level 1 and the dose was escalated to Level 2. At Level 2, 2 of 6 patients experienced dose-limiting toxicities (Grade 4 neutropenia in 1 patient and Grade 3 infection in another). Three of 6 patients developed late Grade 2 or 3 pneumonitis. Therefore, the dose was de-escalated to Level 1. An additional 6 patients were enrolled at Level 1, 4 of whom experienced dose-limiting toxicities (incomplete radiotherapy because of Grade 2 pneumonitis in 1 patient and Grade 3 infection in 1, Grade 3 febrile neutropenia in 1, and Grade 3 esophagitis in 1). Moreover, late Grade 3 pneumothorax and Grade 5 pneumonitis occurred in 1 and 1 patient, respectively. Overall, Grade 2, 3 and 5 pneumonitis occurred in 3, 3, and 1 among 16 patients, respectively. Conclusions: Concurrent vinorelbine and thoracic radiotherapy resulted in a high incidence of severe pneumonitis when the standard dose of this agent was used for elderly patients. We therefore recommend caution in the use of this regimen and schedule for elderly patients.« less

  7. Sampling versus systematic full lymphatic dissection in surgical treatment of non-small cell lung cancer.

    PubMed

    Koulaxouzidis, Georgios; Karagkiouzis, Grigorios; Konstantinou, Marios; Gkiozos, Ioannis; Syrigos, Konstantinos

    2013-04-22

    The extent of mediastinal lymph node assessment during surgery for non-small cell cancer remains controversial. Different techniques are used, ranging from simple visual inspection of the unopened mediastinum to an extended bilateral lymph node dissection. Furthermore, different terms are used to define these techniques. Sampling is the removal of one or more lymph nodes under the guidance of pre-operative findings. Systematic (full) nodal dissection is the removal of all mediastinal tissue containing the lymph nodes systematically within anatomical landmarks. A Medline search was conducted to identify articles in the English language that addressed the role of mediastinal lymph node resection in the treatment of non-small cell lung cancer. Opinions as to the reasons for favoring full lymphatic dissection include complete resection, improved nodal staging and better local control due to resection of undetected micrometastasis. Arguments against routine full lymphatic dissection are increased morbidity, increase in operative time, and lack of evidence of improved survival. For complete resection of non-small cell lung cancer, many authors recommend a systematic nodal dissection as the standard approach during surgery, and suggest that this provides both adequate nodal staging and guarantees complete resection. Whether extending the lymph node dissection influences survival or recurrence rate is still not known. There are valid arguments in favor in terms not only of an improved local control but also of an improved long-term survival. However, the impact of lymph node dissection on long-term survival should be further assessed by large-scale multicenter randomized trials.

  8. Current Treatment Algorithms for Patients with Metastatic Non-Small Cell, Non-Squamous Lung Cancer

    PubMed Central

    Melosky, Barbara

    2017-01-01

    The treatment paradigm for metastatic non-small cell, non-squamous lung cancer is continuously evolving due to new treatment options and our increasing knowledge of molecular signal pathways. As a result of treatments becoming more efficacious and more personalized, survival for selected groups of non-small cell lung cancer (NSCLC) patients is increasing. In this paper, three algorithms will be presented for treating patients with metastatic non-squamous, NSCLC. These include treatment algorithms for NSCLC patients whose tumors have EGFR mutations, ALK rearrangements, or wild-type/wild-type tumors. As the world of immunotherapy continues to evolve quickly, a future algorithm will also be presented. PMID:28373963

  9. Surrogate endpoints for overall survival in advanced non-small-cell lung cancer patients with mutations of the epidermal growth factor receptor gene.

    PubMed

    Yoshino, Reiko; Imai, Hisao; Mori, Keita; Takei, Kousuke; Tomizawa, Mai; Kaira, Kyoichi; Yoshii, Akihiro; Tomizawa, Yoshio; Saito, Ryusei; Yamada, Masanobu

    2014-09-01

    Subsequent therapies confound the ability to discern the effect of first-line chemotherapy on overall survival (OS). We investigated whether progression-free survival (PFS), post-progression survival (PPS) and tumor response were valid surrogate endpoints for OS following first-line chemotherapy in individual patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor gene mutations. We retrospectively analyzed 35 patients with advanced NSCLC treated with first-line gefitinib. The associations of PFS, PPS and tumor response with OS were analyzed. PPS was found to be strongly correlated with OS, unlike PFS and tumor shrinkage. The factors significantly associated with PPS were performance status (PS) after first-line treatment, best response to second-line treatment and number of regimens used after disease progression. PPS may be a surrogate for OS in this patient population and further therapy after disease progression following first-line chemotherapy may significantly affect OS. However, a larger study is required to validate these results.

  10. Msi2 Regulates the Aggressiveness of Non-Small Cell Lung Cancer (NSCLC)

    DTIC Science & Technology

    2016-12-01

    Non-small cell lung cancer, invasion, metastasis, pro-invasive signaling, RNA binding proteins, Musashi, TGF-beta, epithelial mesenchymal transition...Non-small cell lung cancer, invasion, metastasis, pro-invasive signaling, RNA binding proteins, Musashi, TGF- beta, epithelial mesenchymal...NOTCH-1 RNA and protein expression in 344SQ and 531LN2 cells (NICD protein level was tested in 344SQ cells as well), Fig. 2 D-F. Surprisingly

  11. Clinical data from the real world: efficacy of Crizotinib in Chinese patients with advanced ALK-rearranged non-small cell lung cancer and brain metastases.

    PubMed

    Xing, Puyuan; Wang, Shouzheng; Hao, Xuezhi; Zhang, Tongtong; Li, Junling

    2016-12-20

    Brain metastasis in non small cell lung cancer (NSCLC) patients is often considered as a terminal stage of advanced disease. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) for ALK-rearranged NSCLC patients. Herein, we conducted a retrospective study to explore how Crizotinib affects the control of brain metastases and the overall prognosis in advanced ALK-rearranged NSCLC patients with brain metastases in Chinese population. A total of 34 patients were enrolled, of whom 20 (58.8%) patients had baseline brain metastases before Crizotinib treatment. Among patients with brain metastases before Crizotinib, overall survival (OS) after brain metastases was significantly longer than that of patients with brain metastases after Crizotinib (median OS, not reached vs. 10.3 months, respectively, p = 0.001). There was also a significant difference in systemic progression-free survival (PFS) between patients developing brain metastases before and after Crizotinib treatment (21.2 months vs. 13.9 months, p = 0.003). In conclusion, ALK-rearranged NSCLC patients with brain metastases before Crizotinib may benefit more from Crizotinib than those developing brain metastases during Crizotinib treatment.

  12. Pemetrexed-Erlotinib, Pemetrexed Alone, or Erlotinib Alone as Second-Line Treatment for East Asian and Non-East Asian Never-Smokers with Locally Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer: Exploratory Subgroup Analysis of a Phase II Trial

    PubMed Central

    Lee, Dae Ho; Lee, Jung Shin; Wang, Jie; Hsia, Te-Chun; Wang, Xin; Kim, Jongseok; Orlando, Mauro

    2015-01-01

    Purpose This subgroup analysis of a phase II trial was conducted to assess possible ethnicity-based trends in efficacy and safety in East Asian (EA) and non-EA populations with nonsquamous non-small cell lung cancer (NSCLC). Materials and Methods Never-smoker patients (n=240) with locally advanced or metastatic nonsquamous NSCLC included 133 EA patients randomized to pemetrexed supplemented with dexamethasone, folic acid, and vitamin B12 plus erlotinib (pemetrexed-erlotinib) (n=41), erlotinib (n=49), or pemetrexed (n=43), and 107 non-EA patients randomized to pemetrexed-erlotinib (n=37), erlotinib (n=33), or pemetrexed (n=37). The primary endpoint, progression-free survival (PFS), was analyzed using a multivariate Cox model. Results Consistent with the results of the overall study, a statistically significant difference in PFS among the three arms was noted in the EA population favoring pemetrexed-erlotinib (overall p=0.003) as compared with either single-agent arm (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29 to 0.79; p=0.004 vs. erlotinib; HR, 0.40; 95% CI, 0.23 to 0.70; p=0.001 vs. pemetrexed). The EA patients treated with pemetrexed-erlotinib achieved a longer median PFS (7.4 months) compared with erlotinib (4.5 months) and pemetrexed (4.0 months). The PFS results also numerically favored pemetrexed-erlotinib in the non-EA population (overall p=0.210) (HR, 0.62; 95% CI, 0.37 to 1.05; p=0.078 vs. erlotinib; HR, 0.75; 95% CI, 0.42 to 1.32; p=0.320 vs. pemetrexed) (median PFS: pemetrexed-erlotinib, 6.7 months; erlotinib, 3.0 months; pemetrexed, 4.4 months). Conclusion The PFS results from this subset analysis in both EA and non-EA populations are consistent with the results in the overall population. The PFS advantage for pemetrexed-erlotinib is significant compared with the single agents in EA patients. PMID:25672577

  13. USP7 promotes cell proliferation through the stabilization of Ki-67 protein in non-small cell lung cancer cells.

    PubMed

    Zhang, Chao; Lu, Jing; Zhang, Quan-Wu; Zhao, Wei; Guo, Jia-Hui; Liu, Shan-Ling; Wu, Ying-Li; Jiang, Bin; Gao, Feng-Hou

    2016-10-01

    The Ki-67 antigen (Ki-67) is the most reliable immunohistochemical marker for evaluation of cell proliferation in non-small cell lung cancer. However, the mechanisms underlying the regulation of protein levels of Ki-67 in non-small cell lung cancer have remained elusive. In this study, we found that Ki-67 and ubiquitin-specific processing protease 7 (USP7) protein were highly expressed in the nucleus of non-small cell lung cancer cells. Furthermore, statistical analysis uncovered the existence of a strong correlation between Ki-67 and USP7 levels. We could also show that the protein levels of Ki-67 in non-small cell lung cancer cells significantly decreased after treatment with P22077, a selective chemical inhibitor of USP7, while the Ki-67 mRNA levels were unperturbed. Similar results were obtained by knocking down USP7 using short hairpin RNA (shRNA) in lung cancer cells. Interestingly, we noticed that ubiquitination levels of Ki-67 increased dramatically in USP7-silenced cells. The tests in vitro and vivo showed a significant delay in tumor cell growth upon knockdown of USP7. Additionally, drug sensitivity tests indicated that USP7-silenced A549 cells had enhanced sensitivity to paclitaxel and docetaxel, while there was no significant change in sensitivity toward carboplatin and cisplatin. Taken together, these data strongly suggest that the overexpression of USP7 might promote cell proliferation by deubiquitinating Ki-67 protein, thereby maintaining its high levels in the non-small cell lung cancer. Our study also hints potential for the development of deubiquitinase-based therapies, especially those targeting USP7 to improve the condition of patients diagnosed with non-small cell lung cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Osimertinib in Treating Participants With Stage I-IIIA EGFR-mutant Non-small Cell Lung Cancer Before Surgery

    ClinicalTrials.gov

    2018-04-27

    EGFR (Epidermal Growth Factor Receptor) Exon 19 Deletion Mutation; EGFR NP_005219.2:p.L858R; EGFR NP_005219.2:p.T790M; Stage I Non-Small Cell Lung Cancer AJCC (American Joint Committee on Cancer) v7; Stage IA Non-Small Cell Lung Carcinoma AJCC v7; Stage IB Non-Small Cell Lung Carcinoma AJCC v7; Stage II Non-Small Cell Lung Cancer AJCC v7; Stage IIA Non-Small Cell Lung Carcinoma AJCC v7; Stage IIB Non-Small Cell Lung Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7

  15. Traditional Chinese Medicine treatment as maintenance therapy in advanced non-small-cell lung cancer: A randomized controlled trial.

    PubMed

    Jiang, Yi; Liu, Ling-Shuang; Shen, Li-Ping; Han, Zhi-Fen; Jian, Hong; Liu, Jia-Xiang; Xu, Ling; Li, He-Gen; Tian, Jian-Hui; Mao, Zhu-Jun

    2016-02-01

    Maintenance therapy for patients with advanced non-small-cell lung cancer (NSCLC) is an increasingly hot topic in the field of clinical NSCLC research. This study aimed to evaluate the effects of Traditional Chinese Medicine (TCM) treatment as maintenance therapy on time to progression (TTP), quality of life (QOL), overall survival (OS) and 1-year survival rate in patients with advanced NSCLC. This study was conducted as a randomized, controlled, open-label trial. 64 non-progressive patients who responded to initial therapy were randomized 1:1 to the TCM arm (treated with herbal injection (Cinobufacini, 20ml/d, d1-d10), herbal decoction (d1-d21) and Chinese acupoint application (d1-d21), n=32) or to the chemotherapy arm (treated with pemetrexed (non-squamous NSCLC, 500mg/m(2), d1), docetaxel (75mg/m(2), d1) or gemcitabine (1250mg/m(2), d1 and d8), n=32). Each therapy cycle was 21 days. They were repeated until disease progression, unacceptable toxicity, or until the patients requested therapy discontinuation. The primary end point was TTP; the secondary end points were QOL, OS and 1-year survival rate. "Intention-to-treat" analysis included all randomized participants. TCM treatment prolonged median TTP for 0.7 months compared with chemotherapy, but it was not statistically significant (3.0 months vs. 2.3 months, P=0.114). Median OS time for TCM treatment did not offer a significant advantage over for chemotherapy (21.5 months vs. 18.8 months, P=0.601). 1-year survival rate of TCM treatment significantly improved than that of chemotherapy (78.1% vs. 53.1%, P=0.035). TCM treatment can significantly improve QOL when compared to chemotherapy as assessed by EORTC QLQ-C30 and EORTC QLQ-LC13 QOL instruments. TCM maintenance treatment had similar effects on TTP and OS compared with maintenance chemotherapy, but it improved patients' QOL and had higher 1-year survival rate. TCM Maintenance treatment is a promising option for advanced NSCLC patients without progression

  16. Oral ifosfamide-mesna: a clinical investigation in advanced non-small-cell lung cancer.

    PubMed

    Manegold, C; Bischoff, H; Fischer, J R; Löchner, S; Peukert, M; Schmähl, A; Drings, P

    1992-11-01

    The purpose of this study was to evaluate the toxicity and response efficacy of fixed-dose oral ifosfamide (OI)-mesna (M) in advanced, non-small-cell lung cancer (NSCLC). OI was given in four different fractionated-dose treatment schedules with a total dose per cycle of either 3.0 g/m2, 6.0 g/m2, 7.5 g/m2 or 10 g/m2 (equivalent to a daily dose of either 750 mg, 1000 mg or 1250 mg.) M was given p.o. by drinking ampules. In the 64 patients (pts) included, a total of 305 treatment cycles were administered with no evidence of severe neurotoxicity. Twenty-two pts (37%) developed mild to moderate CNS toxicity. Neither myelosuppression, alopecia, gastrointestinal toxicity nor urotoxicity were clinical problems. On schedule 2 (6 g/m2), 3 of 14 evaluable pts (21%) had partial remissions (PR), and on schedule 3 (7.5 g/m2) 4 pts (25%) showed PRs. The median duration of response was 9 months (mts) for pts on schedule 2, and 8 mts for pts on schedule 3. We conclude that OIM can easily be tolerated in the same dose usually given intravenously (7.5 g/m2/mts), when patients at high risk for developing CNS toxicity have been previously excluded from therapy. In order to reduce CNS toxicity, it is suggested that the total dose per cycle should not exceed 7.5 g/m2 (1000 mg daily) within a fractionated-dose, 14-day treatment schedule. We further conclude that the tumor response efficacy of OIM in NSCLC is comparable to the one achieved by intravenously-administered IM, whereby the total monthly OI dose should not be less than 6.0 g/m2 (750 mg daily).

  17. Cost-effectiveness of first-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy

    PubMed Central

    Khan, Iftekhar; Morris, Stephen; Hackshaw, Allan; Lee, Siow-Ming

    2015-01-01

    Objective To assess the cost-effectiveness of erlotinib versus supportive care (placebo) overall and within a predefined rash subgroup in elderly patients with advanced non-small-cell lung cancer who are unfit for chemotherapy and receive only active supportive care due to their poor performance status or presence of comorbidities. Setting Between 2005 and 2009, a total of 670 patients with non-small cell lung cancer (NSCLC) were randomised across 78 hospital sites (centres) in the UK. Participants 670 patients with pathologically confirmed stage IIIb-IV NSCLC, unfit for chemotherapy, predominantly poor performance status (>2 on Eastern Cooperative Oncology Group, ECOG) and estimated life expectancy of at least 8 weeks. Patients were followed until disease progression or death, including a subgroup of patients who developed first cycle rash. Interventions Patients were randomised (1:1) to receive best supportive care plus oral placebo or erlotinib (150 mg/day) until disease progression, toxicity or death. Primary outcome Overall survival (OS). Secondary outcomes Progression-free survival (PFS), tumour response and quality adjusted life years (QALY), including within prespecified subgroups. Results The mean incremental cost per QALY in all patients was £202 571/QALY. The probability of cost-effectiveness of erlotinib in all patients was <10% at thresholds up to £100 000. However, within the rash subgroup, the incremental cost/QALY was £56 770/QALY with a probability of cost-effectiveness of about 80% for cost-effectiveness thresholds between £50 000 to £60 000. Conclusions Erlotinib has about 80% chance of being cost-effective at thresholds between £50 000–£60 000 in a subset of elderly poor performance patients with NSCLC unfit for chemotherapy who develop first cycle (28 days) rash. Erlotinib is potentially cost-effective for this population, for which few treatment options apart from best supportive care are available. Trial

  18. Utility values associated with advanced or metastatic non-small cell lung cancer: data needs for economic modeling.

    PubMed

    Brown, Jacqueline; Cook, Keziah; Adamski, Kelly; Lau, Jocelyn; Bargo, Danielle; Breen, Sarah; Chawla, Anita

    2017-04-01

    Cost-effectiveness analyses often inform healthcare reimbursement decisions. The preferred measure of effectiveness is the quality adjusted life year (QALY) gained, where the quality of life adjustment is measured in terms of utility. Areas covered: We assessed the availability and variation of utility values for health states associated with advanced or metastatic non-small cell lung cancer (NSCLC) to identify values appropriate for cost-effectiveness models assessing alternative treatments. Our systematic search of six electronic databases (January 2000 to August 2015) found the current literature to be sparse in terms of utility values associated with NSCLC, identifying 27 studies. Utility values were most frequently reported over time and by treatment type, and less frequently by disease response, stage of disease, adverse events or disease comorbidities. Expert commentary: In response to rising healthcare costs, payers increasingly consider the cost-effectiveness of novel treatments in reimbursement decisions, especially in oncology. As the number of therapies available to treat NSCLC increases, cost-effectiveness analyses will play a key role in reimbursement decisions in this area. Quantifying the relationship between health and quality of life for NSCLC patients via utility values is an important component of assessing the cost effectiveness of novel treatments.

  19. High-dose cisplatin with dipyridamole in advanced non-small cell lung cancer. A Grupo Oncológico Cooperativo del Sur study.

    PubMed

    Vallejo, C T; Rabinovich, M G; Perez, J E; Rodriguez, R; Machiavelli, M R; Leone, B A; Romero, A D; Lacava, J A; Cuevas, M A; Langhi, M J

    1995-06-01

    From March 1991 to October 1992, 41 patients with advanced non-small cell lung cancer (NSCLC) (20 stage IIIB and 21 stage IV) received a regimen consisting of cisplatin (CP) 100 mg/m2 i.v. days 1 and 8, and dipyridamole (DPD) 100 mg p.o. 75 minutes before CP, and then at hours 6, 12, and 18 as first-line chemotherapy. Cycles were repeated every 28 days for a total of 3. Median age was 56 years (range: 40-70). All patients had a performance status 0 to 1 and a weight loss < or = 10%. Squamous-cell carcinoma was diagnosed in 19 patients; adenocarcinoma in 16, and large-cell carcinoma in 6. A total of 37 patients were fully evaluable for response, whereas 39 were assessable for toxicity. No complete responses were observed: 5 patients (14%) achieved partial response; 23 patients (62%) showed no change, and progressive disease was observed in 9 (24%). The median time to treatment failure was 4 months, whereas median survival was 8 months. The average dose intensity received at the end of the third course of therapy was 46 mg/m2/week. There were no drug-related deaths. Toxicity was mild to moderate, with a high incidence of ototoxicity (54%) and emesis (67%). In conclusion, these results failed to demonstrate any significant advantage from a high-dose CP regimen modulated by DPD in patients with advanced NSCLC.

  20. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases.

    PubMed

    Zimmermann, Stefan; Dziadziuszko, Rafal; Peters, Solange

    2014-07-01

    Lung cancer is characterized by the highest incidence of solid tumor-related brain metastases, which are reported with a growing incidence during the last decade. Prognostic assessment may help to identify subgroups of patients that could benefit from more aggressive therapy of metastatic disease, in particular when central nervous system is involved. The recent sub-classification of non-small cell lung cancer (NSCLC) into molecularly-defined "oncogene-addicted" tumors, the emergence of effective targeted treatments in molecularly defined patient subsets, global improvement of advanced NSCLC survival as well as the availability of refined new radiotherapy techniques are likely to impact on outcomes of patients with brain dissemination. The present review focuses on key evidence and research strategies for systemic treatment of patients with central nervous system involvement in non-small cell lung cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Gefitinib provides similar effectiveness and improved safety than erlotinib for advanced non-small cell lung cancer: A meta-analysis.

    PubMed

    Zhang, Wenxiong; Wei, Yiping; Yu, Dongliang; Xu, Jianjun; Peng, Jinhua

    2018-04-01

    The epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib are effective for advanced non-small cell lung cancer (NSCLC). This meta-analysis compared their effectiveness and safety. We searched systematically in PubMed, ScienceDirect, The Cochrane Library, Scopus, Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar for relevant clinical trials regarding gefitinib versus erlotinib for NSCLC. Antitumor effectiveness (overall survival [OS], progression-free survival [PFS], objective response rate [ORR] and disease control rate [DCR]) and adverse effects [AEs]) were assessed. Forty studies comprising 9376 participants were included. The results suggested that gefitinib and erlotinib are effective for advanced NSCLC with comparable PFS (95% confidence intervals [CI]: 0.98-1.11, P = .15), OS (95% CI: 0.93-1.19, P = .45), ORR (95% CI: 0.99-1.16, P = .07), and DCR (95% CI: 0.92-1.03, P = .35). For erlotinib, dose reduction was significantly more frequent (95% CI: 0.10-0.57, P = .001) as were grade 3 to 5 AEs (95% CI: 0.36-0.79, P = .002). In the subgroup analysis, the erlotinib group had a significant higher rate and severity of skin rash, nausea/vomiting, fatigue, and stomatitis. Gefitinib was proven to be the better choice for advanced NSCLC, with equal antitumor effectiveness and fewer AEs compared with erlotinib. Further large-scale, well-designed randomized controlled trials are warranted to confirm our validation.

  2. ERCC1 protein as a guide for individualized therapy of late-stage advanced non-small cell lung cancer.

    PubMed

    Gao, Zhiqiang; Han, Baohui; Shen, Jie; Gu, Aiqin; Qi, Dajiang; Huang, Jinsu; Shi, Chunlei; Xiong, Liwen; Zhao, Yizhuo; Jiang, Liyan; Wang, Huimin; Chen, Yurong

    2011-09-01

    Excision repair cross-complementation group 1 (ERCC1) protein has been associated with cisplatin resistance. The objective of this study was to investigate the correlation between ERCC1 protein levels and the therapeutic effect of individualized therapy in advanced non-small cell lung cancer (NSCLC). A total of 190 advanced NSCLC patients were included in this study. Patients were randomized into either the individualized therapy group or the standard therapy group at a ratio of 2:1. Patients in the standard therapy group were treated with either gemcitabine plus cisplatin or vinorelbine plus cisplatin. The expression of ERCC1 protein in lung cancer tissues of patients from the individualized therapy group was detected with immunohistochemistry. Patients with low ERCC1 levels received either gemcitabine plus cisplatin or vinorelbine plus cisplatin, and patients with high levels received gemcitabine plus vinorelbine. The main outcome assessments were response rate (RR), overall survival (OS) and time to progression (TTP). Follow-up data were recorded until September 30, 2010. RR, 1-year survival rate and TTP were not statistically significant. The median survival time was 10.10 months in the standard therapy group (95% CI 8.48-11.92) and 13.59 months in the individualized therapy group (95% CI 11.86-14.74). The difference in median survival time was significantly different between these groups (P=0.036). The median survival time was longer in the individualized group compared to the standard therapy group. ERCC1 protein expression in advanced NSCLC patients, however, was not significantly correlated with RR, OS and TTP in the individualized therapy group. Therefore, this study suggests that ERCC1 protein levels should be assessed in combination with additional biomarkers to determine an optimal index for individualized therapy in advanced NSCLC patients.

  3. [Clinical Analysis of Icotinib on Beneficiary of 
Advanced Non-small Cell Lung Cancer with EGFR Common Mutation].

    PubMed

    Jiang, Xiaowen; Wang, Wenxian; Zhang, Yiping

    2016-04-20

    Targeted therapy has become an indispensable therapy method in advanced non-small cell lung cancer (NSCLC) treatment. Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) can significantly prolong the survival of patients harboring EGFR gene mutation. Icotinb is China's first EGFR-TKI with independent intellectual property rights. The aim of this study is to investigate the clinical characteristics about the beneficiary of advanced NSCLC patients with EGFR Common mutation who were treated with Icotinib. Retrospectively collect the data about beneficiary [progression-free survival (PFS)≥6 months] and analysis of the related risk factors for prognosis. From September 1, 2011 to September 30, 2015, 231 cases of advanced NSCLC beneficiary with EGFR common mutation were enrolled for treatment with icotinib in Zhejiang Cancer Hospital. The one year benefit rate was 67.9% in the group treated with Icotinib as first line, and in the groupas second line or above was 53.6%, which is statisticallysignificant. The two years benefit rate was 18.7% and 9.3%, respectively. The median PFS of first line group and the second line or above was 16.7 and 12.4 months, respectively. The presence of brain metastasis (P=0.010), Prior chemotherapy (P=0.001), Eastern Cooperative Oncology Group (ECOG) score (P=0.001) were the main factors influencing the prognosis. The most common adverse were skin rashes (51 cases, 22.1%) and diarrhea (27 cases, 11.7%). Icotinib offers long-term clinical benefit and good tolerance for advanced NSCLC harboring EGFR gene mutation. Its advantage groups in addition to the patients with brain metastases and better ECOG score, the curative effect of patients with the first-line treatment is superior to second or further line. 
.

  4. Singapore Cancer Network (SCAN) Guidelines for Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer.

    PubMed

    2015-10-01

    The SCAN lung cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the use of adjuvant systemic therapy for non-small cell lung cancer in Singapore. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. Five international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), European Society of Medical Oncology (2014), National Institute of Clinical Excellence (2012), Scottish Intercollegiate Guidelines Network (2014), and the Cancer Care Council Australia (2012). Recommendations on the selection of patients, chemotherapy regimen, treatment for stage I disease, treatment for positive margins and treatment options for pN2 disease with negative margins were produced. These adapted guidelines form the SCAN Guidelines 2015 for adjuvant systemic therapy of non-small cell lung cancer.

  5. Clinical utility of circulating tumour cell detection in non-small-cell lung cancer.

    PubMed

    Fusi, Alberto; Metcalf, Robert; Krebs, Matthew; Dive, Caroline; Blackhall, Fiona

    2013-12-01

    Recent years have witnessed increased interest in the detection of circulating tumour cells (CTCs) for diagnosis, monitoring, and treatment decision making in patients with cancer. Factors that have led to accelerated research in this field include advances in technologies for examination of intact CTCs, personalised medicine with treatment selection according to molecular characteristics, and continued lack of understanding of the biology of treatment resistance and metastasis. CTCs offer promise as a surrogate for tissue where there is insufficient tissue for molecular analysis and where there is a requirement to serially monitor molecular changes in cancer cells through treatment or on progression. In patients with either small cell or non-small cell lung cancer (NSCLC), there is evidence that CTC number is prognostic and that CTCs counted before and after treatment mirror treatment response. In patients with molecularly defined subtypes of NSCLC, CTCs demonstrate the same molecular changes as the cancer cells of the tumour. However, CTCs are not quite ready for "primetime" in the lung cancer clinic. There are still more questions than answers with respect to the optimal technologies for their detection and analysis, their biological significance, and their clinical utility. Despite this the current pace of progress in CTC technology development seems set to make "liquid biopsies" a clinical reality within the next decade. For the everyday clinician and clinical trialist, it will be important to maintain knowledge of the strengths and weaknesses of the technologies and evolving evidence base for CTCs as a routinely used diagnostic tool.

  6. Efficacy of Pemetrexed-based Chemotherapy in Comparison to Non-Pemetrexed-based Chemotherapy in Advanced, ALK+ Non-Small Cell Lung Cancer.

    PubMed

    Jo, Jaemin; Kim, Se Hyun; Kim, Yu Jung; Lee, Juhyun; Kim, Miso; Keam, Bhumsuk; Kim, Tae Min; Kim, Dong Wan; Heo, Dae Seog; Chung, Jin Haeng; Jeon, Yoon Kyung; Lee, Jong Seok

    2018-03-01

    Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p<0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p<0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03-1.42; p=0.106). Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC. © Copyright: Yonsei University College of Medicine 2018

  7. Alternating sequential chemotherapy with high-dose ifosfamide and doxorubicin/cyclophosphamide for adult non-small round cell soft tissue sarcomas.

    PubMed

    Kawai, Akira; Umeda, Toru; Wada, Takuro; Ihara, Koichiro; Isu, Kazuo; Abe, Satoshi; Ishii, Takeshi; Sugiura, Hideshi; Araki, Nobuhito; Ozaki, Toshifumi; Yabe, Hiroo; Hasegawa, Tadashi; Tsugane, Shoichiro; Beppu, Yasuo

    2005-05-01

    Doxorubicin and ifosfamide are the two most active agents used to treat soft tissue sarcomas. However, because of their overlapping side effects, concurrent administration to achieve optimal doses of each agent is difficult. We therefore conducted a Phase II trial to investigate the efficacy and feasibility of a novel alternating sequential chemotherapy regimen consisting of high dose ifosfamide and doxorubicin/cyclophosphamide in advanced adult non-small round cell soft tissue sarcomas. Adult patients with non-small round cell soft tissue sarcomas were enrolled. The treatment consisted of four sequential courses of chemotherapy that was planned for every 3 weeks. Cycles 1 and 3 consisted of ifosfamide (14 g/m(2)), and cycles 2 and 4 consisted of doxorubicin (60 mg/m(2)) and cyclophosphamide (1200 mg/m(2)). Forty-two patients (median age 47 years) were enrolled. Of the 36 assessable patients, 1 complete response and 16 partial responses were observed, for a response rate of 47.2%. Responses were observed in 57% of patients who had received no previous chemotherapy and 13% of those who had previously undergone chemotherapy. Grade 3-4 neutropenia was observed during 70% of all cycles. Sequential administration of high-dose ifosfamide and doxorubicin/cyclophosphamide has promising activity with manageable side effects in patients with advanced adult non-small round cell soft tissue sarcomas.

  8. Molecular profiling in Italian patients with advanced non-small-cell lung cancer: An observational prospective study.

    PubMed

    Gobbini, Elisa; Galetta, Domenico; Tiseo, Marcello; Graziano, Paolo; Rossi, Antonio; Bria, Emilio; Di Maio, Massimo; Rossi, Giulio; Gregorc, Vanesa; Riccardi, Ferdinando; Scotti, Vieri; Ceribelli, Anna; Buffoni, Lucio; Delmonte, Angelo; Franchina, Tindara; Migliorino, Maria Rita; Cortinovis, Diego; Pisconti, Salvatore; Bordi, Paola; Catino, Annamaria; Maiello, Evaristo; Arizio, Francesca; Novello, Silvia

    2017-09-01

    Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to European and Italian guidelines. However, molecular routine assessment remains still heterogeneous. This observational study aimed to take a picture of the real clinical practice in molecular testing and therapeutic choices in advanced Italian NSCLCs. This study prospectively enrolled newly diagnosed advanced or recurrent NSCLCs referred to 38 Italian centres, from November 2014 to November 2015. Information regarding molecular profiling and treatment choices were collected. Description of patients' outcome included overall survival (OS), progression-free survival in first (PFS1) and second-line (PFS2). Among 1787 patients enrolled, 1388 (78%) performed at least one molecular analysis during the history of disease: 76% were tested for EGFR, 53% for ALK, 27% for KRAS, 16% for ROS1, 14% for BRAF, 5% for HER2, 4% for MET and 1% for FGFR. The remaining 399 patients (22.3%) did not receive any molecular test. Among patients receiving at least one molecular analysis, 583 (42%) presented a molecular alteration. Considering EGFR mutated and/or ALK rearranged patients (402), for which target agents were routinely reimbursed at time of study in Italy, the 86% received a personalized treatment as first and/or second line: the 90% (286) of EGFR mutants received an EGFR tyrosine kinase inhibitor, mostly gefitinib (41.1%) or afatinib (36.4%) while 74% (62) of ALK translocated patients received an ALK inhibitor, mostly crizotinib (64%). Median OS was 9.34 months (95% CI 8.62-10.0), median PFS1 was 4.61 months (95%CI 4.31-4.84) and median PFS2 was 2.76 months (95%CI 2.57-3.19). In the Italian clinical practice, routine molecular assessment was largely applied in NSCLC patients, according to national guidelines, but a low level of ALK test was reached. Most of EGFR mutants an ALK rearranged patients received a personalized treatment as first and/or second line. Copyright © 2017 Elsevier

  9. Implementation status and explanatory analysis of early advance care planning for Stage IV non-small cell lung cancer patients.

    PubMed

    Tokito, Takaaki; Murakami, Haruyasu; Mori, Keita; Osaka, Iwao; Takahashi, Toshiaki

    2015-03-01

    The American Society of Clinical Oncology published the goals of individualized care including advance care planning for advanced cancer patients in 2011. However, no data are available on the implementation status of advance care planning. We retrospectively reviewed the electronic medical records and informed consent forms of consecutive Stage IV non-small cell lung cancer patients treated with chemotherapy between January 2010 and December 2012 at our institution. Two outcomes were defined to investigate the advance care planning implementation status: C-D, the duration from the last day of chemotherapy to death and D-D, that from the day of confirmed do-not-attempt-resuscitation order to death. The study included 136 eligible patients. The advance care planning implementation status in participating patients was as follows: 96 (70%) patients received information on 'incurable disease before first-line chemotherapy', 69 (50%) were informed about 'supportive care before first-line chemotherapy', whereas 43 (32%) learned about their prognosis. The do-not-attempt-resuscitation decision was reflected in 29 patients' will (21%). The median C-D was 64 days. Receipt of ≤2 chemotherapy regimens and provision of prognosis information to patients were significantly associated with long C-D in multivariate analysis. The median D-D was 25 days. Provision of information on supportive care before first-line chemotherapy and provision of prognosis information to patients were significantly associated with long D-D in multivariate analysis. Our results suggest that there is possible benefit from providing information on supportive care before first-line chemotherapy and informing patients about their prognosis in prolonging the duration of supportive care. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. Pretreatment 18F-FDG PET Textural Features in Locally Advanced Non–Small Cell Lung Cancer: Secondary Analysis of ACRIN 6668/RTOG 0235

    PubMed Central

    Ohri, Nitin; Duan, Fenghai; Snyder, Bradley S.; Wei, Bo; Machtay, Mitchell; Alavi, Abass; Siegel, Barry A.; Johnson, Douglas W.; Bradley, Jeffrey D.; DeNittis, Albert; Werner-Wasik, Maria; El Naqa, Issam

    2016-01-01

    In a secondary analysis of American College of Radiology Imaging Network (ACRIN) 6668/RTOG 0235, high pretreatment metabolic tumor volume (MTV) on 18F-FDG PET was found to be a poor prognostic factor for patients treated with chemoradiotherapy for locally advanced non–small cell lung cancer (NSCLC). Here we utilize the same dataset to explore whether heterogeneity metrics based on PET textural features can provide additional prognostic information. Methods Patients with locally advanced NSCLC underwent 18F-FDG PET prior to treatment. A gradient-based segmentation tool was used to contour each patient’s primary tumor. MTV, maximum SUV, and 43 textural features were extracted for each tumor. To address over-fitting and high collinearity among PET features, the least absolute shrinkage and selection operator (LASSO) method was applied to identify features that were independent predictors of overall survival (OS) after adjusting for MTV. Recursive binary partitioning in a conditional inference framework was utilized to identify optimal thresholds. Kaplan–Meier curves and log-rank testing were used to compare outcomes among patient groups. Results Two hundred one patients met inclusion criteria. The LASSO procedure identified 1 textural feature (SumMean) as an independent predictor of OS. The optimal cutpoint for MTV was 93.3 cm3, and the optimal Sum-Mean cutpoint for tumors above 93.3 cm3 was 0.018. This grouped patients into three categories: low tumor MTV (n = 155; median OS, 22.6 mo), high tumor MTV and high SumMean (n = 23; median OS, 20.0 mo), and high tumor MTV and low SumMean (n = 23; median OS, 6.2 mo; log-rank P < 0.001). Conclusion We have described an appropriate methodology to evaluate the prognostic value of textural PET features in the context of established prognostic factors. We have also identified a promising feature that may have prognostic value in locally advanced NSCLC patients with large tumors who are treated with chemoradiotherapy

  11. Successful treatment by pembrolizumab in a patient with end-stage renal disease with advanced non-small cell lung cancer and high PD-L1 expression.

    PubMed

    Ishizuka, Shiho; Sakata, Shinya; Yoshida, Chieko; Takaki, Akira; Saeki, Sho; Nakamura, Kazuyoshi; Fujii, Kazuhiko

    2018-05-10

    We report a 66-year-old Japanese male with end-stage renal disease (ESRD) and advanced non-small cell lung cancer (NSCLC) who was on hemodialysis. The patient harbored high programmed death ligand 1 (PD-L1) expression and was successfully treated with pembrolizumab. Laboratory examination upon diagnosis showed elevated serum creatinine (6.58 mg/dL). We administered pembrolizumab (200 mg/body) and repeated every 3 weeks. His renal dysfunction gradually progressed, hemodialysis was initiated after eight courses of pembrolizumab, and the antitumor effect was maintained at five months after hemodialysis initiation. Therefore, pembrolizumab can be administered for patients with ESRD and advanced NSCLC, who harbor high PD-L1 expression, during preparation for hemodialysis. Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  12. Brain activity correlated with food preferences: a functional study comparing advanced non-small cell lung cancer patients with and without anorexia.

    PubMed

    Sánchez-Lara, Karla; Arrieta, Oscar; Pasaye, Eric; Laviano, Alessandro; Mercadillo, Roberto E; Sosa-Sánchez, Ricardo; Méndez-Sánchez, Nahum

    2013-01-01

    The aim of this study was to examine the brain activity manifested while non-small cell lung cancer (NSCLC) patients with and without anorexia were exposed to visual food stimuli. We included 26 treatment-naïve patients who had been recently diagnosed with advanced NSCLC. Patients with brain metastasis were excluded. The patients were classified into anorectic and non-anorectic groups. Data from functional magnetic resonance imaging based on blood oxygen level-dependent (BOLD) signals were analyzed while the patients perceived pleasant and unpleasant food pictures. The brain records were analyzed with SPM 5 using a voxelwise multiple regression analysis. The non-anorexic patients demonstrated BOLD activation, comprising frontal brain regions in the premotor and the prefrontal cortices, only while watching unpleasant stimuli. The anorectic patients demonstrated no activation while watching the pleasant and unpleasant food pictures. Anorectic patients with lung cancer present a lack of activation in the brain regions associated with food stimuli processing. These results are consistent with experiences in the clinical environment: Patients describe themselves as not experiencing sensations of hunger or having an appetite. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. [Study on qi deficiency syndrome distribution and quality of life in patients with advanced non-small cell lung cancer].

    PubMed

    Yuan, Lin; Zhang, Pei-tong; Yang, Zong-yan

    2011-07-01

    To study the qi deficiency syndrome distribution and quality of life (QOL) of patients with advanced non-small cell lung cancer (NSCLC). A questionnaire survey was conducted in 120 patients with advanced NSCLC using the QOL scale "Functional Assessment of Cancer Therapy" (FACT-L) (Version 4.0). Meanwhile, syndrome typing was performed. On the basis of results of syndrome typing, patients of different syndrome types were grouped and compared, thus studying the distribution of advanced NSCLC patients of qi deficiency syndrome and qi deficiency syndrome correlated QOL features. Qi deficiency, blood stasis, yin deficiency, phlegm and dampness dominated in syndrome types of the 120 patients with advanced NSCLC. Of syndrome types accounting for larger ratios in 112 patients, pure qi deficiency syndrome accounted for 30.36% (34 cases), qi deficiency and blood stasis syndrome for 18. 75% (21 cases), both qi and yin deficiency syndrome for 10. 71% (12 cases). There was no correlation between the appearance of qi deficiency syndrome and patients' age, sex, pathological typing (adenocarcinoma/squamous carcinoma), or the disease duration. NSCLC patients in phase IV were mostly complicated with qi deficiency syndrome (P<0.05). Scores of physical states, emotional states, functional states, and total scores in the FACT-L scale were lower in those complicated with qi deficiency syndrome (89 cases) than in those without complicated qi deficiency syndrome (31 cases), showing statistical difference (P<0.01, P<0.05). The scores of the lung cancer specific module (additional concerns) in the FACT-L scale showed statistical difference, sequenced as qi deficiency and blood stasis syndrome > pure qi deficiency syndrome > both qi and yin deficiency syndrome (P<0.05). Qi deficiency syndrome is the main syndrome of advanced NSCLC. The QOL of advanced NSCLC patients complicated with qi deficiency syndrome was poorer than those without complicated qi deficiency syndrome. Besides, along with

  14. Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer.

    PubMed

    Shiroyama, Takayuki; Suzuki, Hidekazu; Tamiya, Motohiro; Tamiya, Akihiro; Tanaka, Ayako; Okamoto, Norio; Nakahama, Kenji; Taniguchi, Yoshihiko; Isa, Shun-Ichi; Inoue, Takako; Imamura, Fumio; Atagi, Shinji; Hirashima, Tomonori

    2018-01-01

    Programmed death-ligand 1 (PD-L1) expression status is inadequate for indicating nivolumab in patients with non-small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation-related parameters) on progression-free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27-87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin <3.7 g/dL, neutrophil-to-lymphocyte ratio ≥4, and ALI <18 were significantly associated with poor PFS and early progression on univariate analysis. Multivariate analyses revealed that pretreatment ALI <18 was independently associated with inferior PFS (median, 1.4 vs. 3.7 months, P < 0.001) and a higher likelihood of early progression (odds ratio, 2.76; 95% confidence interval 1.44-5.34; P = 0.002). The pretreatment ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  15. Direct costs associated with the disease management of patients with unresectable advanced non-small-cell lung cancer in The Netherlands.

    PubMed

    Pompen, Marjolein; Gok, Murat; Novák, Annoesjka; van Wuijtswinkel, Rob; Biesma, Bonne; Schramel, Franz; Stigt, Jos; Smit, Hans; Postmus, Pieter

    2009-04-01

    Disease management and costs of treatment of patients with unresectable advanced non-small-cell lung cancer (NSCLC) in The Netherlands are not well known. A retrospective medical chart review was performed by collecting data from the time of diagnosis until the time of death or the end of the evaluation period. In addition to the demographic data, information was collected on the overall management of the patient. Hospital resource utilisation data collected included number of outpatient specialist visits, number and length of hospitalisation, type and number of diagnostic and laboratory procedures, type and number of radiotherapy cycles and detailed information on chemotherapy. To evaluate the economic impact of second-line treatment, a distinction was made between patients who received only best supportive care (BSC, group A) and those who received chemotherapy as a second-line treatment in addition to BSC (group B). The study was performed from the hospital perspective and reports on 2005 costs. Of 102 patients, 74 belonged to group A and 28 to group B. Patient management included a multidisciplinary approach, the extent of which depended on symptoms of the disease and presence of metastases. The average total treatment cost per patient per year of unresectable advanced NSCLC in The Netherlands was euro32,840 in group A and euro31,187 in group B. In both groups, hospitalisation was the major cost driver. In group B second-line chemotherapy was the second largest contributor of the costs. In spite of the difference in numbers of treatment lines provided to patients in groups A and B the total average costs per patient per year were comparable. Overall, the management of unresectable advanced NSCLC appeared to conform with current guidelines in The Netherlands. These patients show high medical resource consumption, with hospitalisation being the main cost driver in both groups. As economic arguments are becoming increasingly important in medical decision making on

  16. The role of circulating tumor cells in evaluation of prognosis and treatment response in advanced non-small-cell lung cancer.

    PubMed

    Zhou, Jia; Dong, Fei; Cui, Fang; Xu, Rui; Tang, Xiaokui

    2017-04-01

    Non-small-cell lung cancer (NSCLC) lacks validated biomarkers to predict the prognosis and treatment response. This study investigated whether circulating tumor cells (CTCs) detectable could reminder high risk of distant metastasis, provide prognostic information, and early indicate the response to the conventional therapy in patients with advanced NSCLC. In this single-center prospective study, blood samples for CTC analysis were obtained from 59 patients with previously untreated, stage III or IV NSCLC both before and after administration of two cycles of chemotherapy. CTCs took in peripheral blood were measured by Cell Search detect technique. Carcino-embryonic antigen and count of metastatic sites were positively related to CTC count analyzed by multiple linear regression (P < 0.05). The median overall survival was 11.2 months (95% CI: 10.37-12.03 months) for the baseline CTC ≥ 2 group compared with 8.3 months (95% CI: 7.72-8.88 months) for the CTC < 2 group (log-rank test P < 0.05). Similarly, patients with CTC ≥ 2 at baseline had a significantly shorter median PFS (4.3 months, 95% CI: 3.7-4.9 months) compared with patients with CTC < 2 (6.2 months, 95% CI: 5.59-6.82 months) (log-rank test P < 0.05). For the disease control (stable disease, partial response, or complete response), group CTC value before treatment did not present difference with that after therapy compared by pared-samples T test (t = 1.455, P = 0.154), similar to the result of progressed group (progressive disease) (t = -0.987, P = 0.335). The CTC value of progressed group was higher than that of disease control group either at baseline or post chemotherapy. These data provide an evidence of positive correlation between CTC counts with CEA, as well as count of metastatic sites. Meanwhile, CTCs could be an effective predictor of distant metastasis and poor prognosis. In this study, CTCs are poorly related to treatment response. Whether CTCs

  17. Nintedanib in combination with docetaxel for second-line treatment of advanced non-small-cell lung cancer; GENESIS-SEFH drug evaluation report.

    PubMed

    Espinosa Bosch, María; Asensi Diez, Rocío; García Agudo, Sara; Clopes Estela, Ana

    2016-06-01

    Nintedanib is a triple angiokinase inhibitor that has been approved by the European Agency Medicines (EMA) in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non small cell lung cancer (NSCLC) of adenocarcinoma tumour histology, after first-line chemotherapy. In LUME-Lung 1 clinical trial, the combination of nintedanib plus docetaxel vs. placebo plus docetaxel improved progression free survival (PFS) in NSCLC patients, and improved overall survival in the population of adenocarcinoma patients, particularly in those with progression within 9 months after first line treatment initiation, median 10.9 months ( [95% CI 8.5-12.6] vs. 7.9 months [6.7-9.1]; HR 0.75 [95% CI 0.60-0.92], p=0.0073). The toxicity profile of the combination included a higher incidence of neutropenia, gastro-intestinal (GI) disorders, and liver enzyme elevations; however, this did not cause a detrimental effect on patient quality of life. According to data from the clinical trial mentioned, the addition of nintedanib to docetaxel would lead to an estimated incremental cost-effectiveness ratio (ICER) per year of life with PFS in the overall population of 134,274.47 € (notified price). In the adenocarcinoma population per each life of year gained (LYG), the ICER of adding nintedanib to docetaxel would be 40,886.14 €; while by implementing a sensitivity analysis with a 25% discount in the drug price, the cost per LYG would be 32,364.05 €, and would place it close to the threshold of cost-effectiveness usually considered acceptable in our setting. In view of efficacy and safety results the proposed positioning is to recommend its inclusion in the Hospital Formulary only for adult patients with metastatic or locally recurrent NSCLC with adenocarcinoma histology after first line chemotherapy, with progression < 9 months from the initiation of first line treatment, taking into account the inclusion and exclusion criteria in the

  18. Crizotinib treatment for advanced non-small-cell lung cancer patients: a budget impact analysis based in Thailand.

    PubMed

    Thongprasert, Sumitra; Permsuwan, Unchalee

    2017-05-01

    With the advent of the anaplastic lymphoma kinase (ALK) inhibitor, treatment of ALK-positive advanced non-small-cell lung cancer (NSCLC) patients has become more effective while drug costs are still a major concern. This study aimed to estimate the budget impact of crizotinib versus other standard therapies in Thai advanced NSCLC patients with ALK rearrangement. The budget impact model was developed to estimate the net budget impact of crizotinib compared with no crizotinib considering the payer's perspective over a three-year period. Costs included drugs, ALK testing by FISH, adverse event treatment, administration and monitoring, and best supportive care. Data on costs and population were from a database in Thailand. Costs were presented for the year 2015. A univariate sensitivity analysis was performed to investigate the robustness of our findings. The total net budget impact of crizotinib in three years was 125,576,699 THB (3,480,507 USD), 91,156,049 THB (2,526,498 USD), and 42,724,760 THB (1,184,167 USD) respectively. When considering only patients receiving crizotinib, the expenditure increased by 41,199.70 THB (1141.90 USD), 20,755.02 THB (575.25 USD), and 8834.73 THB (244.87 USD) per patient per month. The main driven costs were from the cost of ALK testing and drugs. Despite its treatment value in ALK-positive patients, crizotinib can only be affordable for Thai patients within upper middle or high economic status. Availability for all patients under current payment models is limited.

  19. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma

    PubMed Central

    Wangari-Talbot, Janet; Hopper-Borge, Elizabeth

    2014-01-01

    Lung cancer is the most commonly diagnosed cancer in the world. “Driver” and “passenger” mutations identified in lung cancer indicate that genetics play a major role in the development of the disease, progression, metastasis and response to therapy. Survival rates for lung cancer treatment have remained stagnant at ~15% over the past 40 years in patients with disseminated disease despite advances in surgical techniques, radiotherapy and chemotherapy. Resistance to therapy; either intrinsic or acquired has been a major hindrance to treatment leading to great interest in studies seeking to understand and overcome resistance. Genetic information gained from molecular analyses has been critical in identifying druggable targets and tumor profiles that may be predictors of therapeutic response and mediators of resistance. Mutated or overexpressed epidermal growth factor receptor (EGFR) and translocations in the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) genes (EML4-ALK) are examples of genetic aberrations resulting in targeted therapies for both localized and metastatic disease. Positive clinical responses have been noted in patients harboring these genetic mutations when treated with targeted therapies compared to patients lacking these mutations. Resistance is nonetheless a major factor contributing to the failure of targeted agents and standard cytotoxic agents. In this review, we examine molecular mechanisms that are potential drivers of resistance in non-small cell lung carcinoma, the most frequently diagnosed form of lung cancer. The mechanisms addressed include resistance to molecular targeted therapies as well as conventional chemotherapeutics through the activity of multidrug resistance proteins. PMID:24634705

  20. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.

    PubMed

    Zhang, Isabella; Zaorsky, Nicholas G; Palmer, Joshua D; Mehra, Ranee; Lu, Bo

    2015-10-01

    The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study.

    PubMed

    Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

    2017-01-01

    Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63-7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects.

  2. Immunotherapy for non-small cell lung cancer: current concepts and clinical trials

    PubMed Central

    Mayor, Marissa; Yang, Neng; Sterman, Daniel; Jones, David R.; Adusumilli, Prasad S.

    2016-01-01

    Recent successes in immunotherapeutic strategies are being investigated to combat cancers that have less than ideal responses to standard of care treatment, such as non-small-cell lung cancer. In this paper, we summarize concepts and the current status of immunotherapy for non-small cell lung cancer, including salient features of the major categories of immunotherapy—monoclonal antibody therapy, immune checkpoint blockade, immunotoxins, anticancer vaccines, and adoptive cell therapy. PMID:26516195

  3. Small interfering RNA-mediated suppression of serum response factor, E2-promotor binding factor and survivin in non-small cell lung cancer cell lines by non-viral transfection.

    PubMed

    Walker, Tobias; Nolte, Andrea; Steger, Volker; Makowiecki, Christina; Mustafi, Migdat; Friedel, Godehard; Schlensak, Christian; Wendel, Hans-Peter

    2013-03-01

    Serum response factor (SRF), E2F1 and survivin are well-known factors involved in a multitude of cancer-related regulation processes. However, to date, no suitable means has been found to apply their potential in the therapy of non-small cell lung cancer (NSCLC). This study deals with questions of small interfering ribonucleic acid (siRNA) transfection efficiency by a non-viral transfection of NSCLC cell-lines and the power of siRNA to transiently influence cell division by specific silencing. Different NSCLC cell lines were cultured under standard conditions and transfected, with specific siRNA targeting SRF, E2F1 and survivin in a non-viral manner. Cells treated with non-specific siRNA (SCR-siRNA) served as controls. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for messenger RNA (mRNA) expression levels. Additionally, transfection efficiency was evaluated by flow cytometry. The analysis of cell proliferation was determined with a CASY cell counter 3 days after transfection with SRF or SCR-siRNA. Transfection of the NSCLC cell lines with specific siRNAs against SRF, E2F1 and survivin resulted in a very considerable reduction of the intracellular mRNA concentration. CASY confirmation of cell viability demonstrated an excellent survival of the cell lines treated with non-specific siRNA, in contrast to with application of specific siRNA. This study reports a reliable transfectability of NSCLC-cell lines by siRNA, initially in a non-viral manner, and a reproducible knockdown of the focussed targets, consequently leading to the death of the tumour cells. This constitutes a strong candidate for a new assessment strategy in the therapy of non-small cell lung cancer.

  4. First-line therapy for advanced non-small cell lung cancer with activating EGFR mutation: is combined EGFR-TKIs and chemotherapy a better choice?

    PubMed

    Wang, Shuyun; Gao, Aiqin; Liu, Jie; Sun, Yuping

    2018-03-01

    As the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the median progression-free survival (PFS) up to 18.9 months. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, which limits the first-line PFS. To overcome the resistance and improve overall survival, researchers have tried to identify the resistance mechanisms and develop new treatment strategies, among which a combination of EGFR-TKIs and cytotoxic chemotherapy is one of the hotspots. The data from preclinical and clinical studies on combined EGFR-TKIs and chemotherapy have shown very interesting results. Here, we reviewed the available preclinical and clinical studies on first-line EGFR-TKIs-chemotherapy combination in patients with advanced NSCLC harboring activating EGFR mutation, aiming to provide evidences for more potential choices and shed light on clinical treatment.

  5. Stereotactic Body Radiation Therapy Followed by Surgery in Treating Patients With Stage I-IIIA Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2017-12-28

    Stage I Non-Small Cell Lung Cancer AJCC v7; Stage IA Non-Small Cell Lung Carcinoma AJCC v7; Stage IB Non-Small Cell Lung Carcinoma AJCC v7; Stage II Non-Small Cell Lung Cancer AJCC v7; Stage IIA Non-Small Cell Lung Carcinoma AJCC v7; Stage IIB Non-Small Cell Lung Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7

  6. Advances in the Treatment of Non-small Cell Lung Cancer: Focus on Nivolumab, Pembrolizumab, and Atezolizumab.

    PubMed

    Leventakos, Konstantinos; Mansfield, Aaron S

    2016-10-01

    Immunotherapy is revolutionizing the treatment of non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, including programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) monoclonal antibodies, are being introduced to routine clinical practice. This review summarizes clinical trials of nivolumab, pembrolizumab, and atezolizumab in patients with NSCLC. These agents have efficacy against NSCLC and a unique toxicity profile. The role of PD-L1 as a predictive biomarker is still unclear, partially because of the nuances of PD-L1 testing. These novel therapies also challenge our existing methodologies of radiologic assessment and efficacy analysis. This new era of immunotherapy has ushered in as much hope for patients as questions from physicians that need to be answered to clarify the optimal use of these agents.

  7. Skeletal muscle radiodensity is prognostic for survival in patients with advanced non-small cell lung cancer.

    PubMed

    Sjøblom, Bjørg; Grønberg, Bjørn H; Wentzel-Larsen, Tore; Baracos, Vickie E; Hjermstad, Marianne J; Aass, Nina; Bremnes, Roy M; Fløtten, Øystein; Bye, Asta; Jordhøy, Marit

    2016-12-01

    Recent research indicates that severe muscular depletion (sarcopenia) is frequent in cancer patients and linked to cachexia and poor survival. Our aim was to investigate if measures of skeletal muscle hold prognostic information in advanced non-small cell lung cancer (NSCLC). We included NSCLC patients with disease stage IIIB/IV, performance status 0-2, enrolled in three randomised trials of first-line chemotherapy (n = 1305). Computed tomography (CT) images obtained before start of treatment were used for body composition analyses at the level of the third lumbar vertebra (L3). Skeletal muscle mass was assessed by measures of the cross sectional muscle area, from which the skeletal muscle index (SMI) was obtained. Skeletal muscle radiodensity (SMD) was measured as the mean Hounsfield unit (HU) of the measured muscle area. A high level of mean HU indicates a high SMD. Complete data were available for 734 patients, mean age 65 years. Both skeletal muscle index (SMI) and muscle radiodensity (SMD) varied largely. Mean SMI and SMD were 47.7 cm 2 /m 2 and 37.4 HU in men (n = 420), 39.6 cm 2 /m 2 and 37.0 HU in women (n = 314). Multivariable Cox regression analyses, adjusted for established prognostic factors, showed that SMD was independently prognostic for survival (Hazard ratio (HR) 0.98, 95% CI 0.97-0.99, p = 0.001), whereas SMI was not (HR 0.99, 95% CI 0.98-1.01, p = 0.329). Low SMD is associated with poorer survival in advanced NSCLC. Further research is warranted to establish whether muscle measures should be integrated into routine practice to improve prognostic accuracy. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  8. Sequential measurements of serum matrix metalloproteinase 9 to monitor chemotherapy responses in patients with advanced non-small-cell lung cancer.

    PubMed

    Qiao, Xiaojuan; Zhai, Xiaoran; Wang, Jinghui; Zhao, Xiaoting; Yang, Xinjie; Lv, Jialin; Ma, Li; Zhang, Lina; Wang, Yue; Zhang, Shucai; Yue, Wentao

    2016-01-01

    Matrix metalloproteinase 9 (MMP-9) plays an important role in tumor invasion and metastasis, including lung cancer. However, whether variations in serum MMP-9 levels can serve as a biomarker for monitoring chemotherapy curative effect remains unclear. This study was designed to investigate the association between variations in serum MMP-9 levels and chemotherapy curative effect in patients with lung cancer. A total of 82 patients with advanced lung cancer were included. All newly diagnosed patients were treated with platinum-based doublet chemotherapy. Serial measurements of serum MMP-9 levels were performed by enzyme-linked immunosorbent assay. In this manner, we chose four time points to examine the association, including before chemotherapy, and 3 weeks after the beginning of the first, second, and fourth cycles of chemotherapy. Compared with the serum level of MMP-9 before progressive disease, patients with progressive disease had elevated serum levels of MMP-9. Compared with the previous time point of collecting specimens, the serum levels of MMP-9 in the patients with a complete response/partial response/stable disease decreased or were maintained stable. The differences of variation in serum MMP-9 levels in patients with different chemotherapy curative effects were all statistically significant after one cycle, two cycles, and four cycles (after one cycle: P<0.001; after two cycles: P<0.001; after four cycles: P=0.01). However, patients with small-cell lung cancer did not exhibit similar test results. The variation in serum MMP-9 levels in patients with non-small-cell lung cancer during chemotherapy was closely related to chemotherapy curative effect and could be useful to monitor chemotherapy curative effect for a small portion of patients.

  9. A single-arm, multicenter, safety-monitoring, phase IV study of icotinib in treating advanced non-small cell lung cancer (NSCLC).

    PubMed

    Hu, Xingsheng; Han, Baohui; Gu, Aiqin; Zhang, Yiping; Jiao, Shun Chang; Wang, Chang-Li; He, Jintao; Jia, Xueke; Zhang, Li; Peng, Jiewen; Wu, Meina; Ying, Kejing; Wang, Junye; Ma, Kewei; Zhang, Shucai; You, Changxuan; Tan, Fenlai; Wang, Yinxiang; Ding, Lieming; Sun, Yan

    2014-11-01

    The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21-95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively. The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Downregulation of long non-coding RNA ENSG00000241684 is associated with poor prognosis in advanced clear cell renal cell carcinoma.

    PubMed

    Su, Hengchuan; Wang, Hongkai; Shi, Guohai; Zhang, Hailiang; Sun, Fukang; Ye, Dingwei

    2018-06-01

    In order to identify potential novel biomarkers of advanced clear cell renal cell carcinoma (ccRCC), we re-evaluated published long non-coding RNA (lncRNA) expression profiling data. The lncRNA expression profiles in ccRCC microarray dataset GSE47352 were analyzed and an independent cohort of 61 clinical samples including 21 advanced and 40 localized ccRCC patients was used to confirm the most statistically significant lncRNAs by real time PCR. Next, the relationships between the selected lncRNAs and ccRCC patients' clinicopathological features were investigated. The effects of LncRNAs on the invasion and proliferation of renal carcinoma cells were also investigated. The PCR results in a cohort of 21 advanced ccRCC and 40 localized ccRCC tissues were used for confirmation of the selected lncRNAs which were statistically most significant. The PCR results showed that the expression of three LncRNA (ENSG00000241684, ENSG00000231721 and NEAT1) were significantly downregulated in advanced ccRCC. Kaplan-Meier analysis revealed that reduced expression of LncRNA ENSG00000241684 and NEAT1 were significantly associated with poor overall survival. The univariate and multivariate Cox regression indicated LncRNA ENSG00000241684 had significant hazard ratios for predicting clinical outcome. LncRNA ENSG00000241684 expression was negatively correlated with pTNM stage. Overexpression of ENSG00000241684 significantly impaired cell proliferation and reduced the invasion ability in 786-O and ACHN cells. lncRNAs are involved in renal carcinogenesis and decreased lncRNA ENSG00000241684 expression may be an independent adverse prognostic factor in advanced ccRCC patients. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  11. Cell-free DNA levels and correlation to stage and outcome following treatment of locally advanced rectal cancer.

    PubMed

    Boysen, Anders Kindberg; Wettergren, Yvonne; Sorensen, Boe Sandahl; Taflin, Helena; Gustavson, Bengt; Spindler, Karen-Lise Garm

    2017-11-01

    Accurate staging of rectal cancer remains essential for optimal patient selection for combined modality treatment, including radiotherapy, chemotherapy and surgery. We aimed at examining the correlation of cell free DNA with the pathologic stage and subsequent risk of recurrence for patients with locally advanced rectal cancer undergoing preoperative chemoradiation. We examined 75 patients with locally advanced rectal cancer receiving preoperative chemoradiation. Blood samples for translational use were drawn prior to rectal surgery. The level of cell free DNA was quantified by digital droplet PCR and expressed as copy number of beta 2 microglobulin. We found a median level of cell free DNA in the AJCC stages I-III of 3100, 8300, and 10,700 copies/mL respectively. For patients with 12 sampled lymph nodes or above, the median level of cell free DNA were 2400 copies/mL and 4400 copies/mL (p = 0.04) for node negative and node positive disease respectively. The median follow-up was 39 months and 11 recurrences were detected (15%). The median level for patients with recurrent disease was 13,000 copies/mL compared to 5200 copies/mL for non-recurrent patients (p = 0.08). We have demonstrated a correlation between the level of total cell free DNA and the pathologic stage and nodal involvement. Furthermore, we have found a trend towards a correlation with the risk of recurrence following resection of localized rectal cancer.

  12. High-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in locally advanced non-small-cell lung cancer: a feasibility study.

    PubMed

    Liu, Yue-E; Lin, Qiang; Meng, Fan-Jie; Chen, Xue-Ji; Ren, Xiao-Cang; Cao, Bin; Wang, Na; Zong, Jie; Peng, Yu; Ku, Ya-Jun; Chen, Yan

    2013-08-11

    Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer (NSCLC) and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear. The purpose of this study was to evaluate the feasibility of utilizing high-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for the treatment of local advanced NSCLC. Untreated patients with unresectable stage IIIA/IIIB NSCLC or patients with a recurrence of NSCLC received accelerated hypofractionated three-dimensional conformal radiotherapy. The total dose was greater than or equal to 60 Gy. The accelerated hypofractionated radiotherapy was conducted once daily at 3 Gy/fraction with 5 fractions per week, and the radiotherapy was completed in 5 weeks. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP. A total of 26 patients (19 previously untreated cases and 7 cases of recurrent disease) received 60Gy-75Gy radiotherapy with concurrent chemotherapy. All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis (88.5%) and radiation pneumonitis (42.3%). The percentages of grade III acute radiation esophagitis and grade III radiation pneumonitis were 15.4% and 7.7%, respectively. Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Two patients received high dose of 75 Gy had grade III late esophageal toxicity, and none had grade IV and above. Grade III and above late lung toxicity did not occur. High-dose accelerated

  13. High-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in locally advanced non-small-cell lung cancer: a feasibility study

    PubMed Central

    2013-01-01

    Background Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer (NSCLC) and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear. The purpose of this study was to evaluate the feasibility of utilizing high-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for the treatment of local advanced NSCLC. Methods Untreated patients with unresectable stage IIIA/IIIB NSCLC or patients with a recurrence of NSCLC received accelerated hypofractionated three-dimensional conformal radiotherapy. The total dose was greater than or equal to 60 Gy. The accelerated hypofractionated radiotherapy was conducted once daily at 3 Gy/fraction with 5 fractions per week, and the radiotherapy was completed in 5 weeks. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP. Results A total of 26 patients (19 previously untreated cases and 7 cases of recurrent disease) received 60Gy-75Gy radiotherapy with concurrent chemotherapy. All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis (88.5%) and radiation pneumonitis (42.3%). The percentages of grade III acute radiation esophagitis and grade III radiation pneumonitis were 15.4% and 7.7%, respectively. Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Two patients received high dose of 75 Gy had grade III late esophageal toxicity, and none had grade IV and above. Grade III and above late lung toxicity did not occur

  14. [The therapeutic value and safety of icotinib as first-line therapy for advanced non-small cell lung cancer patients].

    PubMed

    Chen, H; Wang, H P; Zhang, L; Si, X Y

    2017-01-01

    Objective: To evaluate the safety and efficacy of icotinib as first-line therapy in Chinese non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) sensitive mutations. Methods: Patients with stage ⅢB/Ⅳ NSCLC who had EGFR sensitive mutation and had no previous treatment were enrolled into this study. The response rates, progress free survival (PFS), overall survival (OS), and the safety were analyzed. Results: Ninety advanced adenocarcinoma patients were enrolled in this study, 44 patients had partial response (PR), 42 patients had stable disease (SD), 4 patients had progressive disease (PD), with an overall response rate (ORR) of 48.9%, and a disease control rate (DCR) of 95.6%. The median PFS was 14.9 months (95% CI 13.5-16.3) and the OS was 37.0 weeks (95% CI 27.9-46.1). Patients with brain metastases showed higher ORR( P =0.049). Patients with stage ⅢB had longer PFS than those with stage Ⅳ( P =0.007). The most common adverse events were grade 1-2 skin rash (38 patients, 40.9%). Other adverse events included dry skin, oral mucositis, diarrhea and liver function injury. Three patients withdrew because of severe liver injury or skin rash. No treatment related mortality occurred. Conclusions: Icotinib is effective and safe as first-line treatment for Chinese advanced NSCLC patients with EGFR sensitive mutation.

  15. Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC).

    PubMed

    Gu, Yuanlong; Lv, Huimin; Zhao, Juan; Li, Qi; Mu, Guannan; Li, Jiade; Wuyang, Jiazi; Lou, Ge; Wang, Ruitao; Zhang, Yanqiao; Huang, Xiaoyi

    2017-09-01

    Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P=0.0189 and P=0.0129, respectively). The median OS of the ACT≥4cycles subgroup was significantly longer than that of the ACT<4cycles subgroup (P=0.0316). The percentage of CIK cells in patients who received ≥4cycles of ACT was higher than that in patients treated with <4cycles of ACT (P=0.0376). Notably, CIK cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC. Copyright © 2017. Published by Elsevier B.V.

  16. Relationship of Th17/Treg Cells and Radiation Pneumonia in Locally Advanced Esophageal Carcinoma.

    PubMed

    Wang, Yan; Xu, Gang; Wang, Jie; Li, Xin-Hua; Sun, Ping; Zhang, Wei; Li, Jun-Xia; Wu, Chao-Yang

    2017-08-01

    Radiation pneumonia is a main side-effect that has limited the clinical usage of radiotherapy in locally advanced esophageal carcinoma. T helper cells 17 (Th 17) and T regulatory cells (Tregs) play an important role in inflammatory diseases. The balance between Treg and Th17 cells is a key factor in the progression of many inflammatory and autoimmune diseases. Whether Tregs and Th17 cells are predictive factors of radiation pneumonia has not yet been reported. In this study, we investigated the relationships of Treg/Th17 cells and radiation pneumonia in patients with locally advanced esophageal cancer who received radiotherapy. One hundred and forty-eight patients with locally advanced esophageal cancer who received radical and palliative radiotherapy were enrolled. The levels of Th17 and Treg cells in the blood of patients were detected using flow cytometry at the time point of pre-radiotherapy, 1st, 2nd, 3rd, 4th, 5th and 6th week from the start of radiation and 4 weeks after completion of radiotherapy. Radiation pneumonia was evaluated according to Radiation Therapy Oncology Group's acute radiation pneumonia standards, with the endpoint being grade 2 or above radiation pneumonia. There were 24 cases of radiation pneumonia in 148 cases of locally advanced esophageal cancer patients who underwent radiotherapy. Th17 cells increased and, in contrast, Treg cells decreased in the radiation pneumonia group. The change in the ratio of Th17/Treg was more pronounced and the difference was statistically significant from the 5th week after irradiation compared to patients with no radiation pneumonia (p<0.05). There was no significant difference in dosimetric parameters, including V5, V20, V30 and mean lung dose (MLD) and clinical factors, such as gender, age, smoking history, history of surgery and chemotherapy. The ratio of Th17/Treg cells may be an effective predictive factor of radiation pneumonia. Copyright© 2017, International Institute of Anticancer Research (Dr

  17. Radical-intent hypofractionated radiotherapy for locally advanced non-small-cell lung cancer: a systematic review of the literature.

    PubMed

    Kaster, Tyler S; Yaremko, Brian; Palma, David A; Rodrigues, George B

    2015-03-01

    To identify survival and toxicity characteristics associated with radical-intent hypofractionated radiotherapy for the treatment of stage III non-small-cell lung cancer (NSCLC). Relevant studies were identified from a systematic PubMed search of articles published between January 1990 and January 2014. All studies were peer reviewed and included both retrospective and prospective studies of NSCLC patients being treated with radical hypofractionated radiotherapy. Data on overall survival (OS) and toxicity were extracted from each of the studies where available. Of 685 studies initially identified by the search, a total of 33 studies were found to be relevant and were included in this systematic review. The number of fractions ranged from 15 to 35, the dose per fraction ranged from 2.3 to 3.5 Gy, and the delivered dose ranged from 45.0 to 85.5 Gy. Fifteen of the studies included concurrent chemotherapy, while 18 did not. OS was found to be associated with tumor biological effective dose, with the Pearson correlation coefficient ranging from 0.34 to 0.48. For both concurrent and nonconcurrent chemoradiotherapy acute pulmonary, late esophageal and late pulmonary incidences of toxicity ranged from 1.2% to 12.2%, but had 95% confidence intervals that included zero. The greatest incidence of toxicity was acute esophageal toxicity at 14.9% (95% confidence interval, 0.7%, 29.1%). There is a moderate linear relationship between biological effective dose and OS, and greater acute esophageal toxicity with concurrent chemotherapy. Improving outcomes in stage III NSCLC may involve some form of hypofractionation in the context of systemic concurrent therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future

    PubMed Central

    Chan, Bryan A.

    2015-01-01

    In recent years, there has been a major paradigm shift in the management of non-small cell lung cancer (NSCLC). NSCLC should now be further sub-classified by histology and driver mutation if one is known or present. Translational research advances now allow such mutations to be inhibited by either receptor monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKI). Whilst empirical chemotherapy with a platinum-doublet remains the gold standard for advanced NSCLC without a known driver mutation, targeted therapy is pushing the boundary to significantly improve patient outcomes and quality of life. In this review, we will examine the major subtypes of oncogenic drivers behind NSCLC as well as the development of targeted agents available to treat them both now and in the foreseeable future. PMID:25806345

  19. Alectinib for ALK-positive non-small-cell lung cancer.

    PubMed

    Rossi, Antonio

    2016-08-01

    Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5% of advanced non-small-cell lung cancer (NSCLC) patients. Despite the initial response, after a median of 1-2 years, ALK-positive patients developed an acquired resistance to the ALK-inhibitor crizotinib. Among the most promising second-generation ALK-inhibitors, alectinib is being investigated in crizotinib-naïve and -resistant ALK-positive NSCLC patients. The current state-of-the-art of ALK-inhibitors treatment, and in particular the role of alectinib in this setting, is reviewed and discussed. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken. Expert commentary: Alectinib reports promising results with a good safety profile, becoming a potentially very important option for ALK-translocated NSCLC patients. The preliminary results from the J-ALEX phase III randomized trial performed in ALK-rearranged NSCLC Japanese patients showed a better activity and tolerability of alectinib versus crizotinib.

  20. Imprecision in the Era of Precision Medicine in Non-Small Cell Lung Cancer

    PubMed Central

    Sundar, Raghav; Chénard-Poirier, Maxime; Collins, Dearbhaile Catherine; Yap, Timothy A.

    2017-01-01

    Over the past decade, major advances have been made in the management of advanced non-small cell lung cancer (NSCLC). There has been a particular focus on the identification and targeting of putative driver aberrations, which has propelled NSCLC to the forefront of precision medicine. Several novel molecularly targeted agents have now achieved regulatory approval, while many others are currently in late-phase clinical trial testing. These antitumor therapies have significantly impacted the clinical outcomes of advanced NSCLC and provided patients with much hope for the future. Despite this, multiple deficiencies still exist in our knowledge of this complex disease, and further research is urgently required to overcome these critical issues. This review traces the path undertaken by the different therapeutics assessed in NSCLC and the impact of precision medicine in this disease. We also discuss the areas of “imprecision” that still exist in NSCLC and the modern hypothesis-testing studies being conducted to address these key challenges. PMID:28443282

  1. The relationship between Glasgow Prognostic Score and serum tumor markers in patients with advanced non-small cell lung cancer.

    PubMed

    Jiang, Ai-Gui; Chen, Hong-Lin; Lu, Hui-Yu

    2015-05-10

    Glasgow Prognostic Score (GPS) has been reported as a powerful prognostic tool for patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to assess the relationship between GPS and prognosis related tumor markers in patients with advanced NSCLC. We included 138 advanced NSCLC patients and twenty healthy controls in the study. GPS was calculated by combined serum C-reactive protein (CRP) and albumin. Three serum tumor markers, which included cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), carcinoembryonic antigen (CEA) and tissue polypeptide specific antigen (TPS), were detected by enzyme-linked immunosorbent assay (ELISA). GPS and tumor markers were all assessed before chemotherapy. All patients received at least 2 courses of cisplatin-based chemotherapy. After that, 2 to 5 years follow-up was conducted. Median levels of CYFRA21-1 were 1.5 ng/ml (0.1-3.1 ng/ml) in healthy controls, and 4.6 ng/ml (0.7-35.2 ng/ml) in GPS 0 advanced NSCLC, 11.2 ng/ml (0.4-89.2) ng/ml in GPS 1 advanced NSCLC, and 15.7 ng/ml (2.9-134.6 ng/ml) in GPS 2 advanced NSCLC, respectively. Median levels of CYFRA21-1 were higher in NSCLC patients than in healthy controls, and CYFRA21-1 increased gradually according to GPS category in NSCLC patients (P< 0.05). Similar results were found for median levels of CEA and TPS in healthy controls and NSCLC patients (P < 0.05). In NSCLC patients, positive correlations were found between CYFRA21-1 and GPS, CEA and GPS, TPS and GPS. The Spearman's rank correlation coefficient were 0.67 (P < 0.05), 0.61 (P < 0.05) and 0.55 (P < 0.05), respectively. Survival analyses showed GPS was an independent prognostic factor for advanced NSCLC. CYFRA21-1(>3.3 ng/ml) and TPS (>80 U/l) were related with the prognosis of advanced NSCLC by univariate analyses, but multivariate analyses showed CYFRA21-1, TPS and CEA were not the independent prognostic factors for advanced NSCLC. Our results showed GPS were positive correlated with CYFRA21

  2. Prioritizing molecular markers to test for in the initial workup of advanced non-small cell lung cancer: wants versus needs.

    PubMed

    West, Howard

    2017-09-01

    The current standard of care for molecular marker testing in patients with advanced non-small cell lung cancer (NSCLC) has been evolving over several years and is a product of the quality of the evidence supporting a targeted therapy for a specific molecular marker, the pre-test probability of that marker in the population, and the magnitude of benefit seen with that treatment. Among the markers that have one or more matched targeted therapies, only a few are in the subset for which they should be considered as most clearly worthy of prioritizing to detect in the first line setting in order to have them supplant other first line alternatives, and in only a subset of patients, as defined currently by NSCLC histology. Specifically, this currently includes testing for an activating epidermal growth factor receptor ( EGFR ) mutation or an anaplastic lymphoma kinase ( ALK ) or ROS1 rearrangement. This article reviews the history and data supporting the prioritization of these markers in patients with non-squamous NSCLC, a histologically selected population in whom the probability of these markers combined with the anticipated efficacy of targeted therapies against them is high enough to favor these treatments in the first line setting. In reviewing the evidence supporting this very limited core subset of most valuable molecular markers to detect in the initial workup of such patients, we can also see the criteria by which other actionable markers need to reach in order to be widely recognized as reliably valuable enough to warrant prioritization to detect in the initial workup of advanced NSCLC as well.

  3. Pemetrexed combined with paclitaxel in patients with advanced or metastatic non-small-cell lung cancer: a phase I-II trial.

    PubMed

    Stathopoulos, George P; Dimitroulis, John; Toubis, Michael; Katis, Costas; Karaindros, Dimitris; Stathopoulos, John; Koutandos, John

    2007-07-01

    Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

  4. The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

    PubMed

    Papadimitrakopoulou, Vassiliki; Lee, J Jack; Wistuba, Ignacio I; Tsao, Anne S; Fossella, Frank V; Kalhor, Neda; Gupta, Sanjay; Byers, Lauren Averett; Izzo, Julie G; Gettinger, Scott N; Goldberg, Sarah B; Tang, Ximing; Miller, Vincent A; Skoulidis, Ferdinandos; Gibbons, Don L; Shen, Li; Wei, Caimiao; Diao, Lixia; Peng, S Andrew; Wang, Jing; Tam, Alda L; Coombes, Kevin R; Koo, Ja Seok; Mauro, David J; Rubin, Eric H; Heymach, John V; Hong, Waun Ki; Herbst, Roy S

    2016-08-01

    By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved

  5. Impact of a comprehensive geriatric assessment to manage elderly patients with locally advanced non-small-cell lung cancers: An open phase II study using concurrent cisplatin-oral vinorelbine and radiotherapy (GFPC 08-06).

    PubMed

    Locher, Chrystèle; Pourel, Nicolas; Le Caer, Hervé; Berard, Henri; Auliac, Jean-Bernard; Monnet, Isabelle; Descourt, Renaud; Vergnenègre, Alain; Lafay, Isabelle Martel; Greillier, Laurent; Chouaïd, Christos

    2018-07-01

    Few data have been published on the optimal management of elderly patients with locally advanced non-small-cell lung cancers (La-NSCLC). This prospective, multicenter, phase II study was undertaken to evaluate the ability of a comprehensive geriatric assessment (CGA) to select the elderly La-NSCLC patients who potentially may benefit from concurrent radio-chemotherapy. The main inclusion criteria were: La-NSCLC, >70 years old, at least one measurable target, ECOG performance status (PS) 0/1 and normal CGA. Weekly cisplatin (30 mg/m 2 ) and oral vinorelbine (30 mg/m 2 ) were combined with standard thoracic radiotherapy (66 Gy, 33 fractions) for 6.5 weeks. The primary evaluation criterion was <15% clinically relevant grade >2 toxicity. Secondary criteria were response rates, overall survival (OS) and progression-free survival (PFS). Among the 49 patients screened, 40 were included: 87.5% men, median age: 75.1 (70-84) years, 67.5% with PS 0, 52.5% squamous cell carcinomas. The full concurrent regimen was administrated in 77.5% of the cases (chemotherapy: 85%, radiotherapy: 90%); 22.5% of the patients experienced toxicity grade >2 (with three treatment-imputed deaths), 15% when restricted to clinically relevant >2 grade toxicities. One (2.6%) patient achieved a complete response, 53.8% had partial responses and 35.9% stable disease. Median PFS was 15 (95%CI: 8,7-35,2) months, OS 21.8 (95%CI: 16-NR) months and 1-, 2- and 4-year survival rates were 77.5%, 45% and 34.8%. CGA was able to select fit elderly patients with La-NSCLCs eligible for concurrent chemoradiotherapy with a satisfactory risk/benefit ratio. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Individualized Radical Radiotherapy of Non-Small-Cell Lung Cancer Based on Normal Tissue Dose Constraints: A Feasibility Study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Baardwijk, Angela van; Bosmans, Geert; Boersma, Liesbeth

    2008-08-01

    Purpose: Local recurrence is a major problem after (chemo-)radiation for non-small-cell lung cancer. We hypothesized that for each individual patient, the highest therapeutic ratio could be achieved by increasing total tumor dose (TTD) to the limits of normal tissues, delivered within 5 weeks. We report first results of a prospective feasibility trial. Methods and Materials: Twenty-eight patients with medically inoperable or locally advanced non-small-cell lung cancer, World Health Organization performance score of 0-1, and reasonable lung function (forced expiratory volume in 1 second > 50%) were analyzed. All patients underwent irradiation using an individualized prescribed TTD based on normal tissuemore » dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8-Gy fractions twice daily. No concurrent chemoradiation was administered. Toxicity was scored using the Common Terminology Criteria for Adverse Events criteria. An {sup 18}F-fluoro-2-deoxy-glucose-positron emission tomography-computed tomography scan was performed to evaluate (metabolic) response 3 months after treatment. Results: Mean delivered dose was 63.0 {+-} 9.8 Gy. The TTD was most often limited by the mean lung dose (32.1%) or spinal cord (28.6%). Acute toxicity generally was mild; only 1 patient experienced Grade 3 cough and 1 patient experienced Grade 3 dysphagia. One patient (3.6%) died of pneumonitis. For late toxicity, 2 patients (7.7%) had Grade 3 cough or dyspnea; none had severe dysphagia. Complete metabolic response was obtained in 44% (11 of 26 patients). With a median follow-up of 13 months, median overall survival was 19.6 months, with a 1-year survival rate of 57.1%. Conclusions: Individualized maximal tolerable dose irradiation based on normal tissue dose constraints is feasible, and initial results are promising.« less

  7. LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma.

    PubMed

    Strazisar, Mojca; Mlakar, Vid; Glavac, Damjan

    2009-06-01

    LATS2 is a new member of the LATS tumour suppressor family. The human LATS2 gene is located at chromosome 13q11-12, a hot spot (67%) for loss of heterozygosity (LOH) in non-small cell lung cancer (NSCLC). We screened 129 non-small cell lung cancer samples and 13 lung cancer cell lines, initially for mutations in the LATS2 gene and subsequently for mutations in P53 and K-RAS genes. Either polymorphisms or mutations were identified in over 50 percent of analysed tumours. A novel missense mutation, S1073R, and a large deletion of 8 amino acids in the PAPA-repeat region were detected in 9 and 2 NSCLC tumours, respectively. Those mutations were not identified in the 13 lung cancer cell lines. Mutations were tumour specific and were absent from adjacent normal tissue and healthy controls. Down-regulation of the LATS2 gene was observed in most NSCLC tumours but was not related to any mutation or polymorphism. Tumours with a LATS2 mutation often also harbour a P53 but not K-RAS gene mutation and were mostly in an advanced stage of development, with regional lymph node involvement.

  8. [Prospective randomized study of HMVP, MVP, and HVP regimens in treatment of advanced non-small cell lung cancer].

    PubMed

    Gao, Jian-Fei; Li, Chang-Sheng; Zhang, Bi-Cheng; Du, Guang-Zu; Zhang, Xin-Hua; Wang, Jun; Zhu, Yu-Ze; Ou, Wu-Ling; Yang, Bo

    2004-04-01

    Non-small cell lung cancer (NSCLC) is hyposensitive to the normal first and second-line chemotherapy regimens. Camptothecin derivative is becoming a hot point in the treatment of advanced NSCLC. The objective of this article was to evaluate the response, toxicity, and survival time of HMVP, MVP, and HVP regimens (detail in below) in the treatment of advanced NSCLC. A total of 134 cases with advanced NSCLC was randomized into three groups: HMVP group [46 patients, hydroxycamptothecin (HCPT) 12 mg/m(2) from d1 to d5, mitomycin C (MMC) 6 mg/m(2) d1, vindesine (VDS) 2.5-3 mg/m(2) d1 and d8, cisplatin (DDP) 50 mg/m(2) d2 and d3], MVP group (44 patients, MMC, VDS and DDP were the same as HMVP group) and HVP group (44 patients, HCPT, VDS, DDP were the same as HMVP group). The response rates were 39.54% (17/43), 35.57% (15/42), and 26.19% (11/42) in HMVP, MVP, and HVP groups, respectively; no significant difference was detected among the three groups (P >0.05). No significant difference was detected in the median time of remission, median survival time, and 1-, 2-year survival rates among the three groups. Moreover, no significant difference was detected in grade III-IV leukopenia, grade III-IV thrombocytopenia, grade III-IV nausea and vomiting and grade III-IV constipation among the three groups. The response rate of MVP regimen is slightly lower than that of HMVP regimen, but HMVP regimen do not show obvious superiority. It may increase toxicities such as leukopenia, nausea/vomiting, and constipation. The response rate of HVP regimen is slightly lower than that of MVP regimen.

  9. Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study

    PubMed Central

    Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

    2017-01-01

    Background Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. Patients and methods This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Results Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63–7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Conclusion Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects. PMID:29075129

  10. Role of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer

    PubMed Central

    Liu, Guangbo; Pei, Fen; Yang, Fengqing; Li, Lingxiao; Amin, Amit Dipak; Liu, Songnian; Buchan, J. Ross; Cho, William C.

    2017-01-01

    Non-small-cell lung cancer (NSCLC) constitutes 85% of all lung cancers, and is the leading cause of cancer-related death worldwide. The poor prognosis and resistance to both radiation and chemotherapy warrant further investigation into the molecular mechanisms of NSCLC and the development of new, more efficacious therapeutics. The processes of autophagy and apoptosis, which induce degradation of proteins and organelles or cell death upon cellular stress, are crucial in the pathophysiology of NSCLC. The close interplay between autophagy and apoptosis through shared signaling pathways complicates our understanding of how NSCLC pathophysiology is regulated. The apoptotic effect of autophagy is controversial as both inhibitory and stimulatory effects have been reported in NSCLC. In addition, crosstalk of proteins regulating both autophagy and apoptosis exists. Here, we review the recent advances of the relationship between autophagy and apoptosis in NSCLC, aiming to provide few insights into the discovery of novel pathogenic factors and the development of new cancer therapeutics. PMID:28208579

  11. The emerging role of histology in the choice of first-line treatment of advanced non-small cell lung cancer: implication in the clinical decision-making.

    PubMed

    Rossi, Antonio; Maione, Paolo; Bareschino, Maria Anna; Schettino, Clorinda; Sacco, Paola Claudia; Ferrara, Marianna Luciana; Castaldo, Vincenzo; Gridelli, Cesare

    2010-01-01

    Lung cancer is the leading cause of cancer mortality worldwide. Non-small cell lung cancer (NSCLC), accounting for about 85% of all lung cancers, includes squamous carcinoma, adenocarcinoma and undifferentiated large cell carcinoma. The majority of patients have advanced disease at diagnosis, and medical treatment is the cornerstone of management. Several randomized trials comparing third-generation platinum-based doublets concluded that all such combinations are comparable in their clinical efficacy, failing to document a difference based on histology. However, recent evidences, arising from the availability of pemetrexed, have shown that histology represents an important variable in the decision making. The major progresses in the understanding cancer biology and mechanism of oncogenesis have allowed the development of several potential molecular targets for cancer treatment such as vascular growth factor and its receptors and epidermal growth factor receptor. Targeted drugs seem to be safer or more effective in a specific histology subtype. All of these data have led to choose the optimal first-line treatment of advanced NSCLC based on histologic diagnosis. However, this scenario raises a diagnostic issue: a specific diagnosis of NSCLC histologic subtype is mandatory. This review will discuss these new evidences in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.

  12. A teaching intervention in a contouring dummy run improved target volume delineation in locally advanced non-small cell lung cancer: Reducing the interobserver variability in multicentre clinical studies.

    PubMed

    Schimek-Jasch, Tanja; Troost, Esther G C; Rücker, Gerta; Prokic, Vesna; Avlar, Melanie; Duncker-Rohr, Viola; Mix, Michael; Doll, Christian; Grosu, Anca-Ligia; Nestle, Ursula

    2015-06-01

    Interobserver variability in the definition of target volumes (TVs) is a well-known confounding factor in (multicentre) clinical studies employing radiotherapy. Therefore, detailed contouring guidelines are provided in the prospective randomised multicentre PET-Plan (NCT00697333) clinical trial protocol. This trial compares strictly FDG-PET-based TV delineation with conventional TV delineation in patients with locally advanced non-small cell lung cancer (NSCLC). Despite detailed contouring guidelines, their interpretation by different radiation oncologists can vary considerably, leading to undesirable discrepancies in TV delineation. Considering this, as part of the PET-Plan study quality assurance (QA), a contouring dummy run (DR) consisting of two phases was performed to analyse the interobserver variability before and after teaching. In the first phase of the DR (DR1), radiation oncologists from 14 study centres were asked to delineate TVs as defined by the study protocol (gross TV, GTV; and two clinical TVs, CTV-A and CTV-B) in a test patient. A teaching session was held at a study group meeting, including a discussion of the results focussing on discordances in comparison to the per-protocol solution. Subsequently, the second phase of the DR (DR2) was performed in order to evaluate the impact of teaching. Teaching after DR1 resulted in a reduction of absolute TVs in DR2, as well as in better concordance of TVs. The Overall Kappa(κ) indices increased from 0.63 to 0.71 (GTV), 0.60 to 0.65 (CTV-A) and from 0.59 to 0.63 (CTV-B), demonstrating improvements in overall interobserver agreement. Contouring DRs and study group meetings as part of QA in multicentre clinical trials help to identify misinterpretations of per-protocol TV delineation. Teaching the correct interpretation of protocol contouring guidelines leads to a reduction in interobserver variability and to more consistent contouring, which should consequently improve the validity of the overall study

  13. Weight Gain in Advanced Non-Small-Cell Lung Cancer Patients During Treatment With Split-Course Concurrent Chemoradiotherapy Is Associated With Superior Survival

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gielda, Benjamin T., E-mail: Benjamin_gielda@rush.edu; Mehta, Par; Khan, Atif

    Background: Preoperative concurrent chemoradiotherapy (CRT) is an accepted treatment for potentially resectable, locally advanced, non-small-cell lung cancer (NSCLC). We reviewed a decade of single institution experience with preoperative split-course CRT followed by surgical resection to evaluate survival and identify factors that may be helpful in predicting outcome. Methods and Materials: All patients treated with preoperative split-course CRT and resection at Rush University Medical Center (RUMC) between January 1999 and December 2008 were retrospectively analyzed. Endpoints included overall survival (OS), progression-free survival (PFS), local-regional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS). Patient and treatment related variables were assessed for correlationmore » with outcomes. Results: A total of 54 patients were analyzed, 76% Stage IIIA, 18% Stage IIIB, and 6% oligometastatic. The pathologic complete response (pCR) rate was 31.5%, and the absence of nodal metastases (pN0) was 64.8%. Median OS and 3-year actuarial survival were 44.6 months and 50%, respectively. Univariate analysis revealed initial stage (p < 0.01) and percent weight change during CRT (p < 0.01) significantly correlated with PFS/OS. On multivariate analysis initial stage (HR, 2.4; 95% CI, 1.18-4.90; p = 0.02) and percent weight change (HR, 0.79; 95% CI, 0.67-0.93; p < 0.01) maintained significance with respect to OS. There were no cases of Grade 3+ esophagitis, and there was a single case of Grade 3 febrile neutropenia. Conclusions: The strong correlation between weight change during CRT and OS/PFS suggests that this clinical parameter may be useful as a complementary source of predictive information in addition to accepted factors such as pathological response.« less

  14. Investigating the benefits of molecular profiling of advanced non-small cell lung cancer tumors to guide treatments.

    PubMed

    Alifrangis, Costi; Carter, Philip; Cereser, Biancastella; Chandrasinghe, Pramodh; Belluz, Lisa Del Bel; Lim, Eric; Moderau, Nina; Poyia, Fotini; Tabassum, Neha; Zhang, Hua; Krell, Jonathan; Stebbing, Justin

    2018-02-27

    In this study we utilized data on patient responses to guided treatments, and we evaluated their benefit for a non-small cell lung cancer cohort. The recommended therapies used were predicted using tumor molecular profiles that involved a range of biomarkers but primarily used immunohistochemistry markers. A dataset describing 91 lung non-small cell lung cancer patients was retrospectively split into two. The first group's drugs were consistent with a treatment plan whereby all drugs received agreed with their tumor's molecular profile. The second group each received one or more drug that was expected to lack benefit. We found that there was no significant difference in overall survival or mortality between the two groups. Patients whose treatments were predicted to be of benefit survived for an average of 402 days, compared to 382 days for those that did not ( P = 0.7934). In the matched treatment group, 48% of patients were deceased by the time monitoring had finished compared to 53% in the unmatched group ( P = 0.6094). The immunohistochemistry biomarker for the ERCC1 receptor was found to be a marker that could be used to predict future survival; ERCC1 loss was found to be predictive of poor survival.

  15. Propensity Score–Matched Analysis of Comprehensive Local Therapy for Oligometastatic Non-Small Cell Lung Cancer That Did Not Progress After Front-Line Chemotherapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sheu, Tommy; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Heymach, John V.

    2014-11-15

    Purpose: To retrospectively analyze factors influencing survival in patients with non-small cell lung cancer presenting with ≤3 synchronous metastatic lesions. Methods and Materials: We identified 90 patients presenting between 1998 and 2012 with non-small cell lung cancer and ≤3 metastatic lesions who had received at least 2 cycles of chemotherapy followed by surgery or radiation therapy before disease progression. The median number of chemotherapy cycles before comprehensive local therapy (CLT) (including concurrent chemoradiation as first-line therapy) was 6. Factors potentially affecting overall (OS) or progression-free survival (PFS) were evaluated with Cox proportional hazards regression. Propensity score matching was used to assessmore » the efficacy of CLT. Results: Median follow-up time was 46.6 months. Benefits in OS (27.1 vs 13.1 months) and PFS (11.3 months vs 8.0 months) were found with CLT, and the differences were statistically significant when propensity score matching was used (P ≤ .01). On adjusted analysis, CLT had a statistically significant benefit in terms of OS (hazard ratio, 0.37; 95% confidence interval, 0.20-0.70; P ≤ .01) but not PFS (P=.10). In an adjusted subgroup analysis of patients receiving CLT, favorable performance status (hazard ratio, 0.43; 95% confidence interval, 0.22-0.84; P=.01) was found to predict improved OS. Conclusions: Comprehensive local therapy was associated with improved OS in an adjusted analysis and seemed to favorably influence OS and PFS when factors such as N status, number of metastatic lesions, and disease sites were controlled for with propensity score–matched analysis. Patients with favorable performance status had improved outcomes with CLT. Ultimately, prospective, randomized trials are needed to provide definitive evidence as to the optimal treatment approach for this patient population.« less

  16. Propensity score-matched analysis of comprehensive local therapy for oligometastatic non-small cell lung cancer that did not progress after front-line chemotherapy.

    PubMed

    Sheu, Tommy; Heymach, John V; Swisher, Stephen G; Rao, Ganesh; Weinberg, Jeffrey S; Mehran, Reza; McAleer, Mary Frances; Liao, Zhongxing; Aloia, Thomas A; Gomez, Daniel R

    2014-11-15

    To retrospectively analyze factors influencing survival in patients with non-small cell lung cancer presenting with ≤3 synchronous metastatic lesions. We identified 90 patients presenting between 1998 and 2012 with non-small cell lung cancer and ≤3 metastatic lesions who had received at least 2 cycles of chemotherapy followed by surgery or radiation therapy before disease progression. The median number of chemotherapy cycles before comprehensive local therapy (CLT) (including concurrent chemoradiation as first-line therapy) was 6. Factors potentially affecting overall (OS) or progression-free survival (PFS) were evaluated with Cox proportional hazards regression. Propensity score matching was used to assess the efficacy of CLT. Median follow-up time was 46.6 months. Benefits in OS (27.1 vs 13.1 months) and PFS (11.3 months vs 8.0 months) were found with CLT, and the differences were statistically significant when propensity score matching was used (P ≤ .01). On adjusted analysis, CLT had a statistically significant benefit in terms of OS (hazard ratio, 0.37; 95% confidence interval, 0.20-0.70; P ≤ .01) but not PFS (P=.10). In an adjusted subgroup analysis of patients receiving CLT, favorable performance status (hazard ratio, 0.43; 95% confidence interval, 0.22-0.84; P=.01) was found to predict improved OS. Comprehensive local therapy was associated with improved OS in an adjusted analysis and seemed to favorably influence OS and PFS when factors such as N status, number of metastatic lesions, and disease sites were controlled for with propensity score-matched analysis. Patients with favorable performance status had improved outcomes with CLT. Ultimately, prospective, randomized trials are needed to provide definitive evidence as to the optimal treatment approach for this patient population. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non-Small Cell Lung Cancer.

    PubMed

    Gettinger, Scott N; Wurtz, Anna; Goldberg, Sarah B; Rimm, David; Schalper, Kurt; Kaech, Susan; Kavathas, Paula; Chiang, Anne; Lilenbaum, Rogerio; Zelterman, Daniel; Politi, Katerina; Herbst, Roy S

    2018-06-01

    With expanding indications for programmed death 1 (PD-1) axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria. Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53-0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77-1). Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression. Copyright © 2018

  18. Treating patients with ALK-positive non-small cell lung cancer: latest evidence and management strategy

    PubMed Central

    Liao, Bin-Chi; Shih, Jin-Yuan; Yang, James Chih-Hsin

    2015-01-01

    Rearrangements in anaplastic lymphoma kinase (ALK) gene and echinoderm microtubule-associated protein-like 4 (EML4) gene were first described in a small portion of patients with non-small cell lung cancer (NSCLC) in 2007. Fluorescence in situ hybridization is used as the diagnostic test for detecting an EML4–ALK rearrangement. Crizotinib, an ALK inhibitor, is effective in treating advanced ALK-positive NSCLC, and the US Food and Drug Administration approved it for treating ALK-positive NSCLC in 2011. Several mechanisms of acquired resistance to crizotinib have recently been reported. Second-generation ALK inhibitors were designed to overcome these resistance mechanisms. Two of them, ceritinib and alectinib, were approved in 2014 for advanced ALK-positive NSCLC in the US and Japan, respectively. Heat shock protein 90 (Hsp90) inhibitors also showed activity against ALK-positive NSCLC. Here we review the recent development of crizotinib, ceritinib, alectinib and other second-generation ALK inhibitors as well as Hsp90 inhibitors. We also discuss management strategies for advanced ALK-positive NSCLC. PMID:26327925

  19. Reduced survival in patients with early-stage non-small-cell lung cancer is associated with high pleural endothelial progenitor cell levels.

    PubMed

    Pirro, Matteo; Cagini, Lucio; Mannarino, Massimo R; Andolfi, Marco; Potenza, Rossella; Paciullo, Francesco; Bianconi, Vanessa; Frangione, Maria Rosaria; Bagaglia, Francesco; Puma, Francesco; Mannarino, Elmo

    2016-12-01

    Endothelial progenitor cells are capable of contributing to neovascularization in tumours. In patients with either malignant or transudative pleural effusion, we tested the presence of pleural endothelial progenitor cells. We also measured the number of endothelial progenitor cells in post-surgery pleural drainage of either patients with early non-small-cell lung cancer or control patients with benign lung disease undergoing pulmonary resection. The prospective influence of post-surgery pleural-drainage endothelial progenitor cells on cancer recurrence/survival was investigated. Pleural endothelial progenitor cell levels were quantified by fluorescence-activated cell sorting analysis in pleural effusion of 15 patients with late-stage non-small-cell lung cancer with pleural involvement and in 15 control patients with congestive heart failure. Also, pleural-drainage endothelial progenitor cells were measured in pleural-drainage fluid 48 h after surgery in 64 patients with early-stage non-small-cell lung cancer and 20 benign lung disease patients undergoing pulmonary resection. Cancer recurrence and survival was evaluated in patients with high pleural-drainage endothelial progenitor cell levels. The number of pleural endothelial progenitor cells was higher in non-small-cell lung cancer pleural effusion than in transudative pleural effusion. Also, pleural-drainage endothelial progenitor cell levels were higher in patients with non-small-cell lung cancer than in patients with benign lung disease undergoing pulmonary resection (P < 0.05). Non-small-cell lung cancer patients with high pleural-drainage endothelial progenitor cell levels had a significantly 4.9 higher rate of cancer recurrence/death than patients with lower pleural-drainage endothelial progenitor cell levels, irrespective of confounders. Endothelial progenitor cells are present in the pleural effusion and are higher in patients with late-stage non-small-cell lung cancer with pleural involvement than in

  20. Management of advanced non-small-cell lung cancer in elderly populations.

    PubMed

    Lilenbaum, Rogerio

    2003-11-01

    Elderly patients, defined as those >or= 70 years of age, represent approximately 40% of all patients diagnosed with non-small-cell lung cancer in the United States. Nonetheless, elderly patients have been underrepresented in national cooperative group trials, and many do not receive appropriate treatment. Whereas the benefit of systemic chemotherapy in younger patients is accepted by most clinicians, there remains a great deal of skepticism with respect to older patients, who are often labeled unfit for chemotherapy. More recent studies with a special focus on elderly patients demonstrate that these patients indeed benefit from chemotherapy. The landmark Elderly Lung Cancer Vinorelbine Italian Study Group trial and the Multicentre Italian Lung Cancer in the Elderly Study clarified the role of vinorelbine in the treatment of elderly patients. Retrospective and prospective subgroup analyses from selected North American trials suggested that elderly patients also benefit from platinum-based combinations. Whether elderly patients should be treated with single-agent versus combination chemotherapy is discussed in this review. The available data suggest that patients should be evaluated for chemotherapy based on their performance status and comorbidities rather than age alone. For elderly patients judged fit to receive combination chemotherapy, carboplatin-based regimens are a reasonable option. In elderly patients with less than optimal performance status or significant comorbid conditions, single-agent therapy may be more appropriate.

  1. Radiation Therapy, Chemotherapy, and Soy Isoflavones in Treating Patients With Stage IIIA-IIIB Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2017-05-23

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  2. Alectinib for advanced ALK-positive non-small-cell lung cancer.

    PubMed

    Ly, Ashley C; Olin, Jacqueline L; Smith, Morgan B

    2018-04-15

    The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosage and administration, and place in therapy of alectinib for treatment of patients with non-small-cell lung cancer (NSCLC) are reviewed. In patients with NSCLC driven by mutations of ALK , the gene coding for anaplastic lymphoma kinase (ALK), treatment with the ALK inhibitor crizotinib has been found to provide median progression-free survival (PFS) of 10.9 months; however, therapeutic failures and tumor progression to brain metastases are common with crizotinib use, prompting research to find more potent and tolerable ALK inhibitors that target major oncogenic drivers of NSCLC. Alectinib is a next-generation ALK inhibitor initially approved by the Food and Drug Administration for use in patients with metastatic ALK -positive NSCLC who are intolerant of or have disease progression during crizotinib therapy. In clinical trials, alectinib was found effective for delaying disease progression and, more importantly, reducing brain metastases in patients with NSCLC who developed resistance or intolerance to previous crizotinib therapy. Published data from clinical trials indicate that the most common grade 1 and 2 adverse effects associated with alectinib use are fatigue, constipation, peripheral edema, and myalgia; the most common grade 3 or 4 reactions include increases in creatine phosphokinase, alanine aminotransferase, and aspartate aminotransferase levels. Alectinib appears to be effective and safe for use in patients with metastatic ALK -positive NSCLC, with demonstrated superiority over crizotinib in terms of PFS rates. Research to better define ALK inhibitor resistance mechanisms and alectinib's place in therapy is ongoing. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  3. Clinical pharmacokinetics, safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer.

    PubMed

    Liu, Dongyang; Zhang, Li; Wu, Yiwen; Jiang, Ji; Tan, Fenlai; Wang, Yingxiang; Liu, Yong; Hu, Pei

    2015-09-01

    To receive pharmacokinetics, safety, and anti-tumor activity of icotinib, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in patients with advanced non-small-cell lung cancer (NSCLC). Patients (n=40) with advanced NSCLC were enrolled to receive escalating doses of icotinib, which was administrated on Day 1 followed by 28-day continuous dosing starting from Day 4. Four dosing regimens, 100mg b.i.d., 150 mg b.i.d., 125 mg t.i.d., and 200mg b.i.d. were studied. Pharmacokinetics (PK), safety, and efficacy of icotinib were evaluated. Icotinib was well tolerated in Chinese patients with refractory NSCLC. No toxicity with >3 grades were reported in more than 2 patients under any dose levels. One complete response (3%) and 9 partial responses (23%) were received. Total disease control rate could reach at 73% and median progress-free survival (range) was 154 (17-462) days. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. Mean t1/2β was within 5.31-8.07 h. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. Icotinib with up to 400 mg/day exhibited good tolerance and preliminary antitumor activity in Chinese NSCLC patients. Pharmacokinetics of icotinib and 5 major metabolites were fully investigated in NSCLC patients. Optimized biologic dose (OBD) was finally recommended to be 125 mg t.i.d. for the later clinical study. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Alectinib for treatment of ALK-positive non-small-cell lung cancer.

    PubMed

    Avrillon, Virginie; Pérol, Maurice

    2017-02-01

    Alectinib is a highly selective second-generation ALK inhibitor that is active against most crizotinib ALK resistance mutations, with a good penetration in CNS and a good safety profile. Thanks to the positive results of Phase II trials, alectinib was approved in Japan and by the US FDA for ALK-positive non-small-cell lung cancer (NSCLC) patients pretreated with crizotinib. Recently, the Phase III J-ALEX study demonstrated superiority of alectinib over crizotinib in crizotinib naive ALK-positive NSCLC, with an impressive improvement of progression-free survival. From the results and those expected of Phase III ALEX study, alectinib might become the frontline treatment of ALK-positive NSCLC. This article summarizes the therapeutic options in ALK-positive advanced NSCLC, and the chemical, pharmacodynamics, pharmacokinetics, metabolism and clinical efficacy of alectinib.

  5. Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer

    PubMed Central

    Blackhall, Fiona; Ross Camidge, D; Shaw, Alice T; Soria, Jean-Charles; Solomon, Benjamin J; Mok, Tony; Hirsh, Vera; Jänne, Pasi A; Shi, Yuankai; Yang, Pan-Chyr; Pas, Tommaso De; Hida, Toyoaki; Carpeño, Javier De Castro; Lanzalone, Silvana; Polli, Anna; Iyer, Shrividya; Reisman, Arlene; Wilner, Keith D; Kim, Dong-Wan

    2017-01-01

    Purpose Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. Patients and methods PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients’ tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13. Results 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life. Conclusion The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066

  6. Sample types applied for molecular diagnosis of therapeutic management of advanced non-small cell lung cancer in the precision medicine.

    PubMed

    Han, Yanxi; Li, Jinming

    2017-10-26

    In this era of precision medicine, molecular biology is becoming increasingly significant for the diagnosis and therapeutic management of non-small cell lung cancer. The specimen as the primary element of the whole testing flow is particularly important for maintaining the accuracy of gene alteration testing. Presently, the main sample types applied in routine diagnosis are tissue and cytology biopsies. Liquid biopsies are considered as the most promising alternatives when tissue and cytology samples are not available. Each sample type possesses its own strengths and weaknesses, pertaining to the disparity of sampling, preparation and preservation procedures, the heterogeneity of inter- or intratumors, the tumor cellularity (percentage and number of tumor cells) of specimens, etc., and none of them can individually be a "one size to fit all". Therefore, in this review, we summarized the strengths and weaknesses of different sample types that are widely used in clinical practice, offered solutions to reduce the negative impact of the samples and proposed an optimized strategy for choice of samples during the entire diagnostic course. We hope to provide valuable information to laboratories for choosing optimal clinical specimens to achieve comprehensive functional genomic landscapes and formulate individually tailored treatment plans for NSCLC patients that are in advanced stages.

  7. Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients With Recurrent Stage IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2018-06-28

    c-MET Gene Amplification; MET Exon 14 Mutation; Metastatic Non-Squamous Non-Small Cell Lung Carcinoma; Recurrent Non-Squamous Non-Small Cell Lung Carcinoma; RET/PTC Rearrangement; ROS1 Gene Rearrangement; Stage IV Non-Small Cell Lung Cancer AJCC v7

  8. Multiplex picoliter-droplet digital PCR for quantitative assessment of EGFR mutations in circulating cell-free DNA derived from advanced non-small cell lung cancer patients

    PubMed Central

    Yu, Qian; Huang, Fei; Zhang, Meilin; Ji, Haiying; Wu, Shenchao; Zhao, Ying; Zhang, Chunyan; Wu, Jiong; Wang, Beili; Pan, Baisheng; Zhang, Xin; Guo, Wei

    2017-01-01

    To explore the possible diagnostic value of liquid biopsy, two multiplex panels using picoliter-droplet digital polymerase chain reaction (ddPCR) were established to quantitatively assess the epidermal growth factor receptor (EGFR) mutations in cell-free DNA (cfDNA) extracted from the plasma of advanced non-small cell lung cancer (NSCLC) patients. Plasma samples derived from 22 patients with stage IIIB/IV NSCLC harboring EGFR mutations in matched tumor tissues confirmed by amplification refractory mutation system (ARMS) analysis were subjected to two multiplex ddPCR panels to assess the abundance of tyrosine kinase inhibitor (TKI) -sensitive (19DEL, L858R) and TKI-resistant (T790 M) mutations. Fluctuations in EGFR mutant abundance were monitored by either of the multiplex ddPCR panels for three patients undergoing EGFR-TKI treatment, with serial plasma sample collections over 2 months. The multiplex ddPCR panels applied to plasma cfDNA from advanced NSCLC patients achieved a total concordance rate of 80% with the EGFR mutation profiles obtained by ARMS from matched biopsy tumor specimens (90% for 19DEL, 95% for L858R, 95% for T790M, respectively) and revealed additional mutant alleles in two subjects. The respective sensitivity and specificity were 90.9 and 88.9% for 19DEL, 87.5 and 100% for L858R, 100 and 93.8% for T790M. The fluctuations of EGFR mutant abundance in serial plasma cfDNA were in accordance with the changes in tumor size as assessed by imaging scans. The authors demonstrated the utility of multiplex ddPCR panels with ultra-sensitivity for quantitative analysis of EGFR mutations in plasma cfDNA and obtained promising usefulness in EGFR-TKI decision-making for advanced NSCLC patients. PMID:29067441

  9. [Advances in the Research of the Regulation of Chinese Traditional Medicine Monomer and Its Derivatives on Autophagy in Non-small Cell Lung Cancer].

    PubMed

    Xiang, Meiyi; Li, Ruilei; Zhang, Zhiwei; Song, Xin

    2017-03-20

    The high morbidity and mortality of non-small cell lung cancer (NSCLC) did influence the quality of life of tumor patients world-wide. There is an urgent need to develop new therapies that have high anti-tumor activity and low toxicity side effects. It is widely accepted that autophagy can play diverse roles in carcinogenesis, such as induces pro-death of lung cancer cells or helps the escape from cell death, making it become a proper anticancer target. It's believed that various monomers of Chinese traditional medicine closely correlates to anti-NSCLC activities, and that even could affect the acquired multiple drug resistance (MDR). Furthermore, autophagy might be the underling mechanisms which could play a role as the candidate targets of natural active compounds. Recent studies of terpenoids, alkaloid, dietary polyphenols, saponins and other active ingredients that extracted from a large variety of herbs suggest that different monomer compounds could either regulate the activity of pro-death autophagy or influence the level of protective autophagy of NSCLC cells, thus changing their drug sensitivity and cell viability. This paper aims to give a systemic description of the latest advances about natural compounds and their derivatives that involved in tumorigenesis of NSCLC via inducing the autophagy.

  10. Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases.

    PubMed

    Lo Russo, Giuseppe; Imbimbo, Martina; Corrao, Giulia; Proto, Claudia; Signorelli, Diego; Vitali, Milena; Ganzinelli, Monica; Botta, Laura; Zilembo, Nicoletta; de Braud, Filippo; Garassino, Marina Chiara

    2017-08-29

    The discovery of EGFR mutations and EML4-ALK gene rearrangements has radically changed the therapeutic scenario for patients with advanced non-small cell lung cancer. ALK and EGFR tyrosine-kinase inhibitors showed better activity and efficacy than standard chemotherapy in the first and second line treatment settings, leading to a clear advantage in overall survival of advanced non-small cell lung cancer patients harboring these genetic alterations. Historically the coexistence of EGFR mutations and EML4-ALK rearrangements in the same tumor has been described as virtually impossible. Nevertheless many recent observations seem to show that it is not true in all cases. In this review we will discuss the available literature data regarding this rare group of patients in order to give some suggestions useful for their clinical management. Furthermore we report here two cases of concomitant presence of both alterations that will help us in the development of discussion.

  11. Genetic Association of Curative and Adverse Reactions to Tyrosine Kinase Inhibitors in Chinese advanced Non-Small Cell Lung Cancer patients

    PubMed Central

    Ruan, Yunfeng; Jiang, Jie; Guo, Liang; Li, Yan; Huang, Hailiang; Shen, Lu; Luan, Mengqi; Li, Mo; Du, Huihui; Ma, Cheng; He, Lin; Zhang, Xiaoqing; Qin, Shengying

    2016-01-01

    Epidermal growth factor receptor (EGFR) Tyrosine kinase inhibitor (TKI) is an effective targeted therapy for advanced non-small cell lung cancer (NSCLC) but also causes adverse drug reactions (ADRs) e.g., skin rash and diarrhea. SNPs in the EGFR signal pathway, drug metabolism/ transport pathways and miRNA might contribute to the interpersonal difference in ADRs but biomarkers for therapeutic responses and ADRs to TKIs in Chinese population are yet to be fully investigated. We recruited 226 Chinese advanced NSCLC patients who received TKIs erlotinib, gefitinib and icotinib hydrochloride and systematically studied the genetic factors associated with therapeutic responses and ADRs. Rs884225 (T > C) in EGFR 3′ UTR was significantly associated with lower risk of ADRs to erlotinib (p value = 0.0010, adjusted p value = 0.042). A multivariant interaction four-SNP model (rs884225 in EGFR 3′UTR, rs7787082 in ABCB1 intron, rs38845 in MET intron and rs3803300 in AKT1 5′UTR) was associated with ADRs in general and the more specific drug induced skin injury. The SNPs associated with both therapeutic responses and ADRs indicates they might share a common genetic basis. Our study provided potential biomarkers and clues for further research of biomarkers for therapeutic responses and ADRs in Chinese NSCLC patients. PMID:26988277

  12. Genetic characterization drives personalized therapy for early-stage non-small-cell lung cancer (NSCLC) patients and survivors with metachronous second primary tumor (MST): A case report.

    PubMed

    Ding, Xingchen; Wang, Linlin; Liu, Xijun; Sun, Xindong; Yu, Jinming; Meng, Xue

    2017-03-01

    The pathogenesis and progression of lung cancer is a complicated process in which many genes take part. But molecular gene testing is typically only performed in advanced-stage non-squamous non-small-cell lung cancer (NSCLC). The value of tyrosine kinase inhibitors (TKI) administration is not widely recognized with respect to early-stage NSCLC. Here, we present a case of a man, heavy smoker who initially presented with stage IA lung adenocarcinoma (LADC). Three years after a lung lobectomy, he was diagnosed with advanced lung squamous cell carcinoma (SCC), according to laboratory, imaging, and pathological examinations. The case initially had an early-stage LADC with an L858R epidermal growth factor receptor (EGFR) mutation. A subsequent advanced SCC bearing EGFR L858R/T790M mutations occurred 3 years after surgery. The comprehensive therapy we utilized, including surgical resection for the early-stage lesion and GP chemotherapy and local radiotherapy as the first line therapy along with gefitinib maintenance treatment for the advanced metachronous second primary tumors (MST). The synthetical therapy, have resulted in our patient with remaining alive and progression free for 4.5 years. This case suggests that changes in molecular pathology should be monitored closely throughout cancer progression to guide personalized therapy and improve prognosis. We further review administration of TKI to early-stage NSCLC and to the metachronous second primary tumors (MST) in survivors.

  13. PET-Adjusted Intensity Modulated Radiation Therapy and Combination Chemotherapy in Treating Patients With Stage II-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2018-05-24

    Metastatic Malignant Neoplasm in the Brain; Recurrent Non-Small Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  14. Glutathione S-transferase pi polymorphism contributes to the treatment outcomes of advanced non-small cell lung cancer patients in a Chinese population.

    PubMed

    Chen, J B; Wang, F; Wu, J J; Cai, M

    2016-07-25

    We analyzed the association between polymorphisms in three glutathione S-transferase genes (GSTP1, GSTM1, and GSTT1) and the treatment outcome for advanced non-small cell lung cancer (NSCLC). We recruited 284 NSCLC patients at advanced stage from Department of Radiotherapy in Peace Hospital Attached to Changzhi Medical College between May 2009 and May 2011, who had received cisplatin-based chemotherapy. The GSTP1, GSTM1, and GSTT1 genotyping for was determined using DNA pyrosequencing on an ABI Prism 3100 DNA analyzer. In the Cox proportional hazards model, the IIe/Val and Val/Val genotypes of GSTP1 were associated with lower risk of disease progression compared with the IIe/IIe genotype, and the HRs (95%CIs) were 0.37 (0.18-0.74) and 0.15 (0.06-0.35), respectively. The IIe/Val and Val/Val genotypes significantly decreased risk of death from all causes in patients with NSCLC, and the HRs (95%CIs) were 0.52 (0.29-0.92) and 0.37 (0.17- 0.79), respectively No significant association was observed between GSTM1 and GSTT1 polymorphisms and progression-free survival and overall survival in the NSCLC patients. In summary, we suggest that GSTP1 polymorphisms might influence the treatment outcome of advanced NSCLC patients, and our results could help improve individualized therapy.

  15. Docetaxel, Cisplatin, Pegfilgrastim, and Erlotinib Hydrochloride in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2018-02-01

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  16. Phase 2 Study of Concurrent Cetuximab Plus Definitive Thoracic Radiation Therapy Followed by Consolidation Docetaxel Plus Cetuximab in Poor Prognosis or Elderly Patients With Locally Advanced Non-Small Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dilling, Thomas J.; Extermann, Martine; Kim, Jongphil

    Background: Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab. Methods and Materials: Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-“dry” IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. Themore » primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). Results: From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board–approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications. Conclusions: Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause.« less

  17. The Impact of Local and Regional Disease Extent on Overall Survival in Patients With Advanced Stage IIIB/IV Non-Small Cell Lung Carcinoma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Higginson, Daniel S., E-mail: daniel.higginson@gmail.com; Chen, Ronald C.; Tracton, Gregg

    2012-11-01

    Purpose: Patients with advanced stage IIIB or stage IV non-small cell lung carcinoma are typically treated with initial platinum-based chemotherapy. A variety of factors (eg, performance status, gender, age, histology, weight loss, and smoking history) are generally accepted as predictors of overall survival. Because uncontrolled pulmonary disease constitutes a major cause of death in these patients, we hypothesized that clinical and radiographic factors related to intrathoracic disease at diagnosis may be prognostically significant in addition to conventional factors. The results have implications regarding the selection of patients for whom palliative thoracic radiation therapy may be of most benefit. Methods andmore » Materials: We conducted a pooled analysis of 189 patients enrolled at a single institution into 9 prospective phase II and III clinical trials involving first-line, platinum-based chemotherapy. Baseline clinical and radiographic characteristics before trial enrollment were analyzed as possible predictors for subsequent overall survival. To assess the relationship between anatomic location and volume of disease within the thorax and its effect on survival, the pre-enrollment computed tomography images were also analyzed by contouring central and peripheral intrapulmonary disease. Results: On univariate survival analysis, multiple pulmonary-related factors were significantly associated with worse overall survival, including pulmonary symptoms at presentation (P=.0046), total volume of intrathoracic disease (P=.0006), and evidence of obstruction of major bronchi or vessels on prechemotherapy computed tomography (P<.0001). When partitioned into central and peripheral volumes, central (P<.0001) but not peripheral (P=.74) disease was associated with worse survival. On multivariate analysis with known factors, pulmonary symptoms (hazard ratio, 1.46; P=.042), central disease volume (hazard ratio, 1.47; P=.042), and bronchial/vascular compression (hazard

  18. Phase II study of cisplatin/pemetrexed combined with bevacizumab followed by pemetrexed/bevacizumab maintenance therapy in patients with EGFR-wild advanced non-squamous non-small cell lung cancer.

    PubMed

    Fukushima, Toshirou; Wakatsuki, Yuuki; Kobayashi, Takashi; Sonehara, Kei; Tateishi, Kazunari; Yamamoto, Manabu; Masubuchi, Takeshi; Yoshiike, Fumiaki; Hirai, Kazuya; Hachiya, Tsutomu; Koizumi, Tomonobu

    2018-06-01

    This phase II study was performed to evaluate the efficacy and safety of cisplatin/pemetrexed combined with 15 mg/kg of bevacizumab followed by pemetrexed/bevacizumab maintenance therapy as first-line chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) limited to epidermal growth factor receptor (EGFR)-wild type. Fifty patients with advanced or metastatic EGFR-wild type NSCLC aged < 75 years old were enrolled in the study. The patients were treated with four cycles of cisplatin (75 mg/m 2 , day 1), pemetrexed (500 mg/m 2 , days 1), and bevacizumab (15 mg/kg, day 1), every 3 weeks, followed by pemetrexed plus bevacizumab maintenance until progression for achieving a response over stable disease after induction chemotherapy. Partial response and stable disease were observed in 35 (objective response rate: 70, 95% CI: 55.4-82.1%) and 9 patients, respectively, and 39 (78%) patients received pemetrexed plus bevacizumab maintenance therapy. Median progression-free survival and overall survival periods were 12.0 months (95% CI: 7.5-16.5 months) and 31.0 months (95% CI: 22.2-39.8 months), respectively. Grade 3 adverse events included neutropenia (14%), nausea (10%), anorexia (18%), and hypertension (8%). Coagulation disorder was observed in one patient, but all of these events were reversible and resulted in no treatment-related deaths. The combination of cisplatin/pemetrexed/bevacizumab followed by pemetrexed/bevacizumab maintenance therapy exhibited favorable efficacy and manageable toxicity profiles in patients with EGFR-wild type non-squamous NSCLC (UMIN-CTR number: UMIN000003645).

  19. Crizotinib for Advanced Non-Small Cell Lung Cancer

    Cancer.gov

    A summary of results from an international phase III clinical trial that compared crizotinib versus chemotherapy in previously treated patients with advanced lung cancer whose tumors have an EML4-ALK fusion gene.

  20. Methoxyamine, Pemetrexed Disodium, Cisplatin, and Radiation Therapy in Treating Patients With Stage IIIA-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2018-04-24

    Non-Squamous Non-Small Cell Lung Carcinoma; Stage III Large Cell Lung Carcinoma AJCC v7; Stage III Lung Adenocarcinoma AJCC v7; Stage III Non-Small Cell Lung Cancer AJCC v7; Stage IIIA Large Cell Lung Carcinoma AJCC v7; Stage IIIA Lung Adenocarcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Large Cell Lung Carcinoma AJCC v7; Stage IIIB Lung Adenocarcinoma AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IV Large Cell Lung Carcinoma AJCC v7; Stage IV Lung Adenocarcinoma AJCC v7; Stage IV Non-Small Cell Lung Cancer AJCC v7

  1. Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2018-04-30

    Adenosquamous Lung Carcinoma; Bronchioloalveolar Carcinoma; Large Cell Lung Carcinoma; Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer

  2. EGFR and KRAS mutation status in non-small-cell lung cancer occurring in HIV-infected patients.

    PubMed

    Créquit, Perrine; Ruppert, Anne-Marie; Rozensztajn, Nathalie; Gounant, Valérie; Vieira, T; Poulot, Virginie; Antoine, Martine; Chouaid, Christos; Wislez, Marie; Cadranel, Jacques; Lavole, Armelle

    2016-06-01

    Non-small-cell lung cancer (NSCLC) is the most common non-acquired immune deficiency syndrome-related malignancy responsible for death. Mutational status is crucial for choosing treatment of advanced NSCLC, yet no data is available on the frequency of epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) mutations and their impact on NSCLC in human immunodeficiency virus (HIV)-infected patients (HIV-NSCLC). All consecutive HIV-NSCLC patients diagnosed between June 1996 and August 2013 at two Paris university hospitals were reviewed, with tumor samples analyzed for EGFR and KRAS mutational status. Overall, 63 tumor samples were analyzed out of 73 HIV-NSCLC cases, with 63% of advanced NSCLC. There were 60 non-squamous and nine squamous cell carcinomas, with EGFR and KRAS mutations identified in two (3.3%) and seven (11.5%) tumors, respectively. The proportion of KRAS mutations was 29% if solely the more sensitive molecular techniques were considered. The two patients with advanced adenocarcinoma harboring EGFR mutations exhibited lasting partial response to EGFR-tyrosine kinase inhibitors. Overall survival for patients with advanced NSCLC were >30 months for those with EGFR mutations, <3 months for KRAS mutations (n=2), and the median was 9 months [4.1-14.3] for wild-type (n=34). In multivariate analysis, KRAS mutation and CD4<200 cells/μL were associated with poor prognosis (hazard ratio (HR): 24 [4.1-140.2], p=0.0004; HR: 3.1 [1.3-7.5], p=0.01, respectively). EGFR mutation must be investigated in HIV-NSCLC cases due to its predictive and prognostic impact, whereas KRAS mutation is of poor prognostic value. Clinicians should search for drugs dedicated to this target population. Copyright © 2016. Published by Elsevier Ireland Ltd.

  3. Combination Chemotherapy, Radiation Therapy, and Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-06-04

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  4. Discovery and Validation of Predictive Biomarkers of Survival for Non-small Cell Lung Cancer Patients Undergoing Radical Radiotherapy: Two Proteins With Predictive Value

    PubMed Central

    Walker, Michael J.; Zhou, Cong; Backen, Alison; Pernemalm, Maria; Williamson, Andrew J.K.; Priest, Lynsey J.C.; Koh, Pek; Faivre-Finn, Corinne; Blackhall, Fiona H.; Dive, Caroline; Whetton, Anthony D.

    2015-01-01

    Lung cancer is the most frequent cause of cancer-related death world-wide. Radiotherapy alone or in conjunction with chemotherapy is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Currently there is no predictive marker with clinical utility to guide treatment decisions in NSCLC patients undergoing radiotherapy. Identification of such markers would allow treatment options to be considered for more effective therapy. To enable the identification of appropriate protein biomarkers, plasma samples were collected from patients with non-small cell lung cancer before and during radiotherapy for longitudinal comparison following a protocol that carries sufficient power for effective discovery proteomics. Plasma samples from patients pre- and during radiotherapy who had survived > 18 mo were compared to the same time points from patients who survived < 14 mo using an 8 channel isobaric tagging tandem mass spectrometry discovery proteomics platform. Over 650 proteins were detected and relatively quantified. Proteins which showed a change during radiotherapy were selected for validation using an orthogonal antibody-based approach. Two of these proteins were verified in a separate patient cohort: values of CRP and LRG1 combined gave a highly significant indication of extended survival post one week of radiotherapy treatment. PMID:26425690

  5. Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.

    PubMed

    Kepka, Lucyna; Tyc-Szczepaniak, Dobromira; Bujko, Krzysztof

    2009-07-01

    To determine the efficacy of accelerated hypofractionated three-dimensional conformal radiotherapy (3D-CRT) with dose-per-fraction escalation for treatment of stage III non-small cell lung cancer (NSCLC). Between 2001 and 2007, 173 patients with stage III NSCLC were treated using accelerated 3D-CRT and the simultaneous boost technique. Initially, the total dose of 56.7 Gy (including 39.9 Gy to the elective area) was delivered over 4 weeks in fractions of 2.7 Gy (1.9 Gy to the elective area). The dose-per-fraction escalation study commenced after the outcomes of 70 patients had been evaluated. The dose per fraction was increased from 2.7 through 2.8 Gy (level 1 escalation) to 2.9 Gy (level 2 escalation); the total dose increased, respectively, from 56.7 Gy through 58.8 Gy to 60.9 Gy. The dose to the elective area and the overall treatment time remained unchanged. Fit patients received two to three courses of chemotherapy before radiotherapy. The 2- and 3-year overall survival rates were 32 and 19%, respectively (median survival = 17 months). Of the patients, 7% had grade III acute esophageal toxicity and 6% had grade III or greater late pulmonary toxicity. Two of the nine patients who received the level 2 escalation (60.9 Gy) died of pulmonary toxicity. The study was terminated at a dose of 58.8 Gy and this schema was adopted as the institutional policy for treatment of stage III NSCLC. Although dose escalation with accelerated hypofractionated 3D-CRT was limited, the results and toxicity profiles obtained using this technique are promising.

  6. Nivolumab and Plinabulin in Treating Patients With Stage IIIB-IV, Recurrent, or Metastatic Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2017-08-29

    ALK Gene Translocation; EGFR Activating Mutation; Recurrent Non-Small Cell Lung Carcinoma; ROS1 Gene Translocation; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IV Non-Small Cell Lung Cancer AJCC v7

  7. Management of Resistance to Crizotinib in Anaplastic Lymphoma Kinase-Positive Non-Small-cell Lung Cancer.

    PubMed

    Matikas, Alexios; Kentepozidis, Nikolaos; Georgoulias, Vassilis; Kotsakis, Athanasios

    2016-11-01

    During the past decade, the recognition of an ever-expanding list of driver oncogenic mutations in non-small-cell lung cancer has resulted in rapid therapeutic advances. Since the first description of the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement in 4% of cases of non-small-cell lung cancer in 2007, a highly potent and selective ALK inhibitor, crizotinib, was developed and approved in record time. However, it soon became apparent that although the responses can be dramatic and durable and primary intrinsic resistance to crizotinib is uncommon, the emergence of secondary resistance is inevitable. Efforts to elucidate the specific mechanisms that confer acquired resistance to crizotinib are underway. These have led to the recognition of the role of secondary resistance mutations, of ALK amplification, and of activation of bypass signaling, all of which contribute to resistance to crizotinib. Moreover, the rapid preclinical and clinical development of multiple second-generation ALK inhibitors that exhibit significant clinical activity against crizotinib-resistant disease has provided multiple options to treating physicians, with the ultimate goal the delivery of tailored medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. A large, single-center, real-world study of clinicopathological characteristics and treatment in advanced ALK-positive non-small-cell lung cancer.

    PubMed

    Chen, Gang; Chen, Xi; Zhang, Yaxiong; Yan, Fang; Fang, Wenfeng; Yang, Yunpeng; Hong, Shaodong; Miao, Siyu; Wu, Manli; Huang, Xiaodan; Luo, Youli; Zhou, Cong; Gong, Run; Huang, Yan; Zhou, Ningning; Zhao, Hongyun; Zhang, Li

    2017-05-01

    Crizotinib has achieved astonishing success in advanced non-small-cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. However, no real-world studies described the clinicopathological characteristics and treatment of such patients in China. Patients were consecutively collected from Sun Yat-sen University Cancer Center. Chi-square test was applied to explore the relationship between ALK fusion status and metastasis sites. Kaplan-Meier methods and multivariable analyses were used to estimate progression-free survival (PFS). A total of 291 advanced NSCLC patients (ALK (+), N = 97; both ALK & epidermal growth factor receptor (EGFR) (-), N = 194) were enrolled. The occurrence of brain metastasis in ALK-positive patients was significantly higher than double-negative ones both at baseline (26.5% vs. 16.5%, P = 0.038) and during treatment (25.8% vs. 11.9%, P = 0.003), but opposite for pleural effusion (6.2% vs. 26.9%, P < 0.001 at baseline; 3.1% vs. 10.3%, P = 0.031 during treatment). ALK-positive patients of 53.6% used crizotinib, whereas others only received chemotherapy (37.1%) or supportive care (9.3%). Usage of crizotinib prolonged PFS compared with chemotherapy in ALK-positive patients (median PFS 17.6 m vs. 4.8 m, P < 0.001). ALK-positive NSCLC had more brain metastasis and less pleural effusion than double-negative ones. Crizotinib showed better PFS than chemotherapy in advanced ALK-positive NSCLC at any line. However, half advanced ALK-positive patients never received crizotinib, which was grim and need improving. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  9. Three-state Potts model on non-local directed small-world lattices

    NASA Astrophysics Data System (ADS)

    Ferraz, Carlos Handrey Araujo; Lima, José Luiz Sousa

    2017-10-01

    In this paper, we study the non-local directed Small-World (NLDSW) disorder effects in the three-state Potts model as a form to capture the essential features shared by real complex systems where non-locality effects play a important role in the behavior of these systems. Using Monte Carlo techniques and finite-size scaling analysis, we estimate the infinite lattice critical temperatures and the leading critical exponents in this model. In particular, we investigate the first- to second-order phase transition crossover when NLDSW links are inserted. A cluster-flip algorithm was used to reduce the critical slowing down effect in our simulations. We find that for a NLDSW disorder densities p

  10. Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer.

    PubMed

    Tan, Fenlai; Shi, Yuankai; Wang, Yinxiang; Ding, Lieming; Yuan, Xiaobin; Sun, Yan

    2015-01-01

    Advanced non-small-cell lung cancer (NSCLC) is the main cause for cancer-related mortality. Treatments for advanced NSCLC are largely palliative and a benefit plateau appears to have reached with the platinum-based chemotherapy regimens. EGF receptor (EGFR) tyrosine kinase inhibitors gefitinib, erlotinib and afatinib came up with prolonged progression-free survival and improved quality of life, especially in EGFR-mutated patients. Icotinib is an oral selective EGFR tyrosine kinase, which was approved by China Food and Drug administration in June 2011 for treating advanced NSCLC. Its approval was based on the registered Phase III trial (ICOGEN), which showed icotinib is noninferior to gefitinib. This review will discuss the role of icotinib in NSCLC, and its potential application and ongoing investigations.

  11. The Immune Landscape of Non-Small Cell Lung Cancer: Utility of Cytologic and Histologic Samples Obtained Through Minimally Invasive Pulmonary Procedures.

    PubMed

    Beattie, Jason; Yarmus, Lonny; Wahidi, Momen M; Rivera, M Patricia; Gilbert, Christopher; Maldonado, Fabien; Czarnecka, Kasia; Argento, Angela; Chen, Alexander; Herth, Felix; Sterman, Daniel H

    2018-05-14

    The success of immune checkpoint inhibitors and the discovery of useful biomarkers to predict response to these agents is shifting much of the focus of personalized care for non-small cell lung cancer towards harnessing the immune response. With further advancement, more effective immunotherapy options will emerge along with more useful biomarkers. Paradoxically, minimally invasive small biopsy and cytology specimens have become the primary method for diagnosis of patients with advanced disease, as well for initial diagnosis and staging in earlier stage disease. For the benefit of these patients, we will continue to learn how to do more with less. In this perspective, we review aspects of immunobiology that underlie the current state of the art of existing and emerging immunologic biomarkers that hold potential to enhance the care of patients with non-small cell lung cancer. We address practical considerations for acquiring patient samples that accurately reflect disease immune status. We also propose a paradigm shift wherein the most important sample types that need to be proven in pioneering basic science and translation work and subsequent clinical trials are the specimens most often obtained clinically.

  12. Detection of ALK rearrangements in malignant pleural effusion cell blocks from patients with advanced non-small cell lung cancer: a comparison of Ventana immunohistochemistry and fluorescence in situ hybridization.

    PubMed

    Wang, Weiya; Tang, Yuan; Li, Jinnan; Jiang, Lili; Jiang, Yong; Su, Xueying

    2015-02-01

    Surgical resections or tumor biopsies are often not available for patients with late-stage non-small cell lung cancer (NSCLC). Cytological specimens, such as malignant pleural effusion (MPE) cell blocks, are critical for molecular testing. Currently, diagnostic methods to identify anaplastic lymphoma kinase (ALK) rearrangements include fluorescence in situ hybridization (FISH), real-time reverse transcriptase-polymerase chain reaction (RT-PCR), and immunohistochemistry (IHC). In the current study, the authors compared Ventana ALK IHC assays and ALK FISH to detect ALK rearrangements in MPE cell blocks from patients with advanced NSCLC. The ALK IHC assay and ALK FISH were performed on 63 MPE cell blocks. RT-PCR analysis was performed as additional validation in cases in which a discrepancy was observed between the IHC assay and FISH results. The Ventana ALK IHC assay was found to be informative for all 63 samples, and 8 cases were positive. Fifty-eight cases were interpretable for FISH detection, and 6 were positive. The concordance between IHC and FISH was 100% among the 58 cases. Of the 5 uninterpretable ALK FISH cases, 2 cases and 3 cases, respectively, were ALK IHC positive and negative. One of the 2 ALK IHC-positive cases also demonstrated a positive result in the RT-PCR assay and the patient benefited from crizotinib treatment. MPE cell blocks can be used successfully for the detection of ALK rearrangement when tumor tissue is not available. The Ventana ALK IHC assay is an effective screening method for ALK rearrangement in MPE cell blocks from patients with advanced NSCLC, demonstrating high agreement with FISH results. © 2014 American Cancer Society.

  13. Brigatinib for the treatment of ALK-positive advanced non-small cell lung cancer patients.

    PubMed

    Passaro, A; Prelaj, A; Pochesci, A; Spitaleri, G; Rossi, G; Del Signore, E; Catania, C; de Marinis, F

    2017-08-01

    Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease. Nowadays, brigatinib is under evaluation in different clinical trials exploring TKI-naive patients in the first-line setting. On the basis of its significant activity results, brigatinib received approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. Copyright 2017 Clarivate Analytics.

  14. Expression of metastasis-associated lung adenocarcinoma transcript 1 long non-coding RNA in vitro and in patients with non-small cell lung cancer.

    PubMed

    Lin, Ling; Li, Haiyan; Zhu, Yefei; He, Susu; Ge, Hongfei

    2018-06-01

    The present study aimed to investigate the association between the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) long non-coding RNA (lncRNA) and the recurrence of non-small cell lung cancer (NSCLC) and to elucidate the potential mechanisms of MALAT1 in vitro . Between 1 June 1, 2010 and December 30, 2016, NSCLC tumor tissues and adjacent non-cancerous tissues were obtained from 120 patients with NSCLC, who had undergone surgical resection at Taizhou Hospital of Wenzhou Medical University (Linhai, China). The total RNA of tissues and cells were extracted and the expression of MALAT1 was determined using a wound healing assay and reverse transcription quantitative polymerase chain reaction. In addition, MALAT1 expression in A549 cells was silenced using small interfering RNA. The proliferation, migration and invasion of cells were then assessed using a CellTiter 96 kit and Transwell assays. MALAT1 expression was significantly increased in NSCLC samples compared with expression in adjacent non-cancerous tissues. Furthermore, the expression of MALAT1 in patients with NSCLC that exhibited recurrence was markedly higher than in those that did not. The results of the present study also demonstrated significant associations between high expression of MALAT1 and female sex, Tumor-Node-Metastasis advanced stage, vessel invasion, pathological differentiation and recurrence of patients with NSCLC. The proliferative, migratory and invasive abilities of MALAT1-silenced A549 cells were significantly decreased compared with those of control cells. MALAT1 expression was significantly increased in NSCLC tissues and was revealed to serve a role in the progression of NSCLC.

  15. Clinical roundtable monograph: Recent advances in taxanes for the first-line treatment of advanced non-small cell lung cancer.

    PubMed

    Socinski, Mark A; Govindan, Ramaswamy; Spigel, David

    2012-10-01

    Treatments for non-small cell lung cancer (NSCLC) are based on the broad categories of squamous or non-squamous histology. Frontline treatment options include pemetrexed and cisplatin, pemetrexed and a taxane, gemcitabine with cisplatin, and the addition of bevacizumab to a taxane and carboplatin. Pemetrexed is used for maintenance therapy for non-squamous NSCLC, whereas patients with squamous NSCLC lack easy options for maintenance therapy. nab-Paclitaxel overcomes the solubility and toxicity issues of solvent-based paclitaxel, and the albumin in nab-paclitaxel improves the concentration of the drug in the tumor. A recent phase III trial in NSCLC compared nab-paclitaxel with carboplatin versus solvent-based paclitaxel with carboplatin, and found improved overall response rates (ORRs) in the nab-paclitaxel arm (33% vs 25%; P=.005). In a subset analysis, NSCLC patients with squamous histology had a higher ORR (41%) with nab-paclitaxel than with solvent-based paclitaxel (24%; P<.001). Another subset analysis found that patients ages 70 years and older had improved overall survival (median 19.9 months) with nab-paclitaxel compared with solvent-based paclitaxel (median 10.4 months; P=.009). Patients in the nab-paclitaxel arm had less neuropathy, less hearing loss, and fewer interruptions in daily living than patients in the solvent-based paclitaxel arm.

  16. Immunotherapy of non-small cell lung cancer: report from an international experts panel meeting of the Italian association of thoracic oncology.

    PubMed

    Gridelli, Cesare; Ascierto, Paolo A; Barberis, Massimo C P; Felip, Enriqueta; Garon, Edward B; O'brien, Mary; Senan, Suresh; Casaluce, Francesca; Sgambato, Assunta; Papadimitrakopoulou, Vali; De Marinis, Filippo

    2016-12-01

    The potential long term survival gain, related to immune adaptability and memory, the potential activity across multiple tumour types through targeting the immune system, and the opportunity for combinations offered by the unique mechanism of actions and safety profile of these new agents, all support the role of immunotherapy in the cancer treatment pathway or paradigm. Areas covered: The authors discuss the recent advances in the understanding of immunology and antitumor immune responses that have led to the development of new immunotherapies, including monoclonal antibodies that inhibit immune checkpoint pathways, such as Programmed Death-1 (PD-1) and Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4). Currently, two PD-1 inhibitors are available in clinical practice for treatment of advanced non-small cell lung cancer (NSCLC): nivolumab and pembrolizumab. Expert opinion: Ongoing research will dictate future strategies, including the potential incorporation of immunotherapy in stage dependent treatment settings (early stage locally advanced disease and first line therapy for metastatic disease). Immunotherapy combinations are promising avenues, and careful selection of patients, doses of each agent and information supporting strategies (i.e. concomitant or sequential) is still needed.

  17. Erlotinib usage after prior treatment with gefitinib in advanced non-small cell lung cancer: A clinical perspective and review of published literature.

    PubMed

    Singh, Navneet; Jindal, Aditya; Behera, Digambar

    2014-12-10

    Erlotinib and gefitinib are among the most widely researched, used and available molecularly targeted therapies for treatment of advanced non-small cell lung cancer (NSCLC). They are both tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). In the past decade, there have been reports on clinical benefit from use of erlotinib after gefitinib failure in NSCLC patients. A review of published literature on this focussed topic is provided herein. Pooled analysis of published literature shows that majority of patients were female (60.6%), non-smokers (64.5%), had adenocarcinoma histology (88.3%) and were of East Asian ethnicity (92.3%). Presence of sensitizing EGFR mutation was detected in 48.4% of subjects. Disease control rates with prior gefitinib therapy and with subsequent erlotinib treatment were 79.4% and 45.4% respectively. Based upon our review, the most important predictive factor for clinical benefit from erlotinib identified was previous response to gefitinib. The exact explanations for the potential benefit from erlotinib use in this patient population is still not known and further studies are required to determine the role of molecular mechanisms especially those related to resistance to initial EGFR TKI therapy.

  18. Efficacy and safety of icotinib in Chinese patients with advanced non-small cell lung cancer after failure of chemotherapy.

    PubMed

    Shao, Lan; Zhang, Beibei; He, Chunxiao; Lin, Baochai; Song, Zhengbo; Lou, Guangyuan; Yu, Xinmin; Zhang, Yiping

    2014-01-01

    The preclinical experiments and several clinical studies showed icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in Chinese patients with advanced non-small cell lung cancer (NSCLC) who failed previous chemotherapy. We performed a retrospective study of the efficacy and safety of icotinib monotherapy in a different and more recent sample of Chinese patients. The clinical data of 149 patients with advanced NSCLC who were admitted to Zhejiang Cancer Hospital from August 1, 2011 to July 31, 2012 were retrospectively analyzed. All patients were given icotinib treatment after the failure of previous chemotherapy. Univariate and multivariate analyses were conducted based on the Kaplan Meier method and Cox proportional hazards model. The objective response rate was 33/149 and disease control rate was 105/149. No complete response occurred. Median progression free survival (PFS) with icotinib treatment was 5.03 months (95% CI: 3.51 to 6.55). Median overall survival was 12.3 months (95% CI: 10.68 to 13.92). Multivariate analysis showed that the mutation of EGFR and one regimen of prior chemotherapy were significantly associated with longer PFS. At least one drug related adverse event was observed in 65.8% (98/149) of patients, but mostly grade 1 or 2 and reversible and none grade 4 toxicity. Icotinib monotherapy is an effective and well tolerated regimen for Chinese patients with NSCLC after the failure of chemotherapy. It is a promising agent and further study with icotinib in properly conducted trials with larger patient samples and other ethnic groups is warranted.

  19. Clinical outcomes using carbon-ion radiotherapy and dose-volume histogram comparison between carbon-ion radiotherapy and photon therapy for T2b-4N0M0 non-small cell lung cancer-A pilot study.

    PubMed

    Shirai, Katsuyuki; Kawashima, Motohiro; Saitoh, Jun-Ichi; Abe, Takanori; Fukata, Kyohei; Shigeta, Yuka; Irie, Daisuke; Shiba, Shintaro; Okano, Naoko; Ohno, Tatsuya; Nakano, Takashi

    2017-01-01

    The safety and efficacy of carbon-ion radiotherapy for advanced non-small cell lung cancer have not been established. We evaluated the clinical outcomes and dose-volume histogram parameters of carbon-ion radiotherapy compared with photon therapy in T2b-4N0M0 non-small cell lung cancer. Twenty-three patients were treated with carbon-ion radiotherapy between May 2011 and December 2015. Seven, 14, and 2 patients had T2b, T3, and T4, respectively. The median age was 78 (range, 53-91) years, with 22 male patients. There were 12 adenocarcinomas, 8 squamous cell carcinomas, 1 non-small cell lung carcinoma, and 2 clinically diagnosed lung cancers. Eleven patients were operable, and 12 patients were inoperable. Most patients (91%) were treated with carbon-ion radiotherapy of 60.0 Gy relative biological effectiveness (RBE) in 4 fractions or 64.0 Gy (RBE) in 16 fractions. Local control and overall survival rates were calculated. Dose-volume histogram parameters of normal lung and tumor coverages were compared between carbon-ion radiotherapy and photon therapies, including three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT). The median follow-up of surviving patients was 25 months. Three patients experienced local recurrence, and the 2-year local control rate was 81%. During follow-up, 5 patients died of lung cancer, and 1 died of intercurrent disease. The 2-year overall survival rate was 70%. Operable patients had a better overall survival rate compared with inoperable patients (100% vs. 43%; P = 0.04). There was no grade ≥2 radiation pneumonitis. In dose-volume histogram analysis, carbon-ion radiotherapy had a significantly lower dose to normal lung and greater tumor coverage compared with photon therapies. Carbon-ion radiotherapy was effectively and safely performed for T2b-4N0M0 non-small cell lung cancer, and the dose distribution was superior compared with those for photon therapies. A Japanese multi-institutional study is

  20. Management of localized and locally advanced renal tumors. A contemporary review of current treatment options.

    PubMed

    Brookman-May, S; Langenhuijsen, J F; Volpe, A; Minervini, A; Joniau, S; Salagierski, M; Roscigno, M; Akdogan, B; Vandromme, A; Rodriguez-Faba, O; Marszalek, M

    2013-06-01

    About 70% of patients with renal cell carcinoma present with localized or locally advanced disease at primary diagnosis. Whereas these patients are potentially curable by surgical treatment alone, a further 20% to 30% of patients are diagnosed with primary metastatic disease. Although over the past years medical treatment for metastatic patients has nearly completely changed from immunotherapy to effective treatment with targeted agents, metastatic disease still represents a disease status which is not curable. Also in patients with metastatic disease, surgical treatment of the primary tumor plays an important role, since local tumor related complications can be avoided or minimized by surgery. Furthermore, also improvement of overall survival has been proven for surgery in metastatic patients when combined with cytokine treatment. Hence, surgical combined with systemic treatment as a multi-modal, adjuvant, and neo-adjuvant treatment is also required in patients with advanced or metastatic disease. A growing number of elderly and comorbid patients are currently diagnosed with small renal masses, which has led to increased attention paid to alternative ablative treatment modalities as well as active surveillance strategies, which are applied in order to avoid unnecessary overtreatment in these patients. Since surgical treatment also might enhance the risk of chronic kidney disease with consecutive cardiac disorders as well as reduced overall survival, ablative techniques and active surveillance are increasingly applied. In this review article we focus on current surgical and none-surgical treatment options for the management of patients with localized, locally advanced, and metastatic renal cell carcinoma.

  1. Comparison of Glasgow prognostic score and prognostic index in patients with advanced non-small cell lung cancer.

    PubMed

    Jiang, Ai-Gui; Chen, Hong-Lin; Lu, Hui-Yu

    2015-03-01

    Previous studies have shown that Glasgow prognostic score (GPS) and prognostic index (PI) are also powerful prognostic tool for patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to compare the prognostic value between GPS and PI. We enrolled consecutive patients with advanced NSCLC in this prospective cohort. GPS and PI were calculated before the onset of chemotherapy. The prognosis outcomes included 1-, 3-, and 5-year progression-free survival and overall survival (OS). The performance of two scores in predicting prognosis was analyzed regarding discrimination and calibration. 138 patients were included in the study. The area under the receiver operating characteristic curve for GPS predicting 1-year DFS was 0.62 (95 % confidence interval (CI) 0.56-0.68, P < 0.05), and the area under curve for PI predicting 1-year DFS was 0.57 (95 % CI 0.52-0.63). Delong's test showed that GPS was more accurate than PI in predicting 1-year DFS (P < 0.05). Similar results of discriminatory power were found for predicting 3-year DFS, 1-year OS, and 3-year OS. The predicted 1-year DFS by GPS 0, GPS 1, and GPS 2 were 62.5, 42.1, and 23.1 %, respectively, while actual 1-year DFS by GPS 0, GPS 1, and GPS 2 were 61.1, 43.8, and 27.2 %, respectively. Calibration of the Hosmer and Lemeshow statistic showed good fit of the predicted 1-year DFS to the actual 1-year DFS by GPS (χ(2) = 4.326, P = 0.462), while no fit was found between the predicted 1-year DFS and the actual 1-year DFS by PI (χ(2) = 15.234, P = 0.091). Similar results of calibration power were found for predicting 3-year DFS, 5-year DFS, 1-year OS, 3-year OS, and 5-year OS by GPS and PI. GPS is more accurate than PI in predicting prognosis for patients with advanced NSCLC. GPS can be used as a useful and simple tool for predicting prognosis in patients with NSCLC. However, GPS only can be used for preliminary assessment because of low predicting accuracy.

  2. Completion pneumonectomy and chemoradiotherapy as treatment options in local recurrence of non-small-cell lung cancer

    PubMed Central

    Sławiński, Grzegorz; Musik, Martyna; Marciniak, Łukasz; Dyszkiewicz, Wojciech; Piwkowski, Cezary; Gałęcki, Bartłomiej

    2015-01-01

    Introduction The selection of treatment for local recurrence in patients with non-small-cell lung cancer (NSCLC) depends on the possibility of performing a radical tumor resection, the patient's performance status, and cardiopulmonary efficiency. Compared with chemoradiotherapy, surgical treatment offers a greater chance of long-term survival, but results in completion pneumonectomy and is associated with a relatively high rate of complications. Aim of the study Aim of the study was to evaluate early and long-term results of surgery and conservative treatment (chemoradiotherapy) in patients with local NSCLC recurrence. Material and methods Between 1998 and 2011, 1697 NSCLC patients underwent lobectomy or bilobectomy at the Department of Thoracic Surgery in Poznań. Among them, 137 patients (8.1%) were diagnosed with cancer recurrence; chemotherapy or chemoradiotherapy was provided to 116 patients; 21 patients (15.3%) were treated with completion pneumonectomy. The median time from primary surgery to recurrence was 13.4 months. No metastases to N2 lymph nodes were observed among the patients undergoing surgery; in 7 patients N1 lymph node metastases were confirmed. Results The rate of complications after surgery was significantly higher in comparison with conservative therapy (80.9% vs. 48.3%). Patients treated with surgery were most likely to suffer from complications associated with the circulatory system (80.9%), while hematologic complications were dominant in the group undergoing oncological treatment (41.4%). There were no perioperative deaths after completion pneumonectomy. The age of the patients was the only factor which significantly influenced the incidence of complications in both groups of patients. Analysis of the survival curves demonstrated statistically significant differences in survival between the groups treated with surgery, chemoradiotherapy, and chemotherapy (p = 0.00001). Five-year survival probability was significantly higher among patients

  3. Pembrolizumab combined with stereotactic body radiotherapy in a patient with human immunodeficiency virus and advanced non-small cell lung cancer: a case report.

    PubMed

    Li, Dongqi; He, Chuanchun; Xia, Yaoxiong; Du, Yaxi; Zhang, Jing

    2018-04-23

    Pembrolizumab has significantly improved outcomes in patients with advanced non-small cell lung cancer. Combining programmed death-1 inhibitor with stereotactic body radiotherapy showed a slight toxicity and good benefits in recent clinical trials. However, patients infected with human immunodeficiency virus were excluded from most trials because it was assumed that their anti-tumor immunity was compromised compared with immunocompetent patients. In June 2016, a 52-year-old Chinese man presented with human immunodeficiency virus and lung adenocarcinoma (T1bN3M1b). From November 2016 to December 2016, systemic chemotherapy and palliative radiotherapy for bone metastasis of femoral neck were carried out, but the tumor progressed. In January 2017, after immunochemistry detection of programmed death-1 and programmed death-ligand 1 expression (both > 50%), pembrolizumab was started. Three weeks after pembrolizumab, we combined stereotactic body radiotherapy for the primary lung tumor. He received no comfort and his CD4 lymphocyte count was stable. Human immunodeficiency virus-ribonucleic acid remained below the limits of detection. In March 2017, after three cycles of pembrolizumab and 5 weeks of stereotactic body radiotherapy therapy, he suddenly presented with palpitations. Emergency computed tomography scanning showed massive pericardial effusion and interstitial pneumonia. So we interrupted the pembrolizumab use and initiated treatment with prednisolone 1 mg/kg; however, the tumor progressed. Then, his CD4 lymphocyte count declined. Finally he died in June 2017 due to dyscrasia. Pembrolizumab combined with SBRT therapy for patients with human immunodeficiency virus infection and non-small cell lung cancer may lead to serious immune-related adverse events and more clinical trials are needed.

  4. Effects of combined Chinese drugs and chemotherapy in treating advanced non-small cell lung cancer.

    PubMed

    Chen, Yan-zhi; Li, Zhan-dong; Gao, Fei; Zhang, Ying; Sun, Hong; Li, Ping-ping

    2009-12-01

    To evaluate the efficacy and side effects of combined Chinese drugs and chemotherapy in treating advanced non-small cell lung cancer (NSCLC). Sixty-three patients with stage III B and IV NSCLC hospitalized from October 2001 to October 2008 were enrolled and assigned to two groups using a randomizing digital table, with 33 patients in the treatment group and 30 in the control group. They were all treated with the Navelbine and Cisplatin (NP) chemotherapy, but to the treatment group the Chinese drugs Shengmai Injection () by intravenous dripping and Gujin Granule () by oral intake were given additionally. The main observation indexes were response rate (RR), median survival time, 1-year survival rate and median time to progression (TTP); secondary observation indexes were side effects and cycles of chemotherapy. Altogether, 61 patients (33 from the treatment group and 28 from the control group) completed the observation and were assessable. RR was 48.5% (16/33) in the treatment group and 32.2% (9/28) in the control group, and the median survival time were 13 months and 9 months, respectively; the difference between the two groups was significant (P=0.0373 and P=0.014 respectively). However, the differences between groups were insignificant in terms of 1-year survival rate [51.5% (17/33) vs 46.4% (13/28), P=0.4042], median TTP (5.95 months vs 4.64 months, P=0.3242), grade III or IV bone marrow inhibition occurrence rate [33.3% (11/33) vs 39.3% (11/28), P=0.3500], and mean cycles of chemotherapy applied (2.94+/-0.94 cycles vs 2.75+/-0.75 cycles, P=0.4100). Combined Chinese drugs and chemotherapy can enhance the short-term therapeutic efficacy in the treatment of NSCLC and prolong patients' median survival time, but show no evident impact on TTP.

  5. Small and Medium-Sized Information Technology Firms: Assessment of Non-Local Partnership Facilitators

    ERIC Educational Resources Information Center

    Findikoglu, Melike Nur

    2012-01-01

    A two-phased qualitative study was conducted to explore the facilitators of non-local (i.e. domestic or international) partnerships formed by small- and medium-sized firms (SME). Rooted in trust, proximity and dynamic capabilities lenses, the study focused on behaviors of SMEs performing in dynamic, competitive and highly interlinked industry, the…

  6. MMP-9/ANC score as a predictive biomarker for efficacy of bevacizumab plus platinum doublet chemotherapy in patients with advanced or recurrent non-squamous non-small cell lung cancer.

    PubMed

    Hiura, Kazuya; Shiraishi, Akiko; Suzuki, Chinami; Takamura, Kei; Yamamoto, Makoto; Komori, Hitoshi; Watanabe, Yasuhiro; Iwaki-Egawa, Sachiko

    2015-01-01

    Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), which is a key regulator of tumor angiogenesis. To evaluate biomarkers to predict the benefit of paclitaxel and carboplatin plus bevacizumab (PCB) therapy in patients with advanced or recurrent non-squamous non-small cell lung cancer. Among 21 patients treated with PCB, 10 were included in the good responder group and 11 in the non-responder group. Serum VEGF, MMP-2 and MMP-9 were measured using ELISA. There were no significant differences in these markers levels between groups. However, the good responder group showed a significantly higher pre-treatment MMP-9/ absolute neutrophil count (ANC) score than the non-responder group before the treatment (p= 0.014), and there was a positive correlation between the score and the tumor reduction rate (r= 0.57, p= 0.016). Furthermore, by dividing patients into a high scoring group (MMP-9/ANC ≥ median, n= 11) and a low scoring group (MMP-9/ANC < median, n= 10), former group showed a significant improvement in the median progression-free survival compared with latter group (636 vs. 196 days, p = 0.032). MMP-9/ANC score before PCB treatment may be a suitable biomarker to assess the anti-tumor effects of PCB therapy.

  7. Health care resource use among patients with advanced non-small cell lung cancer: the PIvOTAL retrospective observational study.

    PubMed

    Lee, Dae Ho; Isobe, Hiroshi; Wirtz, Hubert; Aleixo, Sabina Bandeira; Parente, Phillip; de Marinis, Filippo; Huang, Min; Arunachalam, Ashwini; Kothari, Smita; Cao, Xiting; Donnini, Nello; Woodgate, Ann-Marie; de Castro, Javier

    2018-03-01

    Data are scarce regarding real-world health care resource use (HCRU) for non-small cell lung cancer (NSCLC). An understanding of current clinical practices and HCRU is needed to provide a benchmark for rapidly evolving NSCLC management recommendations and therapeutic options. The objective of this study was to describe real-world HCRU for patients with advanced NSCLC. This multinational, retrospective chart review study was conducted at academic and community oncology sites in Italy, Spain, Germany, Australia, Japan, South Korea, Taiwan, and Brazil. Deidentified data were drawn from medical records of 1440 adults (≥18 years old) who initiated systemic therapy (2011 to mid-2013) for a new, confirmed diagnosis of advanced or metastatic (stage IIIB or IV) NSCLC. We summarized HCRU associated with first and subsequent lines of systemic therapy for advanced/metastatic NSCLC. The proportion of patients who were hospitalized at least once varied by country from 24% in Italy to 81% in Japan during first-line therapy and from 22% in Italy to 84% in Japan during second-line therapy; overall hospitalization frequency was 2.5-11.1 per 100 patient-weeks, depending on country. Emergency visit frequency also varied among countries (overall from 0.3-5.9 per 100 patient-weeks), increasing consistently from first- through third-line therapy in each country. The outpatient setting was the most common setting of resource use. Most patients in the study had multiple outpatient visits in association with each line of therapy (overall from 21.1 to 59.0 outpatient visits per 100 patient-weeks, depending on country). The use of health care resources showed no regular pattern associated with results of tests for activating mutations of the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. HCRU varied across countries. These findings suggest differing approaches to the clinical management of advanced NSCLC among the eight countries

  8. Real-World Data on Prognostic Factors for Overall Survival in EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Gefitinib.

    PubMed

    Yao, Zong-Han; Liao, Wei-Yu; Ho, Chao-Chi; Chen, Kuan-Yu; Shih, Jin-Yuan; Chen, Jin-Shing; Lin, Zhong-Zhe; Lin, Chia-Chi; Chih-Hsin Yang, James; Yu, Chong-Jen

    2017-09-01

    This study aimed to identify independent prognostic factors for overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation and receiving gefitinib as first-line treatment in real-world practice. We enrolled 226 patients from June 2011 to May 2013. During this period, gefitinib was the only EGFR-tyrosine kinase inhibitor reimbursed by the Bureau of National Health Insurance of Taiwan. The median progression-free survival and median OS were 11.9 months (95% confidence interval [CI]: 9.7-14.2) and 26.9 months (21.2-32.5), respectively. The Cox proportional hazards regression model revealed that postoperative recurrence, performance status (Eastern Cooperative Oncology Grade [ECOG] ≥2), smoking index (≥20 pack-years), liver metastasis at initial diagnosis, and chronic hepatitis C virus (HCV) infection were independent prognostic factors for OS (hazard ratio [95% CI] 0.3 [0.11-0.83], p  = .02; 2.69 [1.60-4.51], p  < .001; 1.92 [1.24-2.97], p  = .003; 2.26 [1.34-3.82], p  = .002; 3.38 [1.85-7.78], p  < .001, respectively). However, brain metastasis (BM) at initial diagnosis or intracranial progression during gefitinib treatment had no impact on OS (1.266 [0.83-1.93], p  = .275 and 0.75 [0.48-1.19], p  = .211, respectively). HCV infection, performance status (ECOG ≥2), newly diagnosed advanced NSCLC without prior operation, and liver metastasis predicted poor OS in EGFR mutation-positive advanced NSCLC patients treated with first-line gefitinib; however, neither BM at initial diagnosis nor intracranial progression during gefitinib treatment had an impact on OS. The finding that chronic hepatitis C virus (HCV) infection might predict poor overall survival (OS) in epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (NSCLC) patients treated with first-line gefitinib may raise awareness of benefit from anti

  9. Fluorogenic RNA Mango aptamers for imaging small non-coding RNAs in mammalian cells.

    PubMed

    Autour, Alexis; C Y Jeng, Sunny; D Cawte, Adam; Abdolahzadeh, Amir; Galli, Angela; Panchapakesan, Shanker S S; Rueda, David; Ryckelynck, Michael; Unrau, Peter J

    2018-02-13

    Despite having many key roles in cellular biology, directly imaging biologically important RNAs has been hindered by a lack of fluorescent tools equivalent to the fluorescent proteins available to study cellular proteins. Ideal RNA labelling systems must preserve biological function, have photophysical properties similar to existing fluorescent proteins, and be compatible with established live and fixed cell protein labelling strategies. Here, we report a microfluidics-based selection of three new high-affinity RNA Mango fluorogenic aptamers. Two of these are as bright or brighter than enhanced GFP when bound to TO1-Biotin. Furthermore, we show that the new Mangos can accurately image the subcellular localization of three small non-coding RNAs (5S, U6, and a box C/D scaRNA) in fixed and live mammalian cells. These new aptamers have many potential applications to study RNA function and dynamics both in vitro and in mammalian cells.

  10. Positron Emission Tomography for Assessing Local Failure After Stereotactic Body Radiotherapy for Non-Small-Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang Xu; Liu Hui; Balter, Peter

    2012-08-01

    Purpose: We analyzed whether positron emission tomography (PET)/computed tomography standardized uptake values (SUVs) after stereotactic body radiotherapy (SBRT) could predict local recurrence (LR) in non-small-cell lung cancer (NSCLC). Methods and Materials: This study comprised 128 patients with Stage I (n = 68) or isolated recurrent/secondary parenchymal (n = 60) NSCLC treated with image-guided SBRT to 50 Gy over 4 consecutive days; prior radiotherapy was allowed. PET/computed tomography scans were obtained before therapy and at 1 to 6 months after therapy, as well as subsequently as clinically indicated. Continuous variables were analyzed with Kruskal-Wallis tests and categorical variables with Pearson chi-squaremore » or Fisher exact tests. Actuarial local failure rates were calculated with the Kaplan-Meier method. Results: At a median follow-up of 31 months (range, 6-71 months), the actuarial 1-, 2-, and 3-year local control rates were 100%, 98.5%, and 98.5%, respectively, in the Stage I group and 95.8%, 87.6%, and 85.8%, respectively, in the recurrent group. The cumulative rates of regional nodal recurrence and distant metastasis were 8.8% (6 of 68) and 14.7% (10 of 68), respectively, for the Stage I group and 11.7% (7 of 60) and 16.7% (10 of 60), respectively, for the recurrent group. Univariate analysis showed that SUVs obtained 12.1 to 24 months after treatment for the Stage I group (p = 0.007) and 6.1 to 12 months and 12.1 to 24 months after treatment for the recurrent group were associated with LR (p < 0.001 for both). Of the 128 patients, 17 (13.3%) had ipsilateral consolidation after SBRT but no elevated metabolic activity on PET; none had LR. The cutoff maximum SUV of 5 was found to have 100% sensitivity, 91% specificity, a 50% positive predictive value, and a 100% negative predictive value for predicting LR. Conclusions: PET was helpful for distinguishing SBRT-induced consolidation from LR. SUVs obtained more than 6 months after SBRT for NSCLC

  11. A unique cell-surface protein phenotype distinguishes human small-cell from non-small-cell lung cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Baylin, S.B.; Gazdar, A.F.; Minna, J.D.

    1982-08-01

    Radioiodination (/sup 125/I) and two-dimensional polyacrylamide gel electrophoresis was used to determine that small-(oat) cell lung carcinoma (SCC)-a tumor with neuroedocrine features-possesses a surface protein pattern distinct from the other types of lung cancer cells (squamous, adeno-, and large-cell undifferentiated carcinoma). Twelve distinguishing proteins, 40 to 70 kilodaltons (kDal), characterized four separate lines of SCC; three of these, designated E (60 kDal; pI = 7.3), S (30 kDal; pI = 6.0), and U 57 kDal; pI = 5.6), may be unique SCC gene products and were identified only in (/sup 35/S)methionine labeling of SCC and not in non-SCC or humanmore » fibroblasts. Two lines of adeno-, one of squamous, and one of undifferentiated large-cell lung carcinoma exhibited similar surface protein patterns to one another. Nine distinguishing proteins (40 to 100 kDal) and at least five large proteins (>100 kDal) were unique to these lines. The surface protein phenotypes for SCC and non-SCC were distinct from those for human lymphoblastoid cells and fibroblasts. However, the neuroendocrine features of SCC were further substantiated because 6 of the 12 distinguishing SCC surface proteins, including E and U, were identified on human neuroblastoma cells. The proteins identified should (i) help define differentiation steps for normal and neoplastic bronchial epithelial cells, (ii) prove useful in better classifying lung cancers, and (iii) be instrumental in tracing formation of neuroendocrine cells.« less

  12. New targeted treatments for non-small-cell lung cancer - role of nivolumab.

    PubMed

    Zago, Giulia; Muller, Mirte; van den Heuvel, Michel; Baas, Paul

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage of disease, where it is no longer amenable to curative treatment. During the last decades, the survival has only improved significantly for lung cancer patients who have tumors harboring a driver mutation. Therefore, there is a clear unmet need for effective therapies for patients with no mutation. Immunotherapy has emerged as an effective treatment for different cancer types. Nivolumab, a monoclonal inhibitory antibody against PD-1 receptor, can prolong survival of NSCLC patients, with a manageable toxicity profile. In two Phase III trials, nivolumab was compared to docetaxel in patients with, respectively, squamous (CheckMate 017) and non-squamous NSCLC (CheckMate 057). In both trials, nivolumab significantly reduced the risk of death compared to docetaxel (41% and 27% lower risk of death for squamous and non-squamous NSCLC, respectively). Therefore, nivolumab has been approved in the US and in Europe as second-line treatment for advanced NSCLC. Unfortunately, accurate predictive factors for patient selection are lacking, making it difficult to decide who will benefit and who will not. Currently, there are many ongoing trials that evaluate the efficacy of nivolumab in different settings and in combination with other agents. This paper reviews the present literature about the role of nivolumab in the treatment of NSCLC. Particular attention has been given to efficacy studies, toxicity profile, and current and emerging predictive factors.

  13. Non-Small Cell Lung Cancer Treatment (PDQ®)—Patient Version

    Cancer.gov

    Non-small cell lung cancer (NSCLC) treatment options include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Laser therapy, photodynamic therapy, cryosurgery, and electrocautery may be used. Learn more about NSCLC in this expert-reviewed summary.

  14. Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (An ALCHEMIST Treatment Trial)

    ClinicalTrials.gov

    2018-06-28

    Stage IB Non-Small Cell Lung Carcinoma AJCC v7; Stage II Non-Small Cell Lung Cancer AJCC v7; Stage IIA Non-Small Cell Lung Carcinoma AJCC v7; Stage IIB Non-Small Cell Lung Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7

  15. Gefitinib in Treating Patients With Stage IB, II, or IIIA Non-small Cell Lung Cancer That Was Completely Removed by Surgery

    ClinicalTrials.gov

    2014-12-19

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer

  16. Post-Progression Survival Associated with Overall Survival in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Docetaxel Monotherapy as Second-Line Chemotherapy.

    PubMed

    Kotake, Mie; Miura, Yosuke; Imai, Hisao; Mori, Keita; Sakurai, Reiko; Kaira, Kyoichi; Tomizawa, Yoshio; Minato, Koichi; Saito, Ryusei; Hisada, Takeshi

    2017-01-01

    In patients with non-small-cell lung cancer (NSCLC), the effects of second-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. Therefore, using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) and post-progression survival (PPS) with OS in patients with advanced NSCLC treated with docetaxel monotherapy as second-line chemotherapy. Between April 2002 and December 2014, data from 86 patients with advanced NSCLC who underwent second-line docetaxel monotherapy following first-line treatment with platinum combination chemotherapy were analyzed. The relationships of PFS and PPS with OS were analyzed at the individual level. Spearman rank correlation and linear regression analyses showed that PPS was strongly associated with OS (r = 0.86, p < 0.05, R2 = 0.93), whereas PFS was moderately correlated with OS (r = 0.50, p < 0.05, R2 = 0.21). Performance status at the end of second-line treatment and the number of regimens after progression beyond second-line chemotherapy were significantly associated with PPS (p < 0.05). In patients with advanced NSCLC with unknown oncogenic driver mutations undergoing docetaxel monotherapy as second-line chemotherapy, when compared with PFS, PPS had a stronger association with OS. This finding suggests that subsequent treatment after disease progression following second-line docetaxel monotherapy has a significant influence on OS. © 2017 S. Karger AG, Basel.

  17. [Suppression of WIFI transcript and protein in non-small cell lung carcinomas].

    PubMed

    Korobko, E V; Kalinichenko, S V; Shepelev, M V; Zborovskaia, I B; Allakhverdiev, A K; Zinov'eva, M V; Vinogradova, T V; Sverdlov, E D; Korobko, I V

    2007-01-01

    Changes in WIFI expression, an extracellular inhibitor of Wnt pathway, in non-small cell lung carcinomas were analyzed. Frequent (67% cases) suppression of WIFI transcript in non-small cell lung carcinomas were found. Our results, together with previously published data, suggest that inhibition of WIFI expression often occurs in squamous cell carcinomas and is less typical of adenocarcinomas. It was also found that a decrease in the WIFI transcript in tumors is parallel to concomitant suppression of the WIFI protein level. Our results provide further evidence that the WIFI suppression is a frequent event in the lung carcinogenesis, which might lead to disregulation of Wnt signaling pathway and contribute to tumor progression.

  18. The suitability of small biopsy and cytology specimens for EGFR and other mutation testing in non-small cell lung cancer

    PubMed Central

    Wang, Shu; Yu, Bing; Ng, Chiu Chin; Mercorella, Belinda; Selinger, Christina I.; O’Toole, Sandra A.

    2015-01-01

    Background Patients with advanced non-small cell lung cancer (NSCLC) benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) when their tumor harbors an activating EGFR mutation. As the majority of NSCLC patients present with advanced disease, cytology and small biopsy specimens are frequently the only tissue available for mutation testing, but can pose challenges due to low tumor content. We aim to better define the suitability of these specimens for mutation testing. Methods NSCLC cases referred to our institution for mutation testing over a 15-month period were retrospectively reviewed. Specimens were tested for mutations including EGFR, KRAS, and BRAF, using a multiplex PCR assay (OncoCarta Panel v1.0) and analyzed on the Agena Bioscience MassARRAY platform. Results A total of 146 specimens were tested, comprising 53 (36.3%) resection specimens (including 28 lung resection specimens), 55 (37.7%) small biopsy specimens and 38 (26%) cytology specimens. Of 142 cases with sufficient DNA for mutation testing, EGFR mutations were detected in 31 specimens (21.8%), KRAS mutations in 31 specimens (21.8%) and BRAF mutations in three specimens (2.1%). There was no significant difference in the EGFR mutation rate between lung resection (10 of 28 cases; 35.7%), small biopsy (9 of 53 cases; 17%), and cytology specimens (8 of 36 cases; 22.2%). Conclusions Our results support the utility of small biopsy and cytology specimens for mutation testing. Careful evaluation of the adequacy of small specimens is required to minimize the risk of false negative or positive results. PMID:25870794

  19. Phase I Study of Oral S-1 Plus Cisplatin With Concurrent Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kaira, Kyoichi; Sunaga, Noriaki; Yanagitani, Noriko

    Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: S-1 was administered orally twice daily for 14 days and cisplatin on Days 1 and 8 of each cycle; this was repeated every 3 weeks. Doses of each drug were planned as follows: level 0, 50/40; level 1, 60/40; level 2, 70/40; level 3, 80/40 (S-1 [mg/m{sup -2}/day{sup -1}]/cisplatin [mg/m{sup -2}/day{sup -1}]). Thoracic radiation therapy was administered in 2 Gy fractions five times weekly to amore » total dose of 60 Gy. Results: Ten patients were enrolled in this study. All patients received 60 Gy of thoracic radiotherapy and 7 (70%) patients received four cycles of chemotherapy. At level 1, 2 of 3 patients experienced a delay exceeding 10 days in the cisplatin administration of Day 29. Grade 4 neutropenia and Grade 3 fever occurred in 1 and 1 patients, respectively. Nonhematologic toxicities were mild. None developed {>=}Grade 3 esophagitis or lung toxicity. At level 0, 2 of 7 patients developed dose-limiting toxicity. Thus, level 1 was considered the MTD and Level 0 was selected as the RD. Objective responses were seen in all patients. Conclusions: The RD is the level 0 dose, and this regimen is a feasible and well-tolerated regimen for the treatment of patients with Stage III NSCLC.« less

  20. Dynamic changes in quality of life after three first-line therapies for EGFR mutation-positive advanced non-small-cell lung cancer.

    PubMed

    Yang, Szu-Chun; Lin, Chien-Chung; Lai, Wu-Wei; Chang, Sheng-Mao; Hwang, Jing-Shiang; Su, Wu-Chou; Wang, Jung-Der

    2018-01-01

    Three different tyrosine kinase inhibitors have been approved as first-line therapies for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer with similar overall survival. This study determined dynamic changes in quality of life (QoL) for patients using these therapies after controlling for potential confounders. From 2011 to 2016, we prospectively assessed the utility values and QoL scores of patients using the EuroQol five-dimension and World Health Organization Quality-of-Life - Brief questionnaires. QoL functions after initiation of treatment were estimated using a kernel-smoothing method. Dynamic changes in major determinants were repeatedly assessed for constructing mixed models. A total of 344 patients were enrolled, with 934 repeated assessments. After controlling for performance status, disease progression, EGFR mutation subtype and other confounders, the mixed models showed significantly lower QoL scores for afatinib versus gefitinib in the physical, psychological and social domains, and 10 facets. The differences seemed to appear 10 months after initiation of treatment. In contrast, there was no significant difference between erlotinib and gefitinib in the scores of all domains and facets. QoL in patients receiving afatinib seemed to be lower than in those receiving gefitinib. Since the sample sizes in this study were relatively small, more studies are warranted to corroborate these results.

  1. Impact of Reflex EGFR/ ALK Testing on Time to Treatment of Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

    PubMed

    Cheema, Parneet K; Menjak, Ines B; Winterton-Perks, Zoe; Raphael, Simon; Cheng, Susanna Y; Verma, Sunil; Muinuddin, Ahmad; Freedman, Ryan; Toor, Nevkeet; Perera, Joseph; Anaka, Matthew; Victor, J Charles

    2017-02-01

    Optimal first-line systemic therapy for patients with advanced nonsquamous (nonsq) non-small-cell lung cancer (NSCLC) requires confirmation of EGFR/ ALK status, which can delay treatment. We evaluated the impact of reflex testing, defined as pathologists initiating EGFR/ ALK testing at the time of diagnosis of nonsq NSCLC, on time to treatment (TTT). We conducted a retrospective review of patients with nonsq NSCLC with medical oncology consultation at Sunnybrook Odette Cancer Centre between March 18, 2010 and April 30, 2014. Data were compared during routine and reflex testing. TTT was defined as the interval between the first medical oncology visit with advanced NSCLC and the initiation of systemic therapy. A total of 306 patients were included (n = 232 for routine testing, n = 74 for reflex testing). There was a trend to improvement in median TTT with reflex testing (36 days [interquartile range {IQR}, 16 to 71 days v 26 days [IQR, 8 to 41 days], P = .071). Omitting patients with intentional delays in systemic therapy for low-volume disease, poor performance status, comorbidity management, and/or radiation therapy, median TTT improved (34 days [IQR, 15 to 67 days] v 22 days [IQR, 8 to 42 days], P = .049). Time to optimal first-line systemic therapy according to published guidelines improved (median, 36 days [IQR, 16 to 91 days] v 24 days [IQR, 8 to 43 days], P = .036). There was no impact on receipt of any first-line systemic therapy (55% v 59%, P = .66). The quality of biomarker testing improved, with fewer unsuccessful tests ( EGFR, 14% v 4%, P = .039; and ALK, 17% v 3%, P = .037). Reflex testing of EGFR/ ALK improved the time to optimal systemic therapy and the quality of biomarker testing for patients with advanced nonsq NSCLC.

  2. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and non-small cell lung cancer.

    PubMed

    Siemianowicz, Krzysztof; Gminski, Jan; Garczorz, Wojciech; Slabiak, Natalia; Goss, Malgorzata; Machalski, Marek; Magiera-Molendowska, Helena

    2003-01-01

    Two mutations of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) may lead to a decreased activity of the enzyme. These mutations may change a risk of some cancers. We evaluated these two polymorphisms of MTHFR in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NCSCL). All lung cancer patients had statistically significantly higher percentage of MTHFR 677TT genotype in comparison with non-cancer controls. There were no statistically significant differences in the distribution of MTHFR 1298 genotypes. Neither of the polymorphisms presented any statistically significant differences between SCLC and NSCLC.

  3. Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: rationale, evidence and place in therapy

    PubMed Central

    Ricciuti, Biagio; Baglivo, Sara; Paglialunga, Luca; De Giglio, Andrea; Bellezza, Guido; Chiari, Rita; Crinò, Lucio; Metro, Giulio

    2017-01-01

    The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit. Unfortunately, virtually all patients who initially respond to treatment develop acquired resistance to EGFR-TKIs within 9–14 months. The EGFR T790M secondary mutation has emerged as a cause of treatment failure in approximately 60% of resistant cases. To date, several compounds designed with the aim to overcome T790M-mediated resistance are under clinical investigation. The aim of this review is to discuss emerging data regarding the third-generation EGFR-TKI, osimertinib, for the treatment of EGFR T790M mutant advanced NSCLC. PMID:28607578

  4. Association of CHEK2 polymorphisms with the efficacy of platinum-based chemotherapy for advanced non-small-cell lung cancer in Chinese never-smoking women.

    PubMed

    Xu, Wen; Liu, Di; Yang, Yang; Ding, Xi; Sun, Yifeng; Zhang, Baohong; Xu, Jinfu; Su, Bo

    2016-09-01

    Cell cycle checkpoint kinase 2 (CHEK2) plays an essential role in the repair of DNA damage. Single nucleotide polymorphisms (SNPs) in DNA repair genes are thought to influence treatment effects and survival of cancer patients. This study aimed to investigate the relationship between polymorphisms in the CHEK2 gene and efficacy of platinum-based doublet chemotherapy in never-smoking Chinese female patients with advanced non-small-cell lung cancer (NSCLC). Using DNA from blood samples of 272 Chinese advanced NSCLC non-smoking female patients treated with first-line platinum-based chemotherapy, we have analyzed the relationships between four SNPs in the CHEK2 gene and clinical outcomes. We found that overall survival (OS) was significantly associated with CHEK2 rs4035540 (Log-Rank P=0.020), as well as the CHEK2 rs4035540 dominant model (Log-Rank P=0.026), especially in the lung adenocarcinoma group. After multivariate analysis, patients with rs4035540 A/G genotype had a significantly better OS than those with the G/G genotype (HR =0.67, 95% CI, 0.48-0.93; P=0.016). In the toxicity analysis, it was observed that patients with the CHEK2 rs4035540 A/A genotype had a higher risk of gastrointestinal toxicity than the G/G genotype group (P=0.009). However, there are no significant associations between chemotherapy treatments and genetic variations. Our findings indicate that SNPs in CHEK2 are related to Chinese advanced NSCLC never-smoking female patients receiving platinum-based doublet chemotherapy in China. Patients with rs4035540 A/G genotype have a better OS. And patients with rs4035540 A/A genotype have a higher risk of gastrointestinal toxicity. These results point to a direction for predicting the prognosis for Chinese never-smoking NSCLC female patients. However, there are no significant associations between chemotherapy treatments and SNPs in CHEK2 , which need more samples to the further study.

  5. Association of CHEK2 polymorphisms with the efficacy of platinum-based chemotherapy for advanced non-small-cell lung cancer in Chinese never-smoking women

    PubMed Central

    Xu, Wen; Liu, Di; Yang, Yang; Ding, Xi; Sun, Yifeng; Zhang, Baohong

    2016-01-01

    Background Cell cycle checkpoint kinase 2 (CHEK2) plays an essential role in the repair of DNA damage. Single nucleotide polymorphisms (SNPs) in DNA repair genes are thought to influence treatment effects and survival of cancer patients. This study aimed to investigate the relationship between polymorphisms in the CHEK2 gene and efficacy of platinum-based doublet chemotherapy in never-smoking Chinese female patients with advanced non-small-cell lung cancer (NSCLC). Methods Using DNA from blood samples of 272 Chinese advanced NSCLC non-smoking female patients treated with first-line platinum-based chemotherapy, we have analyzed the relationships between four SNPs in the CHEK2 gene and clinical outcomes. Results We found that overall survival (OS) was significantly associated with CHEK2 rs4035540 (Log-Rank P=0.020), as well as the CHEK2 rs4035540 dominant model (Log-Rank P=0.026), especially in the lung adenocarcinoma group. After multivariate analysis, patients with rs4035540 A/G genotype had a significantly better OS than those with the G/G genotype (HR =0.67, 95% CI, 0.48–0.93; P=0.016). In the toxicity analysis, it was observed that patients with the CHEK2 rs4035540 A/A genotype had a higher risk of gastrointestinal toxicity than the G/G genotype group (P=0.009). However, there are no significant associations between chemotherapy treatments and genetic variations. Conclusions Our findings indicate that SNPs in CHEK2 are related to Chinese advanced NSCLC never-smoking female patients receiving platinum-based doublet chemotherapy in China. Patients with rs4035540 A/G genotype have a better OS. And patients with rs4035540 A/A genotype have a higher risk of gastrointestinal toxicity. These results point to a direction for predicting the prognosis for Chinese never-smoking NSCLC female patients. However, there are no significant associations between chemotherapy treatments and SNPs in CHEK2, which need more samples to the further study. PMID:27747004

  6. Non-Small Cell Lung Cancer Treatment (PDQ®)—Health Professional Version

    Cancer.gov

    Non-small cell lung cancer (NSCLC) treatment options include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Get detailed information about newly diagnosed and recurrent NSCLC in this summary for clinicians.

  7. Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Westover, Kenneth D.; Loo, Billy W.; Gerber, David E.

    2015-09-01

    Purpose: Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. Methods and Materials: Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiationmore » therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. Results: Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59). Conclusions: Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of

  8. Adherence to Survivorship Care Guidelines in Health Care Providers for Non-Small Cell Lung Cancer and Colorectal Cancer Survivor Care

    ClinicalTrials.gov

    2017-04-05

    Adenocarcinoma of the Lung; Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Squamous Cell Lung Cancer; Stage I Colon Cancer; Stage I Rectal Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Colon Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIA Rectal Cancer; Stage IIB Colon Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIB Rectal Cancer; Stage IIC Colon Cancer; Stage IIC Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer

  9. Impact of a planned dose interruption of dacomitinib in the treatment of advanced non-small-cell lung cancer (ARCHER 1042)

    PubMed Central

    Kim, Dong-Wan; Garon, Edward B.; Jatoi, Aminah; Keefe, Dorothy M.; Lacouture, Mario E.; Sonis, Stephen; Gernhardt, Diana; Wang, Tao; Giri, Nagdeep; Doherty, Jim P.; Nadanaciva, Sashi; O’Connell, Joseph; Sbar, Eric; Cho, Byoung Chul

    2017-01-01

    Objectives Dacomitinib is a pan-HER inhibitor for advanced non-small-cell lung cancer (NSCLC). We explored the impact of a planned 4-day dacomitinib dose interruption on plasma exposure of dacomitinib and adverse events (AEs) of interest in Cohort III of the ARCHER 1042 study. Materials and methods Patients, treatment-naïve for advanced NSCLC with EGFR activating mutations, received oral dacomitinib 45 mg QD (once daily). A planned dose interruption occurred in Cycle 1 from Days 11 through 14. The primary endpoint was the pharmacokinetic (PK) characteristics of dacomitinib in Cycle 1 Day 10 and during dose interruption. Secondary endpoints included safety and concomitant medications used to treat AEs of interest. Results Cohort III enrolled 25 patients. Median plasma Cmax of dacomitinib in Cycle 1 Day 10 was 83.40 ng/mL. Average median plasma dacomitinib concentration during the 4-day dose interruption was 42.63 ng/mL. In the first 8 weeks of treatment 1) 80% of patients used concomitant medications for dermatologic AEs, 76% for diarrhea, and 44% for stomatitis, and 2) all patients experienced treatment-emergent AEs and 28% had all-causality Grade 3 AEs. Conclusion At 45 mg QD dosing, PK parameters of plasma dacomitinib in Cycle 1 Day 10 were comparable to that obtained in Cycle 1 Day 14 from other dacomitinib studies. Average median plasma dacomitinib concentration during the 4-day dose interruption was approximately half of the median plasma Cmax of dacomitinib observed prior to dose interruption. The toxicity profile was consistent with that from other studies of dacomitinib. PMID:28285698

  10. Melatonin as a potential anticarcinogen for non-small-cell lung cancer

    PubMed Central

    Han, Jing; Wang, Dongjin; Di, Shouyin; Hu, Wei; Liu, Dong; Li, Xiaofei; Reiter, Russel J.; Yan, Xiaolong

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is a leading cause of death from cancer worldwide. Melatonin, an indoleamine discovered in the pineal gland, exerts pleiotropic anticancer effects against a variety of cancer types. In particular, melatonin may be an important anticancer drug in the treatment of NSCLC. Herein, we review the correlation between the disruption of the melatonin rhythm and NSCLC incidence; we also evaluate the evidence related to the effects of melatonin in inhibiting lung carcinogenesis. Special focus is placed on the oncostatic effects of melatonin, including anti-proliferation, induction of apoptosis, inhibition of invasion and metastasis, and enhancement of immunomodulation. We suggest the drug synergy of melatonin with radio- or chemotherapy for NSCLC could prove to be useful. Taken together, the information complied herein may serve as a comprehensive reference for the anticancer mechanisms of melatonin against NSCLC, and may be helpful for the design of future experimental research and for advancing melatonin as a therapeutic agent for NSCLC. PMID:27102150

  11. Switch maintenance therapy with docetaxel and bevacizumab after induction therapy with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous non-small cell lung cancer: a phase II study.

    PubMed

    Nishimoto, Koji; Karayama, Masato; Inui, Naoki; Yasui, Hideki; Hozumi, Hironao; Suzuki, Yuzo; Furuhashi, Kazuki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Inami, Nao; Matsuura, Shun; Kaida, Yusuke; Matsui, Takashi; Asada, Kazuhiro; Matsuda, Hiroyuki; Fujii, Masato; Toyoshima, Mikio; Imokawa, Shiro; Suda, Takafumi

    2018-06-16

    Switch maintenance therapy, using alternative agents that were not administered during induction chemotherapy, is a treatment option for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab is known to increase the efficacy of other chemotherapeutic agents; however, switch maintenance therapy with docetaxel and bevacizumab has not been adequately studied. The goal of this study was to evaluate the efficacy and safety of switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab. Chemotherapy-naïve non-squamous NSCLC patients received induction therapy of four cycles of cisplatin (75 mg/m 2 ), pemetrexed (500 mg/m 2 ), and bevacizumab (15 mg/kg). Patients who achieved disease control after induction therapy then received maintenance therapy with docetaxel (50 mg/m 2 ) and bevacizumab (15 mg/kg) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival from enrollment. This study enrolled 49 NSCLC patients, among which 38 (77.6%) completed the four cycles of induction therapy and received maintenance therapy. The median progression-free survival from enrollment was 7.8 months (95% confidence interval: 4.7-11.0 months). The most common toxicities of grade 3 or higher were neutropenia (68.4%), leukopenia (50.0%), febrile neutropenia (31.8%), and hypertension. Switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab demonstrated modest efficacy and frequent hematologic toxicity in non-squamous NSCLC patients.

  12. Emerging Trends in the Management of Brain Metastases from Non-small Cell Lung Cancer.

    PubMed

    Churilla, Thomas M; Weiss, Stephanie E

    2018-05-07

    To summarize current approaches in the management of brain metastases from non-small cell lung cancer (NSCLC). Local treatment has evolved from whole-brain radiotherapy (WBRT) to increasing use of stereotactic radiosurgery (SRS) alone for patients with limited (1-4) brain metastases. Trials have established post-operative SRS as an alternative to adjuvant WBRT following resection of brain metastases. Second-generation TKIs for ALK rearranged NSCLC have demonstrated improved CNS penetration and activity. Current brain metastasis trials are focused on reducing cognitive toxicity: hippocampal sparing WBRT, SRS for 5-15 metastases, pre-operative SRS, and use of systemic targeted agents or immunotherapy. The role for radiotherapy in the management of brain metastases is becoming better defined with local treatment shifting from WBRT to SRS alone for limited brain metastases and post-operative SRS for resected metastases. Further trials are warranted to define the optimal integration of newer systemic agents with local therapies.

  13. Downregulation of long non-coding RNA LET predicts poor prognosis and increases Notch signaling in non-small cell lung cancer

    PubMed Central

    Li, Shengwen; Zhao, Hui; Li, Jianqiang; Zhang, Aizheng; Wang, Haibin

    2018-01-01

    Long non-coding RNAs (lncRNAs) have been found to be dysregulated in a variety of tumors. The lncRNA-Low Expression in Tumor (LET) is a recently identified lncRNA, but its expression pattern and biological significance in human non-small cell lung cancer (NSCLC) are still largely unknown. In this study, we found that lncRNA-LET was significantly downregulated in human NSCLC lung tissues and cell lines. Decreased lncRNA-LET expression was strongly associated with advanced tumor stages and poorer overall survival of NSCLC patients. Functionally, overexpression of lncRNA-LET in NSCLC H292 cells significantly suppressed cell proliferation, migration and invasion, and promoted cell cycle arrest and apoptosis, while knockdown of lncRNA-LET in NSCLC H1975 cells showed an opposite effect, pointing to a tumor-suppressive role for lncRNA-LET in NSCLC. Mechanistically, we demonstrated that lncRNA-LET overexpression significantly reduced the expression of Notch1 intracellular Domain (NICD1) in H292 cells while knockdown of lncRNA-LET increased NICD1 expression in H1975 cells. Similarly, NSCLC lung tissues with high levels of lncRNA-LET had lower NICD1 expression. Thus, our results provide a strong rationale for lncRNA-LET to be used as a prognostic indicator and a potent therapeutic target for NSCLC patients, and highlight a novel lncRNA-LET/Notch axis in regulating NSCLC cell fate and tumor progression. PMID:29416684

  14. The role of alectinib in the treatment of advanced ALK-rearranged non-small-cell lung cancer.

    PubMed

    Srinivasamaharaj, Srividya; Salame, Bilal Khameze; Rios-Perez, Jorge; Kloecker, Goetz; Perez, Cesar A

    2016-12-01

    The identification of anaplastic lymphoma kinase (ALK) gene rearrangements in subsets of non-small cell lung cancer patients has provided with unparalleled opportunities to hinder the progression of this disease through targeting the activity of these specific molecules. Unfortunately most patients develop disease progression in less than a year of treatment with crizotinib, the first-generation ALK-inhibitor. Areas covered: We review the resistance mechanisms to ALK inhibitors as well as an overview of the clinical activity of the alectinib, a second generation ALK inhibitor. Expert commentary: Second generation ALK inhibitors as alectinib and ceritinib can overcome crizotinib-resistant mutations and improve central nervous system control. Novel third-generation inhibitors and combination of agents give hope of achieving an even longer disease control in the next decade.

  15. Economic evaluation of first-line and maintenance treatments for advanced non-small cell lung cancer: a systematic review.

    PubMed

    Chouaïd, Christos; Crequit, Perinne; Borget, Isabelle; Vergnenegre, Alain

    2015-01-01

    During these last years, there have been an increased number of new drugs for non-small cell lung cancer (NSCLC), with a growing financial effect on patients and society. The purpose of this article was to review the economics of first-line and maintenance NSCLC treatments. We reviewed economic analyses of NSCLC therapies published between 2004 and 2014. In first-line settings, in unselected patients with advanced NSCLC, the cisplatin gemcitabine doublet appears to be cost-saving compared with other platinum doublets. In patients with nonsquamous NSCLC, the incremental cost-effectiveness ratios (ICERs) per life-year gained (LYG) were $83,537, $178,613, and more than $300,000 for cisplatin-pemetrexed compared with, respectively, cisplatin-gemcitabine, cisplatin-carboplatin-paclitaxel, and carboplatin-paclitaxel-bevacizumab. For all primary chemotherapy agents, use of carboplatin is associated with slightly higher costs than cisplatin. In all the analysis, bevacizumab had an ICER greater than $150,000 per quality-adjusted life-year (QALY). In epidermal growth factor receptor mutated advanced NSCLC, compared with carboplatin-paclitaxel doublet, targeted therapy based on testing available tissue yielded an ICER of $110,644 per QALY, and the rebiopsy strategy yielded an ICER of $122,219 per QALY. Compared with the triplet carboplatin-paclitaxel-bevacizumab, testing and rebiopsy strategies had ICERs of $25,547 and $44,036 per QALY, respectively. In an indirect comparison, ICERs per LYG and QALY of erlotinib versus gefitinib were $39,431 and $62,419, respectively. In anaplastic lymphoma kinase-positive nonsquamous advanced NSCLC, the ICER of first-line crizotinib compared with that of chemotherapy was $255,970 per QALY. For maintenance therapy, gefitinib had an ICER of $19,214 per QALY, erlotinib had an ICER of $127,343 per LYG, and pemetrexed had an ICER varying between $183,589 and $205,597 per LYG. Most recent NSCLC strategies are based on apparently no cost

  16. Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors and Non-Small Cell Lung Cancer (NSCLC) - Advances in Molecular Diagnostic Techniques to Facilitate Targeted Therapy.

    PubMed

    Ghafoor, Qamar; Baijal, Shobhit; Taniere, Phillipe; O'Sullivan, Brendan; Evans, Matthew; Middleton, Gary

    2017-12-21

    A subset of patients with non-small cell lung cancer (NSCLC) respond well to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), due to the presence of sensitising mutations in the gene encoding EGFR. Mutations associated with resistance to first generation EGFR TKIs have also been identified, which lead to therapeutic failure and the requirement for new drugs. Three generations of EGFR TKIs have been developed and either have been, or are being, evaluated as first and/or second line therapeutic agents. In this review, we consider the advances in molecular diagnostic techniques that are used, or are in development, to facilitate the targeted EGFR TKI therapy of patients with NSCLC. A literature search was conducted in May 2017 using PubMed, and spanning the period September 2005 (EU approval date of erlotinib) to May 2017. Search terms used were: EGFR TKI, NSCLC, clinical trial, erlotinib, gefitinib, afatinib, EGFR mutations, Exon 19 deletion, and Leu858Arg. The use of molecular data, in conjunction with other clinical and diagnostic information, will assist physicians to make the best therapeutic choice for each patient with advanced NSCLC. Personalized medicine and a rapidly developing therapy landscape will enable these patients to achieve optimal responses to EGFR TKIs.

  17. [Comparison of the Efficacy and Safety of Icotinib with Standard Second-line 
Chemotherapy in Previously Treated Advanced Non-small Cell Lung Cancer].

    PubMed

    Yao, Shuyang; Qian, Kun; Wang, Ruotian; Li, Yuanbo; Zhang, Yi

    2015-06-01

    This study compared the efficacy and safety of icotinib with standard second-line chemotherapy (single-agent docetaxel or pemetrexed) in previously treated advanced non-small cell lung cancer (NSCLC). Thirty-two consecutive patients treated with icotinib and 33 consecutive patients treated with standard second-line chemotherapy in Xuanwu Hospital from January 2012 to July 2013 were enrolled in our retrospective research. The Response Evaluation Criteria in Solid Tumors were used to evaluate the tumor responses, and the progression-free survival (PFS) was evaluated by Kaplan-Meier method. Icotinib was comparable with standard second-line chemotherapy for advanced NSCLC in terms of overall response rate (ORR) (28.1% vs 18.2%, P=0.341), disease control rate (DFS)(43.8% vs 45.5%, P=0.890), and PFS (4.3 months vs 3.8 months, P=0.506). In the icotinib group, the ORR of epidermal growth factor receptor (EGFR) mutant was significantly higher than that of EGFR unknown or wild type (P=0.017). In multivariate analysis, age, gender, histology, and the optimum first-line treatment response were dependent prognostic factors based on the PFS of the icotinib group. The incidence of adverse events was significantly fewer in the icotinib group than in the chemotherapy group (P=0.001). Compared with the standard second-line chemotherapy, icotinib is active in the treatment of advanced NSCLC patients, especially with EGFR unknown in the second line, with an acceptable adverse event profile.

  18. 76 FR 35450 - Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-17

    ...] Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer... entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics... draft guidance for industry entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

  19. Challenges in the current antiangiogenic treatment paradigm for patients with non-small cell lung cancer.

    PubMed

    Wozniak, Antoinette

    2012-05-01

    Patients with non-small cell lung cancer (NSCLC) often present with advanced disease and cure rates are dismal with currently available treatment. Novel therapies including small molecule tyrosine kinase inhibitors and monoclonal antibodies are being developed to target angiogenesis, an essential step in tumorigenesis and metastasis. The only antiangiogenic agent currently approved for treatment of NSCLC is bevacizumab, although numerous other antiangiogenic inhibitors (e.g., sorafenib, sunitinib, cediranib, motesanib, BIBF 1120) are in clinical trials. Individualized treatment algorithms may improve patient outcomes and new evidence suggests that biomarkers may guide treatment decisions. We present an overview of the molecular pathways involved in angiogenesis, discuss clinical trials of bevacizumab and developmental antiangiogenic agents, and address the challenges of developing individualized treatment paradigms for NSCLC, particularly the use of biomarkers. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  20. Cetuximab for treating non-small cell lung cancer.

    PubMed

    Mazzarella, Luca; Guida, Alessandro; Curigliano, Giuseppe

    2018-04-01

    Epidermal Growth Factor Receptor (EGFR)-dependent signaling plays a crucial role in epithelial cancer biology, and dictated the development of several targeting agents. The mouse-human chimeric antibody Cetuximab was among the first to be developed. After about two decades of clinical research it has gained a significant place in the management of advanced colorectal and head and neck cancers, whereas its development in non small cell lung cancer (NSCLC) has not led to a place in routine clinical practice, because of marginal clinical benefit despite statistically significant Phase III trials. Recent data from ongoing trials suggest that more careful selection based on molecular markers may identify good responders. Areas covered: In this article, the authors review the literature concerning basic science studies identifying EGFR as a therapeutic target, pharmacological development of Cetuximab, its pharmacodynamics and pharmacokinetics, and clinical trials on Cetuximab in NSCLC, focusing on recent findings on putative predictive biomarkers. Expert opinion: Cetuximab currently has no role in NSCLC treatment outside of research settings. We argue that failure to identify a predictive biomarker early on has hampered its chances to enter routine practice. Although recent research suggests benefit in highly selected patient subsets, its potential impact is severely dampened by lack of regulatory body approval and the emergence of competitors for the same niches.

  1. Atezolizumab: feasible second-line therapy for patients with non-small cell lung cancer? A review of efficacy, safety and place in therapy.

    PubMed

    Jean, Fanny; Tomasini, Pascale; Barlesi, Fabrice

    2017-12-01

    Advanced non-small cell lung cancer (NSCLC) prognosis is still poor and has recently been reformed by the development of immune checkpoint inhibitors and the approval of anti-PD-1 (programmed cell-death 1) treatments such as nivolumab and pembrolizumab in second line. More recently, atezolizumab (MDPL 3280A), a programmed cell-death-ligand 1 (PD-L1) inhibitor, was also studied in this setting. Here, we report a review of the literature assessing the efficacy, safety, and place of atezolizumab in the second-line treatment of advanced NSCLC. We performed a literature search of PubMed, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference on Lung Cancer meetings. Atezolizumab showed a good tolerance profile and efficacy in comparison with docetaxel for second-line treatment of advanced NSCLC. Potential predictive biomarkers also have to be assessed.

  2. Atezolizumab: feasible second-line therapy for patients with non-small cell lung cancer? A review of efficacy, safety and place in therapy

    PubMed Central

    Jean, Fanny; Tomasini, Pascale; Barlesi, Fabrice

    2017-01-01

    Advanced non-small cell lung cancer (NSCLC) prognosis is still poor and has recently been reformed by the development of immune checkpoint inhibitors and the approval of anti-PD-1 (programmed cell-death 1) treatments such as nivolumab and pembrolizumab in second line. More recently, atezolizumab (MDPL 3280A), a programmed cell-death-ligand 1 (PD-L1) inhibitor, was also studied in this setting. Here, we report a review of the literature assessing the efficacy, safety, and place of atezolizumab in the second-line treatment of advanced NSCLC. We performed a literature search of PubMed, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference on Lung Cancer meetings. Atezolizumab showed a good tolerance profile and efficacy in comparison with docetaxel for second-line treatment of advanced NSCLC. Potential predictive biomarkers also have to be assessed. PMID:29449897

  3. Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients.

    PubMed

    Cadranel, Jacques; Cortot, Alexis B; Lena, Hervé; Mennecier, Bertrand; Do, Pascal; Dansin, Eric; Mazieres, Julien; Chouaid, Christos; Perol, Maurice; Barlesi, Fabrice; Robinet, Gilles; Friard, Sylvie; Thiberville, Luc; Audigier-Valette, Clarisse; Vergnenegre, Alain; Westeel, Virginie; Slimane, Khemaies; Buturuga, Alexandru; Moro-Sibilot, Denis; Besse, Benjamin

    2018-01-01

    Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase ( ALK ) positive ( ALK + ) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK + or ROS proto-oncogene 1 positive ( ROS1 + ) tumours. Patients received oral ceritinib (750 mg·day -1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK + NSCLC and 13 had ROS1 + NSCLC. The median age of ALK + patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK + NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4%) and those receiving prior crizotinib for >5 months (51.6% versus 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day -1 ) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK + NSCLC.

  4. Characterization of osimertinib (AZD9291)-resistant non-small cell lung cancer NCI-H1975/OSIR cell line

    PubMed Central

    Guo, Xia; Fong, Chi Man Vivienne; Chen, Xiuping; Lu, Jin-Jian

    2016-01-01

    Osimertinib (OSI, also known as AZD9291) is the newest FDA-approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. However, resistance to OSI is likely to progress and the study of potential OSI-resistant mechanisms in advanced is necessary. Here, the OSI-resistant NCI-H1975/OSIR cells were established. After cells developed resistance to OSI, cell proliferation was decreased while cell migration and invasion were increased. The NCI-H1975/OSIR cells exhibited more resistance to gefitinib, erlotinib, afatinib, rociletinib, doxorubicin, and fluorouracil, meanwhile showing higher sensitivity to paclitaxel, when compared with NCI-H1975 cells. In addition, the NCI-H1975/OSIR cells did not display multidrug resistance phenotype. The activation and expression of EGFR were decreased after cells exhibited resistance. Compared with NCI-H1975 cells, the activation of ERK and AKT in NCI-H1975/OSIR cells could not be significantly inhibited by OSI treatment. Navitoclax (ABT-263)-induced cell viability inhibition and apoptosis were more significant in NCI-H1975/OSIR cells than that in NCI-H1975 cells. Moreover, these effects of navitoclax in NCI-H1975/OSIR cells could be reversed by pretreatment of Z-VAD-FMK. Collectively, loss of EGFR could pose as one of the OSI-resistant mechanisms and navitoclax might be the candidate drug for OSI-resistant NSCLC patients. PMID:27835594

  5. Prior cancer does not adversely affect survival in locally advanced lung cancer: A national SEER-medicare analysis.

    PubMed

    Laccetti, Andrew L; Pruitt, Sandi L; Xuan, Lei; Halm, Ethan A; Gerber, David E

    2016-08-01

    Management of locally advanced non-small cell lung cancer is among the most highly contested areas in thoracic oncology. In this population, a history of prior cancer frequently results in exclusion from clinical trials and may influence therapeutic decisions. We therefore determined prevalence and prognostic impact of prior cancer among these patients. We identified patients>65years of age diagnosed 1992-2009 with locally advanced lung cancer in the Surveillance, Epidemiology, and End Results-Medicare linked dataset. We characterized prior cancer by prevalence, type, stage, and timing. We compared all-cause and lung cancer-specific survival between patients with and without prior cancer using propensity score-adjusted Cox regression. 51,542 locally advanced lung cancer patients were included; 15.8% had a history of prior cancer. Prostate (25%), gastrointestinal (17%), breast (16%), and other genitourinary (15%) were the most common types of prior cancer, and 76% percent of prior cancers were localized or in situ stage. Approximately half (54%) of prior cancers were diagnosed within 5 years of the index lung cancer date. Patients with prior cancer had similar (propensity-score adjusted hazard ratio [HR] 0.96; 95% CI, 0.94-0.99; P=0.005) and improved lung cancer-specific (HR 0.84; 95% CI, 0.81-0.86; P<0.001) survival compared to patients with no prior cancer. For patients with locally advanced lung cancer, prior cancer does not adversely impact clinical outcomes. Patients with locally advanced lung cancer and a history of prior cancer should not be excluded from clinical trials, and should be offered aggressive, potentially curative therapies if otherwise appropriate. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Methodology of health-related quality of life analysis in phase III advanced non-small-cell lung cancer clinical trials: a critical review.

    PubMed

    Fiteni, Frédéric; Anota, Amélie; Westeel, Virginie; Bonnetain, Franck

    2016-02-18

    Health-related quality of life (HRQoL) is recognized as a component endpoint for cancer therapy approvals. The aim of this review was to evaluate the methodology of HRQoL analysis and reporting in phase III clinical trials of first-line chemotherapy in advanced non-small cell lung cancers (NSCLC). A search in MEDLINE databases identified phase III clinical trials in first-line chemotherapy for advanced NSCLC, published between January 2008 to December 2014. Two authors independently extracted information using predefined data abstraction forms. A total of 55 phase III advanced NSCLC trials were identified. HRQoL was declared as an endpoint in 27 studies (49%). Among these 27 studies, The EORTC questionnaire Quality of Life Questionnaire C30 was used in 13 (48%) of the studies and The Functional Assessment of Cancer Therapy-General was used in 12 (44%) trials. The targeted dimensions of HRQoL, the minimal clinically important difference and the statistical approaches for dealing with missing data were clearly specified in 13 (48.1%), 9 (33.3%) and 5 (18.5%) studies, respectively. The most frequent statistical methods for HRQoL analysis were: the mean change from baseline (33.3%), the linear mixed model for repeated measures (22.2%) and time to HRQoL score deterioration (18.5%). For each targeted dimension, the results for each group, the estimated effect size and its precision were clearly reported in 4 studies (14.8%), not clearly reported in 11 studies (40.7%) and not reported at all in 12 studies (44.4%). This review demonstrated the weakness and the heterogeneity of the measurement, analysis, and reporting of HRQoL in phase III advanced NSCLC trials. Precise and uniform recommendations are needed to compare HRQoL results across publications and to provide understandable messages for patients and clinicians.

  7. Clinical outcome of fiducial-less CyberKnife radiosurgery for stage I non-small cell lung cancer

    PubMed Central

    Jung, In-Hye; Jung, Jinhong; Cho, Byungchul; Kwak, Jungwon; Je, Hyoung Uk; Choi, Wonsik; Jung, Nuri Hyun; Kim, Su Ssan; Choi, Eun Kyung

    2015-01-01

    Purpose To evaluate the treatment results in early stage non-small cell lung cancer patients who have undergone fiducial-less CyberKnife radiosurgery (CKRS). Materials and Methods From June 2011 to November 2013, 58 patients underwent CKRS at Asan Medical Center for stage I lung cancer. After excluding 14 patients, we retrospectively reviewed the records of the remaining 44 patients. All analyses were performed using SPSS ver. 21. Results The median age at diagnosis was 75 years. Most patients had inoperable primary lung cancer with a poor pulmonary function test with comorbidity or old age. The clinical stage was IA in 30 patients (68.2%), IB in 14 (31.8%). The mean tumor size was 2.6 cm (range, 1.2 to 4.8 cm), and the tumor was smaller than 2 cm in 12 patients (27.3%). The radiation dose given was 48-60 Gy in 3-4 fractions. In a median follow-up of 23.1 months, local recurrence occurred in three patients (2-year local recurrence-free survival rate, 90.4%) and distant metastasis occurred in 13 patients. All patients tolerated the radiosurgery well, only two patients developing grade 3 dyspnea. The most common complications were radiation-induced fibrosis and pneumonitis. Eight patients died due to cancer progression. Conclusion The results showed that fiducial-less CKRS shows comparable local tumor control and survival rates to those of LINAC-based SABR or CKRS with a fiducial marker. Thus, fiducial-less CKRS using Xsight lung tracking system can be effectively and safely performed for patients with medically inoperable stage I non-small cell lung cancer without any risk of procedure-related complication. PMID:26157678

  8. Liquid biopsy based biomarkers in non-small cell lung cancer for diagnosis and treatment monitoring.

    PubMed

    Pérez-Callejo, David; Romero, Atocha; Provencio, Mariano; Torrente, María

    2016-10-01

    Advances in the knowledge of the biology of non-small cell lung cancer (NSCLC) have revealed molecular information used for systemic cancer therapy targeting metastatic disease, with an important impact on patients overall survival (OS) and quality of life. However, a biopsy of overt metastases is an invasive procedure limited to certain locations and not easily acceptable in the clinic. Moreover, a single biopsy cannot reflect the clonal heterogeneity of the tumor. The analysis of peripheral blood samples of cancer patients represents a new source of cancer-derived material, known as liquid biopsy, and its components can be obtained from almost all body fluids. These components have shown to reflect characteristics of the status of both the primary and metastatic diseases, helping the clinicians to move towards a personalized medicine. The present review focuses on the liquid biopsy components: circulating tumor cells (CTCS), circulating free DNA (cfDNA), exosomes and tumor-educated platelets (TEP); the isolation technologies used and their potential use for non-invasive screening, early diagnosis, prognosis, response to treatment and real time monitoring of the disease, in NSCLC patients.

  9. Pathobiological implications of MUC4 in non-small-cell lung cancer.

    PubMed

    Majhi, Prabin Dhangada; Lakshmanan, Imayavaramban; Ponnusamy, Moorthy P; Jain, Maneesh; Das, Srustidhar; Kaur, Sukhwinder; Shimizu, Su Tomohiro; West, William W; Johansson, Sonny L; Smith, Lynette M; Yu, Fang; Rolle, Cleo E; Sharma, Poonam; Carey, George B; Batra, Surinder K; Ganti, Apar Kishor

    2013-04-01

    Altered expression of MUC4 plays an oncogenic role in various cancers, including pancreatic, ovarian, and breast. This study evaluates the expression and role of MUC4 in non-small-cell lung cancer (NSCLC). We used a paired system of MUC4-expressing (H292) and MUC4-nonexpressing (A549) NSCLC cell lines to analyze MUC4-dependent changes in growth rate, migration, and invasion using these sublines. We also evaluated the alterations of several tumor suppressor, proliferation, and metastasis markers with altered MUC4 expression. Furthermore, the association of MUC4 expression (by immunohistochemistry) in lung cancer samples with patient survival was evaluated. MUC4-expressing lung cancer cells demonstrated a less proliferative and metastatic phenotype. Up-regulation of p53 in MUC4-expressing lung cancer cells led to the accumulation of cells at the G2/M phase of cell cycle progression. MUC4 expression attenuated Akt activation and decreased the expression of Cyclins D1 and E, but increased the expression of p21 and p27. MUC4 expression abrogated cancer cell migration and invasion by altering N- & E-cadherin expression and FAK phosphorylation. A decrease in MUC4 expression was observed with increasing tumor stage (mean composite score: stage I, 2.4; stage II, 1.8; stage III, 1.4; and metastatic, 1.2; p = 0.0093). Maximal MUC4 expression was associated with a better overall survival (p = 0.042). MUC4 plays a tumor-suppressor role in NSCLC by altering p53 expression in NSCLC. Decrease in MUC4 expression in advanced tumor stages also seems to confirm the novel protective function of MUC4 in NSCLC.

  10. Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study.

    PubMed

    Morrow, C J; Trapani, F; Metcalf, R L; Bertolini, G; Hodgkinson, C L; Khandelwal, G; Kelly, P; Galvin, M; Carter, L; Simpson, K L; Williamson, S; Wirth, C; Simms, N; Frankliln, L; Frese, K K; Rothwell, D G; Nonaka, D; Miller, C J; Brady, G; Blackhall, F H; Dive, C

    2016-06-01

    Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, 'liquid biopsies' such as circulating tumour cells (CTCs) are minimally invasive and easier to obtain. Here, we present a clinical case study of a NSCLC patient with advanced metastatic disease, a never smoker whose primary tumour was EGFR and ALK wild-type. We demonstrate for the first time, tumorigenicity of their CTCs to generate a patient CTC-derived eXplant (CDX). CTCs were enriched at diagnosis and again 2 months later during disease progression from 10 ml blood from a 48-year-old NSCLC patient and implanted into immunocompromised mice. Resultant tumours were morphologically, immunohistochemically, and genetically compared with the donor patient's diagnostic specimen. Mice were treated with cisplatin and pemetrexed to assess preclinical efficacy of the chemotherapy regimen given to the donor patient. The NSCLC CDX expressed lung lineage markers TTF1 and CK7 and was unresponsive to cisplatin and pemetrexed. Examination of blood samples matched to that used for CDX generation revealed absence of CTCs using the CellSearch EpCAM-dependent platform, whereas size-based CTC enrichment revealed abundant heterogeneous CTCs of which ∼80% were mesenchymal marker vimentin positive. Molecular analysis of the CDX, mesenchymal and epithelial CTCs revealed a common somatic mutation confirming tumour origin and showed CDX RNA and protein profiles consistent with the predominantly mesenchymal phenotype. This study shows that the absence of NSCLC CTCs detected by CellSearch (EpCAM(+)) does not preclude CDX generation, highlighting epithelial to mesenchymal transition and the

  11. Personalized treatment in advanced ALK-positive non-small cell lung cancer: from bench to clinical practice

    PubMed Central

    Passaro, Antonio; Lazzari, Chiara; Karachaliou, Niki; Spitaleri, Gianluca; Pochesci, Alessia; Catania, Chiara; Rosell, Rafael; de Marinis, Filippo

    2016-01-01

    The discovery of anaplastic lymphoma kinase (ALK) gene rearrangements and the development of tyrosine kinase inhibitors (TKI) that target them have achieved unprecedented success in the management of patients with ALK-positive non-small cell lung cancer (NSCLC). Despite the high efficacy of crizotinib, the first oral ALK TKI approved for the treatment of ALK-positive NSCLC, almost all patients inevitably develop acquired resistance, showing disease progression in the brain or in other parenchymal sites. Second- or third-generation ALK TKIs have shown to be active in crizotinib-pretreated or crizotinib-naïve ALK-positive patients, even in those with brain metastases. In this review, the current knowledge regarding ALK-positive NSCLC, focusing on the biology of the disease and the available therapeutic options are discussed. PMID:27799783

  12. [Efficacy and Survival Analysis of Apatinib in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer after Failure of First-line Treatment].

    PubMed

    Wang, Xuemin; Zhang, Weihong; Du, Weijiao; Zhang, Xinwei; Ren, Xiubao; Cao, Shui

    2017-11-20

    The efficacy of second or third-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients is low. The use of targeted drugs brings survival benefit for some patients. Apatinib, as a novel small molecule antiangiogenic drug, has demonstrated satisfactory anticancer activity across a broad range of malignancies. The aim of this study is to evaluate the efficacy and safety of apatinib in patients with advanced NSCLC after first-line treatment failure. A retrospective study of 128 patients was conducted to evaluate the safety, short-term efficacy and survival status with different regimens. Kaplan-Meier method and Cox regression model were used for analysis. Compared with chemotherapy alone, the median progression free survival (PFS) in apatinib monotherapy, chemotherapy alone and apatinib combined with chemotherapy were 3.0 (P=0.381), 3.7 and 6.0 months (P<0.001), respectively. The median overall survival (OS) were 6.0 (P=0.494), 6.5 and 9.0 months (P=0.001), respectively. The incidence of adverse events in grades 3-4 were 18.5%, 15.8% and 16.0%, respectively (P=0.947). Different treatment regimens (P=0.018) and performance status (PS)(P<0.001) were the independent factors of PFS. The smoking history (P=0.014), treatment regimens (P=0.002) and PS (P<0.001) were independent influencing factors of OS. Apatinib has a good security. After first-line treatment failure of lung cancer, chemotherapy combined with apatinib in second or third-line is beneficial in PFS and OS when compared with chemotherapy alone. But when making comparison between apatinib monotherapy and chemotherapy alone, there is no significant difference in PFS and OS. Patients who never smoke or has a better PS or use combination therapy have longer survival time.
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  13. Genetic Contribution to Non-Squamous, Non-Small Cell Lung Cancer in Non-Smokers.

    PubMed

    Carr, Shamus R; Akerley, Wallace; Cannon-Albright, Lisa

    2018-04-04

    Lung carcinogenesis is strongly influenced by environmental and heritable factors. The genetic contribution to the different histologies is unknown. A population-based computerized genealogy resource linked to a statewide cancer registry of lung cancer cases (n=5408) was analyzed to evaluate the heritable contribution to lung cancer histology in smoking (n=1751) and non-smoking cases (n=818). Statistical methods were used to test for significant excess relatedness of lung cancer cases. Significant excess distant relatedness was observed for all lung cancer histology subgroups analyzed except the small cell lung cancer subset (p=0.213). When smoking and non-smoking histologic subsets of lung cancer were considered, excess relatedness was observed only in non-smoking NSCLC (n=653; p=0.026) and, particularly, in those non-smokers with non-squamous histology (n=561; p=0.036). Sixty one pedigrees were identified which demonstrated a significant excess risk of non-smoking, non-squamous lung cancer cases; and an excess of female cases was observed among the cases in these high-risk pedigrees. This analysis supports a genetic predisposition to lung cancer carcinogenesis in non-smoking, non-squamous NSCLC cases. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  14. Pretreatment red blood cell total folate is associated with response to pemetrexed in stage IV non-squamous non-small-cell lung cancer

    PubMed Central

    Bagley, Stephen J.; Vitale, Steven; Zhang, Suhong; Aggarwal, Charu; Evans, Tracey L.; Alley, Evan W.; Cohen, Roger B.; Langer, Corey J.; Blair, Ian A.; Vachani, Anil; Whitehead, Alexander S.

    2016-01-01

    Objectives Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Prior studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic marker of cellular folate status, was associated with response to pemetrexed-based chemotherapy in advanced non-squamous non-small-cell lung cancer (NSCLC). Materials and methods We conducted a prospective cohort study of patients with stage IV non-squamous NSCLC receiving first-line chemotherapy containing pemetrexed. Pretreatment RBC total folate was quantified using liquid chromatography/mass spectrometry. We then compared objective response rate (ORR) between patients with RBC total folate concentrations above and below an optimal cut-off value determined from the receiver operating characteristic (ROC) curve. A logistic regression model was used to adjust for age, sex, and use of bevacizumab. Results The ORR was 62% (32 of 52 patients). ROC analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and non-responders. Patients with RBC total folate below 364.5 nM had an ORR of 27%, compared to 71% in patients with RBC total folate above this value (p=0.01). This difference persisted after adjusting for age, sex, and use of bevacizumab (OR 0.07, 95% CI 0.01 - 0.57, p=0.01). Conclusions Low pretreatment RBC total folate is associated with inferior response to pemetrexed-based chemotherapy in stage IV non-squamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response. PMID:27863923

  15. The Efficacy and Safety of Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Chemotherapy: A Single-Arm, Multi-Center, Prospective Study.

    PubMed

    Hu, Xingsheng; Zhang, Li; Shi, Yuankai; Zhou, Caicun; Liu, Xiaoqing; Wang, Dong; Song, Yong; Li, Qiang; Feng, Jifeng; Qin, Shukui; Xv, Nong; Zhou, Jianying; Zhang, Li; Hu, Chunhong; Zhang, Shucai; Luo, Rongcheng; Wang, Jie; Tan, Fenlai; Wang, Yinxiang; Ding, Lieming; Sun, Yan

    2015-01-01

    Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125 mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety. From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9-6.6 m) and 5.4 months (95%CI 3.1-7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127). In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy. ClinicalTrials.gov NCT02486354.

  16. Cancer cachexia, sarcopenia and biochemical markers in patients with advanced non-small cell lung cancer-chemotherapy toxicity and prognostic value.

    PubMed

    Srdic, Drazena; Plestina, Sanja; Sverko-Peternac, Ana; Nikolac, Nora; Simundic, Ana-Maria; Samarzija, Miroslav

    2016-11-01

    Cancer cachexia and sarcopenia are frequently observed in cancer patients and associated with poor survival. The majority of studies of cancer cachexia and sarcopenia have been done in patients with solid tumors of different origins, and there are currently no good predictors of the benefit of chemotherapy or factors that predict survival in advanced cancer. The purpose of our prospective study was to evaluate prevalence of cachexia and sarcopenia using international consensus definition and criteria for diagnosis in patients with diagnosed advanced non-small cell lung cancer (NSCLC) stage IIIB and IV and their relation to chemotherapy toxicity and survival prediction. A secondary aim was to compare several biochemical markers (CRP, IL-6, protein, and albumin) with time to tumor progression in order to assess prognostic value or to guide a treatment. Between December 2013 and April 2015, the prospective cohort study of 100 Caucasian patients with advanced NSCLC stage IIIB or IV, who were referred consecutively to Department for Respiratory Diseases "Jordanovac," was evaluated. Anthropometric measurements and biochemical data (CRP, albumin, protein, IL-6, haemoglobin) together with body composition measurements (total muscle cross-sectional area, lumbar skeletal muscle index) were obtained for each patient before starting with platinum-doublet therapy. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment and time-to-tumor progression was determined prospectively. One hundred patients with advanced lung cancer were recruited: 67 were male and median age was 64 years. The median time to disease progression was 187 days. The prevalence of cachexia and sarcopenia in study cohort was 69 and 47 %, respectively. CRP, IL-6, and albumin concentration in cachectic compared to non-cachectic patients

  17. New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib

    PubMed Central

    Rothschild, Sacha I

    2016-01-01

    Rearrangements in ALK gene and EML4 gene were first described in 2007. This genomic aberration is found in about 2%–8% of non-small-cell lung cancer (NSCLC) patients. Crizotinib was the first ALK tyrosine kinase inhibitor licensed for the treatment of metastatic ALK-positive NSCLC based on a randomized Phase III trial. Despite the initial treatment response of crizotinib, disease progression inevitably develops after approximately 10 months of therapy. Different resistance mechanisms have recently been described. One relevant mechanism of resistance is the development of mutations in ALK. Novel ALK tyrosine kinase inhibitors have been developed to overcome these mutations. Ceritinib is an oral second-generation ALK inhibitor showing clinical activity not only in crizotinib-resistant ALK-positive NSCLC but also in treatment-naïve ALK-positive disease. In this paper, preclinical and clinical data of ceritinib are reviewed, and its role in the clinical setting is put into perspective. PMID:27217763

  18. New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib.

    PubMed

    Rothschild, Sacha I

    2016-01-01

    Rearrangements in ALK gene and EML4 gene were first described in 2007. This genomic aberration is found in about 2%-8% of non-small-cell lung cancer (NSCLC) patients. Crizotinib was the first ALK tyrosine kinase inhibitor licensed for the treatment of metastatic ALK-positive NSCLC based on a randomized Phase III trial. Despite the initial treatment response of crizotinib, disease progression inevitably develops after approximately 10 months of therapy. Different resistance mechanisms have recently been described. One relevant mechanism of resistance is the development of mutations in ALK. Novel ALK tyrosine kinase inhibitors have been developed to overcome these mutations. Ceritinib is an oral second-generation ALK inhibitor showing clinical activity not only in crizotinib-resistant ALK-positive NSCLC but also in treatment-naïve ALK-positive disease. In this paper, preclinical and clinical data of ceritinib are reviewed, and its role in the clinical setting is put into perspective.

  19. xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression.

    PubMed

    Ji, Xiangming; Qian, Jun; Rahman, S M Jamshedur; Siska, Peter J; Zou, Yong; Harris, Bradford K; Hoeksema, Megan D; Trenary, Irina A; Heidi, Chen; Eisenberg, Rosana; Rathmell, Jeffrey C; Young, Jamey D; Massion, Pierre P

    2018-05-23

    Many tumors increase uptake and dependence on glucose, cystine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer research. Recent studies demonstrated that smoking could induce the expression of xCT (SLC7A11) in oral cancer cells, suggesting that overexpression of xCT may support lung tumor progression. We hypothesized that overexpression of xCT occurs in lung cancer cells to satisfy the metabolic requirements for growth and survival. Our results demonstrated that 1) xCT was highly expressed at the cytoplasmic membrane in non-small cell lung cancer (NSCLC), 2) the expression of xCT was correlated with advanced stage and predicted a worse 5-year survival, 3) targeting xCT transport activity in xCT overexpressing NSCLC cells with sulfasalazine decreased cell proliferation and invasion in vitro and in vivo and 4) increased dependence on glutamine was observed in xCT overexpressed normal airway epithelial cells. These results suggested that xCT regulate metabolic requirements during lung cancer progression and be a potential therapeutic target in NSCLC.

  20. Evaluation of EML4-ALK Fusion Proteins in Non-Small Cell Lung Cancer Using Small Molecule Inhibitors12

    PubMed Central

    Li, Yongjun; Ye, Xiaofen; Liu, Jinfeng; Zha, Jiping; Pei, Lin

    2011-01-01

    The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from an inversion within chromosome 2p occurs in approximately 5% of non-small cell lung cancer and is mutually exclusive with Ras and EGFR mutations. In this study, we have used a potent and selective ALK small molecule inhibitor, NPV-TAE684, to assess the oncogenic role of EML4-ALK in non-small cell lung cancer (NSCLC). We show here that TAE684 inhibits proliferation and induces cell cycle arrest, apoptosis, and tumor regression in two NSCLC models that harbor EML4-ALK fusions. TAE684 inhibits EML4-ALK activation and its downstream signaling including ERK, AKT, and STAT3. We used microarray analysis to carry out targeted pathway studies of gene expression changes in H2228 NSCLC xenograft model after TAE684 treatment and identified a gene signature of EML4-ALK inhibition. The gene signature represents 1210 known human genes, and the top biologic processes represented by these genes are cell cycle, DNA synthesis, cell proliferation, and cell death. We also compared the effect of TAE684 with PF2341066, a c-Met and ALK small molecule inhibitor currently in clinical trial in cancers harboring ALK fusions, and demonstrated that TAE684 is a much more potent inhibitor of EML4-ALK. Our data demonstrate that EML4-ALK plays an important role in the pathogenesis of a subset of NSCLC and provides insight into the mechanism of EML4-ALK inhibition by a small molecule inhibitor. PMID:21245935

  1. The Risk of Neutropenia and Leukopenia in Advanced Non-Small Cell Lung Cancer Patients Treated With Erlotinib

    PubMed Central

    Zhou, Jian-Guo; Tian, Xu; Cheng, Long; Zhou, Quan; Liu, Yuan; Zhang, Yu; Bai, Yu-ju; Ma, Hu

    2015-01-01

    Abstract Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a critical member of systemic therapy for advanced non-small-cell lung cancer (NSCLC). Erlotinib is the first-generation EGFR-TKIs, the National Comprehensive Cancer Network (NCCN) guidelines recommend it as a first-line agent in patients with sensitizing EGFR mutations. However, the safety of erlotinib plus chemotherapy (CT) or erlotinib alone for advanced NSCLC remains controversial. We carried out a systematic meta-analysis to determine the overall risk of neutropenia and leukopenia associated with erlotinib. PubMed, EMBASE, CBM, CNKI, WanFang database, The Cochrane library, Web of Science, as well as abstracts presented at ASCO conferences and ClinicalTrials.gov were searched to identify relevant studies. RR with 95% CIs for neutropenia and leukopenia were all extracted. The random-effects model was used to calculate pooled RRs and 95% CIs. Power calculation was performed using macro embedded in SAS software after all syntheses were conducted. We identified 12 eligible studies involving 3932 patients. Erlotinib plus CT or alone relative to CT is associated with significantly decreased risks of neutropenia and leukopenia in patients with advanced NSCLC (RR, 0.38; 95% CI, 0.21–0.71; P = 0.00; incidence: 9.9 vs. 35.2%) and (RR, 0.32; 95% CI, 0.11–0.93; P = 0.04; incidence: 3.5 vs. 11.6%), respectively. The subgroup analysis by erlotinb with or without CT showed that erlotinib combine with CT have no significance decrease the relative risks of neutropenia or leukopenia (RR, 0.98; 95% CI, 0.78–1.23; P = 0.87; incidence: 26.2 vs. 30.5%) and (RR, 0.81; 95% CI, 0.34–1.95; P = 0.64; incidence: 6.5 vs. 9.3%), respectively. However, erlotinib alone could decrease incidence of neutropenia (RR, 0.14; 95% CI, 0.07–0.27; P = 0.00; incidence: 3.7 vs. 40.8%) or leukopenia (RR, 0.07; 95% CI, 0.01–0.45; P = 0.01; incidence: 0.8 vs. 15.7%). The power analysis

  2. Nivolumab, Cisplatin, and Pemetrexed Disodium or Gemcitabine Hydrochloride in Treating Patients With Stage I-IIIA Non-small Cell Lung Cancer That Can Be Removed by Surgery

    ClinicalTrials.gov

    2018-03-02

    Non-Squamous Non-Small Cell Lung Carcinoma; Stage I Non-Small Cell Lung Cancer; Stage IA Non-Small Cell Lung Carcinoma; Stage IB Non-Small Cell Lung Carcinoma; Stage II Non-Small Cell Lung Cancer; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer

  3. Prospects and progress of atezolizumab in non-small cell lung cancer.

    PubMed

    Vansteenkiste, Johan; Wauters, Els; Park, Keunchil; Rittmeyer, Achim; Sandler, Alan; Spira, Alexander

    2017-06-01

    Immunotherapy has recently come to the forefront of oncology treatment as a potential means of combating cancer by restoring the body's adaptive cancer-immunity cycle. Atezolizumab is a monoclonal antibody agent that specifically targets programmed death ligand 1 (PD-L1), a key molecule in the cancer-immunity pathway, to block binding to its receptors PD-1 and B7.1. Areas covered: This review covers the role of atezolizumab in the treatment of non-small-cell lung cancer (NSCLC). Several studies have reported promising efficacy in this indication. The phase II FIR and BIRCH studies evaluated atezolizumab monotherapy across different lines of therapy in NSCLC selected by PD-L1 expression status. The randomized POPLAR and OAK trials of atezolizumab versus docetaxel in previously treated NSCLC reported improved efficacy in the atezolizumab arm. Several ongoing studies yet to report data are also described and treatment-related adverse events are discussed. Expert opinion: Clinical trials have shown that atezolizumab has a favorable risk-benefit ratio compared with standard chemotherapy in second-line treatment of non-oncogene-driven advanced NSCLC. Promising response rates and survival over 2 years has been reported in the first-line setting; however, more research is needed in this setting and in evaluating combinatorial strategies to treat NSCLC.

  4. Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer.

    PubMed

    Soejima, Kenzo; Yasuda, Hiroyuki; Hirano, Toshiyuki

    2017-01-01

    Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3 rd generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1 st or 2 nd generation EGFR-TKIs. A recent phase I/II clinical trial with osimertinib for advanced NSCLC patients with known sensitizing EGFR mutations and documented disease progression on prior EGFR-TKIs revealed promising effect with acceptable toxicities. Areas covered: This article summarizes current understanding and available preclinical and clinical data on osimertinib and also discusses future directions. The literature search included PubMed and the latest articles from international conferences. Expert commentary: The development of osimertinib has provided new therapeutic options for NSCLC patients harboring T790 M. Compared with other EGFR-TKIs including rociletinib, osimertinib seems to possess an advantage with respect to the effect and safety profile among existing EGFR-TKIs. However, tumor progression still occurs even when treating with osimertinib. A further understanding of the mechanisms of resistance is eagerly anticipated in order to develop next generation EGFR-TKIs.

  5. Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer.

    PubMed

    Govindan, Ramaswamy; Szczesna, Aleksandra; Ahn, Myung-Ju; Schneider, Claus-Peter; Gonzalez Mella, Pablo Fernando; Barlesi, Fabrice; Han, Baohui; Ganea, Doina Elena; Von Pawel, Joachim; Vladimirov, Vladimir; Fadeeva, Natalia; Lee, Ki Hyeong; Kurata, Takayasu; Zhang, Li; Tamura, Tomohide; Postmus, Pieter E; Jassem, Jacek; O'Byrne, Kenneth; Kopit, Justin; Li, Mingshun; Tschaika, Marina; Reck, Martin

    2017-10-20

    Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma

  6. Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014.

    PubMed

    Nixon, Nancy A; Khan, Omar F; Imam, Hasiba; Tang, Patricia A; Monzon, Jose; Li, Haocheng; Sun, Gavin; Ezeife, Doreen; Parimi, Sunil; Dowden, Scot; Tam, Vincent C

    2017-12-01

    Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. © 2017 American Cancer Society. © 2017 American Cancer Society.

  7. Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair.

    PubMed

    Li, Xiao-Qin; Ren, Jin; Chen, Ping; Chen, Yu-Jiao; Wu, Min; Wu, Yan; Chen, Kang; Li, Jian

    2018-05-31

    For the majority of patients with advanced non-small cell lung cancer (NSCLC), the standard of care remains platinum-based chemotherapy. However, cisplatin resistance is a big obstacle to the treatment, and elucidation of its mechanism is warranted. In this study, we showed that there was no difference in intracellular uptake of cisplatin or the removal of platinum-DNA adducts between a cisplatin-resistant NSCLC cell line (A549/DR) and a cisplatin-sensitive NSCLC cell line (A549). However, the capacity to repair DNA interstrand crosslinks (ICLs) and double-strand breaks (DSBs) was significantly enhanced in the A549/DR cell line compared to 3 cisplatin-sensitive cell lines. We found that the protein and mRNA expression levels of Pol η, a Y-family translesion synthesis (TLS) polymerase, were markedly increased upon cisplatin exposure in A549/DR cells compared with A549 cells. Furthermore, intracellular co-localization of Pol η and proliferation cell nuclear antigen (PCNA) induced by cisplatin or cisplatin plus gemcitabine treatment was inhibited by depleting ataxia telangiectasia mutated and Rad-3-related (ATR). Pol η depletion by siRNA sensitized A549/DR cells to cisplatin; co-depletion of Pol η and ATR further increased A549/DR cell death induced by cisplatin or cisplatin plus gemcitabine compared to depletion of Pol η or ATR alone, concomitant with inhibition of DNA ICL and DSB repair and accumulation of DNA damage. No additional sensitization effect of co-depleting Pol η and ATR was observed in A549 cells. These results demonstrate that co-inhibition of Pol η and ATR reverses the drug resistance of cisplatin-resistant NSCLC cells by blocking the repair of DNA ICLs and DSBs induced by cisplatin or cisplatin plus gemcitabine.

  8. Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations.

    PubMed

    Tamura, Tomoki; Kato, Yuka; Ohashi, Kadoaki; Ninomiya, Kiichiro; Makimoto, Go; Gotoda, Hiroko; Kubo, Toshio; Ichihara, Eiki; Tanaka, Takehiro; Ichimura, Koichi; Maeda, Yoshinobu; Hotta, Katsuyuki; Kiura, Katsuyuki

    2018-01-01

    Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39; 95 %CI: 1.00-5.68; p < 0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Epidermal growth factor receptor and anaplastic lymphoma kinase testing and mutation prevalence in patients with advanced non-small cell lung cancer in Switzerland: A comprehensive evaluation of real world practices.

    PubMed

    Ess, S M; Herrmann, C; Frick, H; Krapf, M; Cerny, T; Jochum, W; Früh, M

    2017-11-01

    In order to improve outcomes, identification of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes has become crucial in advanced non-small-cell lung cancer (NSCLC). The aim of the present study is to analyse time trends and frequency of testing, factors affecting testing as well as prevalence of mutations in the Swiss population. We analysed EGFR and ALK testing in a cohort of patients with newly diagnosed metastasised non-squamous NSCLC in the catchment area of the cancer registry Eastern Switzerland in the years 2008-2014. We analysed prevalence of mutations and studied clinicopathological characteristics and survival of tested and non-tested patients and of patients with and without mutations. Among 718 patients identified, 11% (51/447) harboured an EGFR mutation in the exons 18, 19 or 21 and further 12% (31/265) showed a positive test result for ALK rearrangements. In non-smokers the proportions of mutations were 31% and 23% respectively. Testing rates increased over time and reached 79% in 2014. We observed significantly lower testing rates and poorer survival in elderly, patients with limited life expectancy and patients treated at hospitals not involved in clinical research. Outcomes can be further improved in a considerable proportion of patients with advanced non-squamous NSCLC. © 2017 John Wiley & Sons Ltd.

  10. The protein kinase C (PKC) inhibitors combined with chemotherapy in the treatment of advanced non-small cell lung cancer: meta-analysis of randomized controlled trials.

    PubMed

    Zhang, L L; Cao, F F; Wang, Y; Meng, F L; Zhang, Y; Zhong, D S; Zhou, Q H

    2015-05-01

    The application of newer signaling pathway-targeted agents has become an important addition to chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). In this study, we evaluated the efficacy and toxicities of PKC inhibitors combined with chemotherapy versus chemotherapy alone for patients with advanced NSCLC systematically. Literature retrieval, trials selection and assessment, data collection, and statistic analysis were performed according to the Cochrane Handbook 5.1.0. The outcome measures were tumor response rate, disease control rate, progression-free survival (PFS), overall survival (OS), and adverse effects. Five randomized controlled trials, comprising totally 1,005 patients, were included in this study. Meta-analysis showed significantly decreased response rate (RR 0.79; 95 % CI 0.64-0.99) and disease control rate (RR 0.90; 95 % CI 0.82-0.99) in PKC inhibitors-chemotherapy groups versus chemotherapy groups. There was no significant difference between the two treatment groups regarding progression-free survival (PFS, HR 1.05; 95 % CI 0.91-1.22) and overall survival (OS, HR 1.00; 95 % CI 0.86-1.16). The risk of grade 3/4 neutropenia, leucopenia, and thrombosis/embolism increased significantly in PKC inhibitors combination groups as compared with chemotherapy alone groups. The use of PKC inhibitors in addition to chemotherapy was not a valid alternative for patients with advanced NSCLC.

  11. Molecular evidence of viral DNA in non-small cell lung cancer and non-neoplastic lung

    DOE PAGES

    Robinson, Lary A.; Jaing, Crystal J.; Campbell, Christine Pierce; ...

    2016-07-14

    Although ~20% of human cancers are caused by microorganisms, only suspicion exists for a microbial cause of lung cancer. Potential infectious agents were investigated in non-small cell lung cancer (NSCLC) and non-neoplastic lung. Seventy NSCLC tumours (33 squamous cell carcinomas, 17 adenocarcinomas, 10 adenocarcinomas with lepidic spread, and 10 oligometastases) and 10 non-neoplastic lung specimens were evaluated for molecular evidence of microorganisms. Tissues were subjected to the Lawrence Livermore Microbial Detection Array, an oncovirus panel of the International Agency for Research on Cancer, and human papillomavirus (HPV) genotyping. Associations were examined between microbial prevalence, clinical characteristics, and p16 and EGFRmore » expression. Retroviral DNA was observed in 85% squamous cell carcinomas, 47% adenocarcinomas, and 10% adenocarcinomas with lepidic spread. Human papillomavirus DNA was found in 69% of squamous cell carcinomas with 30% containing high-risk HPV types. No significant viral DNA was detected in non-neoplastic lung. Patients with tumours containing viral DNA experienced improved long-term survival compared with patients with viral DNA-negative tumours. Lastly, most squamous cell carcinomas and adenocarcinomas contained retroviral DNA and one-third of squamous cell carcinomas contained high-risk HPV DNA. Viral DNA was absent in non-neoplastic lung. Trial results encourage further study of the viral contribution to lung carcinogenesis.« less

  12. Molecular evidence of viral DNA in non-small cell lung cancer and non-neoplastic lung

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Robinson, Lary A.; Jaing, Crystal J.; Campbell, Christine Pierce

    Although ~20% of human cancers are caused by microorganisms, only suspicion exists for a microbial cause of lung cancer. Potential infectious agents were investigated in non-small cell lung cancer (NSCLC) and non-neoplastic lung. Seventy NSCLC tumours (33 squamous cell carcinomas, 17 adenocarcinomas, 10 adenocarcinomas with lepidic spread, and 10 oligometastases) and 10 non-neoplastic lung specimens were evaluated for molecular evidence of microorganisms. Tissues were subjected to the Lawrence Livermore Microbial Detection Array, an oncovirus panel of the International Agency for Research on Cancer, and human papillomavirus (HPV) genotyping. Associations were examined between microbial prevalence, clinical characteristics, and p16 and EGFRmore » expression. Retroviral DNA was observed in 85% squamous cell carcinomas, 47% adenocarcinomas, and 10% adenocarcinomas with lepidic spread. Human papillomavirus DNA was found in 69% of squamous cell carcinomas with 30% containing high-risk HPV types. No significant viral DNA was detected in non-neoplastic lung. Patients with tumours containing viral DNA experienced improved long-term survival compared with patients with viral DNA-negative tumours. Lastly, most squamous cell carcinomas and adenocarcinomas contained retroviral DNA and one-third of squamous cell carcinomas contained high-risk HPV DNA. Viral DNA was absent in non-neoplastic lung. Trial results encourage further study of the viral contribution to lung carcinogenesis.« less

  13. Trametinib, Combination Chemotherapy, and Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2018-05-23

    KRAS Activating Mutation; Recurrent Non-Small Cell Lung Carcinoma; Stage III Non-Small Cell Lung Cancer AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7

  14. Correlation of MSH3 polymorphisms with response and survival in advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy.

    PubMed

    Xu, X-L; Yao, Y-L; Xu, W-Z; Feng, J-G; Mao, W-M

    2015-04-15

    Mismatch repair (MMR) genes, as well as the nucleotide excision repair genes, play an important role in removing cisplatin-DNA adducts, and the mutation of MMR genes in tumors can lead to a decreased response to platinum-based therapies. We examined MutS homolog 3 (MSH3), a mismatch repair gene, and whether polymorphisms of MSH3 were associated with response and survival in advanced non-small cell lung cancer (NCSLC) patients who were treated with platinum-based chemotherapy. The peripheral blood of 180 advanced NCSLC patients who were treated with first-line platinum-based chemotherapy was collected to determine the patients' genotypes of MSH3. The three genotypes of the MSH3 polymorphisms rs26279, rs1650697 and rs1105524 were investigated. A statistically significant association was observed between the polymorphism rs26279 (Ala1054Thr) and sensitivity to platinum-based chemotherapy (P = 0.014). A significant correlation was found between rs1105524 and progression-free survival (PFS), with the G/A and A/A genotypes (median survival time: 14.27 months; 95%CI = 9.80-18.75) suffering shorter survival than patients with the G/G genotype (median survival time: 26.37 months; 95%CI = 15.03-37.71) (P = 0.04). Our results showed that single nucleotide polymorphisms in MSH3 had an impact on the chemotherapy response and prognosis of advanced NCSLC patients who were treated with platinum-based chemotherapy.

  15. Atezolizumab for the treatment of non-small cell lung cancer.

    PubMed

    Santini, Fernando C; Rudin, Charles M

    2017-09-01

    The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1). Areas covered: This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay. Expert commentary: PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate.

  16. Exosomes derived from mesenchymal non-small cell lung cancer cells promote chemoresistance.

    PubMed

    Lobb, Richard J; van Amerongen, Rosa; Wiegmans, Adrian; Ham, Sunyoung; Larsen, Jill E; Möller, Andreas

    2017-08-01

    Non-small cell lung cancer (NSCLC) is the most common lung cancer type and the most common cause of mortality in lung cancer patients. NSCLC is often associated with resistance to chemotherapeutics and together with rapid metastatic spread, results in limited treatment options and poor patient survival. NSCLCs are heterogeneous, and consist of epithelial and mesenchymal NSCLC cells. Mesenchymal NSCLC cells are thought to be responsible for the chemoresistance phenotype, but if and how this phenotype can be transferred to other NSCLC cells is currently not known. We hypothesised that small extracellular vesicles, exosomes, secreted by mesenchymal NSCLC cells could potentially transfer the chemoresistance phenotype to surrounding epithelial NSCLC cells. To explore this possibility, we used a unique human bronchial epithelial cell (HBEC) model in which the parental cells were transformed from an epithelial to mesenchymal phenotype by introducing oncogenic alterations common in NSCLC. We found that exosomes derived from the oncogenically transformed, mesenchymal HBECs could transfer chemoresistance to the parental, epithelial HBECs and increase ZEB1 mRNA, a master EMT transcription factor, in the recipient cells. Additionally, we demonstrate that exosomes from mesenchymal, but not epithelial HBECs contain the ZEB1 mRNA, thereby providing a potential mechanism for the induction of a mesenchymal phenotype in recipient cells. Together, this work demonstrates for the first time that exosomes derived from mesenchymal, oncogenically transformed lung cells can transfer chemoresistance and mesenchymal phenotypes to recipient cells, likely via the transfer of ZEB1 mRNA in exosomes. © 2017 UICC.

  17. An alternative way to initiate Notch1 signaling in non-small cell lung cancer

    PubMed Central

    Yang, Yi-Lin; Jablons, David

    2014-01-01

    Non-small cell lung cancer (NSCLC) cells activate Notch1 signaling to promote cell proliferation and facilitate their survival. It now emerges that endothelial Delta-like ligand 4 (Dll4) may mediate Notch1 activation and inhibit tumor cell growth. PMID:25806306

  18. A phase II study of combination chemotherapy with docetaxel and carboplatin for patients with advanced or metastatic non-small cell lung cancer.

    PubMed

    Kasahara, Kazuo; Kimura, Hideharu; Shibata, Kazuhiko; Araya, Tomoyuki; Sone, Takashi; Oribe, Yoshitaka; Furusho, Shiho; Kita, Toshiyuki; Shirasaki, Hiroki; Oribe, Yoshitaka; Yoshimi, Yuzo; Ueda, Akihito; Tachibana, Hideki; Shintani, Hiromoto; Mizuguchi, Masayuki; Nishi, Kohichi; Fujimura, Masaki; Nakao, Shinji

    2006-01-01

    The aim of this phase II study was to evaluate the efficacy of combination chemotherapy consisting of docetaxel and carboplatin in patients with inoperable non-small cell lung cancer (NSCLC). For this multicenter phase II study, the eligibility criteria included histologically or cytologically proven inoperable NSCLC, measurable lesions, Eastern Cooperative Oncology Group performance status (PS) 0-2, adequate organ and bone marrow functions, and written informed consent. Patients received 60 mg/m2 of docetaxel and carboplatin (target AUC 5.5) on day 1 every 3 weeks until disease progression. The primary end-point of this study was response rate and the secondary end-points were toxicities, time to progression and overall survival. A total of 40 patients were enrolled and 39 patients were eligible. A complete response and partial response were observed in 1 and 13 patients, respectively. An objective response rate was 35.9% (95% confidential interval [CI] 20.8-51.0%). The median time to progression was 5.2 months and the median overall survival was 12.0 months. The 1- and 2-year survival rates were 53.8% and 25.1%, respectively. The major toxicities were leukocytopenia and neutropenia. Grade 3 or 4 thrombocytopenia was rare and non-hematological toxicities were generally mild. Grade 3 non-hematological toxicities were observed in 6 patients (2 with nausea and vomiting, 1 with diarrhea, 1 with elevated transaminase levels, 1 with allergic reaction and 1 with edema). No grade 4 non-hematological toxicities were observed. Docetaxel and carboplatin combination chemotherapy was well tolerated and active in Japanese patients with advanced or metastatic NSCLC.

  19. Trial-Based Cost-Utility Analysis of Icotinib versus Gefitinib as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer in China.

    PubMed

    Zhang, Chunxiang; Zhang, Hongmei; Shi, Jinning; Wang, Dong; Zhang, Xiuwei; Yang, Jian; Zhai, Qizhi; Ma, Aixia

    2016-01-01

    Our objective is to compare the cost-utility of icotinib and gefitinib for the second-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Model technology was applied to assess the data of randomized clinical trials and the direct medical costs from the perspective of the Chinese healthcare system. Five-year quality-adjusted life years (QALYs) and incremental cost-utility ratios (ICURs) were calculated. One-way and probabilistic sensitivity analyses (PSA) were performed. Our model suggested that the median progression-free survival (PFS) was 4.2 months in the icotinib group and 3.5 months in the gefitinib group while they were 4.6 months and 3.4 months, respectively, in the trials. The 5-year QALYs was 0.279 in the icotinib group and 0.269 in the gefitinib group, and the according medical costs were $10662.82 and $13127.57. The ICUR/QALY of icotinib versus gefitinib presented negative in this study. The most sensitive parameter to the ICUR was utility of PFS, ranging from $-1,259,991.25 to $-182,296.61; accordingly the icotinib treatment consistently represented a dominant cost-utility strategy. The icotinib strategy, as a second-line therapy for advanced NSCLC patients in China, is the preferred strategy relative to gefitinib because of the dominant cost-utility. In addition, icotinib shows a good curative effect and safety, resulting in a strong demand for the Chinese market.

  20. Trial-Based Cost-Utility Analysis of Icotinib versus Gefitinib as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer in China

    PubMed Central

    Zhang, Chunxiang; Zhang, Hongmei; Shi, Jinning; Wang, Dong; Zhang, Xiuwei; Yang, Jian; Zhai, Qizhi; Ma, Aixia

    2016-01-01

    Background Our objective is to compare the cost-utility of icotinib and gefitinib for the second-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Methods Model technology was applied to assess the data of randomized clinical trials and the direct medical costs from the perspective of the Chinese healthcare system. Five-year quality-adjusted life years (QALYs) and incremental cost-utility ratios (ICURs) were calculated. One-way and probabilistic sensitivity analyses (PSA) were performed. Results Our model suggested that the median progression-free survival (PFS) was 4.2 months in the icotinib group and 3.5 months in the gefitinib group while they were 4.6 months and 3.4 months, respectively, in the trials. The 5-year QALYs was 0.279 in the icotinib group and 0.269 in the gefitinib group, and the according medical costs were $10662.82 and $13127.57. The ICUR/QALY of icotinib versus gefitinib presented negative in this study. The most sensitive parameter to the ICUR was utility of PFS, ranging from $-1,259,991.25 to $-182,296.61; accordingly the icotinib treatment consistently represented a dominant cost-utility strategy. Conclusions The icotinib strategy, as a second-line therapy for advanced NSCLC patients in China, is the preferred strategy relative to gefitinib because of the dominant cost-utility. In addition, icotinib shows a good curative effect and safety, resulting in a strong demand for the Chinese market. PMID:27015267

  1. Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer.

    PubMed

    Daga, Haruko; Takeda, Koji; Okada, Hideaki; Miyazaki, Masaki; Ueda, Shinya; Kaneda, Hiroyasu; Okamoto, Isamu; Yoh, Kiyotaka; Goto, Koichi; Konishi, Koichi; Sarashina, Akiko; Tanaka, Tetsuya; Kaiser, Rolf; Nakagawa, Kazuhiko

    2015-12-01

    This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After ≥4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was <33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade ≥3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.

  2. The safety and efficacy of carboplatin plus nanoparticle albumin-bound paclitaxel in the treatment of non-small cell lung cancer patients with interstitial lung disease.

    PubMed

    Yasuda, Yuichiro; Hattori, Yoshihiro; Tohnai, Rie; Ito, Shoichi; Kawa, Yoshitaka; Kono, Yuko; Urata, Yoshiko; Nogami, Munenobu; Takenaka, Daisuke; Negoro, Shunichi; Satouchi, Miyako

    2018-01-01

    The optimal chemotherapy regimen for non-small cell lung cancer patients with interstitial lung disease is unclear. We therefore investigated the safety and efficacy of carboplatin plus nab-paclitaxel as a first-line regimen for non-small cell lung cancer in patients with interstitial lung disease. We retrospectively reviewed advanced non-small cell lung cancer patients with interstitial lung disease who received carboplatin plus nab-paclitaxel as a first-line chemotherapy regimen at Hyogo Cancer Center between February 2013 and August 2016. interstitial lung disease was diagnosed according to the findings of pretreatment chest high-resolution computed tomography. Twelve patients were included (male, n = 11; female, n = 1). The overall response rate was 67% and the disease control rate was 100%. The median progression free survival was 5.1 months (95% CI: 2.9-8.3 months) and the median overall survival was 14.9 months (95% CI: 4.8-not reached). A chemotherapy-related acute exacerbation of interstitial lung disease was observed in one patient; the extent of this event was Grade 2. There were no treatment-related deaths. Carboplatin plus nab-paclitaxel, as a first-line chemotherapy regimen for non-small cell lung cancer, showed favorable efficacy and safety in patients with preexisting interstitial lung disease. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  3. Treating ALK-positive non-small cell lung cancer

    PubMed Central

    Tsiara, Anna; Tsironis, Georgios; Lykka, Maria; Liontos, Michalis; Bamias, Aristotelis; Dimopoulos, Meletios-Athanasios

    2018-01-01

    Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients. However, the acquired resistance to crizotinib and its diminished efficacy to the central nervous system (CNS) relapse led to the development of several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib. To date, four ALK TKIs, crizotinib, ceritinib, alectinib and brigatinib have received approval from the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) and even more agents are currently under investigation for the treatment of ALK-rearranged NSCLC. However, the optimal frontline approach and the exact sequence of ALK inhibitors are still under consideration. Recently announced results of phase III trials recognized higher efficacy of alectinib compared to crizotinib in first-line setting, even in patients with CNS involvement. In this review, we will discuss the current knowledge regarding the biology of the ALK-positive NSCLC, the available therapeutic inhibitors and we will focus on the raised issues from their use in clinical practise. PMID:29862230

  4. Exploring Boron Neutron Capture Therapy for non-small cell lung cancer.

    PubMed

    Farías, Rubén O; Bortolussi, Silva; Menéndez, Pablo R; González, Sara J

    2014-12-01

    Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with (10)B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells. The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced. Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments. The optimal neutron energy is within [500 eV-3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases. Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235-238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options. Copyright © 2014 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

  5. Treatment patterns and survival in patients with ALK-positive non-small-cell lung cancer: a Canadian retrospective study.

    PubMed

    Kayaniyil, S; Hurry, M; Wilson, J; Wheatley-Price, P; Melosky, B; Rothenstein, J; Cohen, V; Koch, C; Zhang, J; Osenenko, K; Liu, G

    2016-12-01

    Crizotinib was the first agent approved for the treatment of anaplastic lymphoma kinase ( ALK )-positive (+) non-small-cell lung cancer (nsclc), followed by ceritinib. However, patients eventually progress or develop resistance to crizotinib. With limited real-world data available, the objective of the present work was to evaluate treatment patterns and survival after crizotinib in patients with locally advanced or metastatic ALK + nsclc in Canada. In this retrospective study at 6 oncology centres across Canada, medical records of patients with locally advanced or metastatic ALK + nsclc were reviewed. Demographic and clinical characteristics, treatments, and outcomes data were abstracted. Analyses focused on patients who discontinued crizotinib treatment. Of the 97 patients included, 9 were crizotinib-naïve, and 39 were still receiving crizotinib at study end. The 49 patients who discontinued crizotinib treatment were included in the analysis. Of those 49 patients, 43% received ceritinib at any time, 20% subsequently received systemic chemotherapy only (but never ceritinib), and 37% received no further treatment or died before receiving additional treatment. Median overall survival from crizotinib discontinuation was shorter in patients who did not receive ceritinib than in those who received ceritinib (1.7 months vs. 20.4 months, p < 0.001). In a multivariable analysis, factors associated with poorer survival included lack of additional therapies (particularly ceritinib), male sex, and younger age, but not smoking status; patients of Asian ethnicity showed a nonsignificant trend toward improved survival. A substantial proportion of patients with ALK + nsclc received no further treatment or died before receiving additional treatment after crizotinib. Treatment with systemic agents was associated with improved survival, with ceritinib use being associated with the longest survival.

  6. Targeting HER2 in the treatment of non-small cell lung cancer.

    PubMed

    Mar, Nataliya; Vredenburgh, James J; Wasser, Jeffrey S

    2015-03-01

    Oncogenic driver mutations have emerged as major treatment targets for molecular therapies in a variety of cancers. HER2 positivity has been well-studied in breast cancer, but its importance is still being explored in non-small cell lung cancer (NSCLC). Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for gene mutations. The prognostic and predictive significance of these tests remain to be validated, with an emerging association between HER2 gene mutations and response to HER2 targeted therapies. Despite the assay used to determine the HER2 status of lung tumors, all patients with advanced HER2 positive lung adenocarcinoma should be evaluated for treatment with targeted agents. Several clinical approaches for inclusion of these drugs into patient treatment plans exist, but there is no defined algorithm specific to NSCLC. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Targeted Therapies in Non-Small Cell Lung Cancer—Beyond EGFR and ALK

    PubMed Central

    Rothschild, Sacha I.

    2015-01-01

    Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called “driver mutations”) for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed. PMID:26018876

  8. Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK.

    PubMed

    Rothschild, Sacha I

    2015-05-26

    Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called "driver mutations") for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed.

  9. Peptide ligands targeting integrin alpha3beta1 in non-small cell lung cancer.

    PubMed

    Lau, Derick; Guo, Linlang; Liu, Ruiwu; Marik, Jan; Lam, Kit

    2006-06-01

    Lung cancer is one of the most common cancers and is the leading cause of cancer death. We wish to identify peptide ligands for unique cell surface receptors of non-small lung cancer with the hope of developing these ligands as diagnostic and therapeutic agents. Using the method of 'one-bead one-peptide' combinatorial chemistry, a library of random cyclic octapeptides was synthesized on polystyrene beads. This library was used to screen for peptides that promoted attachment of lung adenocarcinoma cells employing a 'cell-growth-on-bead' assay. Consensus peptide sequences of cNGXGXXc were identified. These peptides promoted cell adhesion by targeting integrin alpha3beta1 over-expressed in non-small lung cancer cells. These peptide beads can be applied to capture cancer cells in malignant pleural fluid for purpose of diagnosis of lung cancer.

  10. Evaluation of tumour vaccine immunotherapy for the treatment of advanced non-small cell lung cancer: a systematic meta-analysis.

    PubMed

    Wang, Min; Cao, Jun-Xia; Liu, Yi-Shan; Xu, Bei-Lei; Li, Duo; Zhang, Xiao-Yan; Li, Jun-Li; Liu, Jin-Long; Wang, Hai-Bo; Wang, Zheng-Xu

    2015-04-14

    Our meta-analysis performed a systematic evaluation on the therapeutic efficacy and safety of tumour vaccines for the treatment of advanced non-small cell lung cancer (NSCLC). Systematic review and meta-analysis of randomised controlled trials (RCT). PubMed, the Cochrane Center Register of Controlled Trials, Science Direct and EMBASE were searched from January 1980 until January 2015. RCT were included; the control arm had to receive either placebo or chemotherapy or no treatment. The quality of the data from individual papers was assessed for overall survival (OS), clinical response rate and side effects. Overall, 11 RCT of advanced NSCLC with a total of 3986 patients were conducted for meta-analysis. The results showed that the vaccine arm significantly extended primary endpoint median overall survival compared with control group (p<0.00001) (HR 0.760; 95% CI 0.644 to 0.896; p=0.001). Three subgroup patients with tumour vaccine at 1-year, 2-year and 3-year survival rates also gained significant benefits compared with their corresponding control group (p=0.0004, 0.03 and 0.19, respectively). Besides, a significant improvement in median time to progression (TTP), median progression-free survival (PFS) and a trend of improvement in objective response rate were observed after tumour vaccine treatment (p=0.001, 0.005 and 0.05, respectively; median PFS HR 0.842; 95% CI 0.744 to 0.954; p=0.007). A few severe adverse effects occurred in the tumour vaccine group, but fewer side effects were observed in the vaccine group compared with the control group (p<0.00001). Taken together, NSCLC tumour vaccines markedly prolong median OS (p<0.00001), median TTP (p=0.001) and median PFS (p=0.005), improve clinical response rate (p=0.05) and lessen adverse side effects (p<0.00001). Our meta-analysis suggests tumour vaccines improve the efficacy of the treatment, and also provide superiority in treatment of patients with advanced NSCLC among a variety of immunotherapy strategies

  11. Diagnosis of B-Cell Non-Hodgkin Lymphomas with Small-/Intermediate-Sized Cells in Cytopathology

    PubMed Central

    Schwock, Joerg; Geddie, William R.

    2012-01-01

    Fine needle sampling is a fast, safe, and potentially cost-effective method of obtaining tissue for cytomorphologic assessment aimed at both initial triage and, in some cases, complete diagnosis of patients that present clinically with lymphadenopathy. The cytologic diagnosis of B-cell non-Hodgkin lymphomas composed of small-/intermediate-sized cells, however, has been seen as an area of great difficulty even for experienced observers due to the morphologic overlap between lymphoma and reactive lymphadenopathies as well as between the lymphoma entities themselves. Although ancillary testing has improved diagnostic accuracy, the results from these tests must be interpreted within the morphological and clinical context to avoid misinterpretation. Importantly, the recognition of specific cytologic features is crucial in guiding the appropriate selection of ancillary tests which will either confirm or refute a tentative diagnosis. For these reasons, we here review the cytologic characteristics particular to five common B-cell non-Hodgkin lymphomas which typically cause the most diagnostic confusion based on cytological assessment alone: marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and lymphoplasmacytic lymphoma. We summarize the most pertinent cytomorphologic features for each entity as well as for reactive lymphoid hyperplasia, contrast them with each other to facilitate their recognition, and highlight common diagnostic pitfalls. PMID:22693682

  12. Simultaneous diagnostic platform of genotyping EGFR, KRAS, and ALK in 510 Korean patients with non-small-cell lung cancer highlights significantly higher ALK rearrangement rate in advanced stage.

    PubMed

    Kim, Tae-Jung; Park, Chan Kwon; Yeo, Chang Dong; Park, Kihoon; Rhee, Chin Kook; Kim, Jusang; Kim, Seung Joon; Lee, Sang Haak; Lee, Kyo-Young; Yoon, Hyoung-Kyu

    2014-09-01

    Simultaneous genotyping has advantages in turnaround time and detecting the real mutational prevalence in unresectable non-small-cell lung cancer (NSCLC), a group not previously genetically characterized. We developed simultaneous panel of screening EGFR and KRAS mutations by direct sequencing or PNA clamping, and ALK rearrangement by fluorescent in situ hybridization (FISH) in multicenter manner. Of 510 NSCLC Korean patients, simultaneous genotyping identified mutations of EGFR (29.0%) and KRAS (8.6%) and rearrangement of ALK (9.2%). Seven patients had overlaps in mutations. Although several well-known associations between genotypes and clinical characteristics were identified, we found no relationship between ALK rearrangement and sex or smoking history. Unlike the other genotype mutations, ALK rearrangement was associated with advanced disease. Among the ALK-negative group, patients with 10-15% of ALK FISH split shared characteristics, such as younger age and advanced stage disease, more with the ALK-positive group (>15% ALK FISH split) than <10% ALK FISH split group. Simultaneous panel genotyping revealed more prevalent ALK rearrangements than reported in previous studies and their strong association with advanced stage irrespective of sex or smoking history. ALK rearrangement seems to be a marker for aggressive tumor biology and should be assessed in advanced disease. © 2014 Wiley Periodicals, Inc.

  13. SU-E-T-630: Predictive Modeling of Mortality, Tumor Control, and Normal Tissue Complications After Stereotactic Body Radiotherapy for Stage I Non-Small Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lindsay, WD; Oncora Medical, LLC, Philadelphia, PA; Berlind, CG

    Purpose: While rates of local control have been well characterized after stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC), less data are available characterizing survival and normal tissue toxicities, and no validated models exist assessing these parameters after SBRT. We evaluate the reliability of various machine learning techniques when applied to radiation oncology datasets to create predictive models of mortality, tumor control, and normal tissue complications. Methods: A dataset of 204 consecutive patients with stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT) at the University of Pennsylvania between 2009 and 2013more » was used to create predictive models of tumor control, normal tissue complications, and mortality in this IRB-approved study. Nearly 200 data fields of detailed patient- and tumor-specific information, radiotherapy dosimetric measurements, and clinical outcomes data were collected. Predictive models were created for local tumor control, 1- and 3-year overall survival, and nodal failure using 60% of the data (leaving the remainder as a test set). After applying feature selection and dimensionality reduction, nonlinear support vector classification was applied to the resulting features. Models were evaluated for accuracy and area under ROC curve on the 81-patient test set. Results: Models for common events in the dataset (such as mortality at one year) had the highest predictive power (AUC = .67, p < 0.05). For rare occurrences such as radiation pneumonitis and local failure (each occurring in less than 10% of patients), too few events were present to create reliable models. Conclusion: Although this study demonstrates the validity of predictive analytics using information extracted from patient medical records and can most reliably predict for survival after SBRT, larger sample sizes are needed to develop predictive models for normal tissue toxicities and more

  14. Mature Follow-Up for High-Risk Stage I Non-Small-Cell Lung Carcinoma Treated With Sublobar Resection and Intraoperative Iodine-125 Brachytherapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Colonias, Athanasios, E-mail: acolonia@wpahs.or; Drexel University College of Medicine, Allegheny Campus, Pittsburgh, PA; Betler, James

    2011-01-01

    Purpose: To update the Allegheny General Hospital experience of high-risk Stage I non-small-cell lung cancer patients treated with sublobar resection and intraoperative {sup 125}I Vicryl mesh brachytherapy. Methods and Materials: Between January 5, 1996 and February 19, 2008, 145 patients with Stage I non-small-cell lung cancer who were not lobectomy candidates because of cardiopulmonary compromise underwent sublobar resection and placement of {sup 125}I seeds along the resection line. The {sup 125}I seeds embedded in Vicryl suture were attached with surgical clips to a sheet of Vicryl mesh, inserted over the target area, and prescribed to a 0.5-cm planar margin. Results:more » The mean target area, total activity, number of seeds implanted, and prescribed total dose was 33.3 cm{sup 2} (range, 18.0-100.8), 20.2 mCi (range, 11.1-29.7), 46 (range, 30-100), and 117 Gy (range, 80-180), respectively. The median length of the surgical stay was 6 days (range, 1-111), with a perioperative mortality rate of 3.4%. At a median follow-up of 38.3 months (range, 1-133), 6 patients had developed local recurrence (4.1%), 9 had developed regional failure (6.2%), and 25 had distant failure (17.2%). On multivariate analysis, no patient- or tumor-specific factors or surgical or dosimetric factors were predictive of local recurrence. The overall median survival was 30.5 months with a 3- and 5-year overall survival rate of 65% and 35%, respectively. Conclusion: {sup 125}I brachytherapy for high-risk, Stage I non-small-cell lung cancer after sublobar resection is well tolerated and associated with a low local failure rate.« less

  15. [Arf6, RalA and BIRC5 protein expression in non small cell lung cancer].

    PubMed

    Knizhnik, A V; Kovaleva, O B; Laktionov, K K; Mochal'nikova, V V; Komel'kov, A V; Chevkina, E M; Zborovskaia, I B

    2011-01-01

    Evaluation of tumor markers expression pattern which determines individual progression parameters is one of the major topics in molecular oncopathology research. This work presents research on expression analysis of several Ras-Ral associated signal transduction pathway proteins (Arf6, RalA and BIRC5) in accordance with clinical criteria in non small cell lung cancer patients. Using Western-blot analysis and RT-PCR Arf6, RalA and BIRC5 expression has been analyzed in parallel in 53 non small cell lung cancer samples of different origin. Arf6 protein expression was elevated in 55% non small cell lung cancer tumor samples in comparison with normal tissue. In the group of squamous cell lung cancer Arf6 expression elevation was observed more often. RalA protein expression was decreased in comparison to normal tissue samples in 64% of non small cell lung cancer regardless to morphological structure. Correlation between RalA protein expression decrease and absence of regional metastases was revealed for squamous cell lung cancer. BIRC5 protein expression in tumor samples versus corresponding normal tissue was 1.3 times more often elevated in the squamous cell lung cancer group (in 76% tumor samples). At the same time elevation of BIRC5 expression was fixed only in 63% of adenocarcinoma tumor samples. A statistically significant decrease (p = 0.0158) of RalA protein expression and increase (p = 0.0498) of Arf6 protein expression in comparison with normal tissue was found for T1-2N0M0 and T1-2N1-2M0 groups of squamous cell lung cancer correspondingly.

  16. Amplicon-based next-generation sequencing of plasma cell-free DNA for detection of driver and resistance mutations in advanced non-small cell lung cancer.

    PubMed

    Guibert, N; Hu, Y; Feeney, N; Kuang, Y; Plagnol, V; Jones, G; Howarth, K; Beeler, J F; Paweletz, C P; Oxnard, G R

    2018-04-01

    Genomic analysis of plasma cell-free DNA is transforming lung cancer care; however, available assays are limited by cost, turnaround time, and imperfect accuracy. Here, we study amplicon-based plasma next-generation sequencing (NGS), rather than hybrid-capture-based plasma NGS, hypothesizing this would allow sensitive detection and monitoring of driver and resistance mutations in advanced non-small cell lung cancer (NSCLC). Plasma samples from patients with NSCLC and a known targetable genotype (EGFR, ALK/ROS1, and other rare genotypes) were collected while on therapy and analyzed blinded to tumor genotype. Plasma NGS was carried out using enhanced tagged amplicon sequencing of hotspots and coding regions from 36 genes, as well as intronic coverage for detection of ALK/ROS1 fusions. Diagnostic accuracy was compared with plasma droplet digital PCR (ddPCR) and tumor genotype. A total of 168 specimens from 46 patients were studied. Matched plasma NGS and ddPCR across 120 variants from 80 samples revealed high concordance of allelic fraction (R2 = 0.95). Pretreatment, sensitivity of plasma NGS for the detection of EGFR driver mutations was 100% (30/30), compared with 87% for ddPCR (26/30). A full spectrum of rare driver oncogenic mutations could be detected including sensitive detection of ALK/ROS1 fusions (8/9 detected, 89%). Studying 25 patients positive for EGFR T790M that developed resistance to osimertinib, 15 resistance mechanisms could be detected including tertiary EGFR mutations (C797S, Q791P) and mutations or amplifications of non-EGFR genes, some of which could be detected pretreatment or months before progression. This blinded analysis demonstrates the ability of amplicon-based plasma NGS to detect a full range of targetable genotypes in NSCLC, including fusion genes, with high accuracy. The ability of plasma NGS to detect a range of preexisting and acquired resistance mechanisms highlights its potential value as an alternative to single mutation

  17. Case Report: Osimertinib achieved remarkable and sustained disease control in an advanced non-small-cell lung cancer harboring EGFR H773L/V774M mutation complex.

    PubMed

    Yang, Minglei; Tong, Xiaoling; Xu, Xiang; Zheng, Enkuo; Ni, Junjun; Li, Junfang; Yan, Junrong; Shao, Yang W; Zhao, Guofang

    2018-07-01

    Missense mutations in EGFR exon 20 are rare in non-small-cell lung cancer (NSCLC), and mostly insensitive to the first generation tyrosine kinase inhibitors (TKIs) of EGFR. However, their responses to the third generation TKI are unclear. Here, we reported a patient with advanced NSCLC harboring a rare EGFR H773L/V774M mutation complex. Although he was irresponsive to the first generation TKI gefitinib, he demonstrated sustained disease control to osimertinib, suggesting that this complex is an activating mutation of EGFR and can be suppressed by osimertinib. The follow-up genetic profiling revealed multiple acquired new mutations that might be related to his resistance to osimertinib. This finding would provide valuable experience for future treatment of the same mutations. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer.

    PubMed

    Guérin, Annie; Sasane, Medha; Zhang, Jie; Macalalad, Alexander R; Galebach, Philip; Jarvis, John; Kageleiry, Andrew; Culver, Kenneth; Wu, Eric Q; Wakelee, Heather

    2015-06-01

    Approximately 2-8% of non-small cell lung cancer (NSCLC) patients have rearrangements in the anaplastic lymphoma kinase gene (ALK). ALK-targeted therapy is available to patients with tumors known to be ALK+. This chart review study described characteristics of patients with ALK+ NSCLC, patterns of ALK testing and subsequent treatments, and oncologists' experience with ALK testing in the US. US oncologists provided information in September and October of 2013 on patients from their practice diagnosed with ALK+ locally advanced or metastatic NSCLC, including the timing of ALK testing and treatment received after testing. Participating oncologists were also surveyed about their experience with ALK testing. 27 oncologists provided data on 273 ALK+ NSCLC patients. Patients' median age was 67 years upon NSCLC diagnosis. Smoking history varied, with 33% nonsmokers, 33% light smokers, and 33% heavy smokers. Patients were racially diverse: 59% White, 18% Black, 13% Asian, and 10% other. Upon diagnosis of advanced/metastatic NSCLC, patients who were either not tested (19%) or initially tested negative/inconclusive (1%) all received first-line chemotherapy; the other 219 patients (80%) tested positive, with 133 (61%) receiving an ALK inhibitor and 78 (29%) receiving chemotherapy as first-line treatment. Many oncologists stated being more likely to test for ALK rearrangements among Asians, nonsmokers, and light smokers. In this sample, ALK+ NSCLC patients were racially diverse with mixed smoking history. One in five patients were not tested before first-line therapy. Oncologists reported being more likely to consider ALK testing for patients with particular smoking and race characteristics. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Detection of brain-directed autoantibodies in the serum of non-small cell lung cancer patients.

    PubMed

    Banjara, Manoj; Ghosh, Chaitali; Dadas, Aaron; Mazzone, Peter; Janigro, Damir

    2017-01-01

    Antibodies against brain proteins were identified in the plasma of cancer patients and are defined to cause paraneoplastic neurological syndromes. The profiles of brain-directed antibodies in non-small cell lung cancer (NSCLC) are largely unknown. Here, for the first time, we compared autoantibodies against brain proteins in NSCLC (n = 18) against those present in age-matched non-cancer control subjects (n = 18) with a similar life-style, habit, and medical history. Self-recognizing immunoglobulin (IgG) are primarily directed against cells in the cortex (P = 0.008), hippocampus (P = 0.003-0.05), and cerebellum (P = 0.02). More specifically, IgG targets were prominent in the pyramidal, Purkinje, and granule cell layers. Furthermore, autoimmune IgG signals were localized to neurons (81%), astrocytes (48%), and endothelial (29%) cells. While cancer sera yielded overall higher intensity signals, autoantigens of 100, 65, 45, 37, and 30 kDa molecular weights were the most represented. Additionally, a group of 100 kDa proteins seem more prevalent in female adenocarcinoma patients (4/5, 80%). In conclusion, our results revealed autoantigen specificity in NSCLC, which implicitly depends on patient's demographics and disease history. Patients at risk for lung cancer but with no active disease revealed that the immune profile in NSCLC is disease-dependent.

  20. Molecular Testing for Targeted Therapy in Advanced Non-Small Cell Lung Cancer: Suitability of Endobronchial Ultrasound Transbronchial Needle Aspiration.

    PubMed

    Casadio, Chiara; Guarize, Juliana; Donghi, Stefano; Di Tonno, Clementina; Fumagalli, Caterina; Vacirca, Davide; Dell'Orto, Patrizia; De Marinis, Filippo; Spaggiari, Lorenzo; Viale, Giuseppe; Barberis, Massimo

    2015-10-01

    Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure that has revolutionized the diagnosis and staging of lung cancer. The goal of the present study was to investigate the yield and applicability of molecular testing in the specimens obtained by EBUS-TBNA from patients with advanced non-small cell lung cancer (NSCLC), comparing the results with a series of patients who underwent diagnostic surgical procedures in the same institution. The study followed 306 consecutive patients with clinically diagnosed primary lung cancer who had the EBUS-TBNA procedure. EGFR and KRAS mutations were evaluated on cytologic specimens by Sanger sequencing and Cobas real-time polymerase chain reaction, whereas ALK rearrangement was tested by fluorescence in situ hybridization. The results were compared with those obtained from a series of 1,000 NSCLC surgical samples routinely analyzed. Molecular testing was possible in 96.9% of the samples obtained by EBUS-TBNA. EGFR (exons 18-21) mutations were found in 16.9%, KRAS mutation (exons 2-3) in 31.6%, and ALK rearrangement in 3.9% of the cases. In the surgical series, the mutations' distribution were 14.8%, 29.0%, and 3.4%, respectively. There were no statistical differences between the two series. Our study demonstrates that EBUS-TBNA can be effectively used not just for diagnosis but also for complete mutational testing. Copyright© by the American Society for Clinical Pathology.

  1. Molecular and Histological Changes in Post-Treatment Biopsies of Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Study.

    PubMed

    Vatrano, S; Righi, L; Vavalá, T; Rapa, I; Busso, M; Izzo, S; Cappia, S; Veltri, A; Papotti, M; Scagliotti, G V; Novello, S

    2016-04-01

    Recently, in advanced non-small cell lung cancer (NSCLC), standard chemotherapy was flanked by biological agents directed against genomic abnormalities, including EGFR and ALK alterations, that significantly improved patient outcome. Despite these achievements, tumour progression almost always occurs and a reassessment of the tumour genetic profile may contribute to modulating the therapeutic regimen. Resampling may provide tissue for additional tests to detect acquired resistance and/or new genetic alterations, but the currently available information is limited. Histological and genetic reassessments of biopsy or surgical tissue samples from 50 non-squamous NSCLC patients before and after at least one systemic treatment were performed. EGFR, KRAS, BRAF, PIK3CA and HER2 mutations were sequenced, p.T790M was identified with real-time PCR, and ALK and MET genomic alterations by fluorescence in situ hybridization. Overall in baseline biopsies, 37/50 (74 %) tumours had genetic alterations, either single (52 %) or multiple (22 %). Among them, 16 were EGFR mutations and 6 ALK rearrangements. In the second tissue sampling, 54 % of cases had additional genomic changes, including newly acquired alterations (81 %) or losses (18 %). The commonest changes were MET amplification and p.T790M mutation. One case had a histological shift from adenocarcinoma to small cell carcinoma. The remarkable number of molecular changes following systemic therapy and the genetic complexity of some cases underline the value of histological and molecular re-evaluation of lung cancer to tailor the most appropriate therapy during disease progression.

  2. Alectinib for the treatment of ALK-positive stage IV non-small cell lung cancer.

    PubMed

    Wong, K M; Noonan, S; O'Bryant, C; Jimeno, A

    2015-03-01

    Our increased understanding of the molecular subsets of non-small cell lung cancer (NSCLC) has led to the development of highly effective targeted therapies. In particular, the outcomes of patients with advanced NSCLC driven by the EML4-ALK fusion protein, which comprise 3-5% of cases, have remarkably improved with the use of crizotinib, an oral multi-tyrosine kinase inhibitor that targets ALK. However, patients inevitably develop progression while on crizotinib due to various mechanisms of resistance. Alectinib is a novel oral small molecule that inhibits ALK with high potency and selectivity, and demonstrates promising antitumor effects in NSCLC. Preclinical studies have shown that it is also active against several mutant forms of ALK that confer resistance to crizotinib, including the gatekeeper mutation L1196M. Moreover, an objective response rate of over 90% was observed in a phase I trial. Due to the impressive results of early phase studies, alectinib was approved for the treatment of advanced ALK-positive NSCLC in Japan, while it has been granted a breakthrough therapy designation by the FDA. A phase III trial is currently ongoing. This review will describe the biology and significance of ALK rearrangements in NSCLC, ALK inhibition by crizotinib and mechanisms of resistance, as well as the preclinical and clinical evidence for the novel ALK inhibitor alectinib. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

  3. The Efficacy and Safety of Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Chemotherapy: A Single-Arm, Multi-Center, Prospective Study

    PubMed Central

    Shi, Yuankai; Zhou, Caicun; Liu, Xiaoqing; Wang, Dong; Song, Yong; Li, Qiang; Feng, Jifeng; Qin, Shukui; Xv, Nong; Zhou, Jianying; Zhang, Li; Hu, Chunhong; Zhang, Shucai; Luo, Rongcheng; Wang, Jie; Tan, Fenlai; Wang, Yinxiang; Ding, Lieming; Sun, Yan

    2015-01-01

    Background Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Methods Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety. Results From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9–6.6 m) and 5.4 months (95%CI 3.1–7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127). Conclusions In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy. Trial Registration ClinicalTrials.gov NCT02486354 PMID:26599904

  4. Cost Effectiveness of Alectinib vs. Crizotinib in First-Line Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancer.

    PubMed

    Carlson, Josh J; Suh, Kangho; Orfanos, Panos; Wong, William

    2018-04-01

    The recently completed ALEX trial demonstrated that alectinib improved progression-free survival, and delayed time to central nervous system progression compared with crizotinib in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer. However, the long-term clinical and economic impact of using alectinib vs. crizotinib has not been evaluated. The objective of this study was to determine the potential cost utility of alectinib vs. crizotinib from a US payer perspective. A cost-utility model was developed using partition survival methods and three health states: progression-free, post-progression, and death. ALEX trial data informed the progression-free and overall survival estimates. Costs included drug treatments and supportive care (central nervous system and non-central nervous system). Utility values were obtained from trial data and literature. Sensitivity analyses included one-way and probabilistic sensitivity analyses. Treatment with alectinib vs. crizotinib resulted in a gain of 0.91 life-years, 0.87 quality-adjusted life-years, and incremental costs of US$34,151, resulting in an incremental cost-effectiveness ratio of US$39,312/quality-adjusted life-year. Drug costs and utilities in the progression-free health state were the main drivers of the model in the one-way sensitivity analysis. From the probabilistic sensitivity analysis, alectinib had a 64% probability of being cost effective at a willingness-to-pay threshold of US$100,000/quality adjusted life-year. Alectinib increased time in the progression-free state and quality-adjusted life-years vs. crizotinib. The marginal cost increase was reflective of longer treatment durations in the progression-free state. Central nervous system-related costs were considerably lower with alectinib. Our results suggest that compared with crizotinib, alectinib may be a cost-effective therapy for treatment-naïve patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer.

  5. Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.

    PubMed

    Baker, Amanda F; Hanke, Neale T; Sands, Barbara J; Carbajal, Liliana; Anderl, Janet L; Garland, Linda L

    2014-12-31

    Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.

  6. ALK gene copy number gains in non-small-cell lung cancer: prognostic impact and clinico-pathological correlations.

    PubMed

    Peretti, U; Ferrara, R; Pilotto, S; Kinspergher, S; Caccese, M; Santo, A; Brunelli, M; Caliò, A; Carbognin, L; Sperduti, I; Garassino, M; Chilosi, M; Scarpa, A; Tortora, G; Bria, E

    2016-08-25

    The correlation between ALK gene copy number gain (ALK-CNG) and prognosis in the context of advanced non-small-cell lung cancer (NSCLC) remains a controversial issue. This study aimed to evaluate the association among ALK-CNG according to Fluorescent In Situ Hybridization (FISH), clinical characteristics and survival in resectable and advanced NSCLC. Clinical and pathological data of patients with resectable and advanced NSCLC were retrospectively collected. Tumor tissues were analyzed for ALK-CNG by FISH, and patients were divided in 3 groups/patterns on the basis of ALK signals: disomic [Pattern A], 3-7 signals [Pattern B], >7 signals [Pattern C]. The association between clinical and pathological features and ALK-CNG patterns was evaluated. Disease/progression-free and overall survival (DFS/PFS and OS) were estimated using the Kaplan-Meyer method. A number of 128 (76.6 %) out of the 167 eligible patients were evaluable for ALK-CNG, displaying pattern A, B and C in 71 (42.5 %), 42 (25.1 %) and 15 (9 %) patients, respectively. Gains in ALK-CNG appear to be more frequent in smokers/former smokers than in non-smokers (74.2 % versus 20.4 %, respectively, p = 0.03). Pattern A and C seem more frequently associated with higher T-stage (T3-4), while pattern B appears more represented in lower T-stage (T 1-2) (p = 0.06). No significant differences in survival rate were observed among the above groups. A high ALK-CNG pattern might be associated with smoking status and theoretically it might mirror genomic instability. The implications for prognosis should be prospectively investigated and validated in larger patients' series. We confirm that all the study was performed in accordance with relevant guidelines and regulations and that all the protocol (part of a larger project MFAG 2013 N.14282) was approved by the local Ethics Committee of the Azienda Ospedaliera Universitaria Integrata of Verona on November 11st, 2014.

  7. Palliative Care Intervention in Improving Symptom Control and Quality of Life in Patients With Stage II-IV Non-small Cell Lung Cancer and Their Family Caregivers

    ClinicalTrials.gov

    2017-10-16

    Caregiver; Psychological Impact of Cancer and Its Treatment; Recurrent Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  8. Clinical outcomes of advanced non-small-cell lung cancer patients with EGFR mutation, ALK rearrangement and EGFR/ALK co-alterations.

    PubMed

    Lou, Na-Na; Zhang, Xu-Chao; Chen, Hua-Jun; Zhou, Qing; Yan, Li-Xu; Xie, Zhi; Su, Jian; Chen, Zhi-Hong; Tu, Hai-Yan; Yan, Hong-Hong; Wang, Zhen; Xu, Chong-Rui; Jiang, Ben-Yuan; Wang, Bin-Chao; Bai, Xiao-Yan; Zhong, Wen-Zhao; Wu, Yi-Long; Yang, Jin-Ji

    2016-10-04

    The co-occurrence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular subtype of non-small-cell lung cancer (NSCLC). Herein, we assessed the clinical outcomes and incidence of acquired resistance to tyrosine kinase inhibitors (TKIs) in this subtype. So we enrolled 118 advanced NSCLC treated with TKIs. EGFR mutations and ALK rearrangements were detected by DNA sequencing or Scorpion amplification refractory mutation system and fluorescence in situ hybridization respectively. Immunohistochemistry was used to evaluate the activation of associated proteins. We found that nine in ten patients with EGFR/ALK co-alterations had good response with first-line EGFR TKI, and the objective response rate (ORR) of EGFR TKIs was 80% (8/10) for EGFR/ALK co-altered and 65.5% (55/84) for EGFR-mutant (P = 0.57), with a median progression-free survival (PFS) of 11.2 and 13.2 months, (hazard ratio [HR]=0.95, 95% [CI], 0.49-1.84, P= 0.87). ORR of crizotinib was 40% (2/5) for EGFR/ALK co-altered and 73.9% (17/23) for ALK-rearranged (P= 0.29), with a median PFS of 1.9 and 6.9 months (hazard ratio [HR], 0.40; 95% [CI] 0.15-1.10, P = 0.08). The median overall survival (OS) was 21.3, 23.7, and 18.5 months in EGFR-mutant, ALK-rearranged, and EGFR/ALK co-altered (P= 0.06), and there existed a statistically significant difference in OS between ALK-rearranged and EGFR/ALK co-altered (P=0.03). Taken together, the first-line EGFR-TKI might be the reasonable care for advanced NSCLC harbouring EGFR/ALK co-alterations, whether or nor to use sequential crizotinib should be guided by the status of ALK rearrangement and the relative level of phospho-EGFR and phospho-ALK.

  9. Advances towards the design and development of personalized non-small-cell lung cancer drug therapy.

    PubMed

    Vari, Sabrina; Pilotto, Sara; Maugeri-Saccà, Marcello; Ciuffreda, Ludovica; Cesta Incani, Ursula; Falcone, Italia; Del Curatolo, Anais; Ceribelli, Anna; Gelibter, Alain; De Maria, Ruggero; Tortora, Giampaolo; Cognetti, Francesco; Bria, Emilio; Milella, Michele

    2013-11-01

    Non-small-cell lung cancer (NSCLC) subtypes are driven by specific genetic aberrations. For reasons such as this, there is a call for treatment personalization. The ability to instigate NSCLC fragmentation poses new methodological problems, and new 'driver' molecular aberrations are being discovered at an unprecedented pace. This article describes the clinical development of epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib for EGFR-mutant and anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Further, the authors briefly describe the emerging molecular targets in NSCLC, in terms of both rationale for therapeutic targeting and strategies, for clinical development. Target identification and validation in NSCLC still requires considerable effort, as not all of the molecular alterations are clear 'drivers' nor can they be efficiently targeted with available drugs. However, 50% of the NSCLC cases are without clear-defined molecular aberrations. Clinical trial methodology will need to develop novel paradigms for targeted drug development, aiming at the validation of an ideal 'biology-to-trial' approach. Despite significant challenges, a truly 'personalized' approach to NSCLC therapy appears to be within our reach.

  10. [Phase II clinical trial of nedaplatin in advanced non-small cell lung cancer].

    PubMed

    Xu, Rui-hua; Guan, Zhong-zhen; Jiang, Wen-qi; Huang, He; Hu, Xiao-hua; Xie, Wei-min; Li, Xing-gen; Liu, Ya-li; Pan, Liang-xi; Dai, Ai-di; Zhuang, Wu; Zhang, Chun; Ma, Zhi-yong; Wang, Jian-hua

    2002-12-01

    The aim of this study was to observe the efficacy and the side effects of nedaplatin in treatment of non-small cell lung cancer (NSCLC). This is a multi-center phase II clinical trial. The previously chemotherapy treated patients with NSCLC were administrated nedaplatin alone. Nedaplatin was given at 100 mg/m2, i.v., repeated every 3 weeks. The chemonaive patients with NSCLC were randomized to two groups. The combination trial group was given with nedaplatin + vindesine regimen, and the combination control group with cisplatin + vindesine. Of 138 patients, 16 were in the nedaplatin single drug group; 60 were in the combination trial group; and 62 were in the combination control group. All of the 16 cases in the single drug group, which were treated with platinum previously, achieved 12.5% of response rate. And the combination trial group and control group had a very similar response rate, which were 26.7% versus 25.8%, respectively. The incidence rates of neutropenia and anemia were similar in the two groups. But the incidence rate of thrombocytopenia was higher in the trial group than that in the control group. Nedaplatin has a possibility to result in mild nausea/vomiting. Nedaplatin is an effective platinum drug in the treatment of NSCLC, not only for no previously chemotherapy patients, but also for those patients resistant to cisplatin/carboplatin. Nedaplatin has a good clinical tolerance. And the main adverse reaction was myelosuppression, especially thrombocytopenia.

  11. Synergistic effect of phenformin in non-small cell lung cancer (NSCLC) ionizing radiation treatment.

    PubMed

    Wang, Jia; Xia, Shi'an; Zhu, Zhizhen

    2015-03-01

    Biguanides, used for anti-diabetic drugs, bring more attention in cancer research for their beneficial effects. Phenformin is more potent than metformin. However its potential application as a anti-cancer regent is far behind metformin. In order to investigate any beneficial effect of combination of Phenformin and radiotherapy, non-small cell lung cancer cell lines A549 and H1299 were exposure under different dose of ionizing radiation with or without Phenformin. Results indicated Phenformin showed synergistic effect and could induce more cancer cell apoptosis and inhibition of tumor growth compared with ionizing radiation alone. Furthermore, this synergistic effect may be through different pathway according to cancer cell genotype background. Our results showed Phenformin induced AMPK activation in A549 but not H1299. However, Phenformin activated eIF2α in both cell lines. Our findings implicated Phenformin may be used as radiosensitizer for non-small cell lung cancer therapy.

  12. Non-invasive diagnostic platforms in management of non-small cell lung cancer: opportunities and challenges

    PubMed Central

    Pennell, Nathan A.

    2017-01-01

    Several non-invasive diagnostic platforms are already being incorporated in routine clinical practice in the work up and monitoring of patients with lung cancer. These approaches have great potential to improve patient selection and monitor patients while on therapy, however several challenges exist in clinical validation and standardization of such platforms. In this review, we summarize the current technologies available for non-invasive diagnostic evaluation from the blood of patients with non-small cell lung cancer (NSCLC), and discuss the technical and logistical challenges associated incorporating such testing in clinical practice. PMID:29057238

  13. Liquid biopsy based biomarkers in non-small cell lung cancer for diagnosis and treatment monitoring

    PubMed Central

    Pérez-Callejo, David; Provencio, Mariano

    2016-01-01

    Advances in the knowledge of the biology of non-small cell lung cancer (NSCLC) have revealed molecular information used for systemic cancer therapy targeting metastatic disease, with an important impact on patients overall survival (OS) and quality of life. However, a biopsy of overt metastases is an invasive procedure limited to certain locations and not easily acceptable in the clinic. Moreover, a single biopsy cannot reflect the clonal heterogeneity of the tumor. The analysis of peripheral blood samples of cancer patients represents a new source of cancer-derived material, known as liquid biopsy, and its components can be obtained from almost all body fluids. These components have shown to reflect characteristics of the status of both the primary and metastatic diseases, helping the clinicians to move towards a personalized medicine. The present review focuses on the liquid biopsy components: circulating tumor cells (CTCS), circulating free DNA (cfDNA), exosomes and tumor-educated platelets (TEP); the isolation technologies used and their potential use for non-invasive screening, early diagnosis, prognosis, response to treatment and real time monitoring of the disease, in NSCLC patients. PMID:27826527

  14. Medical treatment of advanced non-small cell lung cancer in elderly patients: a review of the role of chemotherapy and targeted agents.

    PubMed

    Meoni, Giulia; Cecere, Fabiana Letizia; Lucherini, Elisa; Di Costanzo, Francesco

    2013-07-01

    Lung cancer is the leading cause of cancer related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all cases. Half of the patients at diagnosis of NSCLC are over seventy years old; therefore, the elderly represent a large subgroup of patients affected by advanced NSCLC in our clinical practice. Nevertheless, the elderly are under-represented in clinical trials. Given the fact that old age is frequently associated with several comorbidities, poor general conditions and physiologic reduction in organ function, clinicians must carefully choose the best treatment option for elderly patients with advanced NSCLC, always taking into account the expected risks and benefits. In this paper we perform a review of literature evidence regarding the medical treatment of elderly patients affected by advanced NSCLC, encompassing single-agent chemotherapy, doublet chemotherapy and targeted agents. We conclude that single-agent chemotherapy with a third generation agent (vinorelbine, taxanes, gemcitabine) represents a valid treatment option for elderly patients who are not eligible for a combination chemotherapy due to clinical features such as comorbidities, poor performance status and inadequate organ function. Platinum-based doublet chemotherapy shows similar efficacy in elderly patients as compared to their younger counterpart, despite greater treatment related toxicity and it is indicated in elderly patients with ECOG PS: 0-2, adequate organ function and no major comorbidities. Elderly patients affected by epidermal growth factor receptor (EGFR) mutated NSCLC benefit mostly from a tyrosine kinase inhibitor of EGFR (erlotinib, gefitinib) which is associated with a good toxicity profile. Currently there are no available data to strongly support the use of bevacizumab in combination with first line chemotherapy in the treatment of older adults. Elderly patients affected by NSCLC harboring the EML4-ALK translocation could benefit mostly from a treatment

  15. Non-small cell lung cancer therapy in the elderly.

    PubMed

    Gridelli, Cesare; Rossi, Antonio; Maione, Paolo; Schettino, Clorinda; Bareschino, Maria Anna; Palazzolo, Giovanni; Zeppa, Rosario; Ambrosio, Rita; Barbato, Valentina; Sacco, Paola Claudia

    2011-05-01

    To date, lung cancer is still the leading cause of cancer-related mortality worldwide, with the majority of lung cancers arising in the elderly. As a consequence, we can expect an increase in the number of older lung cancer patients considered suitable for chemotherapy in the near future. Elderly patients often have comorbid conditions and progressive physiologic reduction of organ function, which can make the selection of proper treatment daunting. Some patients will be able to tolerate chemotherapy as well as their younger counterparts, whereas others will experience severe toxicity and require treatment modifications. Thus, a major issue is effectively selecting patients suitable for standard or attenuated therapy. A comprehensive geriatric assessment performed at baseline is a useful tool that can help select the best treatment regimen to be administered to elderly patients. Until now, few trials have specifically focused on elderly patients affected by non-small cell lung cancer (NSCLC), particularly those with advanced disease; prospective elderly-specific studies in early stages are still lacking. High priority should be given to evaluating the role of new targeted therapies. Unfortunately, to date, clinical trials that include functional status and comorbidity as part of the geriatric assessment are rare. Future trials, specifically in the elderly population, should include these kinds of evaluations. The most recent therapies for the treatment of elderly patients with NSCLC will be discussed here.

  16. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

    PubMed Central

    Sullivan, Ivana; Planchard, David

    2016-01-01

    The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinib-resistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic. PMID:26753004

  17. Prospective Randomized Phase II Parallel Study of Vinorelbine Maintenance Therapy versus Best Supportive Care in Advanced Non-Small Cell Lung Cancer.

    PubMed

    Khosravi, Adnan; Esfahani-Monfared, Zahra; Seifi, Sharareh; Khodadad, Kian

    2017-01-01

    Maintenance strategy has been used to improve survival in non-small cell lung cancer (NSCLC). We investigated whether switch maintenance therapy with vinorelbine improved progression free survival (PFS) after first-line chemotherapy with gemcitabine plus carboplatin. In this single blind, parallel, phase 2, randomized trial, patients with NSCLC pathology, age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-2, and advanced stage (IIIB and IV) were treated with up to 6 cycles of gemcitabine 1250 mg/m 2 (day 1 and 8) plus carboplatin AUC 5 (day 1) every 3 weeks. Patients who did not show progression after first-line chemotherapy were randomly assigned to receive switch maintenance with vinorelbine (25 mg/m 2 , day 1, 15) or the best supportive care until disease progression. A total of 100 patients were registered, of whom 34 had a non-progressive response to first-line chemotherapy and randomly received maintenance vinorelbine (n=19) or best supportive care (n=15). The hazard ratio of PFS in the vinorelbine group relative to the best supportive care group was 1.097 (95% confidence interval = 0.479-2.510; P-value =0.827). There was no significant difference between the overall survival for the two groups (P=0.068). Switch maintenance strategies are beneficial, but defining the right candidates for treatment is a problem. Moreover, the trial designs do not always reflect the real-world considerations. Switch maintenance therapy with vinorelbine, though had tolerable toxicity, did not improve PFS in patients with NSCLC. Therefore, other agents should be considered in this setting.

  18. Brain Metastases in Oncogene-Addicted Non-Small Cell Lung Cancer Patients: Incidence and Treatment

    PubMed Central

    Remon, J.; Besse, Benjamin

    2018-01-01

    Brain metastases (BM) are common in non-small cell lung cancer patients including in molecularly selected populations, such as EGFR-mutant and ALK-rearranged tumors. They are associated with a reduced quality of life, and are commonly the first site of progression for patients receiving tyrosine kinase inhibitors (TKIs). In this review, we summarize incidence of BM and intracranial efficacy with TKI agents according to oncogene driver mutations, focusing on important clinical issues, notably optimal first-line treatment in oncogene-addicted lung tumors with upfront BM (local therapies followed by TKI vs. TKI monotherapy). We also discuss the potential role of newly emerging late-generation TKIs as new standard treatment in oncogene-addicted lung cancer tumors compared with sequential strategies. PMID:29696132

  19. Treatment outcomes in locally advanced colorectal carcinoma

    PubMed Central

    Harish, K; Narayanaswamy, YV; Nirmala, S

    2004-01-01

    Background Locally advanced colorectal cancers form a distinct subgroup where contiguous organs could be involved without distant metastases and so may be amenable to curative surgical resection. It was our objective to report our experience in treating six such patients with operable locally advanced colorectal carcinomas. Methods We retrospectively reviewed the case notes of 47 patients who were diagnosed with colorectal cancers at M S Ramaiah Medical Teaching Hospital between the years 1996 – 2001. Six patients were identified with T4 lesions, adjacent organ involvement and with no nodal involvement. The treatments and outcomes for these patients were then reviewed. Results Two of three patients with rectal malignancies who underwent pelvic exenteration succumbed to disease recurrence within the first 18 months. One of the three patients with colonic cancers died of non malignant causes. The other two are disease free till date. Conclusions Aggressive multivisceral resections for locally advanced colonic cancers might be appropriate. Rectal cancers when locally advanced may be considered for pelvic exenteration, but a more guarded prognosis may apply. PMID:15527504

  20. Epidermal growth factor receptor in non-small cell lung cancer

    PubMed Central

    2015-01-01

    Following the identification of a group of patients in the initial tyrosine kinase inhibitor (TKI) trials for lung cancer, there has been detailed focus on which patients may benefit from inhibitor therapy. This article reviews the background, genetics and prevalence of epidermal growth factor mutations in non-small cell lung cancer (NSCLC). Additionally, the prevalence in unselected patients is compared against various other reviews. PMID:25870793

  1. Emerging science and therapies in non-small-cell lung cancer: targeting the MET pathway.

    PubMed

    Kris, Mark G; Arenberg, Douglas A; Herbst, Roy S; Riely, Gregory J

    2014-11-01

    During this enduring, learner-driven, interactive CME webseries, lung cancer specialists will address the science and targeted therapies for the MET pathway in non-small cell lung cancer. Over the past decade, research has evolved in the science of identifying targeted biological changes in DNA and individual cancer cells. Along with the advanced understanding of lung cancer mutations, has come the development of specific targeted therapies that improve patient outcomes. The first step in treating a patient with lung cancer is proper diagnosis and staging, applying to the principles of personalize medicine. Our current understanding of lung cancer is that of a collection of diseases individualized through specific mutations. This CME activity reviews the role of the pulmonologist and pathologist in proper tissue acquisition and analysis. This new era of personalized medicine and clinical research advances has changed the way clinicians evaluate and treat patients with lung cancer. The data on lung cancer cell mutations and newer targeted therapies have improved the progression free survival and quality of life of lung cancer patients. This CME activity is designed to present a practical overview of recent evidenced based data of MET targeted therapies for patients with lung cancer. As research continues to evolve, we continue to advance our understanding in the science of lung cancers involving the MET pathway. Evidenced based data supporting newer targeted therapeutics provides insight on applying treatment for optimal outcomes. This CME activity will focus on the individualized treatment strategies using practical decision making for patients with MET expression. This activity has been designed to meet the educational needs of medical oncologists, pathologists, radiation oncologists, surgeons, pulmonologists, internists, and other healthcare clinicians responsible for the care of patients with lung cancer. Online access:http://www.elseviercme.com/516/.

  2. Extended lymphadenectomy for locally advanced and recurrent rectal cancer.

    PubMed

    Georgiou, Panagiotis A; Mohammed Ali, S; Brown, Gina; Rasheed, Shahnawaz; Tekkis, Paris P

    2017-03-01

    The purpose of this study is to assess the value of extended (lateral) lymphadenectomy (EL) in the operative management of locally advanced and recurrent rectal cancer. Patients that underwent exenterative surgery for locally advanced or recurrent rectal cancer between 2006 and 2009 were included in the study. A decision for EL was taken at the local multidisciplinary meeting based on the radiological findings. Perioperative and oncological outcomes were assessed and compared between the EL and non-EL group prospectively. Forty-one consecutive patients were included in the study (EL = 17). The median age was 57 (40-71) for EL and 66 (39-81) years for non-EL. Of patients, 27 (EL = 13) and 14 (EL = 4) underwent pelvic exenteration and abdominosacral resection, respectively. Twelve (EL = 7) patients were diagnosed with locally advanced primary rectal cancer. Thirty-one (EL = 12) patients received neoadjuvant radiotherapy. The median intraoperative time, blood loss and hospital stay were 9 h (3-13), 1.5 l (0.3-7) and 14 days (12-72), respectively, for the EL group, and 8 h (4-15), 1.6 l (0.25-17) and 14 days (10-86), respectively, for the non-EL (p ≥ 0.394). Morbidity was similar between the two groups (EL = 4, non-EL = 9; p = 0.344). Complete tumour resection (R0) was achieved in 30 (73.17%) patients, 12 (70.58%) in the EL group and 18 (75%) in the non-EL group (p = 0.649). There was no significant difference in 5-year survival (EL = 60.7%, non-EL = 75.2%; p = 0.447), local recurrence (EL = 53.6%, non-EL = 65.4%; p = 0.489) and disease-free survival (EL = 53.6%, non-EL = 51.4%; p = 0.814). The present study demonstrated that EL does not provide a statistically significant advantage in survival or recurrence rates, for patients with locally advanced primary or recurrent rectal cancer.

  3. SOX17 promoter methylation in plasma circulating tumor DNA of patients with non-small cell lung cancer.

    PubMed

    Balgkouranidou, Ioanna; Chimonidou, Maria; Milaki, Georgia; Tsaroucha, Emily; Kakolyris, Stylianos; Georgoulias, Vasilis; Lianidou, Evi

    2016-08-01

    SOX17 belongs to the high-mobility group-box transcription factor superfamily and down-regulates the Wnt pathway. The aim of our study was to evaluate the prognostic significance of SOX17 promoter methylation in circulating tumor DNA (ctDNA) in plasma of non-small cell lung cancer (NSCLC) patients. We examined the methylation status of SOX17 promoter in 57 operable NSCLC primary tumors and paired adjacent non-cancerous tissues and in ctDNA isolated from 48 corresponding plasma samples as well as in plasma from 74 patients with advanced NSCLC and 49 healthy individuals. SOX17 promoter methylation was examined by Methylation Specific PCR (MSP). In operable NSCLC, SOX17 promoter was fully methylated in primary tumors (57/57, 100%), and in corresponding ctDNA (27/48, 56.2%) while it was detected in only 1/49 (2.0%) healthy individuals. In advanced NSCLC, SOX17 promoter was methylated in ctDNA in 27/74 (36.4%) patients and OS was significantly different in favor of patients with non-methylated SOX17 promoter (p=0.012). Multivariate analysis revealed that SOX17 promoter methylation in ctDNA was an independent prognostic factor associated with OS in patients with advanced but not operable NSCLC. Our results show that SOX17 promoter is highly methylated in primary tumors and in corresponding plasma samples both in operable and advanced NSCLC. In the advanced setting, SOX17 promoter methylation in plasma ctDNA has a statistical significant influence on NSCLC patient's survival time. Detection of SOX17 promoter methylation in plasma provides prognostic information and merits to be further evaluated as a circulating tumor biomarker in patients with operable and advanced NSCLC.

  4. Crystal digital droplet PCR for detection and quantification of circulating EGFR sensitizing and resistance mutations in advanced non-small cell lung cancer

    PubMed Central

    Madic, Jordan; Remon, Jordi; Honoré, Aurélie; Girard, Romain; Rouleau, Etienne; André, Barbara; Besse, Benjamin; Droniou, Magali; Lacroix, Ludovic

    2017-01-01

    Over the past years, targeted therapies using tyrosine kinase inhibitors (TKI) have led to an increase in progression-free survival and response rate for a subgroup of non-small cell lung cancer (NSCLC) patients harbouring specific gene abnormalities compared with chemotherapy. However long-lasting tumor regression is rarely achieved, due to the development of resistant tumoral subclones, which requires alternative therapeutic approaches. Molecular profile at progressive disease is a challenge for making adaptive treatment decisions. The aim of this study was to monitor EGFR-mutant tumors over time based on the quantity of mutant DNA circulating in plasma (ctDNA), comparing two different methods, Crystal™ Digital™ PCR and Massive Parallel Sequencing (MPS). In plasma circulating cell free DNA (cfDNA) of 61 advanced NSCLC patients we found an overall correlation of 78% between mutated allelic fraction measured by Crystal Digital PCR and MPS. 7 additional samples with sensitizing mutations and 4 additional samples with the resistance mutation were detected with Crystal Digital PCR, but not with MPS. Monitoring levels of both mutation types over time showed a correlation between levels and trends of mutated ctDNA detected and clinical assessment of disease for the 6 patients tested. In conclusion, Crystal Digital PCR exhibited good performance for monitoring mutational status in plasma cfDNA, and also appeared as better suited to the detection of known mutations than MPS in terms of features such as time to results. PMID:28829811

  5. Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component.

    PubMed

    Yang, James Chih-Hsin; Ahn, Myung-Ju; Kim, Dong-Wan; Ramalingam, Suresh S; Sequist, Lecia V; Su, Wu-Chou; Kim, Sang-We; Kim, Joo-Hang; Planchard, David; Felip, Enriqueta; Blackhall, Fiona; Haggstrom, Daniel; Yoh, Kiyotaka; Novello, Silvia; Gold, Kathryn; Hirashima, Tomonori; Lin, Chia-Chi; Mann, Helen; Cantarini, Mireille; Ghiorghiu, Serban; Jänne, Pasi A

    2017-04-20

    Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.

  6. Real-world practice patterns for patients with advanced non-small cell lung cancer: multicenter retrospective cohort study in Japan.

    PubMed

    Isobe, Hiroshi; Mori, Kiyoshi; Minato, Koichi; Katsura, Hideki; Taniguchi, Kazuko; Arunachalam, Ashwini; Kothari, Smita; Cao, Xiting; Kato, Terufumi

    2017-01-01

    Recommended therapies for advanced/metastatic non-small cell lung cancer (NSCLC) have changed with the advent of targeted therapies. The objectives of this retrospective chart review study were to describe treatment patterns, biomarker testing practices, and health care resource use for advanced NSCLC at 5 sites in Japan. We studied anonymized medical record data of patients aged ≥18 years who initiated systemic therapy for newly diagnosed stage IIIB or IV NSCLC from January 2011 through June 2013. Data were analyzed descriptively by histology and mutation status. Overall survival was estimated using the Kaplan-Meier method. We studied 175 patients, including 43 (25%), 129 (74%), and 3 (2%) with squamous, nonsquamous, and unknown NSCLC histology, respectively; 83% had stage IV NSCLC. Overall, 123 patients (70%) were male; the median age was 70 years (range, 47-86); and 33 (19%) were never-smokers. In the nonsquamous cohort, 105 (81%) and 25 (19%) of patients were tested for epidermal growth factor receptor ( EGFR ) mutation and anaplastic lymphoma kinase ( ALK ) rearrangement, respectively; 44 (42%) had EGFR -positive NSCLC and 2 (8%) had ALK -positive NSCLC, including 26/46 (57%) women and 21/46 (46%) never-smokers. In the squamous cohort, 17 (40%) and 4 (9%), respectively, were tested; 1 EGFR -positive tumor was detected. After first-line therapy, 105 (60%) patients received second-line, and 54/105 (51%; or 31% overall) received third-line therapy. EGFR tyrosine kinase inhibitors were most commonly prescribed for EGFR -positive NSCLC across all lines. In the nonsquamous EGFR / ALK -negative/unknown cohort, most received first-line platinum combinations, particularly younger patients (78% ≥75 years vs 93% <75 years old). The average hospitalization was 21 days/admission. The median (95% CI) overall survival from start of first-line therapy was 9.9 months (7.6-11.7) for all patients and 17.9 months (9.9-24.4) for patients with EGFR / ALK -positive status

  7. Correlation of cancer stem cell markers and immune cell markers in resected non-small cell lung cancer.

    PubMed

    Huang, Zhaoqin; Yu, Haining; Zhang, Jianbo; Jing, Haiyan; Zhu, Wanqi; Li, Xiaolin; Kong, Lingling; Xing, Ligang; Yu, Jinming; Meng, Xiangjiao

    2017-01-01

    Background: Recent studies confirmed that immunotherapy showed prominent efficacy in non-small cell lung cancer (NSCLC). Cancer stem cells/cancer initiating cells are resistant to anticancer treatment. The purpose of the study was to analyze the correlation of cancer stem cells/cancer initiating cells and tumor-infiltrating immune cells in NSCLC. Methods: CD133, octamer 4 (OCT-4), CD8, CD56, human leukocyte antigen (HLA) class I and programmed death ligand-1 (PD-L1) were assessed in 172 resected NSCLC samples. The staining was analyzed and scored by the pathologist who was blinded to the clinical pathological data of the patients. Results: High CD8+ T cell infiltration was correlated significantly with squamous cell carcinoma histology (p=0.008). High PD-L1 expression (≥10%) was associated with high tumor status (p=0.043). Pearson's correlation test showed that CD56+ cells were negatively correlated with CD133 expression (r=-0.361, p<0.001) and weakly correlated with negative OCT-4 expression (r=-0.180, p=0.018). There was a strong positive correlation between CD8 and HLA class I (r=0.573, p<0.001). In the survival analysis, high CD8+ T cell infiltration is an independent predictor of improved disease-free survival and overall survival. Patients with low CD133 expression and high CD56 expression had a longer overall survival than those with high CD133 expression and/or low CD56 expression (p=0.013). Conclusion: There is a negative correlation between CD56+ cells and cancer stem cell markers. This correlation may confirm the possibility that natural killer cells can target CD133+ cancer stem cells/cancer initiating cells in non-small cell lung cancer.

  8. Non-Small-Cell Lung Cancer Molecular Signatures Recapitulate Lung Developmental Pathways

    PubMed Central

    Borczuk, Alain C.; Gorenstein, Lyall; Walter, Kristin L.; Assaad, Adel A.; Wang, Liqun; Powell, Charles A.

    2003-01-01

    Current paradigms hold that lung carcinomas arise from pleuripotent stem cells capable of differentiation into one or several histological types. These paradigms suggest lung tumor cell ontogeny is determined by consequences of gene expression that recapitulate events important in embryonic lung development. Using oligonucleotide microarrays, we acquired gene profiles from 32 microdissected non-small-cell lung tumors. We determined the 100 top-ranked marker genes for adenocarcinoma, squamous cell, large cell, and carcinoid using nearest neighbor analysis. Results were validated by immunostaining for 11 selected proteins using a tissue microarray representing 80 tumors. Gene expression data of lung development were accessed from a publicly available dataset generated with the murine Mu11k genome microarray. Self-organized mapping identified two temporally distinct clusters of murine orthologues. Supervised clustering of lung development data showed large-cell carcinoma gene orthologues were in a cluster expressed in pseudoglandular and canalicular stages whereas adenocarcinoma homologues were predominantly in a cluster expressed later in the terminal sac and alveolar stages of murine lung development. Representative large-cell genes (E2F3, MYBL2, HDAC2, CDK4, PCNA) are expressed in the nucleus and are associated with cell cycle and proliferation. In contrast, adenocarcinoma genes are associated with lung-specific transcription pathways (SFTPB, TTF-1), cell adhesion, and signal transduction. In sum, non-small-cell lung tumors histology gene profiles suggest mechanisms relevant to ontogeny and clinical course. Adenocarcinoma genes are associated with differentiation and glandular formation whereas large-cell genes are associated with proliferation and differentiation arrest. The identification of developmentally regulated pathways active in tumorigenesis provides insights into lung carcinogenesis and suggests early steps may differ according to the eventual tumor

  9. Pembrolizumab in the treatment of metastatic non-small cell lung cancer: a review of current evidence

    PubMed Central

    Rihawi, Karim; Gelsomino, Francesco; Sperandi, Francesca; Melotti, Barbara; Fiorentino, Michelangelo; Casolari, Laura; Ardizzoni, Andrea

    2017-01-01

    Immune checkpoint inhibitors (ICPIs) are considered one of the most important breakthroughs in cancer treatment of the past decade; notably, different studies of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have reported impressive clinical activity and durable responses in patients with advanced non-small cell lung cancer (NSCLC). These findings have led to the changing of the current therapeutic algorithm of advanced NSCLC, adding a new standard first-line treatment option for patients with PD-L1-positive tumors. Pembrolizumab, a highly selective anti-PD-1 humanized monoclonal antibody, was approved by the United States Food and Drug Administration (US FDA) in October 2016 for previously untreated metastatic NSCLC patients whose tumors have high PD-L1 expression, tumor proportion score (TPS) ⩾ 50%, as well as for metastatic NSCLC patients whose tumors express PD-L1 with TPS ⩾ 1% progressing on or after platinum-based chemotherapy. However, many issues remain outstanding, mainly regarding the identification of an optimal biomarker which can help selecting patients more likely to respond to ICPIs. In this review, we discuss the clinical results obtained so far with the anti-PD-1 pembrolizumab in advanced NSCLC, commenting on the role of PD-L1 as a predictive factor and providing an update of the future perspectives. PMID:28818019

  10. Accuracy of cytology in sub typing non small cell lung carcinomas.

    PubMed

    Patel, Trupti S; Shah, Majal G; Gandhi, Jahnavi S; Patel, Pratik

    2017-07-01

    Sub typing of non small cell lung carcinoma (NSCLC) has an important task in the era of molecular and targeted therapies. Differentiating between squamous cell carcinoma (SQCC) and adenocarcinoma (ADC) is challenging when limited material is available in lung carcinoma. We investigated the accuracy and feasibility of sub typing NSCLCs in cytology and small biopsy material. Concurrent cytology and biopsy material obtained in a single CT- guided procedure in lung carcinoma over a year period retrospectively. Both materials were individually sub typed and analyzed. Immunohistochemistry (IHC) was performed. Accuracy was determined by comparing the results with IHC. Total 107 of 126 cases of NSCLCs were included for analysis, where both cytology and biopsy material were adequate for interpretation. FNAC allowed tumor typing in 83 (77.6%) cases; 36 (33.6%) were ADC, 47 (43.9%) cases were SQCC and 24 (22.4%) cases diagnosed as Non-small cell carcinoma not otherwise specified (NSCLC-NOS). In biopsy, 86 cases (80.4%) were typed, among which 34 (31.8%) were ADC, 52 (48.6%) were SQCC and 21 (19.6%) were of NSCLC-NOS type. The result of Chi-square index was significant. With the aid of IHC, NSCLC-NOS reduced from 14 (13%) cases to 2 (1.9%) cases. Cytology and small biopsy specimens achieved comparable specificity and accuracy in sub-typing NSCLC and optimal results were obtain when findings from both modalities combine. The advantage of paired specimens is to maximize overall diagnostic yield and the remaining material will be available for ancillary technique like IHC or for molecular testing. Diagn. Cytopathol. 2017;45:598-603. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  11. Molecular breakdown: a comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.

    PubMed

    Noh, Ka-Won; Lee, Mi-Sook; Lee, Seung Eun; Song, Ji-Young; Shin, Hyun-Tae; Kim, Yu Jin; Oh, Doo Yi; Jung, Kyungsoo; Sung, Minjung; Kim, Mingi; An, Sungbin; Han, Joungho; Shim, Young Mog; Zo, Jae Ill; Kim, Jhingook; Park, Woong-Yang; Lee, Se-Hoon; Choi, Yoon-La

    2017-11-01

    Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLCs) show good clinical response to ALK inhibitors. However, some ALK-rearranged NSCLC patients show various primary responses with unknown reasons. Previous studies focused on the clinical aspects of ALK fusions in small cohorts, or were conducted in vitro and/or in vivo to investigate the function of ALK. One of the suggested theories describes how echinoderm microtubule-associated protein-like 4 (EML4)-ALK variants play a role towards different sensitivities in ALK inhibitors. Until now, there has been no integrated comprehensive study that dissects ALK at the molecular level in a large scale. Here, we report the largest extensive molecular analysis of 158 ALK-rearranged NSCLCs and have investigated these findings in a cell line construct experiment. We discovered that NSCLCs with EML4-ALK short forms (variant 3/others) had more advanced stage and frequent metastases than cases with the long forms (variant 1/others) (p = 0.057, p < 0.05). In vitro experiments revealed that EML4-ALK short forms show lower sensitivity to ALK inhibitors than do long forms. Clinical analysis also showed a trend for the short forms showing worse PFS. Interestingly, we found that breakpoints of ALK are evenly distributed mainly in intron 19 and almost all of them undergo a non-homologous end-joining repair to generate ALK fusions. We also discovered four novel somatic ALK mutations in NSCLC (T1151R, R1192P, A1280V, and L1535Q) that confer primary resistance; all of them showed strong resistance to ALK inhibitors, as G1202R does. Through targeted deep sequencing, we discovered three novel ALK fusion partners (GCC2, LMO7, and PHACTR1), and different ALK fusion partners showed different intracellular localization. With our findings that the EML4-ALK variants, new ALK somatic mutations, and novel ALK-fusion partners may affect sensitivity to ALK inhibitors, we stress the importance of targeted therapy to take

  12. Enrichment and characterization of cancer stem cells from a human non-small cell lung cancer cell line.

    PubMed

    Zhao, Changhong; Setrerrahmane, Sarra; Xu, Hanmei

    2015-10-01

    Tumor cells from the same origin comprise different cell populations. Among them, cancer stem cells (CSCs) have higher tumorigenicity. It is necessary to enrich CSCs to determine an effective way to suppress and eliminate them. In the present study, using the non-adhesive culture system, tumor spheres were successfully generated from human A549 non-small cell lung cancer (NSCLC) cell line within 2 weeks. Compared to A549 adherent cells, sphere cells had a higher self-renewal ability and increased resistance to cytotoxic drugs. Sphere cells were more invasive and expressed stem cell markers including octamer‑binding transcription factor 4 (Oct4) and sex-determining region Y-box 2 (Sox2) at high levels. CD133, a disputed marker of lung CSCs, was also upregulated. Tumor sphere cells showed higher tumorigenic ability in vivo, indicating that more CSCs were enriched in the sphere cells. More blood vessels were formed in the tumor generated by sphere cells suggesting the interaction between CSCs and blood vessel. A reliable model of enriching CSCs from the human A549 NSCLC cell line was established that was simple and cost-effective compared to other methods.

  13. Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Yuexia; Li, Xiaohui; Liu, Gang

    2015-01-30

    Highlights: • TIPE2 is down-regulated in NSCLC tissues. • TIPE2 inhibits NSCLC cell proliferation, colony formation and invasion. • TIPE2 reduces the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. - Abstract: The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo.more » We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression.« less

  14. FASTmiR: an RNA-based sensor for in vitro quantification and live-cell localization of small RNAs

    PubMed Central

    Huang, Kun; Doyle, Francis; Wurz, Zachary E.; Tenenbaum, Scott A.; Hammond, Reza K.

    2017-01-01

    Abstract Small RNAs, including microRNAs (miRNAs) and small interfering RNAs (siRNAs), play a variety of important regulatory roles in many eukaryotes. Their small size has made it challenging to study them directly in live cells. Here we describe an RNA-based fluorescent sensor for small RNA detection both in vitro and in vivo, adaptable for any small RNA. It utilizes an sxRNA switch for detection of miRNA–mRNA interactions combined with a fluorophore-binding sequence ‘Spinach’, a GFP-like RNA aptamer for which the RNA–fluorophore complex exhibits strong and consistent fluorescence under an excitation wavelength. Two example sensors, FASTmiR171 and FASTmiR122, can rapidly detect and quantify the levels of miR171 and miR122 in vitro. The sensors can determine relative levels of miRNAs in total RNA extracts with sensitivity similar to small RNA sequencing and northern blots. FASTmiR sensors were also used to estimate the copy number range of miRNAs in total RNA extracts. To localize and analyze the spatial distribution of small RNAs in live, single cells, tandem copies of FASTmiR122 were expressed in different cell lines. FASTmiR122 was able to quantitatively detect the differences in miR122 levels in Huh7 and HEK293T cells demonstrating its potential for tracking miRNA expression and localization in vivo. PMID:28586459

  15. Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer *

    PubMed Central

    Lopes, Gabriel Lima; Vattimo, Edoardo Filippo de Queiroz; de Castro, Gilberto

    2015-01-01

    Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21), first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC) patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC. PMID:26398757

  16. Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer.

    PubMed

    Lopes, Gabriel Lima; Vattimo, Edoardo Filippo de Queiroz; Castro Junior, Gilberto de

    2015-01-01

    Lung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21), first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC) patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC.

  17. Ifosfamide and vinorelbine as first-line chemotherapy for advanced non-small cell lung carcinoma.

    PubMed

    Vallejo, C; Romero, A; Perez, J; Cuevas, M; Lacava, J; Sabatini, C; Dominguez, M; Rodriguez, R; Barbieri, M; Romero Acuña, L; Romero Acuña, J; Langhi, M; Amato, S; Salvadori, M; Ortiz, E; Machiavelli, M; Leone, B

    1996-12-01

    We evaluated the efficacy and toxicity of the novel combination of ifosfamide (IFX) and vinorelbine (VNB) as first-line chemotherapy in patients with stage IIIB and IV non-small cell lung cancer (NSCLC). Between March 1993 and November 1994, 44 patients (17 stage IIIB; 27 stage IV) received a regimen consisting of IFX, 2 g/m2 in a 1-h infusion, days 1-3; mesna, 400 mg/m2 in an i.v. bolus at hours 0 and 4 and 800 mg orally at hour 8, days 1-3; and VNB, 35 mg/ m2 in a 20-min infusion, days 1 and 15. During the first course only, a half dose of VNB (17.5 mg/m2) was administered on days 8 and 22. Courses were repeated every 28 days. Forty patients were fully evaluable for response, and 44 were assessable for toxicity. Objective regression was recorded in 13 of 40 patients (33%). No patient achieved a complete response. Thirteen patients presented a partial response (33%); 17 (42%) had no change; and progressive disease was observed in 10 (25%). The median duration of response was 10 months, and the median time to treatment failure for the whole group was 4 months. Median survival was 11 months. The dose-limiting toxic effect was myelosuppression. Leukopenia occurred in 25 patients (57%) and was grade 3 or 4 in 8 patients (18%). Twelve patients (27%) developed peripheral neurotoxicity, while five had mild IFX-induced CNS toxicity. Phlebitis was observed in 15 of 30 patients (50%) who did not have central implantable venous systems. The IFX-VNB combination exhibited an activity against NSCLC that was among the highest reported for non-cisplatin-containing regimens, with a toxicity profile that was easily managed.

  18. [Technical advancement improves survival in patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving definitive radiotherapy].

    PubMed

    Wang, J B; Jiang, W; Ji, Z; Cao, J Z; Liu, L P; Men, Y; Xu, C; Wang, X Z; Hui, Z G; Liang, J; Lyu, J M; Zhou, Z M; Xiao, Z F; Feng, Q F; Chen, D F; Zhang, H X; Yin, W B; Wang, L H

    2016-08-01

    This study aimed to evaluate the impact of technical advancement of radiation therapy in patients with LA-NSCLC receiving definitive radiotherapy (RT). Patients treated with definitive RT (≥50 Gy) between 2000 and 2010 were retrospectively reviewed. Overall survival (OS), cancer specific survival (CSS), locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) were calculated and compared among patients irradiated with different techniques. Radiation-induced lung injury (RILI) and esophageal injury (RIEI) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0 (NCI-CTCAE 3.0). A total of 946 patients were eligible for analysis, including 288 treated with two-dimensional radiotherapy (2D-RT), 209 with three-dimensional conformal radiation therapy (3D-CRT) and 449 with intensity-modulated radiation therapy (IMRT) respectively. The median follow-up time for the whole population was 84.1 months. The median OS of 2D-RT, 3D-CRT and IMRT groups were 15.8, 19.7 and 23.3 months, respectively, with the corresponding 5-year survival rate of 8.7%, 13.0% and 18.8%, respectively (P<0.001). The univariate analysis demonstrated significantly inferior OS, LRPFS, DMFS and PFS of 2D-RT than those provided by 3D-CRT or IMRT. The univariate analysis also revealed that the IMRT group had significantly loger LRPFS and a trend toward better OS and DMFS compared with 3D-CRT. Multivariate analysis showed that TNM stage, RT technique and KPS were independent factors correlated with all survival indexes. Compared with 2D-RT, the utilization of IMRT was associated with significantly improved OS, LRPFS, DMFS as well as PFS. Compared with 3D-CRT, IMRT provided superior DMFS (P=0.035), a trend approaching significance with regard to LRPFS (P=0.073) but no statistically significant improvement on OS, CSS and PFS in multivariate analysis. The incidence rates of RILI were

  19. Docetaxel With Either Cetuximab or Bortezomib as First-Line Therapy in Treating Patients With Stage III or Stage IV Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-06-03

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Large Cell Lung Cancer; Malignant Pleural Effusion; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  20. Reinforcement Learning Strategies for Clinical Trials in Non-small Cell Lung Cancer

    PubMed Central

    Zhao, Yufan; Zeng, Donglin; Socinski, Mark A.; Kosorok, Michael R.

    2010-01-01

    Summary Typical regimens for advanced metastatic stage IIIB/IV non-small cell lung cancer (NSCLC) consist of multiple lines of treatment. We present an adaptive reinforcement learning approach to discover optimal individualized treatment regimens from a specially designed clinical trial (a “clinical reinforcement trial”) of an experimental treatment for patients with advanced NSCLC who have not been treated previously with systemic therapy. In addition to the complexity of the problem of selecting optimal compounds for first and second-line treatments based on prognostic factors, another primary goal is to determine the optimal time to initiate second-line therapy, either immediately or delayed after induction therapy, yielding the longest overall survival time. A reinforcement learning method called Q-learning is utilized which involves learning an optimal regimen from patient data generated from the clinical reinforcement trial. Approximating the Q-function with time-indexed parameters can be achieved by using a modification of support vector regression which can utilize censored data. Within this framework, a simulation study shows that the procedure can extract optimal regimens for two lines of treatment directly from clinical data without prior knowledge of the treatment effect mechanism. In addition, we demonstrate that the design reliably selects the best initial time for second-line therapy while taking into account the heterogeneity of NSCLC across patients. PMID:21385164

  1. Doxycycline for prevention of erlotinib-induced rash in patients with non-small-cell lung cancer (NSCLC) after failure of first-line chemotherapy: A randomized, open-label trial.

    PubMed

    Deplanque, Gaël; Gervais, Radj; Vergnenegre, Alain; Falchero, Lionel; Souquet, Pierre-Jean; Chavaillon, Jean-Michel; Taviot, Bruno; Fraboulet, Ghislaine; Saal, Hakim; Robert, Caroline; Chosidow, Olivier

    2016-06-01

    Rash is a common epidermal growth factor receptor inhibitor-induced toxicity that can impair quality of life and treatment compliance. We sought to evaluate the efficacy of doxycycline in preventing erlotinib-induced rash (folliculitis) in patients with non-small-cell lung cancer. This open-label, randomized, prospective, phase II trial was conducted in 147 patients with locally advanced or metastatic non-small-cell lung cancer progressing after first-line chemotherapy, randomized for 4 months with erlotinib alone 150 mg/d per os (control arm) or combined with doxycycline 100 mg/d (doxycycline arm). Incidence and severity of rash, compliance, survival, and safety were assessed. Baseline characteristics of the 147 patients were well balanced in the intent-to-treat population. Folliculitis occurred in 71% of patients in the doxycycline arm and 81% in the control arm (P = .175). The severity of folliculitis and other skin lesions was lower in the doxycycline arm compared with the control arm. Other adverse events were reported at a similar frequency across arms. There was no significant difference in survival between treatment arms. The open-label design of the study and the duration of the treatment with doxycycline are limitations. Doxycycline did not reduce the incidence of erlotinib-induced folliculitis, but significantly reduced its severity. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  2. Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules.

    PubMed

    Okuhira, Keiichiro; Shoda, Takuji; Omura, Risa; Ohoka, Nobumichi; Hattori, Takayuki; Shibata, Norihito; Demizu, Yosuke; Sugihara, Ryo; Ichino, Asato; Kawahara, Haruka; Itoh, Yukihiro; Ishikawa, Minoru; Hashimoto, Yuichi; Kurihara, Masaaki; Itoh, Susumu; Saito, Hiroyuki; Naito, Mikihiko

    2017-03-01

    Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein. Copyright © 2017 by

  3. Comparison of monocyte-derived dendritic cells from colorectal cancer patients, non-small-cell-lung-cancer patients and healthy donors.

    PubMed

    Kvistborg, P; Bechmann, C M; Pedersen, A W; Toh, H C; Claesson, M H; Zocca, M B

    2009-12-11

    Dendritic cells (DCs) are bone marrow-derived professional antigen presenting cells. Due to their role as potent inducers of immune responses, these cells are widely used as adjuvant in experimental clinical settings for cancer immune therapy. We have developed a DC-based vaccine using autologous blood monocytes loaded with allogeneic tumor cell lysate rich in cancer/testis antigens. This vaccine has at present been tested for activity in three phase II clinical trials including two cohorts of patients with advanced colorectal cancer (CRC) and one cohort of patients with advanced non-small-cell-lung-cancer (NSCLC). In the present paper we retrospectively compare the maturation profile based on surface marker expression on DCs generated from the three patient cohorts and between cancer patient cohorts and a cohort of healthy donors. Vaccines were generated under cGMP conditions and phenotypic profiles of DC were analyzed by flow cytometry and the obtained data were used as a basis to set guideline values for our quality control of GMP produced DC vaccines. Each vaccine batch was analyzed for the expression of the surface maturation and differentiation molecules CD14, CD1a, CD83, CD86, MHC class II and CCR7, and the optimal expression pattern is considered as CD14(low), CD1a, CD83(high), CD86(high), MHC class II(high) and CCR7(high). In accordance with data from other studies including other types of cancer patients, especially breast cancer patients, we found that the maturation status of the DC batches depends on cancer type and correlates with clinical status of cancer patients included.

  4. Erlotinib Hydrochloride in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Completely Removed by Surgery (An ALCHEMIST Treatment Trial)

    ClinicalTrials.gov

    2018-06-29

    ALK Gene Rearrangement; EGFR Exon 19 Deletion Mutation; EGFR NP_005219.2:p.L858R; Stage IB Non-Small Cell Lung Carcinoma AJCC v7; Stage II Non-Small Cell Lung Cancer AJCC v7; Stage IIA Non-Small Cell Lung Carcinoma AJCC v7; Stage IIB Non-Small Cell Lung Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7

  5. Heart Dose Is an Independent Dosimetric Predictor of Overall Survival in Locally Advanced Non-Small Cell Lung Cancer.

    PubMed

    Speirs, Christina K; DeWees, Todd A; Rehman, Sana; Molotievschi, Alerson; Velez, Maria A; Mullen, Daniel; Fergus, Sandra; Trovo, Marco; Bradley, Jeffrey D; Robinson, Cliff G

    2017-02-01

    In the randomized trial of standard- versus high-dose chemoradiotherapy for locally advanced (LA) NSCLC (Radiation Therapy Oncology Group 0617), overall survival (OS) was worse in the high-dose arm. Although heart dose was suggested as a contributing factor, actionable parameters have not been established. We present an analysis of clinical and dosimetric parameters affecting OS in this patient population, focusing on heart dose. Clinical data were collected on 416 patients with LA NSCLC treated at a single institution, with a subset of 333 available treatment plans recontoured using Radiation Therapy Oncology Group 0617 normal tissue guidelines. Toxicity and dosimetry data were analyzed for 322 patients; multivariate analysis was performed on 251 patients. Dosimetric parameters of radiation to tumor and organs at risk were analyzed with clinical data pertaining to OS, disease-free survival, and toxicity. Patients were treated with radiation therapy to prescribed doses of 50.0 to 84.9 Gy (median 66.0 Gy). Median follow-up was 14.5 months. Median OS was 16.8 months. The 1- and 2-year OS rates were 61.4% and 38.8%, respectively. On multivariate analysis, factors independently associated with worse OS were increasing heart V 50 (volume receiving ≥50 Gy), heart volume, lung V 5 (proportion of the lung structure [excluding the target volume]) receiving at least 5 Gy), bilateral mediastinal lymph node involvement, and lack of concurrent chemotherapy. When stratified by heart V 50 less than 25% versus 25% or greater, the 1-year OS rates were 70.2% versus 46.8% and the 2-year OS rates were 45.9% versus 26.7% (p < 0.0001). Median heart V 50 was significantly higher (20.8% versus 13.9%, p < 0.0001) for patients with cardiac toxicity with a Common Terminology Criteria for Adverse Events grade of 1 or higher. Heart dose is associated with OS and cardiac toxicity for patients with LA NSCLC treated with chemoradiotherapy. Copyright © 2016 International Association for the

  6. Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population*

    PubMed Central

    Hong, Wei; Wang, Kai; Zhang, Yi-ping; Kou, Jun-yan; Hong, Dan; Su, Dan; Mao, Wei-min; Yu, Xin-min; Xie, Fa-jun; Wang, Xiao-jian

    2013-01-01

    Objective: The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C677T excision repair cross-complementation group 1 (ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Methods: A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 C118T were genotyped using the TaqMan methods. Results: The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype (TT or CT) (41.2% versus 19.1%, P=0.01). Median time to progression (TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype (7.6 months versus 5.0 months, P=0.003). No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival. Conclusions: Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum. PMID:23463763

  7. Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop.

    PubMed

    Pirker, Robert; Herth, Felix J F; Kerr, Keith M; Filipits, Martin; Taron, Miquel; Gandara, David; Hirsch, Fred R; Grunenwald, Dominique; Popper, Helmut; Smit, Egbert; Dietel, Manfred; Marchetti, Antonio; Manegold, Christian; Schirmacher, Peter; Thomas, Michael; Rosell, Rafael; Cappuzzo, Federico; Stahel, Rolf

    2010-10-01

    Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have recently been characterized in a subset of patients with advanced non-small cell lung cancer (NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The EGFR-TKI gefitinib has been approved in Europe for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of the EGFR TK. Because EGFR mutation testing is not yet well established across Europe, biomarker-directed therapy only slowly emerges for the subset of NSCLC patients most likely to benefit: those with EGFR mutations. The "EGFR testing in NSCLC: from biology to clinical practice" International Association for the Study of Lung Cancer-European Thoracic Oncology Platform multidisciplinary workshop aimed at facilitating the implementation of EGFR mutation testing. Recommendations for high-quality EGFR mutation testing were formulated based on the opinion of the workshop expert group. Co-operation and communication flow between the various disciplines was considered to be of most importance. Participants agreed that the decision to request EGFR mutation testing should be made by the treating physician, and results should be available within 7 working days. There was agreement on the importance of appropriate sampling techniques and the necessity for the standardization of tumor specimen handling including fixation. Although there was no consensus on which laboratory test should be preferred for clinical decision making, all stressed the importance of standardization and validation of these tests. The recommendations of the workshop will help implement EGFR mutation testing in Europe and, thereby, optimize the use of EGFR-TKIs in clinical practice.

  8. Dynamics of Heat Shock Protein 70 Serum Levels As a Predictor of Clinical Response in Non-Small-Cell Lung Cancer and Correlation with the Hypoxia-Related Marker Osteopontin

    PubMed Central

    Ostheimer, Christian; Gunther, Sophie; Bache, Matthias; Vordermark, Dirk; Multhoff, Gabriele

    2017-01-01

    Hypoxia mediates resistance to radio(chemo)therapy (RT) by stimulating the synthesis of hypoxia-related genes, such as osteopontin (OPN) and stress proteins, including the major stress-inducible heat shock protein 70 (Hsp70). Apart from its intracellular localization, Hsp70 is also present on the plasma membrane of viable tumor cells that actively release it in lipid vesicles with biophysical characteristics of exosomes. Exosomal Hsp70 contributes to radioresistance while Hsp70 derived from dying tumor cells can serve as a stimulator of immune cells. Given these opposing traits of extracellular Hsp70 and the unsatisfactory outcome of locally advanced lung tumors, we investigated the role of Hsp70 in the plasma of patients with advanced, non-metastasized non-small-cell lung cancer (NSCLC) before (T1) and 4–6 weeks after RT (T2) in relation to OPN as potential biomarkers for clinical response. Plasma levels of Hsp70 correlate with those of OPN at T1, and high OPN levels are significantly associated with a decreased overall survival (OS). Due to a therapy-induced reduction in viable tumor mass after RT Hsp70 plasma levels dropped significantly at T2 (p = 0.016). However, with respect to the immunostimulatory capacity of Hsp70 derived from dying tumor cells, patients with higher post-therapeutic Hsp70 levels showed a significantly better response to RT (p = 0.034) than those with lower levels at T2. In summary, high OPN plasma levels at T1 are indicative for poor OS, whereas elevated post-therapeutic Hsp70 plasma levels together with a drop of Hsp70 between T1 and T2, successfully predict favorable responses to RT. Monitoring the dynamics of Hsp70 in NSCLC patients before and after RT can provide additional predictive information for clinical outcome and therefore might allow a more rapid therapy adaptation. PMID:29093708

  9. Treatment Variation of Sequential versus Concurrent Chemoradiotherapy in Stage III Non-Small Cell Lung Cancer Patients in the Netherlands and Belgium.

    PubMed

    Walraven, I; Damhuis, R A; Ten Berge, M G; Rosskamp, M; van Eycken, L; de Ruysscher, D; Belderbos, J S A

    2017-11-01

    Concurrent chemoradiotherapy (CCRT) is considered the standard treatment regimen in non-surgical locally advanced non-small cell lung cancer (NSCLC) patients and sequential chemoradiotherapy (SCRT) is recommended in patients who are unfit to receive CCRT or when the treatment volume is considered too large. In this study, we investigated the proportion of CCRT/SCRT in the Netherlands and Belgium. Furthermore, patient and disease characteristics associated with SCRT were assessed. An observational study was carried out with data from three independent national registries: the Belgian Cancer Registry (BCR), the Netherlands Cancer Registry (NCR) and the Dutch Lung Cancer Audit-Radiotherapy (DLCA-R). Differences in patient and disease characteristics between CCRT and SCRT were tested with unpaired t-tests (for continuous variables) and with chi-square tests (for categorical variables). A prognostic model was constructed to determine patient and disease parameters predictive for the choice of SCRT. This study included 350 patients from the BCR, 780 patients from the NCR and 428 patients from the DLCA-R. More than half of the stage III NSCLC patients in the Netherlands (55%) and in Belgium more than a third (35%) were treated with CCRT. In both the Dutch and Belgian population, higher age and more advanced N-stage were significantly associated with SCRT. Performance score, pulmonary function, comorbidities and tumour volume were not associated with SCRT. In this observational population-based study, a large treatment variation in non-surgical stage III NSCLC patients was observed between and within the Netherlands and Belgium. Higher age and N-stage were significantly associated with the choice for SCRT. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

  10. Can we customize chemotherapy? Individualizing cytotoxic regimens in advanced non-small-cell lung cancer.

    PubMed

    Rosell, Rafael; Manegold, Christian; Moran, Teresa; Garrido, Pilar; Blanco, Remei; Lianes, Pilar; Stahel, Rolf; Trigo, Jose Manuel; Wei, Jia; Taron, Miquel

    2008-03-01

    Metastatic non-small-cell lung cancer remains a fatal disease with a median survival of < 1 year. A critical challenge is to develop predictive markers for customizing platinum-based treatment. The first studies focused on the excision repair cross-complementing 1 (ERCC1) gene in this difficult task. Several layers of evidence indicate that ERCC1 mRNA expression could be a predictive marker for cisplatin alone or in combination with certain drugs such as etoposide, gemcitabine, and 5-fluorouracil but not in combination with antimicrotubule drugs. Several retrospective studies demonstrated an impressive survival advantage for gemcitabine plus cisplatin but not for other combinations in tumors with low ERCC1 expression. A customized phase III ERCC1-based trial met the primary endpoint of improvement in response but not in survival, leading us to hypothesize that docetaxel might not be the most appropriate partner for cisplatin in the presence of low ERCC1 levels or for gemcitabine in the presence of high ERCC1 levels. A phase II study demonstrated the feasibility of combining carboplatin, gemcitabine, docetaxel, and vinorelbine according to ERCC1 and ribonucleotide reductase subunit M1 expression levels. These findings highlight the importance of continual learning, and decision-making strategies for customizing treatment should reflect the limitations of our knowledge. Copyright © 2008 Elsevier Inc. All rights reserved.

  11. Randomized, Multicenter Study of Gefitinib Dose-escalation in Advanced Non-small-cell Lung Cancer Patients Achieved Stable Disease after One-month Gefitinib Treatment

    PubMed Central

    Xue, Cong; Hong, Shaodong; Li, Ning; Feng, Weineng; Jia, Jun; Peng, Jiewen; Lin, Daren; Cao, Xiaolong; Wang, Siyang; Zhang, Weimin; Zhang, Hongyu; Dong, Wei; Zhang, Li

    2015-01-01

    There is no consensus on the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC) and stable disease (SD) after gefitinib therapy. This randomized, open-label, multicenter study aimed to explore whether dose-escalation of gefitinib would improve response and survival in NSCLC patients who achieved SD after one-month of standard gefitinib dosage. Between May 2009 and January 2012, 466 patients were enrolled and 100 eligible patients were randomized (1:1) to receive either a higher dose (500 mg/d; H group) or to continue standard dose (250 mg/d; S group) of gefitinib. Objective response rate (ORR) was similar between the two groups (12.5% vs 12.5%, p = 1.000). There were no significant differences regarding progression-free survival (PFS) and overall survival (OS) between both arms (H group vs S group: median PFS, 5.30 months vs 6.23 months, p = 0.167; median OS, 13.70 months vs 18.87 months, p = 0.156). Therefore, dose-escalation of gefitinib does not confer a response or survival advantage in patients who achieve SD with one month of standard-dose gefitinib treatment. PMID:26216071

  12. Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials

    PubMed Central

    Laporte, Silvy; Squifflet, Pierre; Baroux, Noémie; Fossella, Frank; Georgoulias, Vassilis; Pujol, Jean-Louis; Douillard, Jean-Yves; Kudoh, Shinzohy; Pignon, Jean-Pierre; Quinaux, Emmanuel; Buyse, Marc

    2013-01-01

    Objectives To investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Design Meta-analysis of individual patient data from randomised trials. Setting Five randomised controlled trials comparing docetaxel-based chemotherapy with vinorelbine-based chemotherapy for the first-line treatment of NSCLC. Participants 2331 patients with advanced NSCLC. Primary and secondary outcome measures Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. The surrogate threshold effect was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS. Results The median follow-up of patients still alive was 23.4 months. Median OS was 10 months and median PFS was 5.5 months. The treatment effects on PFS and OS were correlated, whether using centres (R²=0.62, 95% CI 0.52 to 0.72) or prognostic strata (R²=0.72, 95% CI 0.60 to 0.84) as units of analysis. The surrogate threshold effect was a PFS hazard ratio (HR) of 0.49 using centres or 0.53 using prognostic strata. Conclusions These analyses provide only modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC. Only treatments that have a major impact on PFS (risk reduction of at least 50%) would be expected to also have a significant effect on OS. Whether these results also apply to targeted therapies is an open question that requires independent evaluation. PMID:23485717

  13. Induction therapy with carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal radiotherapy in the treatment of locally advanced, unresectable non-small cell lung cancer: preliminary report of a phase I trial.

    PubMed

    Socinski, M A; Clark, J A; Halle, J; Steagall, A; Kaluzny, B; Rosenman, J G

    1997-08-01

    Locally advanced non-small cell lung cancer is optimally managed with chemotherapy and thoracic irradiation, although the most appropriate strategy is not yet defined. In this phase I trial, we use two 21-day cycles of induction chemotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (225 mg/m2 over 3 hours) and carboplatin (area under the concentration-time curve = 6) followed by concurrent weekly paclitaxel (45 mg/m2/wk x 6) and carboplatin (area under the concentration-time curve = 2/wk x 6) and thoracic irradiation. Patients undergo three-dimensional treatment planning (conformal radiotherapy) to define the cancer target volume precisely. The phase I question being addressed in this study is the maximum tolerated radiation dose given concurrently with low-dose paclitaxel and carboplatin. The initial radiation dose is 60 Gy, with dose escalations to 66 Gy, 70 Gy, and 74 Gy being planned. Ten patients have been entered thus far (eight men and two women). Their median age is 67 years (range, 59 to 78 years), and none of the patients has had greater than 5% pretreatment weight loss. Seven of 10 are evaluable for response to induction carboplatin and paclitaxel, with a response rate of 57% (three partial responses and one minor response). Three patients had stable disease and none of the patients had evidence of progressive disease during induction chemotherapy. Three patients have completed all treatment at 60 Gy and one has completed all treatment at 66 Gy. Three of the four patients have had partial responses (75%), with the remaining patient having stable disease. Toxicity in the concurrent chemoradiotherapy portion of the trial thus far has consisted of grade 3 neutropenia in one patient and grade 4 lymphocytopenia in all four patients. No grade 3 or 4 nonhematologic toxicity has been seen. The trial data are not yet mature enough to report on survival. Accrual and treatment is continuing at the 66 Gy radiation dose level.

  14. Can concurrent chemoradiotherapy replace surgery and postoperative radiation for locally advanced stage III/IV tonsillar squamous cell carcinoma?

    PubMed

    Park, Geumju; Lee, Sang-Wook; Kim, Sang Yoon; Nam, Soon Yuhl; Choi, Seung-Ho; Kim, Sung-Bae; Roh, Jong-Lyel; Yoon, Dok Hyun; Kim, Su Ssan; Park, Jin-Hong; Kim, Young Seok; Yoon, Sang Min; Song, Si Yeol; Kim, Jong Hoon; Choi, Eun Kyung; DO Ahn, Seung

    2013-03-01

    To compare surgery and postoperative radiotherapy (PORT) with the non-surgical combination of chemotherapy and radiation therapy (CCRT) for locally advanced squamous cell carcinoma (SCC) of the tonsil by measuring treatment outcomes and treatment-related complications. The records of 114 patients with non-metastatic stage III/IV tonsillar SCC treated between July, 1998 and December, 2010 were reviewed retrospectively. Among the 114 patients, 65 received PORT and 49 received CCRT. In the PORT group, treatment included wide surgical resection of the tumor with neck dissection and administration of PORT to the primary tumor bed with a median dose of 60 Gy. In the CCRT group, a median dose of 70 Gy was delivered to the gross tumor, and 46 patients received concurrent chemotherapy with i.v. cisplatin. The median follow-up time was 58 months in the PORT group and 44 months in the CCRT group. There was no significant difference between PORT and CCRT in terms of 5-year locoregional recurrence-free survival (88.4% vs. 91.4%, p=0.68), distant metastasis-free survival (88.9% vs. 92.3%, p=0.60), disease-free survival (79.5% vs. 84.2%, p=0.63) or overall survival (78.9% vs. 88.9%, p=0.45). More CCRT patients than PORT patients experienced grade 3 (or higher) hematological toxicities and grade 2 pharyngitis during treatment. Chronic toxicity, manifested as swallowing difficulty, dry mouth and trismus, was similar between the two treatment groups. CCRT provides similar levels of local and distant control in patients with locally advanced tonsillar SCC as PORT, yet fails to show any superiority in preserving functions such as swallowing, saliva production, and mastication.

  15. Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer

    PubMed Central

    Kong, Feng-Ming; Ten Haken, Randall K.; Schipper, Matthew; Frey, Kirk A.; Hayman, James; Gross, Milton; Ramnath, Nithya; Hassan, Khaled A.; Matuszak, Martha; Ritter, Timothy; Bi, Nan; Wang, Weili; Orringer, Mark; Cease, Kemp B.; Lawrence, Theodore S.; Kalemkerian, Gregory P.

    2017-01-01

    IMPORTANCE Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. OBJECTIVE To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. INTERVENTION Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. MAIN OUTCOMES AND MEASURES The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. RESULTS The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45–83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median

  16. Clinical Utility of Circulating Tumor Cells in ALK-Positive Non-Small-Cell Lung Cancer.

    PubMed

    Faugeroux, Vincent; Pailler, Emma; Auger, Nathalie; Taylor, Melissa; Farace, Françoise

    2014-01-01

    The advent of rationally targeted therapies such as small-molecule tyrosine kinase inhibitors (TKIs) has considerably transformed the therapeutic management of a subset of patients with non-small-cell lung cancer (NSCLC) harboring defined molecular abnormalities. When such genetic molecular alterations are detected the use of specific TKI has demonstrated better results (overall response rate, progression free survival) compared to systemic therapy. However, the detection of such molecular abnormalities is complicated by the difficulty in obtaining sufficient tumor material, in terms of quantity and quality, from a biopsy. Here, we described how circulating tumor cells (CTCs) can have a clinical utility in anaplastic lymphoma kinase (ALK) positive NSCLC patients to diagnose ALK-EML4 gene rearrangement and to guide therapeutic management of these patients. The ability to detect genetic abnormalities such ALK rearrangement in CTCs shows that these cells could offer new perspectives both for the diagnosis and the monitoring of ALK-positive patients eligible for treatment with ALK inhibitors.

  17. Clinical Utility of Circulating Tumor Cells in ALK-Positive Non-Small-Cell Lung Cancer

    PubMed Central

    Faugeroux, Vincent; Pailler, Emma; Auger, Nathalie; Taylor, Melissa; Farace, Françoise

    2014-01-01

    The advent of rationally targeted therapies such as small-molecule tyrosine kinase inhibitors (TKIs) has considerably transformed the therapeutic management of a subset of patients with non-small-cell lung cancer (NSCLC) harboring defined molecular abnormalities. When such genetic molecular alterations are detected the use of specific TKI has demonstrated better results (overall response rate, progression free survival) compared to systemic therapy. However, the detection of such molecular abnormalities is complicated by the difficulty in obtaining sufficient tumor material, in terms of quantity and quality, from a biopsy. Here, we described how circulating tumor cells (CTCs) can have a clinical utility in anaplastic lymphoma kinase (ALK) positive NSCLC patients to diagnose ALK-EML4 gene rearrangement and to guide therapeutic management of these patients. The ability to detect genetic abnormalities such ALK rearrangement in CTCs shows that these cells could offer new perspectives both for the diagnosis and the monitoring of ALK-positive patients eligible for treatment with ALK inhibitors. PMID:25414829

  18. Surgical management of oligometastatic non-small cell lung cancer.

    PubMed

    Novoa, Nuria M; Varela, Gonzalo; Jiménez, Marcelo F

    2016-11-01

    The oligometastatic stage IV non-small cell lung cancer (NSCLC) offers a new surgical opportunity. New reported data is showing that surgery can offer a reasonable benefit, in terms of long-term survival, to some patients. The advantages of surgical treatment rely on a more adequate patient selection and a better understanding of the biology of these tumors. Currently, mediastinal involvement of the primary tumor can be identified as the most important prognostic variable after curative-intent of synchronous or metachronous metastasis. It seems clear that the routine use of combined FDG-PET and CT will help to detect the more favorable cohort of oligometastatic patients. As expected, pathological T staging of the primary tumor and the completeness of its resection are also crucial factors influencing final results. The real benefit of the local treatment over synchronous or metachronous metastasis is controversial with series showing better outcomes for metachronous lesions than for synchronous and others offering equal results. Also non conclusive results appear when analyzing different sites of metastasis. Retrospective series tend to show different outcomes depending on the affected organ while usually no differences are found in prospective ones. Most of the current evidence is based on retrospective studies on patients collected along extended periods of time. That represents a great limitation to the knowledge on this topic. Some prospective analyses have added some insight, but still the quality of the evidence is too low to allow drawing robust conclusions. As frequently concluded, prospective well designed investigation is requested to ascertain the value of surgery in this specific population of patients with extended NSCLC.

  19. Non-Small Cell Carcinoma of the Lung With Osteoclast-Like Giant Cells.

    PubMed

    Dahm, Hans Helmut

    2017-05-01

    Carcinomas of the lung with benign osteoclast-like giant cells are rare. A literature search showed only 8 previously reported examples. These tumors resemble a giant cell tumor of bone. Many of these tumors, which occur in most epithelium-containing organs, are composed of an undifferentiated, sarcomatoid component that contains benign osteoclast-like giant cells and a conventional carcinoma. In some tumors the epithelial origin may be revealed by immunohistochemistry only; others lack any evidence of an epithelial component. A 59-year-old man had an inoperable tumor in the upper lobe of the left lung. The tumor did not respond to radiation therapy, and chemotherapy resulted in minimal relief of symptoms. Light microscopy of biopsy samples showed benign osteoclast-like giant cells distributed irregularly between proliferations of undifferentiated medium-sized tumor cells. Approximately one third of the undifferentiated tumor cells were cytokeratin AE1/AE3-positive, and a minor alveolar clear cell component of the tumor was cytokeratin 7-positive. The osteoclast-like giant cells were strongly CD68-positive. The clinical and histologic findings supported the diagnosis of a non-small cell carcinoma of the lung with benign osteoclast-like giant cells. The differential diagnosis is composed of giant cell carcinoma, carcinosarcoma, and mesenchymal tumors of the lung.

  20. Resistance to Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) with ALK Rearrangement: Mechanisms, Treatment Strategies and New Targeted Therapies.

    PubMed

    Casaluce, Francesca; Sgambato, Assunta; Sacco, Paola Claudia; Palazzolo, Giovanni; Maione, Paolo; Rossi, Antonio; Ciardiello, Fortunato; Gridelli, Cesare

    2016-01-01

    Non-small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance. Novel second-generation ALK inhibitors are currently in clinical development with promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these, ceritinib in the United States was granted by Food and Drug Administration accelerated approval for treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC patients.

  1. Efficacy of plasma vascular endothelial growth factor in monitoring first-line chemotherapy in patients with advanced non-small cell lung cancer

    PubMed Central

    2009-01-01

    Background Along with the development of new cancer therapeutics, more effective tools for the estimation of response to therapy and prediction of disease progression are required for the better management of inoperable cancer patients. Methods We studied 134 newly diagnosed and primarily untreated advanced non-small cell lung cancer patients and 100 controls. Forty two patients received platinum-based chemotherapy. Plasma VEGF levels were quantified in all samples at baseline and also before second and third chemotherapy cycle in 42 patients and correlated with response to therapy as assessed by computed tomography after the third chemotherapy cycle. Results We observed that, patients who went into remission had significantly lower baseline VEGF levels before second and third cycles of chemotherapy when compared with patients with no change and progression. Plasma VEGF levels showed a greater decrease from cycle 1 to 2 and from cycle 1 to 3 in patients who showed remission in comparison to those with no change or progression. Plasma VEGF levels before the second cycle detected poor response to therapy with a sensitivity and specificity of 76.9% and 75.0%, respectively (area under the ROC curve = 0.724). Early prediction of disease progression was achieved with a sensitivity and specificity of 71.4% for plasma VEGF before cycle 2 (area under the ROC curve = 0.805). The kinetics of VEGF form cycle 1 to 2 and cycle 1 to 3 also gave significant information for predicting disease progression as well as insufficient therapy response. Conclusion Monitoring of plasma VEGF levels during the course of first-line chemotherapy could identify patients who are likely to have insufficient response to therapy and disease progression at an early stage. This may help in individualizing treatment and could lead to better management of the advanced stage lung cancer. PMID:19958548

  2. Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ma, Qing; Yu, Tao; Ren, Yao-Yao

    2014-11-07

    Highlights: • SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). • Knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro. • Overexpression of SAMD9 suppressed proliferation and invasion in A549 cells in vitro. • Depletion of SAMD9 increases tumor formation in vivo. - Abstract: The Sterile Alpha Motif Domain-containing 9 (SAMD9) gene has been recently emphasized during the discovery that it is expressed at a lower level in aggressive fibromatosis and some cases of breast and colon cancer, however, the underlying mechanisms are poorly understood. Here, we found that SAMD9 ismore » down-regulated in human non-small cell lung cancer (NSCLC). Furthermore, knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro and overexpression of SAMD9 suppressed proliferation and invasion in A549 cells. Finally, depletion of SAMD9 increases tumor formation in vivo. Our results may provide a strategy for blocking NSCLC tumorigenesis and progression.« less

  3. Radiofrequency ablation in primary non-small cell lung cancer: What a radiologist needs to know

    PubMed Central

    Bhatia, Shivank; Pereira, Keith; Mohan, Prasoon; Narayanan, Govindarajan; Wangpaichitr, Medhi; Savaraj, Niramol

    2016-01-01

    Lung cancer continues to be one of the leading causes of death worldwide. In advanced cases of lung cancer, a multimodality approach is often applied, however with poor local control rates. In early non-small cell lung cancer (NSCLC), surgery is the standard of care. Only 15-30% of patients are eligible for surgical resection. Improvements in imaging and treatment delivery systems have provided new tools to better target these tumors. Stereotactic body radiation therapy (SBRT) has evolved as the next best option. The role of radiofrequency ablation (RFA) is also growing. Currently, it is a third-line option in stage 1 NSCLC, when SBRT cannot be performed. More recent studies have demonstrated usefulness in recurrent tumors and some authors have also suggested combination of RFA with other modalities in larger tumors. Following the National Lung Screening Trial (NLST), screening by low-dose computed tomography (CT) has demonstrated high rates of early-stage lung cancer detection in high-risk populations. Hence, even considering the current role of RFA as a third-line option, in view of increasing numbers of occurrences detected, the number of potential RFA candidates may see a steep uptrend. In view of all this, it is imperative that interventional radiologists be familiar with the techniques of lung ablation. The aim of this article is to discuss the procedural technique of RFA in the lung and review the current evidence regarding RFA for NSCLC. PMID:27081229

  4. The predictive value of 53BP1 and BRCA1 mRNA expression in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy

    PubMed Central

    Bonanno, Laura; Costa, Carlota; Majem, Margarita; Sanchez, Jose Javier; Gimenez-Capitan, Ana; Rodriguez, Ignacio; Vergenegre, Alain; Massuti, Bartomeu; Favaretto, Adolfo; Rugge, Massimo; Pallares, Cinta; Taron, Miquel; Rosell, Rafael

    2013-01-01

    Platinum-based chemotherapy is the standard first-line treatment for non-oncogene-addicted non-small cell lung cancers (NSCLCs) and the analysis of multiple DNA repair genes could improve current models for predicting chemosensitivity. We investigated the potential predictive role of components of the 53BP1 pathway in conjunction with BRCA1. The mRNA expression of BRCA1, MDC1, CASPASE3, UBC13, RNF8, 53BP1, PIAS4, UBC9 and MMSET was analyzed by real-time PCR in 115 advanced NSCLC patients treated with first-line platinum-based chemotherapy. Patients expressing low levels of both BRCA1 and 53BP1 obtained a median progression-free survival of 10.3 months and overall survival of 19.3 months, while among those with low BRCA1 and high 53BP1 progression-free survival was 5.9 months (P <0.0001) and overall survival was 8.2 months (P=0.001). The expression of 53BP1 refines BRCA1-based predictive modeling to identify patients most likely to benefit from platinum-based chemotherapy. PMID:24197907

  5. Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH).

    PubMed

    Peters, Solange; Gettinger, Scott; Johnson, Melissa L; Jänne, Pasi A; Garassino, Marina C; Christoph, Daniel; Toh, Chee Keong; Rizvi, Naiyer A; Chaft, Jamie E; Carcereny Costa, Enric; Patel, Jyoti D; Chow, Laura Q M; Koczywas, Marianna; Ho, Cheryl; Früh, Martin; van den Heuvel, Michel; Rothenstein, Jeffrey; Reck, Martin; Paz-Ares, Luis; Shepherd, Frances A; Kurata, Takayasu; Li, Zhengrong; Qiu, Jiaheng; Kowanetz, Marcin; Mocci, Simonetta; Shankar, Geetha; Sandler, Alan; Felip, Enriqueta

    2017-08-20

    Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS). Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility-assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1-selected advanced NSCLC, with good

  6. SU-F-J-207: Non-Small Cell Lung Cancer Patient Survival Prediction with Quantitative Tumor Textures Analysis in Baseline CT

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wu, Y; Zou, J; Murillo, P

    Purpose: Chemo-radiation therapy (CRT) is widely used in treating patients with locally advanced non-small cell lung cancer (NSCLC). Determination of the likelihood of patient response to treatment and optimization of treatment regime is of clinical significance. Up to date, no imaging biomarker has reliably correlated to NSCLC patient survival rate. This pilot study is to extract CT texture information from tumor regions for patient survival prediction. Methods: Thirteen patients with stage II-III NSCLC were treated using CRT with a median dose of 6210 cGy. Non-contrast-enhanced CT images were acquired for treatment planning and retrospectively collected for this study. Texture analysismore » was applied in segmented tumor regions using the Local Binary Pattern method (LBP). By comparing its HU with neighboring voxels, the LBPs of a voxel were measured in multiple scales with different group radiuses and numbers of neighbors. The LBP histograms formed a multi-dimensional texture vector for each patient, which was then used to establish and test a Support Vector Machine (SVM) model to predict patients’ one year survival. The leave-one-out cross validation strategy was used recursively to enlarge the training set and derive a reliable predictor. The predictions were compared with the true clinical outcomes. Results: A 10-dimensional LBP histogram was extracted from 3D segmented tumor region for each of the 13 patients. Using the SVM model with the leave-one-out strategy, only 1 out of 13 patients was misclassified. The experiments showed an accuracy of 93%, sensitivity of 100%, and specificity of 86%. Conclusion: Within the framework of a Support Vector Machine based model, the Local Binary Pattern method is able to extract a quantitative imaging biomarker in the prediction of NSCLC patient survival. More patients are to be included in the study.« less

  7. Integrated molecular portrait of non-small cell lung cancers

    PubMed Central

    2013-01-01

    Background Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions Integrated molecular characterization of AC and SCC helped identify clinically relevant markers

  8. Erlotinib Hydrochloride With or Without Carboplatin and Paclitaxel in Treating Patients With Stage III-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2018-06-01

    Adenosquamous Lung Carcinoma; Lung Adenocarcinoma; Malignant Pericardial Effusion; Malignant Pleural Effusion; Minimally Invasive Lung Adenocarcinoma; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IV Non-Small Cell Lung Cancer AJCC v7

  9. Video-assisted thoracoscopic surgery (VATS) right upper lobectomy for non-small-cell lung cancer with an azygos lobe

    PubMed Central

    Samancilar, Ozgur; Kaya, Seyda Ors; Sevinc, Serpil; Akcay, Onur; Ceylan, Kenan Can

    2016-01-01

    Although it is not a pathologically significant entity, cases of azygos lobe (AL) are interesting due to the difficulty of performing video-assisted thoracoscopic surgery (VATS) procedures in the affected patients and the presence of a congenital malformation. Currently, videothoracoscopic surgery has advanced to such a level that most thoracic procedures can be performed with video assistance. However, some technical difficulties may arise in cases with anatomical anomalies such as AL. This report presents the case of a patient with an azygos lobe who underwent videothoracoscopic lung resection due to the presence of non-small-cell lung carcinoma in the upper lobe of the right lung. PMID:28096840

  10. A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer.

    PubMed

    Alvarez, Edwin A; Wolfson, Aaron H; Pearson, J Matt; Crisp, Meredith P; Mendez, Luis E; Lambrou, Nicholas C; Lucci, Joseph A

    2009-05-01

    This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy (RT) for the primary treatment of locally advanced squamous cell carcinoma of the cervix. Eligible patients included those with locally advanced squamous cell cervical cancer without para-aortic lymph node involvement. Docetaxel dose levels were 20 mg/m(2), 30 mg/m(2) and 40 mg/m(2) given intravenously weekly for 6 cycles. Three patients were to be treated at each dose level and 6 to receive the MTD. Fifteen patients completed 4-6 cycles of chemotherapy. One of three patients experienced 2 delayed grade 3 severe adverse events (SAE) at the 20 mg/m(2) dose level consisting of colonic and ureteral obstruction. At the 30 mg/m(2) dose level, 1/4 patients had a probable treatment-related celiotomy due to obstipation and a necrotic tumor. Of the 8 patients treated at the 40 mg/m(2) dose level, 1 experienced grade 3 pneumonitis, likely treatment related. Overall, 10/15 (67%) experienced grade 1 or 2 diarrhea, 6 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. 10 of 16 patients (67%) had no evidence of disease with follow-up ranging from 10-33 months (average 23 months). The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for locally advanced squamous cell carcinoma of the cervix is 40 mg/m(2).

  11. A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS).

    PubMed

    Smit, Egbert F; Wu, Yi-Long; Gervais, Radj; Zhou, Caicun; Felip, Enriqueta; Feng, Jifeng; Guclu, Salih Zeki; Hoiczyk, Mathias; Dorokhova, Elena; Freudensprung, Ulrich; Grange, Susan; Perez-Moreno, Pablo Diego; Mitchell, Lada; Reck, Martin

    2016-09-01

    Active smokers with non-small-cell lung cancer (NSCLC) have increased erlotinib metabolism versus non-smoking patients, which reduces exposure. Therefore, an increased erlotinib dose may be beneficial. The CurrentS study (NCT01183858) assessed efficacy and safety of 300mg erlotinib (E300) as second-line therapy in current smokers with locally advanced or metastatic NSCLC versus the standard 150mg dose (E150). Patients with stage IIIB/IV NSCLC (current smokers who failed first-line platinum-based chemotherapy) were randomized to receive E150 or E300 until progression/death/unacceptable toxicity. progression-free survival (PFS). Secondary endpoints: overall survival (OS), disease control rate and safety. A total of 342 patients were screened; the intent-to-treat population comprised 159 E300 patients and 154 E150 patients. Median PFS was 7.0 versus 6.9 weeks with E300 versus E150, respectively (unstratified hazard ratio [HR]=1.05, 95% confidence interval [CI]: 0.83-1.33; unstratified log-rank P=0.671). Median OS was 6.8 months in both arms (unstratified HR=1.03, 95% CI: 0.80-1.32; unstratified log-rank P=0.846). Overall, 89.2% (E300 arm) and 84.4% (E150 arm) experienced ≥1 adverse event (AE) of any grade (44.3% and 37%, respectively, experienced grade ≥3 AEs); AEs of special interest were reported in 67.7% and 47.4% of patients, respectively. E300 resulted in higher mean plasma concentrations versus E150, however, this did not improve efficacy. Despite the difference in erlotinib exposure, there was no evidence of an incremental efficacy benefit of a higher erlotinib dose versus the standard dose in this population of highly active smokers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Repeated iodine-125 seed implantations combined with external beam radiotherapy for the treatment of locally recurrent or metastatic stage III/IV non-small cell lung cancer: a retrospective study.

    PubMed

    Li, Wei; Dan, Gang; Jiang, Jianqing; Zheng, Yifeng; Zheng, Xiushan; Deng, Dan

    2016-09-13

    Recurrent or metastatic lung cancer is difficult to manage. This retrospective study aimed to assess the efficacy of repeated iodine-125 seed implantations combined with external beam radiotherapy (EBRT) for locally recurrent or metastatic stage-III/IV non-small cell lung cancer (NSCLC). Eighteen previously treated stage-III/IV NSCLC patients with local or metastatic recurrences underwent 1-to-3 iodine-125 implantations. Six of these patients received palliative EBRT and six patients received combined chemotherapy using gemcitabine and cisplatin. Near-term treatment efficacy was evaluated 3 months after seed implantation by comparing changes in tumor size on computed tomography images; the evaluated outcomes were complete response, partial response, stable disease, and local tumor control rate. Long-term efficacy was assessed based on 1- and 2-year survival rates. Patients were followed up for 6 to 50 months. The overall (i.e., complete + partial) response rate was 87.4 %. The local control rates after the first, second, and third years were 94.1, 58.8 and 41.2 %, respectively. The results of this study demonstrated that repeated implantation of radioactive particles combined with EBRT is a safe treatment that effectively controlled local recurrence and metastasis of stage III/IV NSCLC.

  13. Neutrophils dominate the immune cell composition in non-small cell lung cancer. | Office of Cancer Genomics

    Cancer.gov

    The response rate to immune checkpoint inhibitor therapy for non-small-cell lung cancer (NSCLC) is just 20%. To improve this figure, several early phase clinical trials combining novel immunotherapeutics with immune checkpoint blockade have been initiated. Unfortunately, these trials have been designed without a strong foundational knowledge of the immune landscape present in NSCLC. Here, we use a flow cytometry panel capable of measuring 51 immune cell populations to comprehensively identify the immune cell composition and function in NSCLC.

  14. Determination of safe margin in the surgical pathologic specimens of non-small cell carcinoma of the lung.

    PubMed

    Feizi, Iraj; Sokouti, Mohsen; Golzari, Samad E J; Gojazede, Morteza; Farahnak, Mohammad Reza; Hashemzadeh, Shahriar; Rahimi-Rad, Mohammad Hossein

    2013-01-01

    Local recurrences of the tumor at the surgical margin are serious problems in pulmonary resections for lung cancer. The aim of this study is to determine the involved margins and safe distances of the resection sites from tumor for prevention of local recurrences. In this prospective study, 66 patients operated for non-small cell lung carcinoma (NSCLC) from Jan 2006 to Sep 2008 were evaluated. After performing pulmonary resections, multiple biopsies were taken up from 5 mm (A), 10 mm (B), 15 mm (C), and 20 mm (D) distance from tumor. The specimens were studied histopathologically. From a total of66 patients with NSCLC admitted to our referral hospital, 25 (38%) had adenocarcinoma, 18 (27.3%) squamous cell carcinoma, 5 (7.5%) large cell carcinoma, 4 (6%) bronchoalveolar cell carcinoma, 4 (6%) adenoid cystic carcinoma, 3 (4.6%) malignant carcinoid tumor and 7 (10.6%) had metastasis. The most common symptoms were dyspnea and cough. Histopathologically tumor positive margins were found in 84.8% (A), 10.6% (B), 4.5% (C), and 0% (D). There was a significant statistically difference between tumor involvement at distances 5 mm (A) versus 10-20 mm (B-D) (P <0.001). A 20 mm distance from the gross tumor is considered as a safe surgical margin in any type of malignant pulmonary resections for prevention of local surgical recurrences if there was no pathologic examination before surgery.

  15. Anti-PD-1/PD-L1 antibodies in non-small cell lung cancer: the era of immunotherapy.

    PubMed

    Valecha, Gautam Kishore; Vennepureddy, Adarsh; Ibrahim, Uroosa; Safa, Firas; Samra, Bachar; Atallah, Jean Paul

    2017-01-01

    Advanced non-small cell lung cancer (NSCLC) has been conventionally treated with cytotoxic chemotherapy with short-lived responses and significant toxicities. Monoclonal antibodies to programmed death-1 receptor (PD-1) and programmed death ligand 1 (PD-L1) have shown tremendous promise in the treatment of advanced NSCLC in various clinical trials. Areas covered: In this article, we will review the outcomes of various trials of anti-PD-1/anti-PD-L1 antibodies in the treatment of NSCLC. We will also discuss their mechanism of action and toxicities. Expert commentary: Anti-PD-1/PD-L1 antibodies offer several advantages including significant antitumor activity, induction of long lasting responses, and favorable safety profile. Several trials are now being conducted to evaluate their efficacy as first line agents as well as in combination with other agents. More research is also needed to identify other biomarkers, in addition to PD-L1 expression, that could more reliably predict response to these drugs, and aid in better patient selection.

  16. Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.

    PubMed

    Diamond, Jennifer R; Goff, Barbara; Forster, Martin D; Bendell, Johanna C; Britten, Carolyn D; Gordon, Michael S; Gabra, Hani; Waterhouse, David M; Poole, Mark; Ross Camidge, D; Hamilton, Erika; Moore, Kathleen M

    2017-10-01

    Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m 2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m 2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.

  17. Erlotinib plus parenteral nutrition: an opportunity to get through the hardest days of advanced non-small cell lung cancer with cancer anorexia-cachexia syndrome.

    PubMed

    Zang, Yuan-Sheng; Fang, Zheng; Li, Bing

    2013-03-01

    This case study details the poor performance status of a patient with non-small cell lung cancer and cancer anorexia-cachexia syndrome got through the hardest days of high tumor burden and malnutrition, by using a combined therapy of lung cancer-targeted therapy drug and parenteral nutrition. The related literatures were reviewed.

  18. EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer

    PubMed Central

    Nan, Xueli; Xie, Chao; Yu, Xueyan; Liu, Jie

    2017-01-01

    After the discovery of activating mutations in EGFR, EGFR tyrosine kinase inhibitors (TKIs) have been introduced into the first-line treatment of non-small-cell lung cancer (NSCLC). A series of studies have shown that EGFR TKI monotherapy as first-line treatment can benefit NSCLC patients harbouring EGFR mutations. Besides, combination strategies based on EGFR TKIs in the first line treatment have also been proved to delay the occurrence of resistance. In this review, we summarize the scientific literature and evidence of EGFR TKIs as first-line therapy from the first-generation EGFR TKIs to conceptually proposed fourth-generation EGFR TKI, and also recommend the application of monotherapy and combination therapies of the EGFR-based targeted therapy with other agents such as chemotherapy, anti-angiogenic drugs and immunecheckpoint inhibitors. PMID:29088904

  19. Effect of neoadjuvant chemotherapy on the immune microenvironment in non-small cell lung carcinomas as determined by multiplex immunofluorescence and image analysis approaches.

    PubMed

    Parra, Edwin R; Villalobos, Pamela; Behrens, Carmen; Jiang, Mei; Pataer, Apar; Swisher, Stephen G; William, William N; Zhang, Jiexin; Lee, Jack; Cascone, Tina; Heymach, John V; Forget, Marie-Andrée; Haymaker, Cara; Bernatchez, Chantale; Kalhor, Neda; Weissferdt, Annikka; Moran, Cesar; Zhang, Jianjun; Vaporciyan, Ara; Gibbons, Don L; Sepesi, Boris; Wistuba, Ignacio I

    2018-06-06

    better outcome in univariate and multivariate analyses. NCT-NSCLCs exhibited higher levels of PD-L1 expression and T-cell subset regulation than non-NCT-NSCLCs, suggesting that NCT activates specific immune response mechanisms in lung cancer. These results suggest the need for clinical trials and translational studies of combined chemotherapy and immunotherapy prior to surgical resection of locally advanced NSCLC.

  20. A clinicopathologic prediction model for postoperative recurrence in stage Ia non-small cell lung cancer.

    PubMed

    Zhang, Yang; Sun, Yihua; Xiang, Jiaqing; Zhang, Yawei; Hu, Hong; Chen, Haiquan

    2014-10-01

    Controversy remains over the appropriate postoperative management for patients with stage Ia non-small cell lung cancer who underwent complete surgical resection as a result of a heterogeneous prognosis. We aimed to identify the predictive factors for recurrence in these patients to aid in the decision making. We reviewed 344 patients with stage Ia non-small cell lung cancer to analyze the associations between recurrence-free survival and the following clinicopathologic variables: age, gender, smoking history, family history, preoperative serum carcinoembryonic antigen level, type of surgical resection, tumor location, tumor histology, lymphovascular invasion, tumor differentiation, and pathologic T status. Cox multivariate survival analysis revealed that central tumor location (P=.019), stage T1b (P=.006), high histologic grade (including large cell carcinoma, solid predominant, micropapillary predominant, and invasive mucinous adenocarcinoma, P=.007), poor differentiation (P=.022), and lymphovascular invasion (P=.035) were independently associated with recurrence-free survival. A nomogram for predicting the probability of 3-year recurrence-free survival was developed using the 5 variables. This model shows good calibration, reasonable discrimination (concordance index=0.733), and small overfitting (2.6%) demonstrated by bootstrapping. We developed a clinicopathologic prediction model for postoperative recurrence in stage Ia non-small cell lung cancer. This model can help with the selection of appropriate postoperative therapeutic strategies for these patients. Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.