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

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.

PD-L1 expression as poor prognostic factor in patients with non-squamous non-small cell lung cancer.

PubMed

Zhou, Cuiling; Tang, Jianjun; Sun, Huanhuan; Zheng, Xiaobin; Li, Zhanyu; Sun, Tiantian; Li, Jie; Wang, Shuncong; Zhou, Xiuling; Sun, Hongliu; Cheng, Zhibin; Zhang, Hongyu; Ma, Haiqing

2017-08-29

The role of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), especially according to histologic type, remains controversial. The purpose of this study was to assess PD-L1 expression and its association with overall survival (OS) and clinicopathologic characteristics in NSCLC. Formalin-fixed paraffin-embedded specimens were obtained from 108 patients with surgically resected primary NSCLC. PD-L1 expression was assessed via immunohistochemistry using a histochemistry score system. The relationship between OS or clinicopathologic characteristics and PD-L1 expression was evaluated via the Kaplan-Meier method and Cox proportional hazards model, respectively. Of 108 NSCLC specimens, 44 had high PD-L1 expression, which was highly associated with histologic type ( p = 0.003). Patients without PD-L1 expression had remarkably longer OS than those with PD-L1 expression (median OS: 96 months vs. 33 months, p < 0.001). In the subgroup analysis of non-squamous cell carcinoma, OS was more favorable in those without PD-L1 expression than in those with PD-L1 expression (median OS: 113 months vs. 37 months, p < 0.001). Multivariate analysis revealed that PD-L1 expression (95% confidence interval 1.459-4.520, p < 0.001), male sex and higher tumor-node-metastasis stage were significantly correlated with shorter OS. This study demonstrated that PD-L1 expression is an independent prognostic factor for poor survival in NSCLC patients, especially those with non-squamous NSCLC.

PD-L1 expression as poor prognostic factor in patients with non-squamous non-small cell lung cancer

PubMed Central

Zheng, Xiaobin; Li, Zhanyu; Sun, Tiantian; Li, Jie; Wang, Shuncong; Zhou, Xiuling; Sun, Hongliu; Cheng, Zhibin; Zhang, Hongyu; Ma, Haiqing

2017-01-01

Objectives The role of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), especially according to histologic type, remains controversial. The purpose of this study was to assess PD-L1 expression and its association with overall survival (OS) and clinicopathologic characteristics in NSCLC. Materials and methods Formalin-fixed paraffin-embedded specimens were obtained from 108 patients with surgically resected primary NSCLC. PD-L1 expression was assessed via immunohistochemistry using a histochemistry score system. The relationship between OS or clinicopathologic characteristics and PD-L1 expression was evaluated via the Kaplan-Meier method and Cox proportional hazards model, respectively. Results Of 108 NSCLC specimens, 44 had high PD-L1 expression, which was highly associated with histologic type (p = 0.003). Patients without PD-L1 expression had remarkably longer OS than those with PD-L1 expression (median OS: 96 months vs. 33 months, p < 0.001). In the subgroup analysis of non-squamous cell carcinoma, OS was more favorable in those without PD-L1 expression than in those with PD-L1 expression (median OS: 113 months vs. 37 months, p < 0.001). Multivariate analysis revealed that PD-L1 expression (95% confidence interval 1.459-4.520, p < 0.001), male sex and higher tumor-node-metastasis stage were significantly correlated with shorter OS. Conclusions This study demonstrated that PD-L1 expression is an independent prognostic factor for poor survival in NSCLC patients, especially those with non-squamous NSCLC. PMID:28938570

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.

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.

Metastatic squamous cell non-small-cell lung cancer (NSCLC): disrupting the drug treatment paradigm with immunotherapies.

PubMed

Scarpace, Sarah L

2015-01-01

Lung cancer is the third most commonly diagnosed cancer and the leading cause of cancer-related death in the United States. Unlike non-squamous NSCLC, squamous NSCLC rarely harbor epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations for which there are directed therapies, and until the recent approval of immunotherapies for squamous NSCLC, a limited number of traditional cytotoxic chemotherapy drugs have been FDA-approved for use in the treatment of advanced and metastatic squamous NSCLC. Immunotherapies directed at the programmed cell death-1 receptor (PD-1) or its ligand (PD-L1) (nivolumab and pembrolizumab) have demonstrated efficacy in both nonsquamous and squamous cell NSCLC. Because of their similar mechanism of action against the PD-L1/PD-1 pathway, both drugs have similar toxicity profiles related to immune-mediated adverse reactions that can generally be monitored and managed with oral corticosteroids. This paper provides an overview of drug therapy options for squamous cell NSCLC with a focus on the evidence and clinical application of the anti-PD1 therapies. A comparison of the dosing, administration, indications, and differences in the measurement of PD-L1 expression in the clinical trials of nivolumab and pembrolizumab is also provided.

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

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

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.

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

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

Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer.

PubMed

Yamamoto, Noboru; Fujiwara, Yutaka; Tamura, Kenji; Kondo, Shunsuke; Iwasa, Satoru; Tanabe, Yuko; Horiike, Atsushi; Yanagitani, Noriko; Kitazono, Satoru; Inatani, Michiyasu; Tanaka, Jun; Nishio, Makoto

2017-02-01

Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP + BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3 + 3 dose escalation design was applied. In stage 1, 140, 260, or 340 mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors. In stage 2, 260 or 340 mg/day of pictilisib was administered in combination with CP + BEV to 7 patients with advanced non-squamous non-small cell lung cancer. In stage 1, 1 of 6 patients in the 340 mg/day cohort exhibited dose limiting toxicity (DLT) of grade 3 maculopapular rash. The maximum plasma concentration and area under the curve of pictilisib were dose-dependent. A reduction in phosphorylated AKT in platelet rich plasma was observed. No patient had an objective anti-tumor response. In stage 2, DLT was observed in 1 of 3 patients in the 260 mg/day cohort (grade 3 febrile neutropenia), and 2 of 4 patients in the 340 mg/day cohort (1 each of grade 3 febrile neutropenia and grade 3 febrile neutropenia/erythema multiforme). Partial responses were observed in 3 out of 7 patients. In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340 mg once daily. For combination with CP + BEV, tolerability up to 260 mg/day was confirmed.

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.

Phase II Trial of Carboplatin and Pemetrexed Plus Bevacizumab with Maintenance Bevacizumab as a First-line Treatment for Advanced Non-squamous Non-small Cell Lung Cancer in Elderly Patients.

PubMed

Takeoka, Hiroaki; Yamada, Kazuhiko; Naito, Yoshiko; Matsuo, Norikazu; Ishii, Hidenobu; Tokito, Takaaki; Azuma, Koichi; Ichiki, Masao; Hoshino, Tomoaki

2018-06-01

The combination of platinum-doublet chemotherapy with bevacizumab has been established as a first-line treatment option in non-elderly patients with non-squamous (non-sq) non-small cell lung cancer (NSCLC). However, the safety and efficacy of this regimen have not yet been fully established in elderly patients. Chemo-naïve patients with non-sq NSCLC, aged ≥75 years, having a good performance status (Eastern Cooperative Oncology Group performance status 0-1) and adequate organ function were considered eligible. Patients received carboplatin (area under the curve=5 mg/ml/min), pemetrexed (500 mg/m 2 ), and bevacizumab (15 mg/kg) every 3 weeks for up to 4 cycles, followed by maintenance bevacizumab. The primary endpoint was the objective response rate (ORR; target=50%, threshold=30%; Simon's two-stage design), and the secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Twelve patients were enrolled from June 2013 to July 2017. The study was closed because of slow patient accrual. The median patient age was 80 years. Eleven patients (92%) completed 4 cycles of induction chemotherapy. Seven patients achieved a partial response (PR), yielding an ORR of 58%. The median PFS was 8.4 [95% confidence interval (CI)=4.4-10.5] months, and the median OS was 33.9 (95%CI=13.2-43.3) months. Toxicities were generally mild and consistent with previous reports. There were no treatment-related deaths. A regimen comprising carboplatin and pemetrexed plus bevacizumab followed by maintenance bevacizumab is feasible and potentially efficacious in elderly patients with non-sq NSCLC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Oral vinorelbine plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of advanced non-squamous non-small-cell lung cancer: cost minimization analysis in 12 European countries.

PubMed

Grossi, Francesco; Bennouna, Jaafar; Havel, Libor; Hochmair, Maximillian; Almodovar, Teresa

2016-09-01

A combination of vinorelbine and cisplatin is a standard treatment in non-small-cell lung cancer; oral vinorelbine is registered in 45 countries. Pemetrexed and cisplatin are recommended in front-line chemotherapy of non-squamous non-small-cell lung cancer (NS-NSCLC). The objective of this study was to conduct a cost minimization analysis from the perspective of the national health service (NHS) in each of 12 European countries, based on a randomized phase II study in NS-NSCLC (NAVoTRIAL01), with 100 oral vinorelbine plus cisplatin patients (arm A) and 51 pemetrexed plus cisplatin patients (arm B). Country-specific costs and DRG codes considered included those relating to anticancer drugs, administration settings (out-patient/in-patient/at home), serious adverse events (defined as involving hospitalization and considered due to anticancer drugs) and concomitant medications. Relevant costs were calculated based on country-specific reimbursement procedures and official tariffs. Cost and savings per patient. Using the NHS perspective, savings per patient treated with oral vinorelbine ranged from €1317 (Denmark) to €35,001 (Germany). Expressed as percentages, savings per patient treated with oral vinorelbine compared with pemetrexed ranged between 5% (France) and 83% (Czech Republic). Pooled average costs for each treatment arm across the 12 countries resulted in cost savings for payers of €12,871, favoring oral vinorelbine plus cisplatin. Given the reported efficacy with both regimens, this pan-European economic analysis provides compelling evidence supporting oral vinorelbine use over pemetrexed for the treatment of NS-NSCLC. Oral vinorelbine provides similar efficacy and an easily manageable safety profile at lower overall cost per patient treated, combined with an easier/more convenient mode of administration. Sensitivity analysis across varied scenarios demonstrated the robustness of the results. The principle weakness of our study was its reliance upon a

Study protocol: systematic review and meta-analysis of randomized controlled trials in first-line treatment of squamous non-small cell lung cancer

PubMed Central

2014-01-01

Background There is a high unmet need for effective treatments for patients with squamous non-small cell lung cancer (NSCLC). Eli Lilly and Company is conducting a phase III, randomized, multicenter, open-label study of gemcitabine plus cisplatin plus necitumumab (GC + N) versus gemcitabine plus cisplatin (GC) for the first-line treatment of patients with stage IV squamous NSCLC. Given GC is not the only treatment commonly used for the treatment of squamous NSCLC, this study was designed to compare the survival, toxicity, and quality of life outcomes of current treatment strategies for squamous NSCLC in the first-line setting. Methods/Design A systematic review and meta-analysis (including indirect comparisons) of treatments used in squamous NSCLC will be conducted to assess the clinical efficacy (overall and progression-free survival), health-related quality of life (HRQoL), and safety (grade 3–4 toxicity) of GC + N compared to other treatments used in squamous NSCLC. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines will be followed for all aspects of this study. A systematic literature review will be conducted to identify randomized controlled trials evaluating chemotherapy treatment in first-line NSCLC. Eligible articles will be restricted to randomized controlled trials (RCTs) among chemotherapy-naïve advanced NSCLC cancer patients that report outcome data (survival, toxicity, or quality of life) for patients with squamous histology. Following data extraction and validation, data consistency and study heterogeneity will be assessed. A network meta-analysis will be conducted based on the available hazard ratios for overall and progression-free survival, odds ratios for published toxicity data, and mean difference of HRQoL scales. Sensitivity analyses will be conducted. Discussion This is a presentation of the study protocol only. Results and conclusions are pending completion of this study. Systematic review

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

Molecular interplay of pro-inflammatory transcription factors and non-coding RNAs in esophageal squamous cell carcinoma.

PubMed

Sundaram, Gopinath M; Veera Bramhachari, Pallaval

2017-06-01

Esophageal squamous cell carcinoma is the sixth most common cancer in the developing world. The aggressive nature of esophageal squamous cell carcinoma, its tendency for relapse, and the poor survival prospects of patients diagnosed at advanced stages, represent a pressing need for the development of new therapies for this disease. Chronic inflammation is known to have a causal link to cancer pre-disposition. Nuclear factor kappa B and signal transducer and activator of transcription 3 are transcription factors which regulate immunity and inflammation and are emerging as key regulators of tumor initiation, progression, and metastasis. Although these pro-inflammatory factors in esophageal squamous cell carcinoma have been well-characterized with reference to protein-coding targets, their functional interactions with non-coding RNAs have only recently been gaining attention. Non-coding RNAs, especially microRNAs and long non-coding RNAs demonstrate potential as biomarkers and alternative therapeutic targets. In this review, we summarize the recent literature and concepts on non-coding RNAs that are regulated by/regulate nuclear factor kappa B and signal transducer and activator of transcription 3 in esophageal cancer progression. We also discuss how these recent discoveries can pave way for future therapeutic options to treat esophageal squamous cell carcinoma.

Genetic Testing in Screening Patients With Stage IB-IIIA Non-Small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)

ClinicalTrials.gov

2018-06-29

Large Cell Lung Carcinoma; Lung Adenocarcinoma; Stage IB Non-Small Cell Lung Carcinoma AJCC v7; Stage IB Squamous Cell Lung Carcinoma AJCC v7; Stage II Non-Small Cell Lung Cancer AJCC v7; Stage II Squamous Cell Lung Carcinoma AJCC v7; Stage IIA Non-Small Cell Lung Carcinoma AJCC v7; Stage IIA Squamous Cell Lung Carcinoma AJCC v7; Stage IIB Non-Small Cell Lung Carcinoma AJCC v7; Stage IIB Squamous Cell Lung Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIA Squamous Cell Lung Carcinoma AJCC v7

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.

Talactoferrin in Treating Patients With Relapsed or Refractory Non-Small Cell Lung Cancer or Squamous Cell Head and Neck Cancer

ClinicalTrials.gov

2016-07-30

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland 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; Salivary Gland Squamous Cell Carcinoma; Stage III Salivary Gland Cancer; 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 III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; 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 IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; 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 IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral

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

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies.

PubMed

Okamoto, Isamu; Schuette, Wolfgang H W; Stinchcombe, Thomas E; Rodrigues-Pereira, José; San Antonio, Belén; Chen, Jian; Liu, Jingyi; John, William J; Zinner, Ralph G

2017-05-01

This meta-analysis compared safety profiles (selected drug-related treatment-emergent adverse events [TEAEs]) of first-line pemetrexed plus carboplatin (PCb) area under the concentration-time curve 5 mg/min•mL (PCb5) or 6 mg/min•mL (PCb6), two widely used regimens in clinical practice for advanced non-squamous non-small cell lung cancer. All patients received pemetrexed 500 mg/m 2 every 21 days with either of two carboplatin doses for up to 4-6 cycles. Safety profiles of PCb doses were compared using three statistical analysis methods: frequency table analysis (FTA), generalized linear mixed effect model (GLMM), and the propensity score method. Efficacy outcomes of PCb5 and PCb6 regimens were summarized. A total of 486 patients mainly from the US, Europe, and East Asia were included in the analysis; 22% (n = 105) received PCb5 in one trial and 78% (n = 381) received PCb6 in four trials. The FTA comparison demonstrated that PCb5 vs PCb6 was associated with a statistically significantly lower incidence of TEAEs, including all-grade thrombocytopenia, anemia, fatigue, and vomiting, and grade 3/4 thrombocytopenia. In the GLMM analysis, PCb5 patients were numerically less likely to experience all-grade and grade 3/4 neutropenia, anemia, and thrombocytopenia. The propensity score regression analysis showed PCb5 group patients were significantly less likely than PCb6 group patients to experience all-grade hematologic TEAEs and grade 3/4 thrombocytopenia and anemia. After applying propensity score 1:1 matching, FTA analysis showed that the PCb5 group had significantly less all-grade and grade 3/4 hematologic toxicities. Overall efficacy outcomes, including overall survival, progression-free survival, and response rate, were similar between the two carboplatin doses. Acknowledging the limitations of this meta-analysis of five trials, heterogeneous in patient's characteristics and trial designs, the results show that the PCb5 regimen was generally associated

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.

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

Biweekly Carboplatin Plus Gemcitabine as First-Line Treatment of Elderly Patients With Advanced Squamous Non-Small-cell Lung Cancer: A Multicenter Phase I-II Trial by the Hellenic Oncology Research Group.

PubMed

Karampeazis, Athanasios; Vamvakas, Lambros; Kentepozidis, Nikolaos; Polyzos, Aris; Chandrinos, Vassilis; Rigas, Georgios; Christofyllakis, Charalambos; Kotsakis, Athanasios; Hatzidaki, Dora; Pallis, Athanasios G; Georgoulias, Vassilis

2016-11-01

The present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non-small-cell lung cancer (NSCLC). Patients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m 2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m 2 ). The primary endpoint was the overall response rate. A total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study. The biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

Real-world treatment patterns and costs in a US Medicare population with metastatic squamous non-small cell lung cancer.

PubMed

Davis, Keith L; Goyal, Ravi K; Able, Stephen L; Brown, Jacqueline; Li, Li; Kaye, James A

2015-02-01

Despite advances in the treatment of nonsquamous non-small cell lung cancer (NSCLC), therapeutic choices and overall disease course for squamous NSCLC have remained relatively unchanged over the past several years. We provide a detailed account of current treatment patterns, healthcare use, and survival in real-world clinical settings for metastatic squamous NSCLC. Patients aged ≥65 years with metastatic squamous NSCLC diagnosed 2001-2009 were identified and followed through 2010 using the Surveillance, Epidemiology and End Results-Medicare database. Treatment patterns were descriptively analyzed. Multivariate logistic regressions were estimated to identify predictors of treatment pattern events; generalized linear models were estimated for total all-cause and NSCLC-related costs to assess cost drivers. Of 17,133 patients, 72% received cancer-directed therapy (surgery, radiation, chemotherapy, or biologic therapy), whereas 28% received only supportive care. Median survival was significantly longer in patients receiving cancer-directed therapy (8 months) than in patients receiving supportive care only (2 months) (P<0.0001). An agent-specific first-line chemotherapy regimen was identified for 91% of the 7700 patients who received chemotherapy. Among these, the most common first-line regimen was carboplatin-paclitaxel combination therapy (46%). Common second-line regimens were gemcitabine monotherapy (16%) and pemetrexed monotherapy (11%). Factors associated with decreased odds of receiving cancer-directed treatment were black versus white race (OR, 0.72; 95% CI, 0.64-0.82), residence in the West versus South (OR, 0.73; 95% CI, 0.66-0.81), and metastatic disease at initial diagnosis versus progression to metastatic disease (OR, 0.77; 95% CI, 0.70-0.84). Our study shows that prognosis remains poor for patients with metastatic squamous NSCLC, even among those receiving treatment, but particularly for patients limited to supportive care only, highlighting the

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

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.

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

High-grade squamous intraepithelial lesions in pregnant and non-pregnant women.

PubMed

Xavier-Júnior, José Cândido C; Dufloth, Rozany M; do Vale, Diama B; Tavares, Thalita A; Zeferino, Luiz C

2014-04-01

To evaluate if the prevalence of cervical smear results varies between pregnant and non-pregnant women stratified by age group. Observational analytical study with a total sample of 1,336,180 pregnant and non-pregnant women, aged between 20 and 34 years, who underwent cervical cancer screening in the Primary Health Care of the national health system in the area of Campinas in Brazil during the period of 2005-2009. The source is the information system for cervical cancer screening. Data collected on abnormal cervical smears were analyzed using the Chi-square test and Fisher's exact test and the magnitude of the association between pregnancy and high-grade squamous epithelial lesions was analyzed by odds ratio (OR) and estimated values with confidence intervals (CI) of 95%. 15,190 pregnant women and 395,961 non-pregnant women were analyzed and fulfilled the inclusion criteria. Regardless of age, no statistical differences were observed for high-grade squamous intraepithelial lesion prevalence (OR 0.90; CI 0.66-1.23). Taking into account the five-year age groups, however, low-grade squamous intraepithelial lesion was less prevalent in pregnant women aged 20-24 (OR 0.71; 0.54-0.95) and 25-29 years (OR 0.56; 0.35-0.89); also, atypical squamous cells of undetermined significance was more prevalent in non-pregnant women aged 25-29 years (OR 0.72; 0.54-0.97). The study showed that the cytological prevalence of high-grade squamous intraepithelial lesion was similar in pregnant and non-pregnant women, regardless of age. The results indicate that there are no reasons for specific approaches to cervical cancer screening for pregnant women. The examination should be carried out only on pregnant women who have not been tested according to current recommendations. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Non-acid gastro-oesophageal reflux is associated with squamous cell carcinoma of the oesophagus.

PubMed

Kgomo, Mpho; Mokoena, Taole R; Ker, James A

2017-01-01

Squamous cell carcinoma of the oesophagus is a common cancer among South Africans. Due to the absence of effective screening and surveillance programme for early detection and late presentation, squamous cell carcinoma of the oesophagus is usually diagnosed at an advanced stage or when metastasis has already occurred. The 5-year survival is often quoted at 5%-10%, which is poor. To determine the association between oesophageal squamous cell carcinoma (OSCC) and non-acid gastro-oesophageal reflux disease. Study design: A cross-sectional case-control analytical study of patients referred to the Gastroenterology Division of Steve Biko Academic Hospital in Pretoria, South Africa. All patients had combined multichannel impedance and pH studies done and interpreted after upper gastroscopy using the American College of Gastroenterology guidelines by two clinicians. Thirty-two patients with OSCC were recruited: non-acid reflux was found in 23 patients (73%), acid reflux in 2 patients (6%) and 7 patients (22%) had normal multichannel impedance and pH studies.Forty-nine patients matched by age, gender and race were recruited as a control group. Non-acid reflux was found in 11 patients (22%), acid reflux in 31 patients (63%) and 7 patients (14%) had normal multichannel impedance and pH monitoring study. The significance of the association between non-acid reflux and OSCC was tested using χ 2 , and simple logistic regression was used to adjust for the effects of potential confounders.The OR of developing OSCC in patients with non-acid gastro-oesophageal reflux was 8.8 (95% CI 3.2 to 24.5, P<0.0001) in this South African group.Alcohol and smoking had no effect on these results.

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

Simulation and comparison of progression-free survival among patients with non-squamous non-small-cell lung cancer receiving sequential therapy.

PubMed

Walzer, Stefan; Chouaid, Christos; Lister, Johanna; Gultyaev, Dmitry; Vergnenegre, Alain; de Marinis, Filippo; Meng, Jie; de Castro Carpeno, Javier; Crott, Ralph; Kleman, Martin; Ngoh, Charles

2015-01-01

In recent years, the treatment landscape in advanced non-squamous non-small-cell lung cancer (nsNSCLC) has changed. New therapies (e.g., bevacizumab indicated in first line) have become available and other therapies (e.g., pemetrexed in first line and second line) moved into earlier lines in the treatment paradigm. While there has been an expansion of the available treatment options, it is still a key research question which therapy sequence results in the best survival outcomes for patients with nsNSCLC. A therapy-sequencing disease model that approximates treatment outcomes in up to five lines of treatment was developed for patients with nsNSCLC. The primary source of data for progression-free survival (PFS) and time to death was published pivotal trial data. All patients were treatment-naïve and in the PFS state, received first-line treatment with either bevacizumab-based therapy or doublet chemotherapy (including the option of pemetrexed + cisplatin). Patients would then progress to a subsequent line of therapy, remain in PFS or die. In case of progression, it was assumed that each survivor would receive a subsequent line of therapy, based on EMA licensed therapies. Weibull distribution curves were fitted to the data. All bevacizumab-based first-line therapy sequences analyzed achieved total PFS of around 15 months. Bevacizumab + carboplatin + paclitaxel (first line) → pemetrexed (second line) → erlotinib (third line) → docetaxel (fourth line) resulted in total mean PFS time of 15.7 months, for instance. Sequences with pemetrexed in combination with cisplatin in first line achieved total PFS times between 12.6 and 12.8 months with a slightly higher total PFS time achieved when assuming pemetrexed continuation therapy in maintenance after pemetrexed + cisplatin in first-line induction. Overall survival results followed the same trend as PFS. The model suggests that treatment-sequencing strategies starting with a bevacizumab-based combination in first line

Non-acid gastro-oesophageal reflux is associated with squamous cell carcinoma of the oesophagus

PubMed Central

Kgomo, Mpho; Mokoena, Taole R; Ker, James A

2017-01-01

Introduction Squamous cell carcinoma of the oesophagus is a common cancer among South Africans. Due to the absence of effective screening and surveillance programme for early detection and late presentation, squamous cell carcinoma of the oesophagus is usually diagnosed at an advanced stage or when metastasis has already occurred. The 5-year survival is often quoted at 5%–10%, which is poor. Objectives To determine the association between oesophageal squamous cell carcinoma (OSCC) and non-acid gastro-oesophageal reflux disease. Methods Study design A cross-sectional case–control analytical study of patients referred to the Gastroenterology Division of Steve Biko Academic Hospital in Pretoria, South Africa. All patients had combined multichannel impedance and pH studies done and interpreted after upper gastroscopy using the American College of Gastroenterology guidelines by two clinicians. Results Thirty-two patients with OSCC were recruited: non-acid reflux was found in 23 patients (73%), acid reflux in 2 patients (6%) and 7 patients (22%) had normal multichannel impedance and pH studies. Forty-nine patients matched by age, gender and race were recruited as a control group. Non-acid reflux was found in 11 patients (22%), acid reflux in 31 patients (63%) and 7 patients (14%) had normal multichannel impedance and pH monitoring study. Conclusion The significance of the association between non-acid reflux and OSCC was tested using χ2, and simple logistic regression was used to adjust for the effects of potential confounders. The OR of developing OSCC in patients with non-acid gastro-oesophageal reflux was 8.8 (95% CI 3.2 to 24.5, P<0.0001) in this South African group. Alcohol and smoking had no effect on these results. PMID:29177066

[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.

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.

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

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

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.

Circulating Tumor DNA in Predicting Outcomes in Patients With Stage IV Head and Neck Cancer or Stage III-IV Non-small Cell Lung Cancer

ClinicalTrials.gov

2018-01-12

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Salivary Gland Squamous Cell Carcinoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; 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 IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; 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 IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; 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; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

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.

ALK-rearranged squamous cell lung carcinoma responding to crizotinib: A missing link in the field of non-small cell lung cancer?

PubMed

Vergne, Florence; Quéré, Gilles; Andrieu-Key, Sophie; Descourt, Renaud; Quintin-Roué, Isabelle; Talagas, Matthieu; De Braekeleer, Marc; Marcorelles, Pascale; Uguen, Arnaud

2016-01-01

ALK-rearrangements are mainly encountered in lung adenocarcinomas and allow treating patients with anti-ALK targeted therapy. ALK-rearranged squamous cell lung carcinomas are rare tumors that can also respond to anti-ALK-targeted therapy. Nevertheless, ALK screening is not always performed in patients with squamous cell lung carcinomas making the identification and treatment of this molecular tumor subtype challenging. We intend to report a rare case of ALK-rearranged lung squamous cell carcinoma with response to crizotinib therapy. We report clinical, pathological, immunohistochemical and fluorescent in situ hybridization data concerning a patient having an ALK-rearranged squamous cell lung cancer diagnosed in our institution. The patient was a 58-year old woman with a metastatic-stage lung cancer. Histopathological and immunohistochemical analyses were performed on a bronchial biopsy sample and concluded in a non-keratinizing squamous cell lung carcinoma expressing strongly cytokeratin 5/6, p63 and p40, which are classic hallmarks of lung squamous cell carcinomas, but also cytokeratin 7 which is more commonly expressed in lung adenocarcinomas. The tumor did not express thyroid transcription factor-1. ALK rearrangement was searched because of the never-smoker status of the patient and resulted in strong positive fluorescent in situ hybridization test and ALK/p80 immunohistochemistry. The patient responded to crizotinib therapy during 213 days. Our observation points out the interest of considering ALK screening in patients with metastatic lung squamous cell carcinomas, especially in patients lacking a usual heavy-smoker clinical history. The histopathological and immunohistochemical features of this particular tumor highlighting the overlapping criteria between lung adenocarcinomas and rare ALK-rearranged squamous cell lung carcinomas could also be relevant to extend ALK screening to tumors with intermediate phenotypes between squamous cell carcinomas and

Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial.

PubMed

Hanna, Nasser H; Kaiser, Rolf; Sullivan, Richard N; Aren, Osvaldo Rudy; Ahn, Myung-Ju; Tiangco, Beatrice; Voccia, Isabelle; Pawel, Joachim von; Kovcin, Vladimir; Agulnik, Jason; Gaschler-Markefski, Birgit; Barrueco, José; Sikken, Patricia; Schloss, Charles; Kim, Joo-Hang

2016-12-01

LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500mg/m 2 on Day 1 plus nintedanib 200mg orally twice daily or matching placebo on Days 2-21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n=353 nintedanib/pemetrexed; n=360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.70-0.99, p=0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR=1.01, 95% CI 0.85-1.21, p=0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile. Copyright © 2016 Elsevier Ireland Ltd. All rights

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.

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

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

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

Phase I/II study of erlotinib, carboplatin, pemetrexed, and bevacizumab in chemotherapy-naïve patients with advanced non-squamous non-small cell lung cancer harboring epidermal growth factor receptor mutation

PubMed Central

Kurata, Takayasu; Nakaya, Aya; Yokoi, Takashi; Niki, Maiko; Kibata, Kayoko; Takeyasu, Yuki; Torii, Yoshitaro; Katashiba, Yuichi; Ogata, Makoto; Miyara, Takayuki; Nomura, Shosaku

2017-01-01

Background Epidermal growth factor receptor tyrosine kinase inhibitors significantly prolong the progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC). However, most patients develop tumor regrowth and their prognosis remains poor. A new treatment strategy for NSCLC harboring EGFR mutation is therefore necessary. Methods In phase I, eligible patients were administered oral erlotinib daily and intravenous pemetrexed, carboplatin, and bevacizumab every 3 weeks for four cycles with maintenance of pemetrexed and bevacizumab until progressive disease was observed. The dose of erlotinib was 100 mg for dose level 1 and 150 mg for dose level 2. The doses of pemetrexed, carboplatin, and bevacizumab were fixed at 500 mg/m2, area under the concentration–time curve of 6 mg/mL · min, and 15 mg/kg, respectively. The dose-limiting toxicities were grade 3/4 neutropenia with fever or infection, grade 4 leukopenia lasting for ≥7 days, grade 4 thrombocytopenia, grade 3/4 uncontrollable nonhematological toxicity, and delayed administration of the subsequent cycle by >2 weeks because of adverse events. Results Six patients were enrolled in phase I (dose level 1, n = 3; dose level 2, n = 3). During the induction phase, grade 3 neutropenia without fever was observed in one patient at dose level 1 and two patients at dose level 2. Grade 3 anemia was reported in one patient at dose level 1 and grade 3 thrombocytopenia was reported in two patients at dose level 1 and dose level 2, respectively. Conclusion Four-drug combination therapy is a feasible and promising. PMID:28740574

GAB2 Amplification in Squamous Cell Lung Cancer of Non-Smokers

PubMed Central

2017-01-01

Lung squamous cell cancer (SCC) is typically found in smokers and has a very low incidence in non-smokers, indicating differences in the tumor biology of lung SCC in smokers and non-smokers. However, the specific mutations that drive tumor growth in non-smokers have not been identified. To identify mutations in lung SCC of non-smokers, we performed a genetic analysis using arrays comparative genomic hybridization (ArrayCGH). We analyzed 19 patients with lung SCC who underwent surgical treatment between April 2005 and April 2015. Clinical characteristics were reviewed, and DNA was extracted from fresh frozen lung cancer specimens. All of copy number alterations from ArrayCGH were validated using The Cancer Genome Atlas (TCGA) copy number variation (CNV) data of lung SCC. We examined the frequency of copy number changes according to the smoking status (non-smoker [n = 8] or smoker [n = 11]). We identified 16 significantly altered regions from ArrayCGH data, three gain and four loss regions overlapped with the TCGA lung squamous cell carcinoma (LUSC) patients. Within these overlapped significant regions, we detected 15 genes that have been reported in the Cancer Gene census. We also found that the proto-oncogene GAB2 (11q14.1) was significantly amplified in non-smokers patients and vice versa in both ArrayCGH and TCGA data. Immunohistochemical analyses showed that GAB2 protein was relatively upregulated in non-smoker than smoker tissues (37.5% vs. 9.0%, P = 0.007). GAB2 amplification may have an important role in the development of lung SCC in non-smokers. GAB2 may represent a potential biomarker for lung SCC in non-smokers. PMID:28960030

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.

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.

Efficacy and Safety of First-Line Necitumumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in East Asian Patients with Stage IV Squamous Non-small Cell Lung Cancer: A Subgroup Analysis of the Phase 3, Open-Label, Randomized SQUIRE Study.

PubMed

Park, Keunchil; Cho, Eun Kyung; Bello, Maximino; Ahn, Myung-Ju; Thongprasert, Sumitra; Song, Eun-Kee; Soldatenkova, Victoria; Depenbrock, Henrik; Puri, Tarun; Orlando, Mauro

2017-10-01

The phase 3 randomized SQUIRE study revealed significantly longer overall survival (OS) and progression-free survival (PFS) for necitumumab plus gemcitabine and cisplatin (neci+GC) than for gemcitabine and cisplatin alone (GC) in 1,093 patients with previously untreated advanced squamous non-small cell lung cancer (NSCLC). This post hoc subgroup analysis assessed the efficacy and safety of neci+GC among East Asian (EA) patients enrolled in the study. All patients received up to six 3-week cycles of gemcitabine (days 1 and 8, 1,250 mg/m²) and cisplatin (day 1, 75 mg/m²). Patients in the neci+GC arm also received necitumumab (days 1 and 8, 800 mg) until disease progression or unacceptable toxicity. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from stratified Cox proportional hazards models. In EA patients, there were improvements for neci+GC (n=43) versus GC (n=41) in OS (HR, 0.805; 95% CI, 0.484 to 1.341) and PFS (HR, 0.720; 95% CI, 0.439 to 1.180), consistent with the results for non-EA patients observed in the present study. The overall safety data were consistent between EA and non-EA patients. A numerically higher proportion of patients experienced serious adverse events (AEs), grade ≥ 3 AEs, and AEs with an outcome of death for neci+GC versus GC in EA patients and EA patients versus non-EA patients for neci+GC. Although limited by the small sample size and post hoc nature of the analysis, these findings are consistent with those of the overall study and suggest that neci+GC offers a survival advantage and favorable benefit/risk for EA patients with advanced squamous NSCLC.

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.

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.

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

GAB2 Amplification in Squamous Cell Lung Cancer of Non-Smokers.

PubMed

Park, Yu Rang; Bae, Soo Hyeon; Ji, Wonjun; Seo, Eul Ju; Lee, Jae Cheol; Kim, Hyeong Ryul; Jang, Se Jin; Choi, Chang Min

2017-11-01

Lung squamous cell cancer (SCC) is typically found in smokers and has a very low incidence in non-smokers, indicating differences in the tumor biology of lung SCC in smokers and non-smokers. However, the specific mutations that drive tumor growth in non-smokers have not been identified. To identify mutations in lung SCC of non-smokers, we performed a genetic analysis using arrays comparative genomic hybridization (ArrayCGH). We analyzed 19 patients with lung SCC who underwent surgical treatment between April 2005 and April 2015. Clinical characteristics were reviewed, and DNA was extracted from fresh frozen lung cancer specimens. All of copy number alterations from ArrayCGH were validated using The Cancer Genome Atlas (TCGA) copy number variation (CNV) data of lung SCC. We examined the frequency of copy number changes according to the smoking status (non-smoker [n = 8] or smoker [n = 11]). We identified 16 significantly altered regions from ArrayCGH data, three gain and four loss regions overlapped with the TCGA lung squamous cell carcinoma (LUSC) patients. Within these overlapped significant regions, we detected 15 genes that have been reported in the Cancer Gene census. We also found that the proto-oncogene GAB2 (11q14.1) was significantly amplified in non-smokers patients and vice versa in both ArrayCGH and TCGA data. Immunohistochemical analyses showed that GAB2 protein was relatively upregulated in non-smoker than smoker tissues (37.5% vs. 9.0%, P = 0.007). GAB2 amplification may have an important role in the development of lung SCC in non-smokers. GAB2 may represent a potential biomarker for lung SCC in non-smokers. © 2017 The Korean Academy of Medical Sciences.

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

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.

Systemic Treatment Patterns With Advanced or Recurrent Non-small Cell Lung Cancer in Japan: A Retrospective Hospital Administrative Database Study.

PubMed

Wang, Feng; Mishina, Sari; Takai, Shinji; Le, T Kim; Ochi, Kenya; Funato, Kotaro; Matsuoka, Shozo; Ohe, Yuichiro

2017-06-01

Data on the treatment of non-small cell lung cancer (NSCLC) in real-world clinical practice in Japan are limited. This large-scale, retrospective cohort study examined data on patients' characteristics and systemic therapies for advanced or recurrent NSCLC in routine practice in Japan. This study used an electronic health records-based database of health claims and Diagnosis Procedure Combination data from 215 consenting hospitals in Japan. Records from April 2008 to September 2015 were analyzed. Regimens were examined by histology, age, sex, and therapeutic line. Logistic regression analysis was performed to predict which clinical and demographic factors affected patients' probability of receiving first- or second-line therapy or completing first-line platinum-based chemotherapy. Among 16,413 patients, 67.9%, 39.2%, and 22.3% received first-, second-, and third-line systemic treatment, respectively. Treatment was more common in patients aged <75 versus ≥75 years (76.0% vs 51.6%), in female versus male patients (71.6% vs 65.4%), and in patients with nonsquamous versus squamous disease (75.6% vs 61.9%). More than 30 systemic regimens were administered. The most common first-line therapy was platinum-based chemotherapy (nonsquamous, 53.6%; squamous, 73.7%). Non-platinum-based chemotherapy use increased in the second-line setting, but platinum-based chemotherapy use remained high (nonsquamous, 33.9%; squamous, 38.6%). Tyrosine kinase inhibitors were used in 32.0% and 29.4% of patients with nonsquamous NSCLC in the first- and second-line settings, respectively. Switches from first- to second-line platinum-based chemotherapy and from first- to second-line tyrosine kinase inhibitors occurred. Forty-two percent of the patients died during hospitalization. In the logistic regression analysis, factors associated with a decreased likelihood of receiving first-line therapy were male sex, squamous histology, age >75 years, treatment at a general (vs cancer-specific) hospital

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

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.

[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.

Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study.

PubMed

Zhou, C C; Bai, C X; Guan, Z Z; Jiang, G L; Shi, Y K; Wang, M Z; Wu, Y L; Zhang, Y P; Zhu, Y Z

2014-05-01

Bevacizumab is a monoclonal antibody with high antitumor activity against malignant diseases. Previous studies have demonstrated the efficacy of first-line bevacizumab combination therapy in advanced, non-squamous non-small cell lung cancer (NS-NSCLC). SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a subgroup analysis of Chinese patients enrolled in SAiL. Chemo-naive Chinese patients with locally advanced, metastatic or recurrent NSCLC were randomized to receive Bev 15 mg/kg every 3 weeks plus carboplatin + paclitaxel for maximum of six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety. Secondary endpoints included time to progression and overall survival. The Chinese intent-to-treat (ITT) population consists of 198 Chinese patients, among whom 107 (54 %) were non-smokers and 90 (45.5 %) were female. The median cycle of bevacizumab administration was 10 and median duration of bevacizumab treatment was 29.5 weeks. Only eight cases of severe adverse events were observed in the study, which were deemed to be related to bevacizumab. The incidence of AEs over grade 3 in Chinese ITT patients was generally low (<9 %). No new safety signals were reported. Objective response rate in 195 evaluable Chinese patients was 68.8 %, including four complete responses (2.1 %). Time to disease progression (TTP) and overall survival were 8.8 and 18.5 months, respectively. The safety and efficacy of first-line bevacizumab-based treatment in Chinese population with advanced NS-NSCLC are consistent with those in previous studies as well as in Asian subgroup population from SAiL study. No new safety signals were reported.

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

Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508).

PubMed

Argiris, A; Lee, J W; Stevenson, J; Sulecki, M G; Hugec, V; Choong, N W; Saltzman, J N; Song, W; Hansen, R M; Evans, T L; Ramalingam, S S; Schiller, J H

2017-12-01

Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. NCT00955305. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Veliparib With or Without Radiation Therapy, Carboplatin, and Paclitaxel in Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-06-01

Large Cell Lung Carcinoma; Lung Adenocarcinoma; Lung Adenocarcinoma, Mixed Subtype; Minimally Invasive Lung Adenocarcinoma; Squamous 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

[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.

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.

[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.

[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.

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

[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.

[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.

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.

Combination Chemotherapy, Radiation Therapy, and Bevacizumab in Treating Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-03-22

Adenosquamous Lung Carcinoma; Large Cell Lung Carcinoma; Lung Adenocarcinoma; Minimally Invasive Lung Adenocarcinoma; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7

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

Pharmacoeconomic analysis of consolidation therapy with pemetrexed after first-line chemotherapy for non-small cell lung cancer.

PubMed

Tsuchiya, Takanori; Fukuda, Takashi; Furuiye, Masashi; Kawabuchi, Koichi

2011-12-01

Prolongation of progression-free survival and overall survival have been reported with consolidation therapy after first-line chemotherapy in non-small cell lung cancer, but only a few pharmacoeconomic analyses have been performed. We performed a pharmacoeconomic analysis to assess the cost-effectiveness of consolidation therapy with pemetrexed compared with non-consolidation therapy. We developed a Markov model to evaluate the incremental cost-effectiveness ratio (ICER) of consolidation therapy with pemetrexed compared with non-consolidation therapy based on previous reports. We analyzed all histology groups together, and individually analyzed non-squamous cell carcinoma, in which pemetrexed has been shown to be more effective, and squamous cell carcinoma, in which pemetrexed has been shown to be less effective. We conducted a Monte-Carlo simulation to assess the uncertainty for our analysis model and the willingness to pay using thresholds. The ICER for consolidation therapy with pemetrexed was about US$ 109,024/life years gained (LYG) (JPY 12.5 million/LYG) and US$ 203,022/quality-adjusted life years (QALY) (JPY 23.3 million/QALY) for all histology. For non-squamous cell carcinoma, respective values were US$ 80,563/LYG (JPY 9.3 million/LYG) and US$ 150,115/QALY (JPY 17.3 million/QALY). Both % of probability at a threshold of JPY 5.0 million (US$ 43,478) for all histology and non-squamous cell carcinoma were less than 0.1%. This result indicates that it is difficult to use consolidation therapy as the standard of care in Japan while being covered by general medical insurance. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Image-Guided Hypofractionated Radiation Therapy With Stereotactic Body Radiation Therapy Boost and Combination Chemotherapy in Treating Patients With Stage II-III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

ClinicalTrials.gov

2017-06-12

Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous 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

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

Clinical features and treatment outcome of non-small cell lung cancer (NSCLC) patients with uncommon or complex epidermal growth factor receptor (EGFR) mutations

PubMed Central

Fassan, Matteo; Indraccolo, Stefano; Calabrese, Fiorella; Favaretto, Adolfo; Bonanno, Laura; Polo, Valentina; Zago, Giulia; Lunardi, Francesca; Attili, Ilaria; Pavan, Alberto; Rugge, Massimo; Guarneri, Valentina; Conte, PierFranco; Pasello, Giulia

2017-01-01

Introduction Tyrosine-kinase inhibitors (TKIs) represent the best treatment for advanced non-small cell lung cancer (NSCLC) with common exon 19 deletion or exon 21 epidermal growth factor receptor mutation (EGFRm). This is an observational study investigating epidemiology, clinical features and treatment outcome of NSCLC cases harbouring rare/complex EGFRm. Results Among 764 non-squamous NSCLC cases with known EGFRm status, 26(3.4%) harboured rare/complex EGFRm. Patients receiving first-line TKIs (N = 17) achieved median Progression Free Survival (PFS) and Overall Survival (OS) of 53 (IC 95%, 2–105) and 84 (CI 95%, 27–141) weeks respectively, without significant covariate impact. Response Rate and Disease Control Rate (DCR) were 47% and 65%, respectively. Uncommon exon 19 mutations achieved longer OS and PFS and higher DCR compared with exon 18 and 20 mutations. No additional gene mutation was discovered by MassARRAY analysis. TKIs were globally well tolerated. Materials and methods A retrospective review of advanced non-squamous NSCLC harbouring rare/complex EGFRm referred to our Center between 2010 and 2015 was performed. Additional molecular pathways disregulation was explored in selected cases, through MassARRAY analysis. Conclusions Peculiar clinical features and lower TKIs sensitivity of uncommon/complex compared with common EGFRm were shown. Exon 19 EGFRm achieved the best TKIs treatment outcome, while the optimal treatment of exon 18 and 20 mutations should be further clarified. PMID:28427238

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

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.

Comparison of Epidermal Growth Factor Receptor Mutations between Metastatic Lymph Node Diagnosed by EBUS-TBNA and Primary Tumor in Non-Small Cell Lung Cancer

PubMed Central

Kang, Hyo Jae; Hwangbo, Bin; Lee, Jin Soo; Kim, Moon Soo; Lee, Jong Mog; Lee, Geon-Kook

2016-01-01

Introduction Although the use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasing for epidermal growth factor receptor (EGFR) testing in lung cancer, the discordance rate in EGFR mutations between lymph node (LN) samples obtained by EBUS-TBNA and primary tumor (PT) is not well known. Thus, we compared the EGFR mutation status of LN samples obtained by EBUS-TBNA and PTs to estimate the efficacy of using EBUS-TBNA specimens for EGFR testing in advanced, non-squamous, non-small cell lung cancer (NSCLC). Materials and Methods Using data of patients from the EBUS-TBNA database (N = 1914) obtained between January 2009 and January 2013, we identified 100 treatment-naïve, advanced, non-squamous NSCLC patients (stage 3 and 4) with matched LN specimens obtained by EBUS-TBNA and PT specimens. Of these, 74 patients with paired specimens were feasible for EGFR mutation analysis, which we performed using a direct sequencing method. Results Of the 74 cases, at least one major [exon 19 deleted (19del) and L858R] or minor (T790M, exon 20 insertion, and other point mutations) EGFR mutation was detected in 31 cases (41.9%), which included PT (n = 31, 41.9%) and LN (n = 28, 37.8%) specimens. Major mutations were detected in 25 PT (33.8%, 19del = 13, L858R = 12) and 22 LN (29.8%, 19del = 11, L858R = 11) specimens. The discordance rate in major mutations between matched PT and LN specimens was 4.1% (3/74). Among minor mutations, T790M was detected in LN specimen only in 2 cases with L858R in PT and LN. The discordance rate major and minor EGFR mutations combined between matched PT and LN specimens was 12% (9/74). Conclusions We observed a high concordance rate of major EGFR mutations between matched LN specimens sampled by EBUS-TBNA and PTs, suggesting that LN samples obtained by EBUS-TBNA from advanced non-squamous NSCLC patients are effective for use in EGFR mutation testing. PMID:27685950

Relationship of driver oncogenes to long term pemetrexed response in non-small cell lung cancer

PubMed Central

Liang, Ying; Wakelee, Heather A.; Neal, Joel W.

2015-01-01

Background Pemetrexed is approved in the treatment of advanced stage non-squamous non-small-cell lung cancer (NSCLC). The length of response is variable, and we thus sought to identify which clinicopathologic characteristics are associated with long term disease control with pemetrexed. Methods Patients with metastatic NSCLC were identified who received pemetrexed (with or without bevacizumab) for 12 months or longer, either as maintenance treatment after first-line platinum-based chemotherapy or as subsequent treatment. Clinical and pathological characteristics were collected. Results Of a total of 196 patients who received pemetrexed starting in 2007, 25 patients were identified who received pemetrexed for over one year. Of these, 15 patients received pemetrexed with or without bevacizumab as maintenance treatment and 10 patients received pemetrexed as subsequent treatment. Fifteen of the 25 patients (60%) had an oncogenic driver mutation as follows: five (20%) had ROS1 gene rearrangements, four (16%) had ALK gene rearrangements, three (12%) had KRAS mutations, two (8%) had epidermal growth factor receptor (EGFR) mutations, and one (4%) had an NRAS mutation. The median overall survival (OS) was 42.2 months (95% confidence interval [CI]: 37.4–61.3) and median progression free survival (PFS) was 22.1 months (95% CI: 15.1–29.1). Patients with an oncogenic driver mutation had significantly better PFS (p=0.006) and OS (p=0.001). Conclusions Among patients with NSCLC who received pemetrexed for an extended time, those with ALK and ROS1 gene rearrangements are proportionally overrepresented compared with that anticipated in a general non-squamous NSCLC population, and patients with oncogenic driver mutations had improved outcomes. PMID:25665893

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

Real-life effectiveness of erlotinib as second-line treatment of stage IIIB/IV squamous non-small cell lung cancer: Results of the PEPiTA observational study.

PubMed

Monnet, Isabelle; Audigier-Valette, Clarisse; Girard, Nicolas; Vergnenègre, Alain; Molinier, Olivier; Souquet, Pierre Jean; Blanchon, François; Bonnetain, Franck; Taguieva-Pioger, Naila; Lamour, Corinne; Wislez, Marie

2016-08-01

Erlotinib, an inhibitor of tyrosine kinase activity of the epidermal growth factor receptor, is effective in non-small cell lung cancer (NSCLC). Data on erlotinib use in squamous NSCLC are limited. This observational study aimed at evaluating the efficacy and safety of second-line erlotinib in patients with stage IIIB/IV squamous NSCLC in a real-life setting. Patients with predominantly squamous stage IIIB/IV NSCLC, who failed first-line platinum-based therapy, were recruited and followed-up for 12 months. Patients underwent visits each trimester. Data were derived from case report forms, and functional assessment of cancer therapy-lung (FACT-L) questionnaires. A total of 152 patients were enrolled; the majority were males (90%) and mean age was 67.7 years. All patients had squamous (97%) or predominantly squamous (3%) NSCLC, of stage IIIB (21%) or IV (79%). Median progression free survival (PFS) and overall survival were 3 and 5.8 months, respectively. Disease progression was observed in the majority of the patients, mostly due to progression of primary tumour and/or metastatic sites, and led to death in 91/107 of patients. Of the 107 deaths reported, none were due to erlotinib. FACT-L questionnaires were interpretable up to the first visit and were in line with PFS data, showing a relatively good quality of life up to Month 3 (mean total score=78.8). No new or unexpected safety issues were reported. The results of this real-life cohort study like those of previous phase III/IV subgroups study analyses indicate that erlotinib is a valuable option for second-line treatment of stage IIIB/IV squamous NSCLC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

TS, DHFR and GARFT expression in non-squamous cell carcinoma of NSCLC and malignant pleural mesothelioma patients treated with pemetrexed.

PubMed

Uramoto, Hidetaka; Onitsuka, Takamitsu; Shimokawa, Hidehiko; Hanagiri, Takeshi

2010-10-01

Recently, pemetrexed (PEM), a new generation antifolate, has been used for the treatment of patients with advanced non-squamous cell carcinoma (SQ) of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). However, no useful markers for selecting appropriate candidates exist at present. Tumor specimens were collected from 5 lung non-SQ and 8 MPM patients who underwent surgery and received PEM. Real-time PCR and immunohistochemical (IHC) staining of the primary tumor were used to analyze the mRNA and protein expressions of thymidylate synthase (TS)/dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), and to compare the expression status and clinical outcomes. TS, DHFR, and GARFT mRNA levels had a median value of 2.39, 1.70, and 1.40 in non-SQ samples of NSCLC patients. The TS and DHFR protein levels had a mean total score of 2 and 4 in non-SQ of NSCLC patients. TS, DHFR, and GARFT mRNA levels had a median value of 5.55, 3.73, and 3.52 in MPM patients. TS and DHFR protein levels had a mean total expression score of 1 and 3 in MPM patients. No significant correlation was identified between the expression levels of TS/DPD/GARFT mRNA and clinical response for the non-SQ of NSCLC and MPM patients treated with PEM. TS, DHFR, and GARFT mRNA and protein expression may not be useful markers for predicting clinical response in Japanese patients with non-SQ of NSCLC and MPM. Further investigations are necessary in order to develop biomarkers to determine the clinical benefits of PEM treatment.

[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

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.

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.

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.

Gene expression profiling reveals activation of the FA/BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure.

PubMed

Balacescu, Ovidiu; Balacescu, Loredana; Tudoran, Oana; Todor, Nicolae; Rus, Meda; Buiga, Rares; Susman, Sergiu; Fetica, Bogdan; Pop, Laura; Maja, Laura; Visan, Simona; Ordeanu, Claudia; Berindan-Neagoe, Ioana; Nagy, Viorica

2014-04-08

Advanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is due to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this study, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally advanced squamous cervical cancer. Twenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary biopsies harvested prior to therapy were analyzed for whole human gene expression (Agilent) based on the patient's 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular function and canonical pathways between the responding and non-responding patients. The microarray results were validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded cervical cancer samples was used for independent validation of the proteins of interest. A 2859-gene signature was identified to distinguish between responder and non-responder patients. 'DNA Replication, Recombination and Repair' represented one of the most important mechanisms activated in non-responsive cervical tumors, and the 'Role of BRCA1 in DNA Damage Response' was predicted to be the most significantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological staining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with responsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set of 24 samples. Our findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced cervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important information about the

The long tail of molecular alterations in non-small cell lung cancer: a single-institution experience of next-generation sequencing in clinical molecular diagnostics.

PubMed

Fumagalli, Caterina; Vacirca, Davide; Rappa, Alessandra; Passaro, Antonio; Guarize, Juliana; Rafaniello Raviele, Paola; de Marinis, Filippo; Spaggiari, Lorenzo; Casadio, Chiara; Viale, Giuseppe; Barberis, Massimo; Guerini-Rocco, Elena

2018-03-13

Molecular profiling of advanced non-small cell lung cancers (NSCLC) is essential to identify patients who may benefit from targeted treatments. In the last years, the number of potentially actionable molecular alterations has rapidly increased. Next-generation sequencing allows for the analysis of multiple genes simultaneously. To evaluate the feasibility and the throughput of next-generation sequencing in clinical molecular diagnostics of advanced NSCLC. A single-institution cohort of 535 non-squamous NSCLC was profiled using a next-generation sequencing panel targeting 22 actionable and cancer-related genes. 441 non-squamous NSCLC (82.4%) harboured at least one gene alteration, including 340 cases (63.6%) with clinically relevant molecular aberrations. Mutations have been detected in all but one gene ( FGFR1 ) of the panel. Recurrent alterations were observed in KRAS , TP53 , EGFR , STK11 and MET genes, whereas the remaining genes were mutated in <5% of the cases. Concurrent mutations were detected in 183 tumours (34.2%), mostly impairing KRAS or EGFR in association with TP53 alterations. The study highlights the feasibility of targeted next-generation sequencing in clinical setting. The majority of NSCLC harboured mutations in clinically relevant genes, thus identifying patients who might benefit from different targeted therapies. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Gefitinib in Treating Patients With Metastatic or Unresectable Head and Neck Cancer or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-01-11

Anaplastic Thyroid Cancer; Insular Thyroid Cancer; Metastatic Parathyroid Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; 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 Parathyroid Cancer; Recurrent Salivary Gland 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 Thyroid Cancer; Recurrent Verrucous Carcinoma of the Larynx; Stage III Follicular Thyroid Cancer; Stage III Papillary Thyroid Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Larynx; Stage IIIB Non-small Cell Lung Cancer; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVA Basal Cell Carcinoma of the Lip; Stage IVA Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Follicular Thyroid Cancer; Stage IVA Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IVA Lymphoepithelioma of the Oropharynx; Stage IVA Midline Lethal Granuloma of the Paranasal Sinus

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.

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.

Evaluating the cost-effectiveness of afatinib after platinum-based therapy for the treatment of squamous non-small-cell lung cancer in France

PubMed Central

Pignata, Maud; Chouaid, Christos; Le Lay, Katell; Luciani, Laura; McConnachie, Ceilidh; Gordon, James; Roze, Stéphane

2017-01-01

Background and aims Lung cancer has the highest mortality rate of all cancers worldwide. Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers and has an extremely poor prognosis. Afatinib is an irreversible ErbB family blocker designed to suppress cellular signaling and inhibit cellular growth and is approved in Europe after platinum-based therapy for squamous NSCLC. The objective of the present analysis was to evaluate the cost-effectiveness of afatinib after platinum-based therapy for squamous NSCLC in France. Methods The study population was based on the LUX-Lung 8 trial that compared afatinib with erlotinib in patients with squamous NSCLC. The analysis was performed from the perspective of all health care funders and affected patients. A partitioned survival model was developed to evaluate cost-effectiveness based on progression-free survival and overall survival in the trial. Life expectancy, quality-adjusted life expectancy and direct costs were evaluated over a 10-year time horizon. Future costs and clinical benefits were discounted at 4% annually. Deterministic and probabilistic sensitivity analyses were performed. Results Model projections indicated that afatinib was associated with greater life expectancy (0.16 years) and quality-adjusted life expectancy (0.094 quality-adjusted life years [QALYs]) than that projected for erlotinib. The total cost of treatment over a 10-year time horizon was higher for afatinib than erlotinib, EUR12,364 versus EUR9,510, leading to an incremental cost-effectiveness ratio of EUR30,277 per QALY gained for afatinib versus erlotinib. Sensitivity analyses showed that the base case findings were stable under variation of a range of model inputs. Conclusion Based on data from the LUX-Lung 8 trial, afatinib was projected to improve clinical outcomes versus erlotinib, with a 97% probability of being cost-effective assuming a willingness to pay of EUR70,000 per QALY gained, after platinum-based therapy in patients

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

Non-small cell lung cancer patients with EML4-ALK fusion gene are insensitive to cytotoxic chemotherapy.

PubMed

Morodomi, Yosuke; Takenoyama, Mitsuhiro; Inamasu, Eiko; Toyozawa, Ryo; Kojo, Miyako; Toyokawa, Gouji; Shiraishi, Yoshimasa; Takenaka, Tomoyoshi; Hirai, Fumihiko; Yamaguchi, Masafumi; Taguchi, Kenichi; Seto, Takashi; Sugio, Kenji; Ichinose, Yukito

2014-07-01

Although patients with the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase gene (EML4-ALK) re-arrangement and epidermal growth factor gene EGFR mutations have proven sensitive to specific inhibitors, there is currently no consensus regarding the sensitivity of non-small cell lung cancer (NSCLC) patients with such mutations to cytotoxic chemotherapy. The responses to first-line cytotoxic chemotherapy were retrospectively compared between advanced or postoperative recurrent patients with non-squamous NSCLC who harbor the EML4-ALK fusion gene (ALK+), EGFR mutation (EGFR+), or neither abnormality (wild-type). Data for 22 ALK+, 30 EGFR+, and 60 wild-type patients were analyzed. The ALK+ group had a significantly lower response rate than the other two groups. Progression-free survival was significantly shorter in the ALK+ cohort compared to the EGFR+ (p<0.001) and wild-type cohorts (p=0.0121). NSCLC patients with the EML4-ALK fusion gene might be relatively insensitivite to cytotoxic chemotherapy. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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.

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.

Expression of GLUT-1 in oral squamous cell carcinoma in tobacco and non-tobacco users

PubMed Central

Azad, Neha; Kumari Maurya, Malti; Kar, Meenakshi; Goel, Madhu Mati; Singh, Ajay Kumar; Sagar, Mala; Mehrotra, Divya; Kumar, Vijay

2016-01-01

Background GLUTs are a family of proteins that mediate glucose transport through the membrane, expressed in head and neck squamous cell carcinoma. GLUT-1 positivity in malignant cells indicates increased proliferative activity, energy requirements, aggressive behaviour and poor radiation response. Aim To observe the expression of GLUT-1 protein in oral squamous cell carcinoma in tobacco and non-tobacco users and to correlate the expression with histopathological grading and pathological staging. Methods 50 cases (25 tobacco and 25 non-tobacco) of oral squamous cell carcinoma, selected during period of August 2014 to July 2015. Histopathological grading, TNM and staging were done. Immunohistochemical staining was performed using standard protocol for paraffin embedded sections. Analysis was performed on SPSS software (Windows version 17.0). Results Significant association of GLUT-1 expression was found with history of tobacco (p < 0.001), Bryne's grade (p < 0.001), tumour size (p = 0.001), nodal metastasis (p = 0.022) and stage (p < 0.001). Higher GLUT-1 expression in stage II, stage III and stage IV was found as compared to stage I. GLUT-1 immunoexpression also shows progressive switch from membranous to cytoplasmic to combined location correlating with histopathologic grade and pTNM stage. Conclusion GLUT-1 expression correlates significantly with histological grade and pTNM staging of oral squamous cell carcinoma. It also significantly correlates with tobacco addiction. Thus, GLUT-1 expression may serve as a biomarker for patients of oral squamous cell carcinoma. PMID:26937365

A retrospective analysis of efficacy and safety of adding bevacizumab to chemotherapy as first- and second-line therapy in advanced non-small-cell lung cancer (NSCLC).

PubMed

Quan, Rencui; Huang, Jiaxing; Chen, Nan; Fang, Wenfeng; Hu, Zhihuang; Zhan, Jianhua; Zhou, Ting; Zhang, Li; Zhang, Hongyu

2016-08-01

Several phase III clinical trials had authenticated that the addition of bevacizumab to paclitaxel plus carboplatin or gemcitabine plus cisplatin showed encouraging efficacy as first-line therapy for advanced NSCLC patients. However, the benefits of adding bevacizumab to other chemotherapy regimens in first- or second-line therapy have not been reported. To compare the clinical efficacy and safety of bevacizumab concomitant with chemotherapy regimens in patients with advanced NSCLC as first- or second-line therapy, we retrospectively reviewed the effects of adding bevacizumab to chemotherapy regimens in naive-chemotherapy and pre-chemotherapy patients with advanced non-squamous NSCLC. A total of 79 patients with advanced non-squamous NSCLC received at least two cycles of bevacizumab with chemotherapy between October 2010 and December 2013 were selected. Our primary end points were overall response rate (ORR) and disease control rate (DCR). The secondary objective was overall survival (OS) and safety. Seventy-nine patients were included in this study. Overall response rates at first evaluation (after 2 cycles) were 23.1 % (9/39) and 5.0 % (2/40) in first- and second-line therapy (P = 0.020), respectively. And disease control rates were 84.6 % (33/39) and 50 % (20/40), respectively (P = 0.001). The median OS were 27.2 months (95 % CI 13.3-41.1 months) and 29.6 months (95 % CI 6.7-52.5 months), respectively (P = 0.740). Grade 3-4 adverse events included leukopenia (2/39), and neutropenia (3/39) in first-line therapy versus neutropenia (1/40) and thrombocytopenia (2/40) in second-line treatment. In our experience, combination of bevacizumab and chemotherapy had encouraging anti-tumor efficacy as both first- and second-line therapy.

MO19390 (SAiL): bleeding events in a phase IV study of first-line bevacizumab with chemotherapy in patients with advanced non-squamous NSCLC.

PubMed

Dansin, Eric; Cinieri, Saverio; Garrido, Pilar; Griesinger, Frank; Isla, Dolores; Koehler, Manfred; Kohlhaeufl, Martin

2012-06-01

The clinical benefit and safety profile associated with first-line bevacizumab with doublet chemotherapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) was established in two large phase III studies, E4599 and AVAiL. SAiL, a single-arm phase IV study, was conducted to evaluate bevacizumab with a range of first-line chemotherapy regimens in a routine oncology practice setting. This analysis of the SAiL data was undertaken to specifically evaluate bleeding adverse events (AEs) in this study, and to explore potential associations between bleeding and baseline patient and disease characteristics. In total, 2212 patients were evaluated. Bleeding AEs (any grade) occurred in 38.2% of patients (grade ≥ 3 bleeding AEs: 3.6%). Grade ≥ 3 pulmonary hemorrhage and central nervous system bleeding events were observed in 0.7% and 0.1% of patients, respectively. The incidence of grade ≥ 3 bleeding AEs was comparable across patient subgroups defined by central tumor location, tumor cavitation, histology, concomitant anticoagulation therapy and age. The majority (88.6%) of bleeding events resolved or improved, 10.2% persisted and 1.3% led to death; 10.2% of bleeding events required bevacizumab interruption or discontinuation. This analysis from the SAiL trial reaffirms a comparable incidence of clinically significant bleeding associated with first-line bevacizumab and chemotherapy as previous phase III studies in NSCLC patients despite less stringent first-line selection criteria. Grade ≥ 3 bleeding appears to be comparable when analyzed for patient and tumor characteristics, including tumor cavitation and concomitant anticoagulation therapy. Most bleeding events resolved or improved, and interruption/discontinuation of bevacizumab was infrequent in a standard oncology practice setting. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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.

The first liquid biopsy test approved. Is it a new era of mutation testing for non-small cell lung cancer?

PubMed Central

2017-01-01

Specific mutations in epidermal growth factor receptor (EGFR) gene are predictive for response to the EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer patients (NSCLC). According to international guidelines, the molecular testing in patients with advanced NSCLC of a non-squamous subtype is recommended. However, obtain a tissue sample could be challenging. Liquid biopsy allows to determine patients suitable for EGFR-targeted therapy by analysis of circulating-free tumor DNA (cfDNA) in peripheral blood samples and might replace tissue biopsy. It allows to acquire a material in convenient minimally invasive manner, is easily repeatable, could be used for molecular identification and molecular changes monitoring. Many studies show a high concordance rate between tissue and plasma samples testing. When U.S. Food and Drug Administration (FDA) approved the first liquid biopsy test, analysis of driver gene mutation from cfDNA becomes a reality in clinical practice for patients with NSCLC. PMID:28251125

Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers

ClinicalTrials.gov

2018-06-25

Adenoid Cystic Carcinoma; Adnexal Carcinoma; Apocrine Carcinoma; Eccrine Porocarcinoma; Extraocular Cutaneous Sebaceous Carcinoma; Hidradenocarcinoma; Keratoacanthoma; Malignant Sweat Gland Neoplasm; Merkel Cell Carcinoma; Microcystic Adnexal Carcinoma; NK-Cell Lymphoma, Unclassifiable; Non-Melanomatous Lesion; Paget Disease; Papillary Adenocarcinoma; Primary Cutaneous Mucinous Carcinoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Refractory Mycosis Fungoides; Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory T-Cell Non-Hodgkin Lymphoma; Sezary Syndrome; Signet Ring Cell Carcinoma; Skin Basal Cell Carcinoma; Skin Basosquamous Cell Carcinoma; Skin Squamous Cell Carcinoma; Spiradenocarcinoma; Squamous Cell Carcinoma of Unknown Primary Origin; Stage III Skin Cancer; Stage IV Skin Cancer; Sweat Gland Carcinoma; Trichilemmocarcinoma; Vulvar Squamous Cell Carcinoma

[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.

Squamous NSCLC Improves with Atezolizumab Plus Chemo.

PubMed

2018-06-08

A combination of chemotherapy and the PD-L1 inhibitor atezolizumab may be an effective initial therapy for patients with advanced squamous non-small cell lung cancer. In a clinical trial, patients who received the combination had longer progression-free survival, a higher objective response rate, and a longer duration of response than patients who received chemotherapy alone, regardless of PD-L1 expression level. ©2018 American Association for Cancer Research.

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

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.

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

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.

Long non-coding RNA biomarker for human laryngeal squamous cell carcinoma prognosis.

PubMed

Chen, Jingjing; Shen, Zhisen; Deng, Hongxia; Zhou, Wei; Liao, Qi; Mu, Ying

2018-05-15

Long non-coding RNAs (lncRNA) were discovered in tumors. The regulation of lncRNA in human laryngeal squamous cell carcinoma (LSCC) remains incomplete. Uncovering the potential of lncRNA to stratify the prognosis of LSCC and streamline the vast amount of clinical information will affect medical interventions. The surgical resected LSCC tissues, adjacent non-cancerous tissues (ANCT) and lymph node metastatic tissue (LNM) were collected from 76 patients for lncRNA AC008440.10 expression assay. The stages of LSCC and LNM were classified accordingly. We integrated the epigenetic information with enhanced CT imaging and pathological evaluations to predict the patients' survival by comprehensive statistical algorithms using equal weighting. Significant downregulation of lncRNA AC008440.10 was detected in LSCC tumor and metastatic lymph node in advanced stage of patient samples compared with those in early stage. The pattern of differentially expressed AC008440.10 displayed a clear trend that significantly related to tumor progression. The downregulation of lncRNA AC008440.10 correlates with increasing risk of metastasis, poor prognosis and patient survival. The potential for lncRNA AC008440.10 to be developed as a novel biomarker for stratification of the prognosis was especially promising when clinic parameters were hybridized with equal weight, and using a panel of complementary parameters yielded a more powerful predictability of LSCC prognosis than any single parameter individually. Copyright © 2017. Published by Elsevier B.V.

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

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.

Erlotinib and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney, Colorectal, Head and Neck, Pancreatic, or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2014-06-10

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Colon Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; 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 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; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Colon Cancer; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Salivary Gland Cancer; 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

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 ...

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.

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.

Cost-effectiveness of pemetrexed in combination with cisplatin as first line treatment for patients with advanced non-squamous non-small-cell lung cancer in Spain.

PubMed

González García, Jonathan; Gutiérrez Nicolás, Fernando; Nazco Casariego, Gloria Julia; Valcárcel Nazco, Cristina; Batista López, Jose Norberto; Oramas Rodríguez, Juana

2017-01-01

Lung cancer is the third most frequent neoplastic tumour in Spain, with around 27 000 new cases diagnosed per year; 80-95% of these are non-small-cell cancer (NSCLC), and the majority of cases are diagnosed in advanced stages of the disease, and for this reason it is one of the oncologic conditions with higher mortality rates (21.4% mean survival at 5 years). The main treatment regimens used for first-line treatment of NSCLC are: cisplatin/pemetrexed (cis/pem), cisplatin/gemcitabine/ bevacizumab (cis/gem/bev), and carboplatin/paclitaxel/ bevacizumab (carb/pac/bev). The objective of this study was to evaluate the cost-effectiveness ratio of antineoplastic 1st line NSCLC treatment regimens, from the point of view of hospital management. A cost-efficacy mathematical model was prepared, based on a decision tree. The efficacy variable was Progression Free Survival, obtained from the PARAMOUNT, AVAIL and SAIL Phase III clinical trials. The study was conducted from the perspective of the hospital management, considering only the direct costs of drug acquisition. A deterministic sensitivity analysis was conducted to confirm the robustness of outcomes. The PFS obtained in clinical trials with cis/pem, cis/ gem/bev and carb/pac/bev was: 6.9, 6.7 and 6.2 months, respectively. Based on our model, the mean cost of treatment per patient for these regimens was: 19 942 €, 15 594 € and 36 095 €, respectively. The incremental cost-effectiveness ratio per month of additional PFS between cis/pem and cis/gem/bev was 19 303 €. Estimating a 30% reduction in acquisition costs for pemetrexed (Alimta®Eli Lilly Nederland B.V.), due to the forthcoming launch of generic medications, the cis/pem treatment would become the predominant alternative for 1st line treatment of NSCLC patients, by offering the best health results at a lower cost. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Non-squamous cell neoplasms of the larynx: radiologic-pathologic correlation.

PubMed

Becker, M; Moulin, G; Kurt, A M; Dulgerov, P; Vukanovic, S; Zbären, P; Marchal, F; Rüfenacht, D A; Terrier, F

1998-01-01

A variety of benign and malignant non-squamous cell neoplasms may affect the larynx. Most of these uncommon laryngeal neoplasms are located beneath an intact mucosa, making diagnosis difficult with endoscopy alone, and sampling errors may occur if only traditional superficial biopsies are performed. In some laryngeal neoplasms, radiologic evaluation allows the correct diagnosis. Hemangiomas have very high signal intensity at T2-weighted magnetic resonance (MR) imaging and strong enhancement at both computed tomography (CT) and MR imaging after administration of contrast material. Phleboliths, which are pathognomonic for hemangiomas, are easily identified at CT. Chondrogenic tumors typically manifest with coarse or stippled calcifications at CT. Because of their high water content, chondrogenic tumors have very high signal intensity on T2-weighted MR images, whereas only moderate enhancement is observed after administration of contrast material. Lipomas typically manifest at both CT and MR imaging as homogeneous nonenhancing lesions. They are isoattenuating to subcutaneous fat at CT and isointense relative to subcutaneous fat with all MR pulse sequences. Metastases from renal adenocarcinoma typically demonstrate strong contrast enhancement and flow voids at MR imaging, and metastases from melanotic melanoma usually have high signal intensity on T1-weighted MR images and low signal intensity on T2-weighted images owing to the paramagnetic properties of melanin. Although radiologic findings are nonspecific in most other non-squamous cell neoplasms of the larynx (eg, Kaposi sarcoma, hematopoietic tumors, tumors of the minor salivary glands, metastases from amelanotic melanoma), cross-sectional imaging can play an important role in the diagnostic work-up of these unusual tumors by delineating the extent of submucosal tumor spread and directing the endoscopist to the appropriate site for the deep, transmucosal biopsies needed to establish the diagnosis. In addition, CT

[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.

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

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.

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.

Non-solar ultraviolet radiation and the risk of basal and squamous cell skin cancer.

PubMed Central

Bajdik, C. D.; Gallagher, R. P.; Astrakianakis, G.; Hill, G. B.; Fincham, S.; McLean, D. I.

1996-01-01

A case-control study of non-melanocytic skin cancer was conducted among men in the province of Alberta, Canada. Two hundred and twenty-six cases of basal cell carcinoma (BCC), 180 cases of squamous cell carcinoma (SCC) and 406 age-matched controls provided information concerning skin pigmentation, occupational history, recreational activity, exposure to sunlight and sources of non-solar ultraviolet radiation (NSUVR) and other potential risk factors. Our analyses show no evidence of elevated risk for BCC or SCC among subjects exposed to various types of NSUVR. This is in opposition to studies of melanoma that have shown elevated risks for exposure to fluorescent lighting, sunlamps and sunbeds. PMID:8664139

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

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

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.

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

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.

Chimeric Monoclonal Antibody Cetuximab Targeting Epidermal Growth Factor-Receptor in Advanced Non-Melanoma Skin Cancer.

PubMed

Wollina, Uwe; Tchernev, Georgi; Lotti, Torello

2018-01-25

Non-melanoma skin cancer (NMSC) is the most common malignancy in humans. Targeted therapy with monoclonal antibody cetuximab is an option in case of advanced tumor or metastasis. We present and update of the use of cetuximab in NMSC searching PUBMED 2011-2017. The monoclonal antibody cetuximab against epidermal growth factor receptor (EGFR) has been investigated for its use in NMSC during the years 2011 to 2017 by a PUBMED research using the following items: "Non-melanoma skin cancer AND cetuximab," "cutaneous squamous cell carcinoma AND cetuximab," and "basal cell carcinoma AND cetuximab", and "cetuximab AND skin toxicity". Available data were analyzed including case reports. Current evidence of cetuximab efficacy in NMSC was mainly obtained in cutaneous SCC and to a lesser extend in BCC. Response rates vary for neoadjuvant, adjuvant, mono- and combined therapy with cetuximab. Management of cutaneous toxicities is necessary. Guidelines are available. Cetuximab is an option for recurrent or advanced NMSC of the skin. It seems to be justified particularly in very high-risk tumors. There is a need for phase III trials.

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.

[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.

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

[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.

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

Adenylyl cyclase-associated protein 1 in metastasis of squamous cell carcinoma of the head and neck and non-small cell lung cancer

NASA Astrophysics Data System (ADS)

Kakurina, G. V.; Kolegova, E. S.; Cheremisina, O. V.; Zavyalov, A. A.; Shishkin, D. A.; Kondakova, I. V.; Choinzonov, E. L.

2016-08-01

Progression of tumors and metastasis in particular is one of the main reasons of the high mortality rate among cancer patients. The primary role in developing metastases plays cell locomotion which requires remodeling of the actin cytoskeleton. Form, dynamics, localization and mechanical properties of the actin cytoskeleton are regulated by a variety of actin-binding proteins, which include the adenylyl cyclase-associated protein 1 (CAP1). The study is devoted to the investigation of CAP1 level depending on the presence or absence of metastases in patients with squamous cell carcinoma of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC). The results show the contribution of CAP1 to SCCHN and NSCLC progression. We detected the connection between the tissue protein CAP1 level and the stage of NSCLC and SCCHN disease. Also the levels of the CAP1 protein in tissues of primary tumors and metastases in lung cancer were different. Our data showed that CAP is important in the development of metastases, which suggests further perspectives in the study of this protein for projecting metastasis of NSCLC and SCCHN.

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.

[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.

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.

[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.


[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.

Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer.

PubMed

Suzuki, Seiichiro; Karayama, Masato; Inui, Naoki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Kuroishi, Shigeki; Matsuda, Hiroyuki; Yokomura, Koshi; Koshimizu, Naoki; Toyoshima, Mikio; Imokawa, Shiro; Asada, Kazuhiro; Masuda, Masafumi; Yamada, Takashi; Watanabe, Hiroshi; Suda, Takafumi

2016-08-01

Objectives Maintenance therapy is a standard therapeutic strategy in non-squamous non-small-cell lung cancer. However, there is no consensus regarding the benefit of maintenance therapy for patients with squamous cell lung cancer. We assessed maintenance therapy with S-1, an oral fluoropyrimidine agent, following induction therapy with carboplatin and S-1 in patients with squamous cell lung cancer. Methods In this phase II trial, chemotherapy-naïve patients with squamous cell lung cancer were enrolled to induction therapy with four cycles of carboplatin (at an area under the curve of 5 on day 1) and S-1 (80 mg/m(2)/day on days 1-14) in a 28-day cycle. Patients who achieved disease control after induction therapy received maintenance therapy with S-1 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival after administration of maintenance therapy. Results Fifty-one patients were enrolled in the study. The median progression-free survival from the start of maintenance therapy was 3.0 months (95 % confidence interval, 2.5-3.5). The most common toxicities associated with maintenance therapy were anemia, thrombocytopenia, and fatigue, but they were not severe. Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer.

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

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.

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

GTSP1 expression in non-smoker and non-drinker patients with squamous cell carcinoma of the head and neck

PubMed Central

Soares, Pamela de Oliveira; Maluf Cury, Patrícia; Mendoza López, Rossana Verónica; Cernea, Cláudio Roberto; Fukuyama, Erika Erina; Livingstone Alves Figueiredo, David; Gorgonio da Nobrega, Francisco; Curioni, Otavio Alberto; Nunes, Fabio Daumas; Bueno Garcia, Maria Lúcia

2017-01-01

Introduction The main risk factors for head and neck squamous cell carcinoma (HNSCC) are tobacco and alcohol consumption and human papillomavirus (HPV) infection. However, in a subset of patients, no risk factors can be identified. Glutathione S-transferase π (GTSP1) is a carcinogen-detoxifying enzyme that is activated by exposure to carcinogens, and it is associated with a reduction in response to toxic therapies. We studied the expression of GTSP1 in tumor and non-tumor tissue samples from patients with and without these risks to identify whether GTSP1 expression differs according to exposure to carcinogens. Materials and methods Non-smoker/non-drinker (NSND) and smoker/drinker (SD) patients were matched according to age, gender, tumor site, TNM stage, grade and histological variants to establish 47 pairs of patients who have been previously tested for HPV. GTSP1 immunostaining was analyzed using a semi-quantitative method with scores ranging from 0 to 3 according to the area of immunostaining. Results GTSP1 expression was detected in the tumors of both groups. GTSP1 expression was higher in the non-tumor margins of SD patients (p = 0.004). There was no association between GTSP1 expression and positivity for HPV. No differences in survival were observed according to GTSP1 staining in tumors and non-tumor margins. Conclusion This study showed that GTSP1 was expressed in tumors of HNSCC patients regardless of smoking, drinking or HPV infection status. The difference in GTSP1 expression in non-tumor margins between the two groups may have been due to two possible reasons. First, elevated GTSP1 expression in SD patients might be the result of activation of GTSP1 in response to exposure to carcinogens. Second, alternatively, impairment in the detoxifying system of GTSP1, as observed by the reduced expression of GTSP1, might make patients susceptible to carcinogens other than tobacco and alcohol, which may be the underlying mechanism of carcinogenesis in the absence

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.

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.

An Open-Label, Randomized, Controlled Phase II Study of Paclitaxel-Carboplatin Chemotherapy With Necitumumab Versus Paclitaxel-Carboplatin Alone in First-Line Treatment of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer.

PubMed

Spigel, David R; Luft, Alexander; Depenbrock, Henrik; Ramlau, Rodryg; Khalil, Mazen; Kim, Joo-Hang; Mayo, Carlos; Chao, Grace Yi; Obasaju, Coleman; Natale, Ronald

2017-09-01

The combination of necitumumab with gemcitabine-cisplatin significantly improved overall survival (OS) in patients with stage IV squamous non-small-cell lung cancer (NSCLC), in the phase III SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) trial. Paclitaxel-carboplatin was selected as an alternative standard of care in the current phase II study. Patients were randomized (stratified according to Eastern Cooperative Oncology Group performance status and sex) 2:1 to ≤ six 3-week cycles (Q3W) of paclitaxel and carboplatin with or without necitumumab. Chemotherapy was paclitaxel 200 mg/m 2 on day 1 Q3W and carboplatin area under the curve 6 on day 1 Q3W. Necitumumab 800 mg, on days 1 and 8, was continued until disease progression or intolerable toxicity occurred. The primary end point was objective response rate (ORR) on the basis of Response Evaluation Criteria In Solid Tumors version 1.1. One hundred sixty-seven patients were randomized to the necitumumab-containing arm (n = 110) or the chemotherapy-only arm (n = 57). The combination of necitumumab with chemotherapy resulted in an ORR of 48.9% versus 40.0%. Median progression-free survival and OS were 5.4 versus 5.6 months (hazard ratio [HR], 1.0) and 13.2 versus 11.2 months (HR, 0.83; P = .379) in each treatment arm, respectively. Disease control rate was 87.2% versus 84.0%. Grade ≥ 3 adverse events typically associated with epidermal growth factor receptor (EGFR) monoclonal antibodies showing a > 2% increase were hypomagnesemia (5.7% vs. 0) and rash (2.8% vs. 0). Any Grade thromboembolic events occurred in < 4% of patients in either arm. The results of our study support previously reported results that the combination of necitumumab with chemotherapy improves survival in patients with advanced squamous NSCLC and shows a safety profile consistent with that of EGFR monoclonal antibodies. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

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.

Heightening energetic stress selectively targets LKB1-deficient non-small cell lung cancers

PubMed Central

Momcilovic, Milica; McMickle, Robert; Abt, Evan; Seki, Atsuko; Simko, Sarah A.; Magyar, Clara; Stout, David B.; Fishbein, Michael C.; Walser, Tonya C.; Dubinett, Steven M.; Shackelford, David B.

2015-01-01

Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mammalian target of rapamycin complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing co-mutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas (ADCs) and squamous cell carcinomas (SCCs). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1 mutant human cell lines and genetically engineered mouse models of NSCLC that develop both ADCs and SCCs. Specifically, we found that KRAS/LKB1 mutant lung ADCs responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1 mutant adenocarcinomas and squamous cell tumors. PMID:26574479

Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers.

PubMed

Momcilovic, Milica; McMickle, Robert; Abt, Evan; Seki, Atsuko; Simko, Sarah A; Magyar, Clara; Stout, David B; Fishbein, Michael C; Walser, Tonya C; Dubinett, Steven M; Shackelford, David B

2015-11-15

Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mTOR complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing comutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas and squamous cell carcinomas (SCC). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1-mutant human cell lines and genetically engineered mouse models of NSCLC that develop both adenocarcinomas and SCCs. Specifically, we found that KRAS/LKB1-mutant lung adenocarcinomas responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors, thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1-mutant adenocarcinomas and squamous cell tumors. ©2015 American Association for Cancer Research.

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.

Palliative chemotherapy for non-transitional cell carcinomas of the urothelial tract.

PubMed

Hong, Jung Yong; Choi, Moon Ki; Uhm, Ji Eun; Park, Min Jae; Lee, Jeeyun; Park, Se Hoon; Park, Joon Oh; Kim, Won Seog; Kang, Won Ki; Lee, Hyun Moo; Choi, Han Yong; Lim, Hoyeong

2009-01-01

Non-transitional cell carcinomas of the urothelial tract comprise 5-10% of urothelial cancers. Clinical information regarding the clinical behavior and chemotherapy outcome of non-transitional cell carcinomas of the urothelial tract are incomplete due to their rarity. The object of this study was to evaluate the clinical features and the efficacy of palliative chemotherapy in advanced non-transitional cell carcinomas of the urothelial tract. We analyzed the clinical records of 21 consecutive patients who received palliative chemotherapy for unresectable or metastatic non-transitional cell carcinomas of the urothelial tract between January 1995 and November 2007. All the 21 patients received first-line chemotherapy with platinum-based regimens which are known to be effective in transitional cell urothelial carcinomas. The median age of the patients was 57 years (range, 27-71 years). The primary sites of involvement were the bladder, urethra, urachus, and ureter in 43%, 29%, 19%, and 10% of the patients, respectively. Adenocarcinoma was the most common histological type (67%); squamous cell carcinoma and small cell carcinoma comprised 24 and 10% of the histologic types, respectively. With a median duration of follow-up of 32 months (range, 12-71 months), the median overall survival for all 21 patients from the day of first-line chemotherapy was 13 months (95% CI, 6.8-19.2). The expected 1-year survival rate was 50.6% (95% CI, 28.6-72.5). Univariate analysis showed a better median overall survival in patients with adenocarcinoma, compared to non-adenocarcinomas (47 vs. 10 months, P = 0.049). The median overall survival of patients who received platinum-based palliative chemotherapy for advanced non-transitional cell carcinomas was comparable to previous studies for patients with transitional cell carcinomas. Adenocarcinomas appear to have a favorable prognosis for the survival of the patients who received platinum-based chemotherapy for advanced non-transitional cell

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

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 ...

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.

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

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

[Clinical features of non-small cell lung cancer cases].

PubMed

Atici, Atilla G; Erkan, Levent; Findik, Serhat; Uzun, Oğuz; Kandemir, Bedri

2004-01-01

The aim of this study was to evaluate the clinical features of non-small cell lung cancer (NSCLC) cases that were diagnosed in our clinic. The patients who were diagnosed as NSCLC in our clinic between January 1988 and January 1999 were comprised the study group. The files and records of the study group were retrospectively reviewed to identify patients and all the data including demographic characteristics, history, physical examination findings, laboratory values, diagnostic procedures, radiologic findings and staging procedures. The study group included 564 patients (506 male, 58 female). The mean age was 60 years (28-97). 87% of the patients were current smokers or ex-smokers. The most frequent symptoms on admission were cough, sputum, and dyspnea. The most common radiologic finding was a central mass with a diameter of more than 4 cm with an irregular border. The diagnosis was established by histopathologic examination of biopsy specimens obtained by various means, in which bronchoscopy was the sole means of diagnosis in 83% of the patients. Histopathologic examination of the biopsy specimens resulted as follows: 85.8% squamous cell carcinoma, 10.3% adenocarcinoma, 1.4% large cell carcinoma, 0.45% adenosquamous carcinoma, and 2.1% undifferentiated NSCLC. Staging procedures that were done in all patients revealed that 85% of the patients were diagnosed at the stage IIIB and IV. Metastasis was most frequently to the bones followed by brain and liver. In our study squamous cell carcinoma was the most common histopathologic type with a higher percentage than the previous reports in the literature. The percentages of stage IIIB and IV were also higher in our study than previous papers in the literature.

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.

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

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.

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... 

Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study.

PubMed

Paz-Ares, Luis; Mezger, Jörg; Ciuleanu, Tudor E; Fischer, Jürgen R; von Pawel, Joachim; Provencio, Mariano; Kazarnowicz, Andrzej; Losonczy, György; de Castro, Gilberto; Szczesna, Aleksandra; Crino, Lucio; Reck, Martin; Ramlau, Rodryg; Ulsperger, Ernst; Schumann, Christian; Miziara, Jose Elias A; Lessa, Álvaro E; Dediu, Mircea; Bálint, Beatrix; Depenbrock, Henrik; Soldatenkova, Victoria; Kurek, Raffael; Hirsch, Fred R; Thatcher, Nick; Socinski, Mark A

2015-03-01

Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21

Influence of histology and biomarkers on first-line treatment of advanced non-small cell lung cancer in routine care setting: baseline results of an observational study (FRAME).

PubMed

Schnabel, Philipp A; Smit, Egbert; Carpeño, Javier de Castro; Leśniewski-Kmak, Krzysztof; Aerts, Joachim; Kraaij, Kees; Visseren-Grul, Carla; Dyachkova, Yulia; Taipale, Kaisa; Girvan, Allicia; Moro-Sibilot, Denis

2012-12-01

FRAME is a prospective observational study of first-line treatments for advanced non-small cell lung cancer (NSCLC). This interim analysis examines the influence of histology and biomarkers on therapeutic decisions. Baseline characteristic, treatment, and diagnostic procedure data were collected on European patients with stage IIIB/IV NSCLC who were treated with any first-line platinum-based doublet, with or without targeted agents, in routine clinical practice. A total of 1567 patients were observed in 11 countries between April 2009 and February 2011. Patients were mostly non-Asian (96.4%), male (71.5%), smokers (84.4%) with stage IV NSCLC (76.6%) and a performance status of 0-1 (82.2%). Median age was 64 years (range, 33-87). First-line treatments were platinum-based combinations with pemetrexed (36.3%), gemcitabine (23.0%), vinorelbine (19.2%), taxanes (18.9%), or other (2.6%), with concurrent targeted agents in 8.4% of patients (mainly bevacizumab, 7.3%). Diagnosis was based on histology in 70.6%, cytology in 20.3%, and both in 9.1% of patients. The final diagnosis was nonsquamous in 72.2% (including 'not otherwise specified [NOS]' in 11.0%), squamous in 24.4%, and other in 3.4% of patients, with the most common reasons for NOS diagnosis being 'subtyping not technically possible' (42.9%) and 'not important for treatment decision' (40.5%). Only 1.1% (6 patients) in the pemetrexed cohort and 0.9% (1 patient) of patients who received bevacizumab had squamous cell carcinoma. At least one immunohistochemical (IHC) marker was used in 53.5% of patients (thyroid transcription factor-1 [TTF-1]: 47.5%, cytokeratin 7 [CK7]: 38.6%, cytokeratin 5/6 [CK5/6]: 17.9%, p63: 8.8%, cluster of differentiation 56 [CD56]: 4.2%, cytokeratin 14 [CK14]: 1.9%, and other: 24.2%). Testing for additional biomarkers was less common, with the most common being for epidermal growth factor receptor (EGFR) mutation status (26.0%). Physician-reported key factors influencing treatment choice were

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.

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

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.

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.

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

Advanced cutaneous squamous cell carcinoma: A retrospective analysis of patient profiles and treatment patterns-Results of a non-interventional study of the DeCOG.

PubMed

Hillen, Uwe; Leiter, Ulrike; Haase, Sylvie; Kaufmann, Roland; Becker, Jürgen; Gutzmer, Ralf; Terheyden, Patrick; Krause-Bergmann, Albrecht; Schulze, Hans-Joachim; Hassel, Jessica; Lahner, Nina; Wollina, Uwe; Ziller, Fabian; Utikal, Jochen; Hafner, Christine; Ulrich, Jens; Machens, Hans-Günther; Weishaupt, Carsten; Hauschild, Axel; Mohr, Peter; Pföhler, Claudia; Maurer, Jan; Wolff, Patrick; Windemuth-Kieselbach, Christine; Schadendorf, Dirk; Livingstone, Elisabeth

2018-04-14

Advanced cutaneous squamous cell carcinoma (aSCC) is an area of unmet medical need and no treatment standards are established. Recently, an anti-PD-1 inhibitor received FDA breakthrough therapy designation. The aim of the study was to describe the clinical course, therapeutic management and prognosis of aSCC under real-life conditions. In a retrospective study performed in 24 German and Austrian hospitals and doctor's offices, patient and tumour characteristics of patients diagnosed with aSCC between January 1, 2010 and December 31, 2011 and their disease course was documented. Advanced SCC comprised either locally advanced SCCs (laSCC) or metastatic SCCs (mSCC) with any kind of metastatic spread. Data of 190 patients with aSCC were analysed. Median age at time of diagnosis of aSCC was 78 years. LaSCC was diagnosed in 76 patients (40%), 114 patients (60%) had mSCC. Once diagnosed with laSCC, most patients (59%) did not receive any therapy, whereas in 92% of mSCC patients at least one type of therapy was performed. Only 32 patients (29 mSCC, 3 laSCC) received systemic antitumour therapies, mostly EGFR inhibitor-based regimens. Mean duration of response was short (17-months laSCC patients, 3-months mSCC patients). Only 2 patients achieved a complete response, 27% had a partial response, 43% disease stabilisation. At diagnosis of aSCC, ECOG status was 0-1 in most patients. Non-malignant comorbidities influenced the decision on SCC-specific therapy in 39 patients (21%). Our data show the high medical need for efficient and tolerable antitumour therapies and demonstrate that despite older age and comorbidities, most patients can be expected to be fit for treatment. This study provides a historical context for emerging aSCC treatments. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

Pap-tests with non-hyperchromatic dyskariosis are often associated with squamous intraepithelial lesions of the cervix uteri with eosinophilic features.

PubMed

Bellisano, Giulia; Ambrosini-Spaltro, Andrea; Faa, Gavino; Ravarino, Alberto; Piccin, Andrea; Peer, Irmgard; Kasal, Armin; Vittadello, Fabio; Negri, Giovanni

2016-10-01

Squamous intraepithelial lesions of the cervix uteri with eosinophilic features (eosinophilic dysplasia, ED) are a peculiar type of dysplasia with metaplastic phenotype which was described in histological specimens. The cytological features of these lesions have not been studied yet. Histological samples from 66 women with features of ED and positive p16(INK4a) staining were included in the study. Within the previous year, all women had at least one pap-test, whose features were recorded and compared with 31 control samples with high-grade dysplasia of usual type. The previous pap-test showed high-grade dysplastic cells with non-hyperchromatic nuclei in 56/66 (84.8%) cases and metaplastic features in 60/66 (90.9%) cases. Conversely, the dysplastic cells of the usual lesions showed non-hyperchromatic nuclei in 6/31 (19.4%) and metaplastic features in 4/31 (12.9%) cases. Statistical analysis showed significant differences in distribution of the non-hyperchromatic nuclei (P < 0.001), metaplastic features (P < 0.001), presence of both non-hyperchromatic nuclei and metaplastic features (P < 0.001) and usual dysplastic features (P < 0.001) among the study and control groups. A high-grade squamous intraepithelial lesion with non-hyperchromatic nuclei or metaplastic features is often found in the pap-test previous to the histological diagnosis of ED and may represent the cytologic correlate of this particular type of dysplasia. Diagn. Cytopathol. 2016;44:783-786. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Analysis of EML4-ALK rearrangement in non-small cell lung cancer in Argentina.

PubMed

Verzura, María; Batagelj, Emilio; Bagnes, Claudia; Martin, Claudio; Enrico, Diego; Richardet, Eduardo; De la Iglesia, Paola

2018-02-26

Identification of EML4-ALK rearrangement by FISH test has become standard in advanced NSCLC patients. There is limited information about the prevalence and clinical characteristics of ALK translocation in Latin America. The aim of our study was to evaluate this lung cancer subtype features in Argentinian patients and the factibility of FISH test with different methods used for obtaining tissue samples. Between August 2014 and February 2017, 183 non-squamous NSCLC patients were prospectively enrolled from five Argentinian institutions. Different techniques and procedures were used to obtained tissue samples material. ALK determination was performed by FISH and immunohistochemistry (IHC). Correlation with clinico-pathological information and different biopsy procedures was assessed. From 183 non-squamous NSCLC samples, 131 could perform FISH test, finding 123 (93.9%) negative and 8 (6.1%) positive patients. Fifty-one samples were not evaluable by FISH, 35 because of technical problems and 16 due to not/weak signal. The difficulties in obtaining adequate FISH tests were observed significantly more frequently for fine-needle aspiration (FNA) and core-needle biopsy than for excisional and incisional biopsy (p = 0.009). Regarding the procedures, surgery was the most efficient, obtaining only 12.7% (10/79) of not evaluable samples for FISH, while CT guided biopsy and transbronchial biopsy (TBB) failed in 43.8% (21/48) and 41.3% (19/46) of patients respectively (p < 0.001). We observed a significant association between ALK translocation and never smoking habit (p = 0.004). Our ALK rearrangements frequency (6.1%) was similar to the reports worldwide. One of the major determinants for the ALK FISH test success is the quality of the tissue sample obtained. Copyright © 2018 Elsevier Inc. All rights reserved.

Consciousness in humans and non-human animals: recent advances and future directions

PubMed Central

Boly, Melanie; Seth, Anil K.; Wilke, Melanie; Ingmundson, Paul; Baars, Bernard; Laureys, Steven; Edelman, David B.; Tsuchiya, Naotsugu

2013-01-01

This joint article reflects the authors' personal views regarding noteworthy advances in the neuroscience of consciousness in the last 10 years, and suggests what we feel may be promising future directions. It is based on a small conference at the Samoset Resort in Rockport, Maine, USA, in July of 2012, organized by the Mind Science Foundation of San Antonio, Texas. Here, we summarize recent advances in our understanding of subjectivity in humans and other animals, including empirical, applied, technical, and conceptual insights. These include the evidence for the importance of fronto-parietal connectivity and of “top-down” processes, both of which enable information to travel across distant cortical areas effectively, as well as numerous dissociations between consciousness and cognitive functions, such as attention, in humans. In addition, we describe the development of mental imagery paradigms, which made it possible to identify covert awareness in non-responsive subjects. Non-human animal consciousness research has also witnessed substantial advances on the specific role of cortical areas and higher order thalamus for consciousness, thanks to important technological enhancements. In addition, much progress has been made in the understanding of non-vertebrate cognition relevant to possible conscious states. Finally, major advances have been made in theories of consciousness, and also in their comparison with the available evidence. Along with reviewing these findings, each author suggests future avenues for research in their field of investigation. PMID:24198791

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.

Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer.

PubMed

Gettinger, Scott N; Horn, Leora; Gandhi, Leena; Spigel, David R; Antonia, Scott J; Rizvi, Naiyer A; Powderly, John D; Heist, Rebecca S; Carvajal, Richard D; Jackman, David M; Sequist, Lecia V; Smith, David C; Leming, Philip; Carbone, David P; Pinder-Schenck, Mary C; Topalian, Suzanne L; Hodi, F Stephen; Sosman, Jeffrey A; Sznol, Mario; McDermott, David F; Pardoll, Drew M; Sankar, Vindira; Ahlers, Christoph M; Salvati, Mark; Wigginton, Jon M; Hellmann, Matthew D; Kollia, Georgia D; Gupta, Ashok K; Brahmer, Julie R

2015-06-20

Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing. © 2015 by American Society of Clinical Oncology.

The option value of innovative treatments for non-small cell lung cancer and renal cell carcinoma.

PubMed

Thornton Snider, Julia; Batt, Katharine; Wu, Yanyu; Tebeka, Mahlet Gizaw; Seabury, Seth

2017-10-01

To develop a model of the option value a therapy provides by enabling patients to live to see subsequent innovations and to apply the model to the case of nivolumab in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). A model of the option value of nivolumab in RCC and NSCLC was developed and estimated. Data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and published clinical trial results were used to estimate survival curves for metastatic cancer patients with RCC, squamous NSCLC, or nonsquamous NSCLC. To estimate the conventional value of nivolumab, survival with the pre-nivolumab standard of care was compared with survival with nivolumab assuming no future innovation. To estimate the option value of nivolumab, long-term survival trends in RCC and squamous and nonsquamous NSCLC were measured in SEER to forecast mortality improvements that nivolumab patients may live to see. Compared with the previous standard of care, nivolumab extended life expectancy by 6.3 months in RCC, 7.5 months in squamous NSCLC, and 4.5 months in nonsquamous NSCLC, according to conventional methods. Accounting for expected future mortality trends, nivolumab patients are likely to gain an additional 1.2 months in RCC, 0.4 months in squamous NSCLC, and 0.5 months in nonsquamous NSCLC. These option values correspond to 18%, 5%, and 10% of the conventional value of nivolumab, respectively. Option value is important when valuing therapies like nivolumab that extend life in a rapidly evolving area of care.

The relevance of external quality assessment for molecular testing for ALK positive non-small cell lung cancer: results from two pilot rounds show room for optimization.

PubMed

Tembuyser, Lien; Tack, Véronique; Zwaenepoel, Karen; Pauwels, Patrick; Miller, Keith; Bubendorf, Lukas; Kerr, Keith; Schuuring, Ed; Thunnissen, Erik; Dequeker, Elisabeth M C

2014-01-01

Molecular profiling should be performed on all advanced non-small cell lung cancer with non-squamous histology to allow treatment selection. Currently, this should include EGFR mutation testing and testing for ALK rearrangements. ROS1 is another emerging target. ALK rearrangement status is a critical biomarker to predict response to tyrosine kinase inhibitors such as crizotinib. To promote high quality testing in non-small cell lung cancer, the European Society of Pathology has introduced an external quality assessment scheme. This article summarizes the results of the first two pilot rounds organized in 2012-2013. Tissue microarray slides consisting of cell-lines and resection specimens were distributed with the request for routine ALK testing using IHC or FISH. Participation in ALK FISH testing included the interpretation of four digital FISH images. Data from 173 different laboratories was obtained. Results demonstrate decreased error rates in the second round for both ALK FISH and ALK IHC, although the error rates were still high and the need for external quality assessment in laboratories performing ALK testing is evident. Error rates obtained by FISH were lower than by IHC. The lowest error rates were observed for the interpretation of digital FISH images. There was a large variety in FISH enumeration practices. Based on the results from this study, recommendations for the methodology, analysis, interpretation and result reporting were issued. External quality assessment is a crucial element to improve the quality of molecular testing.

Biochip-Based Detection of KRAS Mutation in Non-Small Cell Lung Cancer

PubMed Central

Kriegshäuser, Gernot; Fabjani, Gerhild; Ziegler, Barbara; Zöchbauer-Müller, Sabine; End, Adelheid; Zeillinger, Robert

2011-01-01

This study is aimed at evaluating the potential of a biochip assay to sensitively detect KRAS mutation in DNA from non-small cell lung cancer (NSCLC) tissue samples. The assay covers 10 mutations in codons 12 and 13 of the KRAS gene, and is based on mutant-enriched PCR followed by reverse-hybridization of biotinylated amplification products to an array of sequence-specific probes immobilized on the tip of a rectangular plastic stick (biochip). Biochip hybridization identified 17 (21%) samples to carry a KRAS mutation of which 16 (33%) were adenocarcinomas and 1 (3%) was a squamous cell carcinoma. All mutations were confirmed by DNA sequencing. Using 10 ng of starting DNA, the biochip assay demonstrated a detection limit of 1% mutant sequence in a background of wild-type DNA. Our results suggest that the biochip assay is a sensitive alternative to protocols currently in use for KRAS mutation testing on limited quantity samples. PMID:22272089

Levitation force of small clearance superconductor-magnet system under non-coaxial condition

NASA Astrophysics Data System (ADS)

Xu, Jimin; Jin, Yingze; Yuan, Xiaoyang; Miao, Xusheng

2017-03-01

A novel superconducting tilting-pad bearing was proposed for the advanced research of reusable liquid hydrogen turbopump in liquid rocket. The bearing is a combination of superconducting magnetic bearing and hydrodynamic fluid-film bearing. Since the viscosity of cryogenic fuel to activate superconducting state and form hydrodynamic fluid-film is very low, bearing clearance will be very small. This study focuses on the investigation of superconducting levitation force in this kind of small clearance superconductor-magnet system. Based on Bean critical state model and three-dimensional finite element method, an analysis method is presented to obtain the levitation force under such situation. Since the complicated operational conditions and structural arrangement for application in liquid rocket, center lines of bulk superconductor and magnet rotor will usually be in non-coaxial state. Superconducting levitation forces in axial direction and radial direction under non-coaxial situation are also analyzed by the presented method.

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.

Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.

PubMed

Thatcher, Nick; Hirsch, Fred R; Luft, Alexander V; Szczesna, Aleksandra; Ciuleanu, Tudor E; Dediu, Mircea; Ramlau, Rodryg; Galiulin, Rinat K; Bálint, Beatrix; Losonczy, György; Kazarnowicz, Andrzej; Park, Keunchil; Schumann, Christian; Reck, Martin; Depenbrock, Henrik; Nanda, Shivani; Kruljac-Letunic, Anamarija; Kurek, Raffael; Paz-Ares, Luis; Socinski, Mark A

2015-07-01

and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Eli Lilly and Company. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

[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.

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

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

Chemoradiotherapy for esophageal squamous cell cancer.

PubMed

Sasaki, Yusuke; Kato, Ken

2016-09-01

Chemoradiotherapy has been clinically indicated for patients with resectable esophageal squamous cell carcinoma who refuse surgical resection and in locally advanced unresectable esophageal squamous cell carcinoma patients. Concurrent chemoradiotherapy prolongs survival than radiation therapy alone when given as definitive treatment. Therefore, chemoradiotherapy is recognized as the standard non-invasive treatment for patients with localized esophageal cancer who opt for non-surgical treatment. JCOG9906 showed promising outcomes for stage II/III ESCC patients. But there are some problems about chemoradiotherapy for esophageal squamous cell carcinoma. Late toxicities are sometimes lethal for patients who achieved complete response even after years. Salvage treatment for residual or recurrent disease is unestablished. Modified Radiation Therapy Oncology Group regimen at the dose of 50.4 Gy reduced late toxicities without reducing efficacy. Optimal timings and procedure of salvage surgery and endoscopic therapy is evaluated in JCOG0909. Strategy including salvage therapy after chemoradiotherapy should be considered at the time of starting the treatment. Targeted therapy has not shown adding effect for chemoradiotherapy for esophageal squamous cell carcinoma yet. New agents, such as immune checkpoint inhibitors, are expected to show synergistic effect with chemoradiotherapy for esophageal squamous cell carcinoma. Further investigation is needed. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

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

Advanced dynamical models for very well observed asteroids : perturbations from small bodies, relativity, non - gravitational effects.

NASA Astrophysics Data System (ADS)

Bernardi, Fabrizio; Farnocchia, Davide; Milani, Andrea

2012-08-01

The availability of radar data and high precision optical observations has increased the number of objects with a very well constrained orbit, especially for those objects with a long observed arc. In these cases, the uncertainty of orbital predictions is often dominated by the inaccuracy of the dynamical model. However, the motion of small solar system bodies poses a serious challenge in modeling their dynamics. In particular, for those objects with a chaotic motion small differences in the model are amplified with propagation. Thus, we need to take into account small perturbations too, especially for long - term prediction. An improved dynamical model is relevant in several applications such as assessing the risk of an impact between an asteroid and the Earth. The N - body model describing the motion of a small solar system body includes the Newtonian attraction of the planets. The contribution o f other perturbing bodies has to be taken into account. We propose to include the Moon, two dwarf planets (Ceres and Pluto) and fifteen asteroids (Pallas, Vesta, Juno, Metis, Hygiea, Eunomia, Psyche, Amphitrite, Euphrosyne, Europa, Cybele, Sylvia, Davida, Herculina, Interamnia). The next step is the introduction of the relativity terms due to both the Sun and the planets . Despite their small magnitude, planetary relativistic terms turn out to be relevant for objects experiencing close approaches with a planet. Finally, we discuss non - gravitational effects such as solar radiation pressure and the Yarkovsky effect. In particular, the latter acts as a tiny but secular semimajor axis drift that may decisively drive long - term predictions. These non - gravitational effects are difficult to model as they depend on object ’ s physical properties that are typically unknown. However, a very well observed object can have an orbit precise enough to allow the determination of the parameters defining a non - gravitational perturbation and thus the modeling of the corresponding

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.

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.

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.

The clinicopathological and survival differences between never and ever smokers with non-small cell lung cancer.

PubMed

Muallaoglu, Sadik; Karadeniz, Cemile; Mertsoylu, Huseyin; Ayberk Besen, Ali; Sezer, Ahmet; Murat Sedef, Ali; Kose, Fatih; Ozyilkan, Ozgur

2014-01-01

Cigarette smoking was regarded as the most important carcinogenic factor of lung cancer, yet in recent years lung cancer in never-smokers is an increasingly prominent public health issue. The aim of this study was to assess the epidemiological and clinicopathological characteristics of never-smoker patients with non small cell lung cancer (NSCLC), focusing on clinical risk factors and survival. We retrospectively analyzed 290 NSCLC patients who presented between 2006 and 2011. Differences in clinical features and survival between never- and ever- smoker patients were analyzed. Student's t-test and Mann-Whitney U-test were used to assess the significance of the variables between the groups. Survival curves were calculated using Kaplan-Meier method. Hazard ratio (HR) for death and its 95% confidence interval (CI) were calculated by Cox regression analysis. There were 243 (83.8%) ever-smokers and 47 (16.2%) never-smokers. In never-smokers females predominated (80.9%) as well as patients with adenocarcinomas (78.7%). At the time of analysis 143 (49.3%) patients had died. The 5-year overall survival (OS) rates were not significantly different between never- and ever-smokers (p=0.410) . The median OS of all patients was 26 months (95% CI: 16.8-35.2). The median OS was 23 months (95% CI: 11.8- 34.2) for never-smokers and 30 months ∥95% CI: 19.7-40.3) for ever-smokers (p=0.410). Never-smokers tended to present with more advanced disease than ever-smokers (p<0.004) and also with more advanced age (p<0.001). The HR for death increased with poorer Eastern Cooperative Oncology Group ( ECOG ) performance status (PS) (ECOG 2=3), advanced stage (stage 3=4) and untreated patients. Slightly lower risk for death was registered in patients with adenocarcinoma vs those with squamous cell carcinoma (SCC). Although no difference in survival was seen, definite epidemiologic differences do exist between never- smokers and ever-smokers patients with NSCLC. Future efforts should focus on

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.

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.

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

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.

EGFR Mutation Testing in Patients with Advanced Non-Small Cell Lung Cancer: A Comprehensive Evaluation of Real-World Practice in an East Asian Tertiary Hospital

PubMed Central

Cho, Juhee; Rampal, Sanjay; Han, Joungho; Parasuraman, Bhash; Guallar, Eliseo; Lee, Genehee; Lee, Jeeyun; Shim, Young Mog

2013-01-01

Introduction Guidelines for management of non-small cell lung cancer (NSCLC) strongly recommend EGFR mutation testing. These recommendations are particularly relevant in Asians that have higher EGFR mutation prevalence. This study aims to explore current testing practices, logistics of testing, types of EGFR mutation, and prevalence of EGFR mutations in patients with advanced NSCLC in a large comprehensive cancer center in Korea. Methods Our retrospective cohort included 1,503 NSCLC patients aged ≥18 years, with stage IIIB/IV disease, who attended the Samsung Medical Center in Seoul, Korea, from January 2007 through July 2010. Trained oncology nurses reviewed and abstracted data from electronic medical records. Results This cohort had a mean age (SD) of 59.6 (11.1) years, 62.7% were males, and 52.9% never-smokers. The most common NSCLC histological types were adenocarcinoma (70.5%) and squamous cell carcinoma (18.0%). Overall, 39.5% of patients were tested for EGFR mutations. The proportion of patients undergoing EGFR testing during January 2007 through July 2008, August 2008 through September 2009, and October 2009 through July 2010 were 23.3%, 38.3%, and 63.5%, respectively (P<0.001). The median time elapsed between cancer diagnoses and receiving EGFR testing results was 21 days. EGFR testing was most frequently ordered by oncologists (57.7%), pulmonologists (31.9%), and thoracic surgeons (6.6%). EGFR testing was more commonly requested for women, younger patients, stage IV disease, non-smokers, and adenocarcinoma histology. Of 586 cases successfully tested for EGFR mutations, 209 (35.7%) were positive, including 118 cases with exon 19 deletions and 62 with L858R mutations. EGFR mutation positive patients were more likely to be female, never-smokers, never-drinkers and to have adenocarcinoma. Conclusions In a large cancer center in Korea, the proportion of EGFR testing increased from 2007 through 2010. The high frequency of EGFR mutation positive cases warrants

EGFR mutation testing in patients with advanced non-small cell lung cancer: a comprehensive evaluation of real-world practice in an East Asian tertiary hospital.

PubMed

Choi, Yoon-La; Sun, Jong-Mu; Cho, Juhee; Rampal, Sanjay; Han, Joungho; Parasuraman, Bhash; Guallar, Eliseo; Lee, Genehee; Lee, Jeeyun; Shim, Young Mog

2013-01-01

Guidelines for management of non-small cell lung cancer (NSCLC) strongly recommend EGFR mutation testing. These recommendations are particularly relevant in Asians that have higher EGFR mutation prevalence. This study aims to explore current testing practices, logistics of testing, types of EGFR mutation, and prevalence of EGFR mutations in patients with advanced NSCLC in a large comprehensive cancer center in Korea. Our retrospective cohort included 1,503 NSCLC patients aged ≥18 years, with stage IIIB/IV disease, who attended the Samsung Medical Center in Seoul, Korea, from January 2007 through July 2010. Trained oncology nurses reviewed and abstracted data from electronic medical records. This cohort had a mean age (SD) of 59.6 (11.1) years, 62.7% were males, and 52.9% never-smokers. The most common NSCLC histological types were adenocarcinoma (70.5%) and squamous cell carcinoma (18.0%). Overall, 39.5% of patients were tested for EGFR mutations. The proportion of patients undergoing EGFR testing during January 2007 through July 2008, August 2008 through September 2009, and October 2009 through July 2010 were 23.3%, 38.3%, and 63.5%, respectively (P<0.001). The median time elapsed between cancer diagnoses and receiving EGFR testing results was 21 days. EGFR testing was most frequently ordered by oncologists (57.7%), pulmonologists (31.9%), and thoracic surgeons (6.6%). EGFR testing was more commonly requested for women, younger patients, stage IV disease, non-smokers, and adenocarcinoma histology. Of 586 cases successfully tested for EGFR mutations, 209 (35.7%) were positive, including 118 cases with exon 19 deletions and 62 with L858R mutations. EGFR mutation positive patients were more likely to be female, never-smokers, never-drinkers and to have adenocarcinoma. In a large cancer center in Korea, the proportion of EGFR testing increased from 2007 through 2010. The high frequency of EGFR mutation positive cases warrants the need for generalized testing in

[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.

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.

New Perspectives in the Pharmacological Treatment of Non-Melanoma Skin Cancer.

PubMed

Savoia, Paola; Cremona, Ottavio; Fava, Paolo

2016-01-01

Non-melanoma skin cancers are the most common malignancy in humans, with a basal/squamous cell carcinoma incidence ratio of 4:1 in immunocompetent patients. Basal cell carcinoma rarely metastasizes but commonly causes significant local tissue destruction and disfigurement, whereas squamous cell carcinoma is associated with a substantial risk of recurrence and metastasis; the prognosis in metastatic patients is poor. Surgical approaches give a cure rate greater than 90% if appropriately applied, on the basis of the characteristics of the primary tumors and of the patients, but in selected cases, medical treatment (5-fluorouracil, imiquimod, diclofenac and, more recently, ingenol mebutate) is preferable to invasive procedures and provides a good chance of cure, with generally excellent cosmetic outcomes. In case of advanced and metastatic non-melanoma skin cancer, newly developed molecularly targeted therapy represents a reasonably promising alternative to classical cytostatics. In particular, the monoclonal antibody cetuximab, directed against the epidermal growth factor receptor, is effective and well-tolerated in squamous cell carcinoma patients. Moreover, the recent identification of mutations in the Hedgehog signaling pathway in basal cell carcinoma lead to the development of the smoothened Hedgehog pathway inhibitor vismodegib, that was recently approved for the treatment of locally advanced or metastatic basal cell carcinoma. In this review we provide an overview of the molecular pathways involved in NMSC pathogenesis, focusing on the mechanisms of action, indications, efficacy, side effects and contraindications of new medical treatments that specifically tackle molecular targets of these pathways.

[Non-small cell lung cancer. Subtyping and predictive molecular marker investigations in cytology].

PubMed

Savic, S; Bihl, M P; Bubendorf, L

2012-07-01

The diagnosis and treatment of non-small cell lung cancer (NSCLC) have been revolutionized over the last few years. Requirements for cytopathologists in lung cancer diagnosis have therefore changed. The general diagnostic category of NSLC is no longer sufficient. In addition cytological specimens need to be evaluated for adequacy regarding predictive marker analyses. Accurate NSCLC subtyping with a distinction of adenocarcinoma from squamous cell carcinoma is crucial for treatment decisions as the subtype will decide on the chemotherapy regimen and the choice of predictive marker analyses for targeted treatment. In the majority of cases, the subtype can be diagnosed by morphology alone. Cytology is equally well suited as biopsy specimens for the assessment of molecular predictive markers. The best results are achieved when both cytology and biopsy specimens are compared to choose the most appropriate specimen for morphological subtyping and molecular testing. In this paper, we discuss special issues of NSCLC subtyping and currently recommended predictive molecular marker analyses.

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

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

The Relevance of External Quality Assessment for Molecular Testing for ALK Positive Non-Small Cell Lung Cancer: Results from Two Pilot Rounds Show Room for Optimization

PubMed Central

Tembuyser, Lien; Tack, Véronique; Zwaenepoel, Karen; Pauwels, Patrick; Miller, Keith; Bubendorf, Lukas; Kerr, Keith; Schuuring, Ed; Thunnissen, Erik; Dequeker, Elisabeth M. C.

2014-01-01

Background and Purpose Molecular profiling should be performed on all advanced non-small cell lung cancer with non-squamous histology to allow treatment selection. Currently, this should include EGFR mutation testing and testing for ALK rearrangements. ROS1 is another emerging target. ALK rearrangement status is a critical biomarker to predict response to tyrosine kinase inhibitors such as crizotinib. To promote high quality testing in non-small cell lung cancer, the European Society of Pathology has introduced an external quality assessment scheme. This article summarizes the results of the first two pilot rounds organized in 2012–2013. Materials and Methods Tissue microarray slides consisting of cell-lines and resection specimens were distributed with the request for routine ALK testing using IHC or FISH. Participation in ALK FISH testing included the interpretation of four digital FISH images. Results Data from 173 different laboratories was obtained. Results demonstrate decreased error rates in the second round for both ALK FISH and ALK IHC, although the error rates were still high and the need for external quality assessment in laboratories performing ALK testing is evident. Error rates obtained by FISH were lower than by IHC. The lowest error rates were observed for the interpretation of digital FISH images. Conclusion There was a large variety in FISH enumeration practices. Based on the results from this study, recommendations for the methodology, analysis, interpretation and result reporting were issued. External quality assessment is a crucial element to improve the quality of molecular testing. PMID:25386659

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.

Alterations of immune response of non-small cell lung cancer with Azacytidine

PubMed Central

Easwaran, Hariharan; Mohammad, Helai P.; Vendetti, Frank; VanCriekinge, Wim; DeMeyer, Tim; Du, Zhengzong; Parsana, Princy; Rodgers, Kristen; Yen, Ray-Whay; Zahnow, Cynthia A.; Taube, Janis M.; Brahmer, Julie R.; Tykodi, Scott S.; Easton, Keith; Carvajal, Richard D.; Jones, Peter A.; Laird, Peter W.; Weisenberger, Daniel J.; Tsai, Salina; Juergens, Rosalyn A.; Topalian, Suzanne L.; Rudin, Charles M.; Brock, Malcolm V.; Pardoll, Drew; Baylin, Stephen B.

2013-01-01

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA – Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints – in particular the PD-1/PD-L1 pathway – may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade. PMID:24162015

Silencing of long non-coding RNA CCAT2 depressed malignancy of oral squamous cell carcinoma via Wnt/β-catenin pathway.

PubMed

Ma, Yuji; Hu, Xuanhao; Shang, Chao; Zhong, Ming; Guo, Yan

2017-07-01

Oral squamous cell carcinoma is a common and lethal malignancy affecting the head and neck region. CCAT2 (colon cancer-associated transcript 2) gene is affiliated with long non-coding RNAs, which are often found to have important regulatory roles in cancers. This study aims to assess the expression and clinical significance of CCAT2 gene, identify its malignant biological behaviors, and explore the possible mechanisms in oral squamous cell carcinoma. CCAT2 expression was detected by quantitative real-time polymerase chain reaction, and its relationship with clinical factors was assayed using the Kaplan-Meier survival curve. The biological behaviors of CCAT2 and its potential mechanisms in oral squamous cell carcinoma were explored by the combined use of CCAT2 knockdown technology and the Wnt/β-catenin pathway agonist lithium chloride (LiCl). Our results showed that CCAT2 functioning as a potential oncogene was upregulated in oral squamous cell carcinoma. CCAT2 with high expression level was correlated with poor differentiation, higher T stage, and clinical stage, which made CCAT2 to be a prognostic biomarker in oral squamous cell carcinoma. LiCl-activated Wnt/β-catenin signaling pathway could partly restore the CCAT2-mediated malignant biological behaviors of oral squamous cell carcinoma cells by suppressing β-catenin, CCND1, and MYC and activating glycogen synthase kinase 3 beta expression. These findings might assist in the discovery of novel potential diagnostic and therapeutic target for oral squamous cell carcinoma, thereby improve the effects of clinical treatment in patients.

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

Lymphatic vessel invasion and lymph node metastasis in patients with clinical stage I non-small cell lung cancer.

PubMed

Kang, Du-Young; Lee, Sungsoo

2014-09-01

The aim of this study was to investigate the association between the presence of lymphatic vessel invasion (LVI) in primary tumors and lymph node (LN) metastasis in clinical stage I non-small cell lung cancer (NSCLC) patients. A total of 76 patients who underwent complete resection for clinical stage I adenocarcinoma and squamous cell carcinoma were retrospectively examined. Tumors consisted of 51 cases of adenocarcinoma and 25 cases of squamous cell carcinoma as determined by histology. LN metastasis was detected in 24.4% (19/76) of patients. Factors associated with LN metastasis on univariate analysis included LVI (p < 0.001) and increased tumor dimensions (p < 0.05). Binary logistic regression analysis showed that the presence of LVI (p < 0.001) was the only predictor of LN metastasis. LVI is significantly associated with LN metastasis in patients with clinical stage I NSCLC. These findings may be helpful in determining the most appropriate operative strategy for patients if preoperative detection of LVI becomes feasible. Georg Thieme Verlag KG Stuttgart · New York.

Adherence of Non-O157 Shiga Toxin–Producing Escherichia coli to Bovine Recto-anal Junction Squamous Epithelial Cells Appears to Be Mediated by Mechanisms Distinct from Those Used by O157

PubMed Central

Hovde, Carolyn J.; John, Manohar

2013-01-01

Abstract This study presents evidence that the pattern (diffuse or aggregative) of adherence of clinically relevant non-O157 Shiga toxin–producing Escherichia coli (STEC) to bovine recto-anal junction squamous epithelial cells is similar to that of E. coli O157, although the mechanisms of adherence appear to be distinct. Our results further suggest that novel adhesins, and not Intimin, are likely involved in non-O157 STEC adherence to bovine recto-anal junction squamous epithelial cells. These findings have important implications for the development of efficacious modalities for blocking adherence of non-O157 STEC to bovine gastrointestinal epithelial cells. PMID:23510495

[Analysis of tissue-specific differentially methylated genes with differential gene expression in non-small cell lung cancer].

PubMed

Yin, L G; Zou, Z Q; Zhao, H Y; Zhang, C L; Shen, J G; Qi, L; Qi, M; Xue, Z Q

2014-01-01

Adenocarcinoma (ADC) and squamous cell carcinomas (SCC) are two subtypes of non-small cell lung carcinomas which are regarded as the leading cause of cancer-related malignancy worldwide. The aim of this study is to detect the differentially methylated loci (DMLs) and differentially methylated genes (DMGs) of these two tumor sets, and then to illustrate the different expression level of specific methylated genes. Using TCGA database and Illumina HumanMethylation 27 arrays, we first screened the DMGs and DMLs in tumor samples. Then, we explored the BiologicalProcess terms of hypermethylated and hypomethylated genes using Functional Gene Ontology (GO) catalogues. Hypermethylation intensively occurred in CpG-island, whereas hypomethylation was located in non-CpG-island. Most SCC and ADC hypermethylated genes involved GO function of DNA dependenit regulation of transcription, and hypomethylated genes mainly 'enriched in the term of immune responses. Additionally, the expression level of specific differentially methylated genesis distinctbetween ADC and SCC. It is concluded that ADC and SCC have different methylated status that might play an important role in carcinogenesis.

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

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

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.

[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.

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.

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.

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

25 CFR 170.615 - Can a tribe receive advance payments for non-construction activities?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Can a tribe receive advance payments for non-construction... Agreements Under Isdeaa § 170.615 Can a tribe receive advance payments for non-construction activities? Yes. BIA must make advance payments to a tribe for non-construction activities under 25 U.S.C. 450l for...

25 CFR 170.615 - Can a tribe receive advance payments for non-construction activities?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 25 Indians 1 2011-04-01 2011-04-01 false Can a tribe receive advance payments for non-construction... Agreements Under Isdeaa § 170.615 Can a tribe receive advance payments for non-construction activities? Yes. BIA must make advance payments to a tribe for non-construction activities under 25 U.S.C. 450l for...

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.

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

Comparison of oral microbiota in tumor and non-tumor tissues of patients with oral squamous cell carcinoma

PubMed Central

2012-01-01

Background Bacterial infections have been linked to malignancies due to their ability to induce chronic inflammation. We investigated the association of oral bacteria in oral squamous cell carcinoma (OSCC/tumor) tissues and compared with adjacent non-tumor mucosa sampled 5 cm distant from the same patient (n = 10). By using culture-independent 16S rRNA approaches, denaturing gradient gel electrophoresis (DGGE) and cloning and sequencing, we assessed the total bacterial diversity in these clinical samples. Results DGGE fingerprints showed variations in the band intensity profiles within non-tumor and tumor tissues of the same patient and among the two groups. The clonal analysis indicated that from a total of 1200 sequences characterized, 80 bacterial species/phylotypes were detected representing six phyla, Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, Actinobacteria and uncultivated TM7 in non-tumor and tumor libraries. In combined library, 12 classes, 16 order, 26 families and 40 genera were observed. Bacterial species, Streptococcus sp. oral taxon 058, Peptostreptococcus stomatis, Streptococcus salivarius, Streptococcus gordonii, Gemella haemolysans, Gemella morbillorum, Johnsonella ignava and Streptococcus parasanguinis I were highly associated with tumor site where as Granulicatella adiacens was prevalent at non-tumor site. Streptococcus intermedius was present in 70% of both non-tumor and tumor sites. Conclusions The underlying changes in the bacterial diversity in the oral mucosal tissues from non-tumor and tumor sites of OSCC subjects indicated a shift in bacterial colonization. These most prevalent or unique bacterial species/phylotypes present in tumor tissues may be associated with OSCC and needs to be further investigated with a larger sample size. PMID:22817758

Expression of TMPRSS4 in non-small cell lung cancer and its modulation by hypoxia

PubMed Central

NGUYEN, TRI-HUNG; WEBER, WILLIAM; HAVARI, EVIS; CONNORS, TIMOTHY; BAGLEY, REBECCA G.; McLAREN, RAJASHREE; NAMBIAR, PRASHANT R.; MADDEN, STEPHEN L.; TEICHER, BEVERLY A.; ROBERTS, BRUCE; KAPLAN, JOHANNE; SHANKARA, SRINIVAS

2012-01-01

Overexpression of TMPRSS4, a cell surface-associated transmembrane serine protease, has been reported in pancreatic, colorectal and thyroid cancers, and has been implicated in tumor cell migration and metastasis. Few reports have investigated both TMPRSS4 gene expression levels and the protein products. In this study, quantitative RT-PCR and protein staining were used to assess TMPRSS4 expression in primary non-small cell lung carcinoma (NSCLC) tissues and in lung tumor cell lines. At the transcriptional level, TMPRSS4 message was significantly elevated in the majority of human squamous cell and adenocarcinomas compared with normal lung tissues. Staining of over 100 NSCLC primary tumor and normal specimens with rabbit polyclonal anti-TMPRSS4 antibodies confirmed expression at the protein level in both squamous cell and adenocarcinomas with little or no staining in normal lung tissues. Human lung tumor cell lines expressed varying levels of TMPRSS4 mRNA in vitro. Interestingly, tumor cell lines with high levels of TMPRSS4 mRNA failed to show detectable TMPRSS4 protein by either immunoblotting or flow cytometry. However, protein levels were increased under hypoxic culture conditions suggesting that hypoxia within the tumor microenvironment may upregulate TMPRSS4 protein expression in vivo. This was supported by the observation of TMPRSS4 protein in xenograft tumors derived from the cell lines. In addition, staining of human squamous cell carcinoma samples for carbonic anhydrase IX (CAIX), a hypoxia marker, showed TMPRSS4 positive cells adjacent to CAIX positive cells. Overall, these results indicate that the cancer-associated TMPRSS4 protein is overexpressed in NSCLC and may represent a potential therapeutic target. PMID:22692880

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

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

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.

Immune checkpoint inhibitors for non-small-cell lung cancer: does that represent a 'new frontier'?

PubMed

Pilotto, Sara; Kinspergher, Stefania; Peretti, Umberto; Calio, Anna; Carbognin, Luisa; Ferrara, Roberto; Brunelli, Matteo; Chilosi, Marco; Tortora, Giampaolo; Bria, Emilio

2015-01-01

Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective 'magic bullet', able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.

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.

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

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

PubMed

Li, Yafang; Xiao, Xiangjun; Han, Younghun; Gorlova, Olga; Qian, David; Leighl, Natasha; Johansen, Jakob S; Barnett, Matt; Chen, Chu; Goodman, Gary; Cox, Angela; Taylor, Fiona; Woll, Penella; Wichmann, H-Erich; Manz, Judith; Muley, Thomas; Risch, Angela; Rosenberger, Albert; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Houlston, Richard; Soler Artigas, María; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Liu, Geoffrey; Bojesen, Stig E; Wu, Xifeng; Marchand, Loic Le; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Bertazzi, Pier Alberto; Pesatori, Angela C; Christiani, David C; Caporaso, Neil; Johansson, Mattias; McKay, James D; Brennan, Paul; Hung, Rayjean J; Amos, Christopher I

2018-03-08

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

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.

CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases.

PubMed

Mir, Hina; Singh, Rajesh; Kloecker, Goetz H; Lillard, James W; Singh, Shailesh

2015-04-30

Lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide regardless of the gender. High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined. Here, we present evidence that chemokine receptor CXCR6 and its only natural ligand, CXCL16, are significantly expressed by non-small cell lung cancer (NSCLC) and are involved in the pathobiology of LuCa. CXCR6 expression was significantly higher in two subtypes of NSCLC (adenocarcinomas-ACs and squamous cell carcinoma-SCCs) as compared to non-neoplastic tissue. Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls. Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients. Biological significance of this axis was validated using SCC and AC cell lines. Expression of CXCR6 was higher in AC cells, which also showed higher migratory and invasive potential than SCC. Differences in migratory and invasive potential between AC and SCC were due to differential expression of metalloproteinases following CXCL16 stimulation. Hence, our findings suggest clinical and biological significance of CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target.

CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases

PubMed Central

Mir, Hina; Singh, Rajesh; Kloecker, Goetz H.; Lillard, James W.; Singh, Shailesh

2015-01-01

Lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide regardless of the gender. High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined. Here, we present evidence that chemokine receptor CXCR6 and its only natural ligand, CXCL16, are significantly expressed by non-small cell lung cancer (NSCLC) and are involved in the pathobiology of LuCa. CXCR6 expression was significantly higher in two subtypes of NSCLC (adenocarcinomas-ACs and squamous cell carcinoma-SCCs) as compared to non-neoplastic tissue. Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls. Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients. Biological significance of this axis was validated using SCC and AC cell lines. Expression of CXCR6 was higher in AC cells, which also showed higher migratory and invasive potential than SCC. Differences in migratory and invasive potential between AC and SCC were due to differential expression of metalloproteinases following CXCL16 stimulation. Hence, our findings suggest clinical and biological significance of CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target. PMID:25888629

Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies

PubMed Central

Bath-Hextall, Fiona; Perkins, William; Stanton, Wendy; Leonardi-Bee, Jo

2013-01-01

Objectives To assess the effects of treatments for non-metastatic invasive squamous cell carcinoma (SCC) of the skin using evidence from observational studies, given the paucity of evidence from randomised controlled trials. Design Systematic review of observational studies. Data sources Medline, Embase, to December 2012. Review methods Observational studies of interventions for primary, non-metastatic, invasive, SCC of the skin that reported recurrence during follow-up, quality of life, initial response to treatment, adverse events, cosmetic appearance, or death from disease. Studies were excluded if data for primary cutaneous SCC was not separable from other data. Data were extracted independently by two reviewers. Meta-analysis was performed where appropriate using a random effects model to estimate the pooled proportion of an event with 95% confidence intervals. Results 118 publications were included, covering seven treatment modalities. Pooled estimates of recurrence of SCCs were lowest after cryotherapy (0.8% (95% confidence interval 0.1% to 2%)) and curettage and electrodesiccation (1.7% (0.5% to 3.4%)), but most treated SCCs were small, low risk lesions. After Mohs micrographic surgery, the pooled estimate of local recurrence during variable follow-up periods from 10 studies was 3.0% (2.2% to 3.9%), which was non-significantly lower than the pooled average local recurrence of 5.4% (2.5% to 9.1%) after standard surgical excision (12 studies), and 6.4% (3.0% to 11.0%) after external radiotherapy (7 studies). After an apparently successful initial response of SCCs to photodynamic therapy, pooled average recurrence of 26.4% (12.3% to 43.7%; 8 studies) was significantly higher than other treatments. Evidence was limited for laser treatment (1 study) and for topical and systemic treatments (mostly single case reports or small non-comparative series with limited follow-up). Conclusions Many observational studies have looked at different treatment modalities for

Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.

PubMed

Lansbury, Louise; Bath-Hextall, Fiona; Perkins, William; Stanton, Wendy; Leonardi-Bee, Jo

2013-11-04

To assess the effects of treatments for non-metastatic invasive squamous cell carcinoma (SCC) of the skin using evidence from observational studies, given the paucity of evidence from randomised controlled trials. Systematic review of observational studies. Medline, Embase, to December 2012. Observational studies of interventions for primary, non-metastatic, invasive, SCC of the skin that reported recurrence during follow-up, quality of life, initial response to treatment, adverse events, cosmetic appearance, or death from disease. Studies were excluded if data for primary cutaneous SCC was not separable from other data. Data were extracted independently by two reviewers. Meta-analysis was performed where appropriate using a random effects model to estimate the pooled proportion of an event with 95% confidence intervals. 118 publications were included, covering seven treatment modalities. Pooled estimates of recurrence of SCCs were lowest after cryotherapy (0.8% (95% confidence interval 0.1% to 2%)) and curettage and electrodesiccation (1.7% (0.5% to 3.4%)), but most treated SCCs were small, low risk lesions. After Mohs micrographic surgery, the pooled estimate of local recurrence during variable follow-up periods from 10 studies was 3.0% (2.2% to 3.9%), which was non-significantly lower than the pooled average local recurrence of 5.4% (2.5% to 9.1%) after standard surgical excision (12 studies), and 6.4% (3.0% to 11.0%) after external radiotherapy (7 studies). After an apparently successful initial response of SCCs to photodynamic therapy, pooled average recurrence of 26.4% (12.3% to 43.7%; 8 studies) was significantly higher than other treatments. Evidence was limited for laser treatment (1 study) and for topical and systemic treatments (mostly single case reports or small non-comparative series with limited follow-up). Many observational studies have looked at different treatment modalities for SCC, but the evidence base for the effectiveness of these

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.

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.

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

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

An advanced algorithm for deformation estimation in non-urban areas

NASA Astrophysics Data System (ADS)

Goel, Kanika; Adam, Nico

2012-09-01

This paper presents an advanced differential SAR interferometry stacking algorithm for high resolution deformation monitoring in non-urban areas with a focus on distributed scatterers (DSs). Techniques such as the Small Baseline Subset Algorithm (SBAS) have been proposed for processing DSs. SBAS makes use of small baseline differential interferogram subsets. Singular value decomposition (SVD), i.e. L2 norm minimization is applied to link independent subsets separated by large baselines. However, the interferograms used in SBAS are multilooked using a rectangular window to reduce phase noise caused for instance by temporal decorrelation, resulting in a loss of resolution and the superposition of topography and deformation signals from different objects. Moreover, these have to be individually phase unwrapped and this can be especially difficult in natural terrains. An improved deformation estimation technique is presented here which exploits high resolution SAR data and is suitable for rural areas. The implemented method makes use of small baseline differential interferograms and incorporates an object adaptive spatial phase filtering and residual topography removal for an accurate phase and coherence estimation, while preserving the high resolution provided by modern satellites. This is followed by retrieval of deformation via the SBAS approach, wherein, the phase inversion is performed using an L1 norm minimization which is more robust to the typical phase unwrapping errors encountered in non-urban areas. Meter resolution TerraSAR-X data of an underground gas storage reservoir in Germany is used for demonstrating the effectiveness of this newly developed technique in rural areas.

Ph 1 Study in Subjects With Tumors Requiring Arginine to Assess ADI-PEG 20 With Pemetrexed and Cisplatin

ClinicalTrials.gov

2018-02-21

Pleural Mesothelioma Malignant Advanced; Peritoneal Mesothelioma Malignant Advanced; Non-squamous Non-small Cell Lung Carcinoma Stage IIIB/IV (NSCLC); Metastatic Uveal Melanoma; Hepatocellular Carcinoma (HCC); Glioma; Sarcomatoid Cancers

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.

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

Fabrication of small-scale structures with non-planar features

DOEpatents

Burckel, David B.; Ten Eyck, Gregory A.

2015-11-19

The fabrication of small-scale structures is disclosed. A unit-cell of a small-scale structure with non-planar features is fabricated by forming a membrane on a suitable material. A pattern is formed in the membrane and a portion of the substrate underneath the membrane is removed to form a cavity. Resonators are then directionally deposited on the wall or sides of the cavity. The cavity may be rotated during deposition to form closed-loop resonators. The resonators may be non-planar. The unit-cells can be formed in a layer that includes an array of unit-cells.

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

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.

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.

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

Developing a radiomics framework for classifying non-small cell lung carcinoma subtypes

NASA Astrophysics Data System (ADS)

Yu, Dongdong; Zang, Yali; Dong, Di; Zhou, Mu; Gevaert, Olivier; Fang, Mengjie; Shi, Jingyun; Tian, Jie

2017-03-01

Patient-targeted treatment of non-small cell lung carcinoma (NSCLC) has been well documented according to the histologic subtypes over the past decade. In parallel, recent development of quantitative image biomarkers has recently been highlighted as important diagnostic tools to facilitate histological subtype classification. In this study, we present a radiomics analysis that classifies the adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). We extract 52-dimensional, CT-based features (7 statistical features and 45 image texture features) to represent each nodule. We evaluate our approach on a clinical dataset including 324 ADCs and 110 SqCCs patients with CT image scans. Classification of these features is performed with four different machine-learning classifiers including Support Vector Machines with Radial Basis Function kernel (RBF-SVM), Random forest (RF), K-nearest neighbor (KNN), and RUSBoost algorithms. To improve the classifiers' performance, optimal feature subset is selected from the original feature set by using an iterative forward inclusion and backward eliminating algorithm. Extensive experimental results demonstrate that radiomics features achieve encouraging classification results on both complete feature set (AUC=0.89) and optimal feature subset (AUC=0.91).

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.

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

Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma

PubMed Central

Carbone, Michele; Shimizu, David; Napolitano, Andrea; Tanji, Mika; Pass, Harvey I.; Yang, Haining; Pastorino, Sandra

2016-01-01

The differential diagnosis between pleural malignant mesothelioma (MM) and lung cancer is often challenging. Immunohistochemical (IHC) stains used to distinguish these malignancies include markers that are most often positive in MM and less frequently positive in carcinomas, and vice versa. However, in about 10–20% of the cases, the IHC results can be confusing and inconclusive, and novel markers are sought to increase the diagnostic accuracy. We stained 45 non-small cell lung cancer samples (32 adenocarcinomas and 13 squamous cell carcinomas) with a monoclonal antibody for BRCA1-associated protein 1 (BAP1) and also with an IHC panel we routinely use to help differentiate MM from carcinomas, which include, calretinin, Wilms Tumor 1, cytokeratin 5, podoplanin D2-40, pankeratin CAM5.2, thyroid transcription factor 1, Napsin-A, and p63. Nuclear BAP1 expression was also analyzed in 35 MM biopsies. All 45 non-small cell lung cancer biopsies stained positive for nuclear BAP1, whereas 22/35 (63%) MM biopsies lacked nuclear BAP1 staining, consistent with previous data. Lack of BAP1 nuclear staining was associated with MM (two-tailed Fisher's Exact Test, P = 5.4 × 10−11). Focal BAP1 staining was observed in a subset of samples, suggesting polyclonality. Diagnostic accuracy of other classical IHC markers was in agreement with previous studies. Our study indicated that absence of nuclear BAP1 stain helps differentiate MM from lung carcinomas. We suggest that BAP1 staining should be added to the IHC panel that is currently used to distinguish these malignancies. PMID:27447750

Oral cavity squamous cell carcinoma - characteristics and survival in aboriginal and non-aboriginal Western australians.

PubMed

Frydrych, A M; Slack-Smith, L M; Parsons, R; Threlfall, T

2014-01-01

Squamous cell carcinoma (SCC) is the most common type of malignancy affecting the oral cavity. While exposures to main risk factors for oral SCC such as smoking and alcohol use are higher amongst the Aboriginal people, little is known about oral cancer in this population. This study aimed to describe characteristics and survival of oral SCC in Aboriginal and non-Aboriginal Western Australians. All primary oral SCC cases reported to the Western Australian Cancer Registry (WACR) between 1990 and 1999 were analysed with respect to person characteristics including: date of birth, sex and indigenous status; and disease characteristics including: date of biopsy, disease stage and site as well as date of recurrence and date of death. Exclusion criteria included diagnosis not based on incisional or excisional biopsy, diagnosis other than oral SCC or a history of another malignant neoplasm. Aboriginal individuals were more likely to reside in rural areas. No statistically significant differences in oral SCC characteristics and survival were noted between Aboriginal and non-Aboriginal Western Australians. This study provides new information on person and disease characteristics of Aboriginal Western Australians diagnosed with oral SCC.

Advances in non-dopaminergic treatments for Parkinson's disease

PubMed Central

Stayte, Sandy; Vissel, Bryce

2014-01-01

Since the 1960's treatments for Parkinson's disease (PD) have traditionally been directed to restore or replace dopamine, with L-Dopa being the gold standard. However, chronic L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has resulted in extensive efforts to develop new therapies that work in ways other than restoring or replacing dopamine. Here we describe newly emerging non-dopaminergic therapeutic strategies for PD, including drugs targeting adenosine, glutamate, adrenergic, and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron chelators, anti-inflammatories, neurotrophic factors, and gene therapies. We provide a detailed account of their success in animal models and their translation to human clinical trials. We then consider how advances in understanding the mechanisms of PD, genetics, the possibility that PD may consist of multiple disease states, understanding of the etiology of PD in non-dopaminergic regions as well as advances in clinical trial design will be essential for ongoing advances. We conclude that despite the challenges ahead, patients have much cause for optimism that novel therapeutics that offer better disease management and/or which slow disease progression are inevitable. PMID:24904259

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 ...

Factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

PubMed

Tasneem, Abbas Ali; Luck, Nasir Hassan; Majid, Zain

2018-04-01

Introduction To determine the factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methodology All patients aged >18 years and having a fatty liver on abdominal ultrasound (US), presenting from January 2011 to January 2017, were included. A liver biopsy was performed on all the patients. Results Of 96 patients undergoing liver biopsy for non-alcoholic fatty liver disease (NAFLD), 76 (79.2%) were men. On liver US, diffuse fatty liver (DFL) was noted in 68 (70.8%) patients. Liver biopsy showed non-alcoholic steatohepatitis (NASH) in 78 (81.3%) patients. Factors associated with NASH were male gender, body mass index (BMI) > 27 kg/m 2 , DFL and raised alanine aminotransferase (ALT). A GULAB score (based on gender, US liver findings, lipid (fasting) levels, ALT level and BMI) of ≥5 predicted NASH with 82.05% sensitivity. Factors associated with advanced fibrosis in NAFLD were age >40 years, diabetes mellitus, AST/ALT ratio > 1 and raised GGT. Conclusion NASH is common in patients with male gender, high BMI, DFL on liver US, raised ALT and GULAB score ≥5.

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

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.

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.

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).

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

Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients.

PubMed

Wang, Rui; Zhang, Yang; Pan, Yunjian; Li, Yuan; Hu, Haichuan; Cai, Deng; Li, Hang; Ye, Ting; Luo, Xiaoyang; Zhang, Yiliang; Li, Bin; Shen, Lei; Sun, Yihua; Chen, Haiquan

2015-10-27

To determine the frequency of driver mutations in Chinese non-small cell lung cancer (NSCLC) patients. Comprehensive mutational analysis was performed in 1356 lung adenocarcinoma, 503 squamous cell carcinoma, 57 adenosquamous lung carcinoma, 19 large cell carcinoma and 8 sarcomatoid carcinoma. The effect of EGFR tyrosine kinase inhibitors (TKIs) on EGFR-mutated lung adenocarcinoma patients after disease recurrence was investigated. Mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, ROS1 and RET were mutually exclusive. In lung adenocarcinoma cases "pan-negative" for the seven above-mentioned driver mutations, we also detected two oncogenic EGFR extracellular domain mutations (A289D and R324L), two HER2 extracellular and transmembrane domain mutations (S310Y and V659E), one ARAF S214C mutation and two CD74-NRG1 fusions. Six (1.2%) FGFR3 activating mutations were identified in lung squamous cell carcinoma (five S249C and one R248C). There were three (15.8%) EGFR mutations and four (21.1%) KRAS mutations in large cell carcinoma. Three (37.5%) KRAS mutations were detected in sarcomatoid carcinoma. In EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence, treatment with EGFR TKIs was an independent predictor of better overall survival (HR = 0.299, 95% CI: 0.172-0.519, P < 0.001). We determined the frequency of driver mutations in a large series of Chinese NSCLC patients. EGFR TKIs might improve the survival outcomes of EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence.

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

CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation.

PubMed Central

Ganju, R K; Sunday, M; Tsarwhas, D G; Card, A; Shipp, M A

1994-01-01

The cell surface metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) hydrolyzes a variety of peptide substrates and reduces cellular responses to specific peptide hormones. Because CD10/NEP modulates peptide-mediated proliferation of small cell carcinomas of the lung (SCLC) and normal fetal bronchial epithelium, we evaluated the enzyme's expression in non-small cell lung carcinomas (NSCLC). Bronchoalveolar and large cell carcinoma cell lines had low levels of CD10/NEP expression whereas squamous, adenosquamous, and adenocarcinoma cell lines had higher and more variable levels of the cell surface enzyme. Regional variations in CD10/NEP immunostaining in primary NSCLC specimens prompted us to correlate CD10/NEP expression with cell growth. In primary carcinomas of the lung, clonal NSCLC cell lines and SV40-transformed fetal airway epithelium, subsets of cells expressed primarily CD10/NEP or the proliferating cell nuclear antigen (PCNA). Cultured airway epithelial cells had the lowest levels of CD10/NEP expression when the highest percentage of cells were actively dividing; in addition, these cells grew more rapidly when cell surface CD10/NEP was inhibited. NSCLC cell lines had receptors for a variety of mitogenic peptides known to be CD10/NEP substrates, underscoring the functional significance of growth-related variability in CD10/NEP expression. Images PMID:7962523

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.

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

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.

Comparison of small biopsy specimens and surgical specimens for the detection of EGFR mutations and EML4-ALK in non-small-cell lung cancer.

PubMed

Xiao, DeSheng; Lu, Can; Zhu, Wei; He, QiuYan; Li, Yong; Fu, ChunYan; Zhou, JianHua; Liu, Shuang; Tao, YongGuang

2016-09-13

Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusion genes represent novel oncogenes that are associated with non-small-cell lung cancers (NSCLC). The feasibility of detecting EGFR mutations and ALK fusion genes in small biopsy specimens or surgical specimens was determined. Of the 721 NSCLC patients, a total of 305 cases were positive for EGFR mutations (42.3%). The rate of EGFR mutations in women was significantly higher than that in men. Histologically, the EGFR mutation rate in adenocarcinomas was significantly higher than that in squamous cell carcinomas. No difference in the EGFR mutation rate was observed between surgical specimens (42.1%) and small biopsy specimens (42.4%), which indicated that the EGFR mutation ratios in surgical specimens and small biopsy specimens were not different. In 385 NSCLC patients, 26 cases were positive for EML4-ALK (6.8%). However, 11.7% of the surgical specimens were EML4-ALK-positive, whereas the positive proportion in the small biopsy specimens was only 4.7%, which indicated that EML4-ALK-positive rate in the surgical specimens was significantly higher than that in the small biopsy specimens. Detection of EGFR gene mutations was feasible in small biopsy specimens, and screening for EML4-ALK expression in small biopsy specimens can be used to guide clinical treatments.

An exploratory case study of the impact of expanding cost-effectiveness analysis for second-line nivolumab for patients with squamous non-small cell lung cancer in Canada: Does it make a difference?

PubMed

Shafrin, Jason; Skornicki, Michelle; Brauer, Michelle; Villeneuve, Julie; Lees, Michael; Hertel, Nadine; Penrod, John R; Jansen, Jeroen

2018-04-26

Health technology appraisal agencies often rely on cost-effectiveness analyses to inform coverage decisions for new treatments. These assessments, however, frequently measure a treatment's value from the payer's perspective, and may not capture value generated from reduced caregiving costs, increased productivity, value based on patient risk preferences, option value or the insurance value to non-patients. To examine how using a broader societal perspective of treatment value affects cost-effectiveness estimates, this case study analyzed the net monetary benefit (NMB) of second-line nivolumab treatment of patients with squamous non-small cell lung cancer (NSCLC) in Canada. The comparator was treatment with docetaxel. NMB was measured from three perspectives: (i) traditional payer, (ii) traditional societal and (iii) broad societal. Nivolumab was more effective (increased quality-adjusted life years by 0.66 versus docetaxel), but also increased costs by $100,168 CAD. When valuing a quality-adjusted life year at $150,000, the net monetary benefit from the payer perspective suggested that costs modestly exceed benefits (NMB: -$1031). Adopting a societal perspective, however, nivolumab's benefits outweighed its costs (NMB: +$6752 and +$91,084 from the traditional and broad societal perspectives, respectively). Broadening cost-effectiveness analysis beyond the traditional payer perspective had a significant impact on the result and should be considered in order to capture all treatment benefits and costs of societal relevance. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.

PubMed

Rittmeyer, Achim; Barlesi, Fabrice; Waterkamp, Daniel; Park, Keunchil; Ciardiello, Fortunato; von Pawel, Joachim; Gadgeel, Shirish M; Hida, Toyoaki; Kowalski, Dariusz M; Dols, Manuel Cobo; Cortinovis, Diego L; Leach, Joseph; Polikoff, Jonathan; Barrios, Carlos; Kabbinavar, Fairooz; Frontera, Osvaldo Arén; De Marinis, Filippo; Turna, Hande; Lee, Jong-Seok; Ballinger, Marcus; Kowanetz, Marcin; He, Pei; Chen, Daniel S; Sandler, Alan; Gandara, David R

2017-01-21

Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m 2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall

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.

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

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.

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

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.

Updates on the Management of Non-Melanoma Skin Cancer (NMSC)

PubMed Central

Fahradyan, Artur; Howell, Anna C.; Wolfswinkel, Erik M.; Tsuha, Michaela; Sheth, Parthiv; Wong, Alex K.

2017-01-01

Non-melanoma skin cancers (NMSCs) are the most common malignancy worldwide, of which 99% are basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of skin. NMSCs are generally considered a curable diseases, yet they currently pose an increasing global healthcare problem due to rising incidence. This has led to a shift in emphasis on prevention of NMSCs with development of various skin cancer prevention programs worldwide. This article aims to summarize the most recent changes and advances made in NMSC management with a focus on prevention, screening, diagnosis, and staging. PMID:29104226

[Detection of EML4-ALK fusion gene in non-small cell lung cancer and its clinicopathologic correlation].

PubMed

Zhong, Shan; Zhang, Hai-ping; Zheng, Jie; Bai, Dong-yu; Fu, Li; Chen, Pei-qiong

2013-04-01

To investigate the frequency of EML4-ALK fusion gene in non-small-cell lung cancer (NSCLC) patients, and its correlation with clinicopathologic features. Real-time PCR was used to detect the presence of EML4-ALK fusion gene in 268 cases of NSCLCs using paraffin-embedded tissue samples(among which 164 samples were re-validated by Sanger sequencing). Related clinicopathological correlation was analyzed. EML4-ALK fusion gene was found in 4.1% (11/268) of the cases. One hundred and sixty four samples were verified by Sanger sequencing, and the overall coincidence of the results of two methods (Sanger sequencing and Real-time PCR) was 100%. Female patients (5.9%, 5/85), ≤ 60 years of age (4.3%, 6/140), non-smokers (6.8%, 8/118) and adenocarcinomas (7.6%, 10/132) had a higher mutation rate than that in male patients (3.3%, 6/183), > 60 years of age (4.0%, 5/124), smokers (1.6%, 2/132) and squamous cell carcinomas (1.3%, 1/79), although no statistical significance in age (P = 0.918), gender (P = 0.503), smoking history (P = 0.092) and histological type (P = 0.094). Chinese NSCLC patients have a 4.1% detection rate of EML4-ALK fusion gene in the tumor tissues. Female, non-smoker and adenocarcinoma histological subtype tend to be associated with a higher rate of EML4-ALK gene fusion.

Small non-coding RNAs in streptomycetes.

PubMed

Heueis, Nona; Vockenhuber, Michael-Paul; Suess, Beatrix

2014-01-01

Streptomycetes are Gram-positive, GC-rich, soil dwelling bacteria, occurring ubiquitary throughout nature. They undergo extensive morphological changes from spores to filamentous mycelia and produce a plethora of secondary metabolites. Owing to their complex life cycle, streptomycetes require efficient regulatory machinery for the control of gene expression. Therefore, they possess a large diversity of regulators. Within this review we summarize the current knowledge about the importance of small non-coding RNA for the control of gene expression in these organisms.

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.

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.

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.

[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. 
.

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.

Advancements in non-contact metrology of asphere and diffractive optics

NASA Astrophysics Data System (ADS)

DeFisher, Scott

2017-11-01

Advancements in optical manufacturing technology allow optical designers to implement steep aspheric or high departure surfaces into their systems. Measuring these surfaces with profilometers or CMMs can be difficult due to large surface slopes or sharp steps in the surface. OptiPro has developed UltraSurf to qualify the form and figure of steep aspheric and diffractive optics. UltraSurf is a computer controlled, non-contact coordinate measuring machine. It incorporates five air-bearing axes, linear motors, high-resolution feedback, and a non-contact probe. The measuring probe is scanned over the optical surface while maintaining perpendicularity and a constant focal offset. Multiple probe technologies are available on UltraSurf. Each probe has strengths and weaknesses relative to the material properties, surface finish, and figure error of an optical component. The measuring probes utilize absolute distance to resolve step heights and diffractive surface patterns. The non-contact scanning method avoids common pitfalls with stylus contact instruments. Advancements in measuring speed and precision has enabled fast and accurate non-contact metrology of diffractive and steep aspheric surfaces. The benefits of data sampling with twodimensional profiles and three-dimensional topography maps will be presented. In addition, accuracy, repeatability, and machine qualification will be discussed with regards to aspheres and diffractive surfaces.

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.

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

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.

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

The clinical efficacy observed with inhibitors of programed cell death 1/programed cell death ligand 1 (PD-L1/PD-1) in cancer therapy has prompted studies to characterize the immune response in several tumor types, including lung cancer. However, the immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT) is not yet fully characterized, and it may be therapeutically important. The aim of this retrospective study was to characterize and quantify PD-L1/PD-1 expression and tumor-associated immune cells (TAICs) in surgically resected NSCLCs from patients who received NCT or did not receive NCT (non-NCT). We analyzed immune markers in formalin-fixed, paraffin-embedded tumor tissues resected from 112 patients with stage II/III NSCLC, including 61 non-NCT (adenocarcinoma [ADC] = 33; squamous cell carcinoma [SCC] = 28) and 51 NCT (ADC = 31; SCC = 20). We used multiplex immunofluorescence to identify and quantify immune markers grouped into two 6-antibody panels: panel 1 included AE1/AE3, PD-L1, CD3, CD4, CD8, and CD68; panel 2 included AE1/AE3, PD1, granzyme B, FOXP3, CD45RO, and CD57. PD-L1 expression was higher (> overall median) in NCT cases (median, 19.53%) than in non-NCT cases (median, 1.55%; P = 0.022). Overall, density of TAICs was higher in NCT-NSCLCs than in non-NCT-NSCLCs. Densities of CD3+ cells in the tumor epithelial compartment were higher in NCT-ADCs and NCT-SCCs than in non-NCT-ADCs and non-NCT-SCCs (P = 0.043). Compared with non-NCT-SCCs, NCT-SCCs showed significantly higher densities of CD3 + CD4+ (P = 0.019) and PD-1+ (P < 0.001) cells in the tumor epithelial compartment. Density of CD68+ tumor-associated macrophages (TAMs) was higher in NCT-NSCLCs than in non-NCT-NSCLCs and was significantly higher in NCT-SCCs than in non-NCT-SCCs. In NCT-NSCLCs, higher levels of epithelial T lymphocytes (CD3 + CD4+) and epithelial and stromal TAMs (CD68+) were associated with

Fabrication method for small-scale structures with non-planar features

DOEpatents

Burckel, David Bruce; Ten Eyck, Gregory A.

2016-09-20

The fabrication of small-scale structures is disclosed. A unit-cell of a small-scale structure with non-planar features is fabricated by forming a membrane on a suitable material. A pattern is formed in the membrane and a portion of the substrate underneath the membrane is removed to form a cavity. Resonators are then directionally deposited on the wall or sides of the cavity. The cavity may be rotated during deposition to form closed-loop resonators. The resonators may be non-planar. The unit-cells can be formed in a layer that includes an array of unit-cells.

Prostate specific membrane antigen (PSMA) expression in non-small cell lung cancer

PubMed Central

Heitkötter, Birthe; Schulze, Arik B.; Schliemann, Christoph; Steinestel, Konrad; Trautmann, Marcel; Marra, Alessandro; Hillejan, Ludger; Mohr, Michael; Evers, Georg; Wardelmann, Eva; Rahbar, Kambiz; Görlich, Dennis; Lenz, Georg; Berdel, Wolfgang E.; Hartmann, Wolfgang; Wiewrodt, Rainer; Huss, Sebastian

2017-01-01

Objectives PSMA (prostate-specific membrane antigen) is overexpressed in prostate cancer cells and is reported to be a promising target for antibody-based radioligand therapy in patients with metastasized prostate cancer. Since PSMA expression is not restricted to prostate cancer, the underlying study investigates PSMA expression in non-small cell lung cancer (NSCLC). Material and methods Immunohistochemistry was used to identify PSMA expression in n = 275 samples of NSCLC tissue specimens. By means of CD34 co-expression, the level of PSMA expression in tumor associated neovasculature was investigated. The impact of PSMA expression on clinicopathologic parameters and prognosis was evaluated. Results PSMA tumor cell expression in NSCLC is as low as 6% and was predominantly found in squamous cell carcinoma (p = 0.002). Neovascular PSMA expression was found in 49% of NSCLC. High neovascular PSMA expression was associated with higher tumor grading (G3/G4) (p < 0.001). Neither for PSMA tumor cell expression, nor for PSMA neovascular cell expression prognostic effects were found for the investigated NSCLC cases. Conclusion Here, we report on the expression of PSMA in NSCLC tissue samples. Against the background of a potential treatment with radiolabeled PSMA ligands, our data might serve for the future identification of patients who could benefit from this therapeutic option. PMID:29077706

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.

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.

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.

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.

Advanced Computational Methods for Optimization of Non-Periodic Inspection Intervals for Aging Infrastructure

DTIC Science & Technology

2017-01-05

AFRL-AFOSR-JP-TR-2017-0002 Advanced Computational Methods for Optimization of Non-Periodic Inspection Intervals for Aging Infrastructure Manabu...Computational Methods for Optimization of Non-Periodic Inspection Intervals for Aging Infrastructure 5a.  CONTRACT NUMBER 5b.  GRANT NUMBER FA2386...UNLIMITED: PB Public Release 13. SUPPLEMENTARY NOTES 14. ABSTRACT This report for the project titled ’Advanced Computational Methods for Optimization of

In vivo measurement of non-keratinized squamous epithelium using a spectroscopic microendoscope with multiple source-detector separations

NASA Astrophysics Data System (ADS)

Greening, Gage J.; Rajaram, Narasimhan; Muldoon, Timothy J.

2016-03-01

In the non-keratinized epithelia, dysplasia typically arises near the basement membrane and proliferates into the upper epithelial layers over time. We present a non-invasive, multimodal technique combining high-resolution fluorescence imaging and broadband sub-diffuse reflectance spectroscopy (sDRS) to monitor health at various tissue layers. This manuscript focuses on characterization of the sDRS modality, which contains two source-detector separations (SDSs) of 374 μm and 730 μm, so that it can be used to extract in vivo optical parameters from human oral mucosa at two tissue thicknesses. First, we present empirical lookup tables (LUTs) describing the relationship between reduced scattering (μs') and absorption coefficients (μa) and absolute reflectance. LUTS were shown to extract μs' and μa with accuracies of approximately 4% and 8%, respectively. We then present LUTs describing the relationship between μs', μa and sampling depth. Sampling depths range between 210-480 and 260-620 μm for the 374 and 730 μm SDSs, respectively. We then demonstrate the ability to extract in vivo μs', μa, hemoglobin concentration, bulk tissue oxygen saturation, scattering exponent, and sampling depth from the inner lip of thirteen healthy volunteers to elucidate the differences in the extracted optical parameters from each SDS (374 and 730 μm) within non-keratinized squamous epithelia.

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.

New PD-L1 inhibitors in non-small cell lung cancer - impact of atezolizumab.

PubMed

Seetharamu, Nagashree; Preeshagul, Isabel R; Sullivan, Kevin M

2017-01-01

The era of immunotherapy has changed the face of how we approach treatment for many oncologic and hematologic malignancies. Lung cancer has been in the forefront of checkpoint inhibition for the past 2 years and has paved the path for other subspecialties. While PD-1 inhibitors nivolumab and pembrolizumab have been approved for non-small cell lung cancer (NSCLC), this review focuses on atezolizumab, its landmark studies, and ongoing trials. Atezolizumab is the first programmed death ligand 1 (PD-L1) inhibitor to receive US Food and Drug Administration (FDA) approval for metastatic NSCLC patients who have progressed on frontline chemotherapy. This approval was based on two open-label Phase II multicenter trials, POPLAR (NCT01903993) and BIRCH (NCT02031458). Both studies revealed a benefit in overall survival (OS), progression-free survival, and response rate in the atezolizumab arm when compared to single-agent docetaxol. There were also fewest Grade 3-5 treatment-related adverse events (TRAEs) in the atezolizumab cohort. The open-label randomized Phase III OAK trial (NCT02008227) further established the role of atezolizumab in previously treated NSCLC. This study compared atezolizumab with docetaxel in patients with advanced NSCLC (squamous or nonsquamous histologies) who had progressed on one to two prior chemotherapy regimens. OS in the PD-L1-enriched population was superior in the atezolizumab arm (n=241) at 15.7 months compared with docetaxel (n=222) at 10.3 months (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.58-0.93; p =0.0102). Patients lacking PD-L1 also had survival benefit with atezolizumab with a median OS (mOS) of 12.6 months versus 8.9 months with chemotherapy (HR 0.75, 95% CI 0.59-0.96). Benefit was noted in both squamous and nonsquamous NSCLC subsets and regardless of PD-L1 expressivity. As seen in the POPLAR and BIRCH studies, the toxicity profile was significantly better with immunotherapy. The future is unfolding rapidly as new

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.

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

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.

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.

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.

Long-term safety and survival with gefitinib in select patients with advanced non-small cell lung cancer: Results from the US IRESSA Clinical Access Program (ICAP).

PubMed

Hirsch, Fred R; Sequist, Lecia V; Gore, Ira; Mooradian, Meghan; Simon, George; Croft, Elisabeth F; DeVincenzo, Diana; Munley, Jiefen; Stein, Dara; Freivogel, Klaus; Sifakis, Frangiscos; Bunn, Paul A

2018-06-01

This is the first report of long-term (>10 years) safety, tolerability, and survival data on patients with non-small cell lung cancer (NSCLC) who received treatment with gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Patients with advanced NSCLC (N = 191) who entered the IRESSA Clinical Access Program (ICAP) (June 2011 to January 2013) and had previously obtained a clinical benefit from gefitinib therapy (including patients who had received gefitinib since 2001) were analyzed for adverse events (AEs). A subset of patients (n = 79) underwent retrospective chart review to capture demographic, safety, and survival data. Seventy-five of 191 patients (39%) remained on long-term gefitinib therapy as of September 2016. Overall, serious AEs (SAEs) were reported in 64 patients (34%), the majority of which were attributed to underlying disease or comorbidities; only 3 patients (1.6%) had SAEs that were considered as possibly gefitinib-related. In the retrospective chart review cohort, 70% of patients were women; 58% were former smokers, and 30% were never-smokers; 56% were diagnosed with adenocarcinoma, and 13% were diagnosed with squamous carcinoma. Although EGFR mutational status was tested in only 17 patients (22%), it was assumed that most tumors were EGFR-mutation-positive. The median duration of gefitinib therapy was 11.1 years (7.8 years before and 3.5 years during ICAP), with 10-year and 15-year survival rates of 86% and 59%, respectively, from the initiation of therapy. A subset of long-term NSCLC survivors who were receiving gefitinib had an excellent long-term safety profile. Although it is assumed that most of these patients' tumors harbor EGFR mutations, molecular studies of available tumor specimens are planned to uncover the features that predict long-term survival. Cancer 2018;124:2407-14. © 2018 American Cancer Society. © 2018 American Cancer Society.

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

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.

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

Identification of Logic Relationships between Genes and Subtypes of Non-Small Cell Lung Cancer

PubMed Central

Su, Yansen; Pan, Linqiang

2014-01-01

Non-small cell lung cancer (NSCLC) has two major subtypes: adenocarcinoma (AC) and squamous cell carcinoma (SCC). The diagnosis and treatment of NSCLC are hindered by the limited knowledge about the pathogenesis mechanisms of subtypes of NSCLC. It is necessary to research the molecular mechanisms related with AC and SCC. In this work, we improved the logic analysis algorithm to mine the sufficient and necessary conditions for the presence states (presence or absence) of phenotypes. We applied our method to AC and SCC specimens, and identified lower and higher logic relationships between genes and two subtypes of NSCLC. The discovered relationships were independent of specimens selected, and their significance was validated by statistic test. Compared with the two earlier methods (the non-negative matrix factorization method and the relevance analysis method), the current method outperformed these methods in the recall rate and classification accuracy on NSCLC and normal specimens. We obtained biomarkers. Among biomarkers, genes have been used to distinguish AC from SCC in practice, and other six genes were newly discovered biomarkers for distinguishing subtypes. Furthermore, NKX2-1 has been considered as a molecular target for the targeted therapy of AC, and other genes may be novel molecular targets. By gene ontology analysis, we found that two biological processes (‘epidermis development’ and ‘cell adhesion’) were closely related with the tumorigenesis of subtypes of NSCLC. More generally, the current method could be extended to other complex diseases for distinguishing subtypes and detecting the molecular targets for targeted therapy. PMID:24743794

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

[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.

[ALK gene fusion associated non-small cell lung cancer: automated immunostainer detection and clinicopathologic perspectives].

PubMed

Shen, Qin; Pan, Yi; Yu, Bo; Shi, Shanshan; Liu, Biao; Xu, Yan; Wang, Yanfen; Xia, Qiuyuan; Rao, Qiu; Lu, Zhenfeng; Shi, Qunli; Zhou, Xiaojun

2015-03-01

To explore the automated immunostainer screening anaplastic lymphoma kinase (ALK) gene fusion non-small cell lung cancer (NSCLC) and clinicopathological characteristics of the molecular subtype lung cancers. Methods Five hundred and sixty-six cases of NSCLC were collected over a 16 month period. The test for ALK was performed by Ventana automated immunostainer with anti-ALK D5F3. The histological features, treatment and outcome of patients were assessed. Results Thirty-eight cases (6.7%, 38/566) of NSCLC showed ALK gene fusion. The frequency of ALK gene fusion was higher in male (7.1%, 25/350) than that in female (6.0%, 13/216) patients, but not achieving statistical significance (chi2 = 0.270, P = 0.604). ALK + NSCLC was more significantly more frequent in patients < or = 60 years (9.9%, 28/282) than >60 years (3.5% , 10/284) of age. Histologically, the ALK + NSCLCs were mostly adenocarcinoma (81.6%, 31/38) , among which eighteen cases were solid predominant subtype with mucin production; nine cases were acinar predominant subtype; one case was papillary predominant subtype and three cases were invasive mucinous adenocarcinoma. The ALK + non-adenocarcinoma included three cases of squamous cell carcinoma, three cases of adenosquamous carcinoma and one case of pleomorphic carcinoma. Among the ALK + NSCLC patients, the number of non/light cigarette smokers (86. 8% , 33/38) was more than that of heavy smokers. Twenty-nine cases were stages III and IV; twenty-nine cases showed lymph node metastasis; twenty cases showed metastases mostly to brain and bone; and one case showed EGFR gene mutation coexisting with ALK gene fusion. Twelve of fifteen patients received crizotinib therapy and remained stable. Conclusions NSCLC with ALK gene rearrangement shows distinctive clinical and histological features. Ventana-IHC may he a feasible and valid technique for detection of ALK rearrangement in NSCLC.

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

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.

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.

Non-target captures during small mammal trapping with snap traps

Treesearch

David G. Peitz; Philip A. Tappe; Ronald E. Thill; Roger W. Perry; M. Anthony Melchiors; T. Bently Wigley

2001-01-01

There is little published information available on non-target captures during small mammal trapping. We used a variety of snap traps baited with a rolled oat-peanut butter mix to capture 2,054 individuals from 9 genera of small mammals in a study of small mammal and avian community structure in riparian areas and adjacent loblolly pine (Pinus taeda) plantations. We...

Clinical framework for next generation sequencing based analysis of treatment predictive mutations and multiplexed gene fusion detection in non-small cell lung cancer

PubMed Central

Levéen, Per; Brunnström, Hans; Reuterswärd, Christel; Holm, Karolina; Jönsson, Mats; Annersten, Karin; Rosengren, Frida; Jirström, Karin; Kosieradzki, Jaroslaw; Ek, Lars; Borg, Åke; Planck, Maria; Jönsson, Göran; Staaf, Johan

2017-01-01

Precision medicine requires accurate multi-gene clinical diagnostics. We describe the implementation of an Illumina TruSight Tumor (TST) clinical NGS diagnostic framework and parallel validation of a NanoString RNA-based ALK, RET, and ROS1 gene fusion assay for combined analysis of treatment predictive alterations in non-small cell lung cancer (NSCLC) in a regional healthcare region of Sweden (Scandinavia). The TST panel was clinically validated in 81 tumors (99% hotspot mutation concordance), after which 533 consecutive NSCLCs were collected during one-year of routine clinical analysis in the healthcare region (˜90% advanced stage patients). The NanoString assay was evaluated in 169 of 533 cases. In the 533-sample cohort 79% had 1-2 variants, 12% >2 variants and 9% no detected variants. Ten gene fusions (five ALK, three RET, two ROS1) were detected in 135 successfully analyzed cases (80% analysis success rate). No ALK or ROS1 FISH fusion positive case was missed by the NanoString assay. Stratification of the 533-sample cohort based on actionable alterations in 11 oncogenes revealed that 66% of adenocarcinomas, 13% of squamous carcinoma (SqCC) and 56% of NSCLC not otherwise specified harbored ≥1 alteration. In adenocarcinoma, 10.6% of patients (50.3% if including KRAS) could potentially be eligible for emerging therapeutics, in addition to the 15.3% of patients eligible for standard EGFR or ALK inhibitors. For squamous carcinoma corresponding proportions were 4.4% (11.1% with KRAS) vs 2.2%. In conclusion, multiplexed NGS and gene fusion analyses are feasible in NSCLC for clinical diagnostics, identifying notable proportions of patients potentially eligible for emerging molecular therapeutics. PMID:28415793

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

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.

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

Miniaturized GPS Tags Identify Non-breeding Territories of a Small Breeding Migratory Songbird.

PubMed

Hallworth, Michael T; Marra, Peter P

2015-06-09

For the first time, we use a small archival global positioning system (GPS) tag to identify and characterize non-breeding territories, quantify migratory connectivity, and identify population boundaries of Ovenbirds (Seiurus aurocapilla), a small migratory songbird, captured at two widely separated breeding locations. We recovered 15 (31%) GPS tags with data and located the non-breeding territories of breeding Ovenbirds from Maryland and New Hampshire, USA (0.50 ± 0.15 ha, mean ± SE). All non-breeding territories had similar environmental attributes despite being distributed across parts of Florida, Cuba and Hispaniola. New Hampshire and Maryland breeding populations had non-overlapping non-breeding population boundaries that encompassed 114,803 and 169,233 km(2), respectively. Archival GPS tags provided unprecedented pinpoint locations and associated environmental information of tropical non-breeding territories. This technology is an important step forward in understanding seasonal interactions and ultimately population dynamics of populations throughout the annual cycle.

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.

Concurrent chemo-radiotherapy with S-1 as an alternative therapy for elderly Chinese patients with non-metastatic esophageal squamous cancer: evidence based on a systematic review and meta-analysis.

PubMed

Song, Guo-Min; Tian, Xu; Liu, Xiao-Ling; Chen, Hui; Zhou, Jian-Guo; Bian, Wei; Chen, Wei-Qing

2017-06-06

This systematic review and meta-analysis aims to systematically assess the effects of concurrent chemo-radiotherapy (CRT) compared with radiotherapy (RT) alone for elderly Chinese patients with non-metastatic esophageal squamous cancer. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), China Biomedical Literature Database (CBM), and China National Knowledge Infrastructure (CNKI) databases. We retrieved randomized controlled trials on concurrent CRT with Gimeraciland Oteracil Porassium (S-1) compared with RT alone for aged Chinese patients with non-metastatic esophageal squamous cancer performed until August 2016. Eight eligible studies involving 536 patients were subjected to meta-analysis. As a response rate measure, a relative risk (RR) of 1.37 [95% confidence intervals (CIs): 1.24, 1.53; P = 0.00], which reached statistical significance, was estimated when concurrent CRT with S-1 was performed compared with RT alone. Sensitivity analysis on response rate confirmed the robustness of the pooled result. The RR values of 1.44 (95% CIs: 1.22, 1.70; P = 0.00) and 1.77 (95% CIs: 1.26, 2.48; P = 0.00) estimated for 1- and 2-year survival rate indices, respectively, were also statistically significant. The incidence of adverse events was similar in both groups. This review concluded that concurrent CRT with S-1 can improve the efficacy and prolong the survival period of elderly Chinese patients with non-metastatic esophageal squamous cancer and does not significantly increase the acute adverse effects of RT alone.

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

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

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.

[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.

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

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.

Histology-based Combination Induction Chemotherapy for Elderly Patients with Clinical Stage III Non-small Cell Lung Cancer.

PubMed

Banna, Giuseppe L; Parra, Hector Josè Soto; Castaing, Marine; Dieci, Maria Vittoria; Anile, Giuseppe; Nicolosi, Maurizio; Strano, Salvatore; Marletta, Francesco; Guarneri, Valentina; Conte, Pierfranco; Lal, Rohit

2017-07-01

To explore the feasibility and activity of a histology-based induction combination chemotherapy for elderly patients with clinical stage III non-small cell lung cancer (NSCLC). Patients aged ≥70 years with stage IIIA and IIIB lung squamous cell carcinoma (SCC) or adenocarcinoma were treated with three cycles of carboplatin and gemcitabine or pemetrexed, respectively, followed by definitive radiotherapy or surgery. The primary endpoint was the overall response rate (ORR) following induction. Twenty-seven patients, with a median age of 74 years (range=70-80 years) were treated for adenocarcinoma in 14 (52%) and SCC in 13 (48%), clinical stage IIIA in eight (30%) and IIIB in 19 (70%). Grade 3 or 4 toxicity was reported for five patients (18.5%). The ORR was 46% in 12 (partial responses) out of 26 assessable patients. Histology-based induction combination chemotherapy is active and feasible in elderly patients with stage III NSCLC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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

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

Recombinant EphB4-HSA Fusion Protein With Standard Chemotherapy Regimens in Treating Patients With Advanced or Metastatic Solid Tumors

ClinicalTrials.gov

2017-07-15

Head and Neck Squamous Cell Carcinoma; Metastatic Pancreatic Adenocarcinoma; Non-Resectable Cholangiocarcinoma; Pancreatic Adenocarcinoma; Recurrent Gallbladder Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Stage III Pancreatic Cancer; Stage IIIA Gallbladder Cancer; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Gallbladder Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Gallbladder Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Pancreatic Cancer; Unresectable Gallbladder Carcinoma; Unresectable Pancreatic Cancer

Loss of Bad expression confers poor prognosis in non-small cell lung cancer.

PubMed

Huang, Yi; Liu, Dan; Chen, Bojiang; Zeng, Jing; Wang, Lei; Zhang, Shangfu; Mo, Xianming; Li, Weimin

2012-09-01

Proapoptotic BH-3-only protein Bad (Bcl-Xl/Bcl-2-associated death promoter homolog, Bad) initiates apoptosis in human cells, and contributes to tumorigenesis and chemotherapy resistant in malignancies. This study explored association between the Bad expression level and prognosis in patients with non-small cell lung cancer (NSCLC). In our study, a cohort of 88 resected primary NSCLC cases were collected and analyzed. Bad expression level was determined via immunohistochemical staining assay. The prognostic significances of Bad expression were evaluated with univariate and multivariate survival analysis. The results showed that compared with normal lung tissues, Bad expression level significantly decreased in NSCLC (P < 0.05). Bad expression was associated with adjuvant therapy status. Loss of Bad independently predicted poor prognosis in whole NSCLC cohort and early stage subjects (T1 + T2 and N0 + N1) (all P < 0.05). Overall survival time was also drastically shortened for Bad negative phenotype in NSCLC patients with smoking history, especially lung squamous cell carcinoma (all P < 0.05). In conclusion, this study provided clinical evidence that loss of Bad is an independent and powerful predictor of adverse prognosis in NSCLC. Bad protein could be a new biomarker for selecting individual therapy strategies and predicting therapeutic response in subjects with NSCLC.

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.

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.

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.

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

Oral tongue squamous cell carcinoma (OTSCC): alcohol and tobacco consumption versus non-consumption. A study in a Portuguese population.

PubMed

Albuquerque, Rui; López-López, José; Marí-Roig, Antonio; Jané-Salas, Enric; Roselló-Llabrés, Xavier; Santos, Jorge Rosa

2011-01-01

There has been an increase in the incidence of carcinoma of the tongue, particularly among alcohol and tobacco non-users. However, the number of studies that would allow a better understanding of etiological factors and clinical features, particularly in the Portuguese population, is very limited. This study was based on patients with squamous cell carcinoma of the anterior two thirds of the tongue that were treated at the Department of Head and Neck Surgery of the "Instituto Portugues de Oncologia de Lisboa - Francisco Gentil" (IPOLFG) in Lisbon, Portugal, between January 1, 2001 and December 31, 2009. The patients were divided in alcohol and tobacco users and non-users in order to evaluate the differences between these 2 groups based on gender, age, tumor location, denture use, and tumor size, metastasis and stage. Of the 354 cases, 208 were users and 146 were non-users. The main location in both groups was the lateral border of the tongue. Denture use showed no significant effect in both study groups. It was possible to conclude that patients who did not drink or smoke were older and presented with smaller tumor size, lower incidence of ganglion metastasis and lower tumor stage compared with alcohol and tobacco users.

Functional Interplay between Small Non-Coding RNAs and RNA Modification in the Brain.

PubMed

Leighton, Laura J; Bredy, Timothy W

2018-06-07

Small non-coding RNAs are essential for transcription, translation and gene regulation in all cell types, but are particularly important in neurons, with known roles in neurodevelopment, neuroplasticity and neurological disease. Many small non-coding RNAs are directly involved in the post-transcriptional modification of other RNA species, while others are themselves substrates for modification, or are functionally modulated by modification of their target RNAs. In this review, we explore the known and potential functions of several distinct classes of small non-coding RNAs in the mammalian brain, focusing on the newly recognised interplay between the epitranscriptome and the activity of small RNAs. We discuss the potential for this relationship to influence the spatial and temporal dynamics of gene activation in the brain, and predict that further research in the field of epitranscriptomics will identify interactions between small RNAs and RNA modifications which are essential for higher order brain functions such as learning and memory.

New PD-L1 inhibitors in non-small cell lung cancer – impact of atezolizumab

PubMed Central

Seetharamu, Nagashree; Preeshagul, Isabel R; Sullivan, Kevin M

2017-01-01

The era of immunotherapy has changed the face of how we approach treatment for many oncologic and hematologic malignancies. Lung cancer has been in the forefront of checkpoint inhibition for the past 2 years and has paved the path for other subspecialties. While PD-1 inhibitors nivolumab and pembrolizumab have been approved for non-small cell lung cancer (NSCLC), this review focuses on atezolizumab, its landmark studies, and ongoing trials. Atezolizumab is the first programmed death ligand 1 (PD-L1) inhibitor to receive US Food and Drug Administration (FDA) approval for metastatic NSCLC patients who have progressed on frontline chemotherapy. This approval was based on two open-label Phase II multicenter trials, POPLAR (NCT01903993) and BIRCH (NCT02031458). Both studies revealed a benefit in overall survival (OS), progression-free survival, and response rate in the atezolizumab arm when compared to single-agent docetaxol. There were also fewest Grade 3–5 treatment-related adverse events (TRAEs) in the atezolizumab cohort. The open-label randomized Phase III OAK trial (NCT02008227) further established the role of atezolizumab in previously treated NSCLC. This study compared atezolizumab with docetaxel in patients with advanced NSCLC (squamous or nonsquamous histologies) who had progressed on one to two prior chemotherapy regimens. OS in the PD-L1-enriched population was superior in the atezolizumab arm (n=241) at 15.7 months compared with docetaxel (n=222) at 10.3 months (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.58–0.93; p=0.0102). Patients lacking PD-L1 also had survival benefit with atezolizumab with a median OS (mOS) of 12.6 months versus 8.9 months with chemotherapy (HR 0.75, 95% CI 0.59–0.96). Benefit was noted in both squamous and nonsquamous NSCLC subsets and regardless of PD-L1 expressivity. As seen in the POPLAR and BIRCH studies, the toxicity profile was significantly better with immunotherapy. The future is unfolding rapidly as new

Non-invasive imaging of actinic cheilitis and squamous cell carcinoma of the lip.

PubMed

Lupu, Mihai; Caruntu, Ana; Caruntu, Constantin; Boda, Daniel; Moraru, Liliana; Voiculescu, Vlad; Bastian, Alexandra

2018-05-01

An early diagnosis is of overwhelming importance for the management and prognosis of mucocutaneous cancer. Actinic cheilitis (AC), defined by the clonal expansion of genomically unstable keratinocytes, is the most common potentially malignant lesion affecting the lips. Squamous cell carcinoma (SCC) is the most frequent oral malignancy, and there is strong evidence that the majority of the SCCs of the lip originate from AC. There is considerable difficulty in discerning between dysplasia and invasive carcinomas solely on a clinical basis. Although dermoscopy has become an essential tool for skin tumor evaluation, reflectance confocal microscopy (RCM) is a non-invasive imaging technology that has proved itself extremely useful in the diagnosis and monitoring of several skin diseases, including AC and SCC. The present study aimed to re-emphasize the usefulness of RCM in the early detection of malignant transformation, using AC and SCC of the lips as working examples. Due to the apparent innocuousness of AC for numerous patients, it is not possible to overstress the importance of a correct and early diagnosis, proper treatment and long-term patient follow-up as being essential for preventing the progression to lip SCC, or for its timely diagnosis.

Non-invasive imaging of actinic cheilitis and squamous cell carcinoma of the lip

PubMed Central

Lupu, Mihai; Caruntu, Ana; Caruntu, Constantin; Boda, Daniel; Moraru, Liliana; Voiculescu, Vlad; Bastian, Alexandra

2018-01-01

An early diagnosis is of overwhelming importance for the management and prognosis of mucocutaneous cancer. Actinic cheilitis (AC), defined by the clonal expansion of genomically unstable keratinocytes, is the most common potentially malignant lesion affecting the lips. Squamous cell carcinoma (SCC) is the most frequent oral malignancy, and there is strong evidence that the majority of the SCCs of the lip originate from AC. There is considerable difficulty in discerning between dysplasia and invasive carcinomas solely on a clinical basis. Although dermoscopy has become an essential tool for skin tumor evaluation, reflectance confocal microscopy (RCM) is a non-invasive imaging technology that has proved itself extremely useful in the diagnosis and monitoring of several skin diseases, including AC and SCC. The present study aimed to re-emphasize the usefulness of RCM in the early detection of malignant transformation, using AC and SCC of the lips as working examples. Due to the apparent innocuousness of AC for numerous patients, it is not possible to overstress the importance of a correct and early diagnosis, proper treatment and long-term patient follow-up as being essential for preventing the progression to lip SCC, or for its timely diagnosis. PMID:29725529

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.

Safety Study of SEA-CD40 in Cancer Patients

ClinicalTrials.gov

2018-06-21

Cancer; Carcinoma; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Hematologic Malignancies; Hodgkin Disease; Lymphoma; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Melanoma; Neoplasms; Neoplasm Metastasis; Neoplasms, Head and Neck; Neoplasms, Squamous Cell; Non-Small Cell Lung Cancer; Non-Small Cell Lung Cancer Metastatic; Non-small Cell Carcinoma; Squamous Cell Cancer; Squamous Cell Carcinoma; Squamous Cell Carcinoma of the Head and Neck; Squamous Cell Neoplasm; Lymphoma, Non-Hodgkin

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.

Effects of advancing gestation and non-Caucasian race on ductus arteriosus gene expression

PubMed Central

Waleh, Nahid; Barrette, Anne Marie; Dagle, John M.; Momany, Allison; Jin, Chengshi; Hills, Nancy K.; Shelton, Elaine L.; Reese, Jeff; Clyman, Ronald I.

2015-01-01

Objective To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA). Study design We collected three sets of DA tissue (n=93, n=89, n=91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "Non-Caucasian" DA. We used RT-PCR to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "Non-Caucasian" race, and gene expression. Results Mature gestation and Non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (e.g., calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all three tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "Non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "Non-Caucasian" DA. Conclusions Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "Non-Caucasian" PDA, making it more likely to close when inhibited by indomethacin. PMID:26265282

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.

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.

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

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

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

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.

Risk factors and survival outcome for non-elective referral in non-small cell lung cancer patients--analysis based on the National Lung Cancer Audit.

PubMed

Beckett, P; Tata, L J; Hubbard, R B

2014-03-01

Survival after diagnosis of lung cancer is poor and seemingly lower in the UK than other Western countries, due in large part to late presentation with advanced disease precluding curative treatment. Recent research suggests that around one-third of lung cancer patients reach specialist care after emergency presentation and have a worse survival outcome. Confirmation of these data and understanding which patients are affected may allow a targeted approach to improving outcomes. We used data from the UK National Lung Cancer Audit in a multivariate logistic regression model to quantify the association of non-elective referral in non-small cell lung cancer patients with covariates including age, sex, stage, performance status, co-morbidity and socioeconomic status and used the Kaplan-Meier method and Cox proportional hazards model to quantify survival by source of referral. In an analysis of 133,530 cases of NSCLC who presented 2006-2011, 19% of patients were referred non-electively (following an emergency admission to hospital or following an emergency presentation to A&E). This route of referral was strongly associated with more advanced disease stage (e.g. in Stage IV - OR: 2.34, 95% CI: 2.14-2.57, p<0.001) and worse performance status (e.g. in PS 4 - OR: 7.28, 95% CI: 6.75-7.86, p<0.001), but was also independently associated with worse socioeconomic status, and extremes of age. These patients were more likely to have died within 1 year of diagnosis (hazard ratio of 1.51 (95% CI: 1.49-1.54) after adjustment for key clinical variables. Our data confirm and quantify poorer survival in lung cancer patients who are referred non-electively to specialist care, which is more common in patients with poorer performance status, higher disease stage and less advantaged socioeconomic status. Work to tackle this late presentation should be urgently accelerated, since its realisation holds the promise of improved outcomes and better healthcare resource utilisation. Copyright �

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.

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.

Elevated circulating level of osteopontin is associated with advanced disease state of non-small cell lung cancer.

PubMed

Chang, Yoon Soo; Kim, Hyung Jung; Chang, Joon; Ahn, Chul Min; Kim, Sung Kyu; Kim, Se Kyu

2007-09-01

Osteopontin (OPN) plays important roles in tumor progression and metastasis through binding to OPN receptors such as alpha(v)beta(beta) integrin and CD44, and its overexpression in tumor is associated poor clinical outcome of NSCLC patients. Circulating OPN levels, measured by ELISA in 130 NSCLC cases that had not been treated for cancer at the time of sampling, were analyzed according to clinical, pathologic parameters and single nucleotide polymorphisms (SNPs) in the OPN gene promoter. Advanced disease states had higher circulating levels of OPN (T4 versus T1-3, N3 versus N0-2, and M1 versus M0, P=.029, .001, and .001, respectively, Kruskal-Wallis H-test), reflected by higher level of OPN in stage IV than stage I-III (P=.029, Kruskal-Wallis H-test). Among the clinical and pathological parameters including age, gender, smoking status, histologic subtypes and grade of differentiation, smoking status influences circulating OPN level showing higher level of OPN in ex-smokers than current and non-smokers (P=.038, Kruskal-Wallis H-test). Variation at nucleotide (nt) -443 of the OPN gene promoter had no influence on circulating OPN levels, however, patients with G/G at nt -156 showed higher concentrations of OPN than those with G/GG or GG/GG (P=.003, Kruskal-Wallis H-test). A patient with G/G at nt -156 was more frequently diagnosed with advanced stage (IIIB-IV) than with early stage (I-IIIA) NSCLC (P=.048, Mantel-Haenszel-test). In multivariate analysis, stage is the only independent factor influencing circulating level of OPN. Although circulating level of OPN in the patients with bone metastasis was higher than in those without bone metastasis (P=.028, Mann-Whitney U-test), there was no difference in the OPN levels between bone metastasis group and non-bone metastasis group. Given that the elevated levels of OPN is associated with advanced stages of NSCLC, elucidating OPN regulatory mechanisms may contribute to the development of a new therapeutic modality for NSCLC.

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

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.

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.

Development/Modernization of an Advanced Non-Light Water Reactor Probabilistic Risk Assessment

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

Henneke, Dennis W.; Robinson, James

In 2015, GE Hitachi Nuclear Energy (GEH) teamed with Argonne National Laboratory (Argonne) to perform Research and Development (R&D) of next-generation Probabilistic Risk Assessment (PRA) methodologies for the modernization of an advanced non-Light Water Reactor (non-LWR) PRA. This effort built upon a PRA developed in the early 1990s for GEH’s Power Reactor Inherently Safe Module (PRISM) Sodium Fast Reactor (SFR). The work had four main tasks: internal events development modeling the risk from the reactor for hazards occurring at-power internal to the plant; an all hazards scoping review to analyze the risk at a high level from external hazards suchmore » as earthquakes and high winds; an all modes scoping review to understand the risk at a high level from operating modes other than at-power; and risk insights to integrate the results from each of the three phases above. To achieve these objectives, GEH and Argonne used and adapted proven PRA methodologies and techniques to build a modern non-LWR all hazards/all modes PRA. The teams also advanced non-LWR PRA methodologies, which is an important outcome from this work. This report summarizes the project outcomes in two major phases. The first phase presents the methodologies developed for non-LWR PRAs. The methodologies are grouped by scope, from Internal Events At-Power (IEAP) to hazards analysis to modes analysis. The second phase presents details of the PRISM PRA model which was developed as a validation of the non-LWR methodologies. The PRISM PRA was performed in detail for IEAP, and at a broader level for hazards and modes. In addition to contributing methodologies, this project developed risk insights applicable to non-LWR PRA, including focus-areas for future R&D, and conclusions about the PRISM design.« less

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.

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

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.

Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing

PubMed Central

Liu, Pengyuan; Morrison, Carl; Wang, Liang; Xiong, Donghai; Vedell, Peter; Cui, Peng; Hua, Xing; Ding, Feng; Lu, Yan; James, Michael; Ebben, John D.; Xu, Haiming; Adjei, Alex A.; Head, Karen; Andrae, Jaime W.; Tschannen, Michael R.; Jacob, Howard; Pan, Jing; Zhang, Qi; Van den Bergh, Francoise; Xiao, Haijie; Lo, Ken C.; Patel, Jigar; Richmond, Todd; Watt, Mary-Anne; Albert, Thomas; Selzer, Rebecca; Anderson, Marshall; Wang, Jiang; Wang, Yian; Starnes, Sandra; Yang, Ping; You, Ming

2012-01-01

Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2. PMID:22510280

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.

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.

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.

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.

[Tripartite-motif protein 25 and pyruvate kinase M2 protein expression in non-small cell lung cancer].

PubMed

Jing, Huai-Zhi; Qiu, Feng; Chen, Shi-Zhi; Su, Lin; Qu, Can

2015-03-01

To investigate the expression of tripartite-motif protein 25 (TRIM25) and pyruvate kinase M2 (PKM2) protein in non-small cell lung cancer (NSCLC) and explore their role in the occurrence and progression of NSCLC. The expressions of TRIM25 and PKM2 protein were detected in 60 NSCLC specimens and 20 adjacent normal lung tissue (>5 cm from the lesions) with immunofluorescence histochemical method and in 10 fresh specimens of NSCLC with Western blotting. The results were analyzed in relation with the clinicopathological features of the patients. The positivity rates of TRIM25 expression was 45% in the 60 lung carcinoma specimens, significantly higher than that in the 20 normal lung tissues (10%, P=0.005). TRIM25 protein was expressed in 28.6% of lung adenocarcinoma tissues and in 59.4% of squamous carcinoma tissues (P=0.017). TRIM25 protein expression was positively correlated with the TNM stages and lymph node metastasis of NSCLC (P<0.05). The expressions of PKM2 protein in 60 cases of lung carcinoma was 73.3%,while in 20 cases of normal lung tissues the expressions was 30%(P=0.001). The positivity rates of PKM2 expression differed significantly between lung adenocarcinoma and squamous carcinoma (57.1% vs 87.5%, P=0.008). An inverse correlation was noted between TRIM25 and PKM2 expressions (P=0.026). TRIM25 and PKM2 protein may participate in the occurrence and progression of NSCLC, and their expressions are inversely correlated.

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.

Preselection based on clinical characteristics in German non-small-cell lung cancer patients screened for EML4-ALK translocation.

PubMed

Tufman, Amanda Laura Helen; Edelmann, Martin; Gamarra, Fernando; Reu, Simone; Borgmeier, Astrid; Schrödl, Kathrin; Zauber, Regine; Müller-Lisse, Ullrich; Huber, Rudolf Maria

2014-01-01

The advent of multiple molecular targets in advanced non-small-cell lung cancer (NSCLC) has brought new treatments, but also new logistic and technical considerations, to the clinician. The small size of endoscopic biopsies and the increasing number of relevant but uncommon markers has increased the need for rational approaches to molecular testing. We present the results of clinical preselection before EML4-ALK testing in a German NSCLC cohort. Patients with stage IV NSCLC were included. Clinicians were encouraged to consider screening epidermal growth factor receptor wild-type adenocarcinoma patients with a limited smoking history, relatively young age, or who had benefited from chemotherapy for a relatively long period. Break-apart fluorescence in situ hybridization using archived paraffin tissue was performed in a central facility. From April 2010 to September 2011 we included 61 patients: mean age 56.6 years, 41% women, 90% adenocarcinoma, 5% large-cell, and 5% squamous cell cancers. Only three patients had activating epidermal growth factor receptor mutations; 16.4% of patients were positive for EML4-ALK fusion. The anaplastic lymphoma kinase (ALK)-positive patients included 60% women, tended to be younger, had smoked less, and had received significantly more systemic therapy, on average 3.7 lines of treatment over 3 years, before ALK-testing compared with the ALK-negative patients. Long periods of progression-free survival were experienced by ALK-positive patients treated with pemetrexed, vinorelbine, or cetuximab. EML4-ALK fusion is uncommon, reported in about 5% of NSCLC patients; however, clinical preselection increased the yield of testing to 16.4%. EML4-ALK positive patients seem to have distinct clinical features and show long responses to a number of systemic therapies.

Small cell type neuroendocrine carcinoma colliding with squamous cell carcinoma at esophagus

PubMed Central

Yang, Luoluo; Sun, Xun; Zou, Yabin; Meng, Xiangwei

2014-01-01

Collision tumor is an extremely rare tumor which defined as the concrescence of two distinct primaries neoplasms. We report here a case of collision tumor at lower third esophagus composed of small cell type neuroendocrine carcinoma (NEC), which is an very rare, highly aggressive and poorly prognostic carcinoma and squamous cell carcinoma (SqCC). In our case, pathologically, the small cell carcinoma display the characteristic of small, round, ovoid or spindle-shaped tumor cells with scant cytoplasm, which colliding with a moderately differentiated squamous cell carcinoma. Immunohistochemical staining demonstrated positive activities for CD56, synaptophysin, 34βE12, CK 5/6, ki-67 (70%-80%), but negative for CD99, chromogranin A, and TTF-1. Accurate diagnosis was made base on these findings. PMID:24817981

Non-contact method for characterization of small size thermoelectric modules.

PubMed

Manno, Michael; Yang, Bao; Bar-Cohen, Avram

2015-08-01

Conventional techniques for characterization of thermoelectric performance require bringing measurement equipment into direct contact with the thermoelectric device, which is increasingly error prone as device size decreases. Therefore, the novel work presented here describes a non-contact technique, capable of accurately measuring the maximum ΔT and maximum heat pumping of mini to micro sized thin film thermoelectric coolers. The non-contact characterization method eliminates the measurement errors associated with using thermocouples and traditional heat flux sensors to test small samples and large heat fluxes. Using the non-contact approach, an infrared camera, rather than thermocouples, measures the temperature of the hot and cold sides of the device to determine the device ΔT and a laser is used to heat to the cold side of the thermoelectric module to characterize its heat pumping capacity. As a demonstration of the general applicability of the non-contact characterization technique, testing of a thin film thermoelectric module is presented and the results agree well with those published in the literature.

HPV- and non-HPV-related subtypes of penile squamous cell carcinoma (SCC): Morphological features and differential diagnosis according to the new WHO classification (2015).

PubMed

Sanchez, Diego F; Cañete, Sofía; Fernández-Nestosa, María José; Lezcano, Cecilia; Rodríguez, Ingrid; Barreto, José; Alvarado-Cabrero, Isabel; Cubilla, Antonio L

2015-05-01

The majority of penile carcinomas are squamous cell carcinomas originating in the squamous mucosa covering the glans, coronal sulcus, or inner surface of the foreskin, the 3 latter sites comprising the penile anatomical compartments. There is a variegated spectrum of subtypes of penile squamous cell carcinomas according to recent classification schemes. Currently, because of etiological and prognostic considerations, 2 morphologically and molecularly distinctive groups of subtypes of penile SCCs based on the presence of HPV were delineated. The predominant cell composition of tumors associated with HPV is the basaloid cell, which is the hallmark and best tissue marker for the virus. Tumors negative for the virus, however, are preferentially of lower grade and keratinizing maturing neoplasms with the exception of sarcomatoid carcinoma. HPV is detected in research studies by PCR or in situ hybridization (ISH) technologies, but p16 immunohistochemical stain is an adequate and less-expensive surrogate that is useful in the routine practice of pathology. The aim of this review is to demonstrate the variable morphological phenotypic expression of penile tumors separating non-HPV- and HPV-related neoplasms and to add morphological information that will justify subclassifying squamous cell carcinomas in a number of special subtypes. A brief discussion of the differential diagnosis in each category is also provided. Copyright © 2015 Elsevier Inc. All rights reserved.

Parent-Child Communication and Adjustment Among Children With Advanced and Non-Advanced Cancer in the First Year Following Diagnosis or Relapse.

PubMed

Keim, Madelaine C; Lehmann, Vicky; Shultz, Emily L; Winning, Adrien M; Rausch, Joseph R; Barrera, Maru; Gilmer, Mary Jo; Murphy, Lexa K; Vannatta, Kathryn A; Compas, Bruce E; Gerhardt, Cynthia A

2017-09-01

To examine parent-child communication (i.e., openness, problems) and child adjustment among youth with advanced or non-advanced cancer and comparison children. Families (n = 125) were recruited after a child's diagnosis/relapse and stratified by advanced (n = 55) or non-advanced (n = 70) disease. Comparison children (n = 60) were recruited from local schools. Children (ages 10-17) reported on communication (Parent-Adolescent Communication Scale) with both parents, while mothers reported on child adjustment (Child Behavior Checklist) at enrollment (T1) and one year (T2). Openness/problems in communication did not differ across groups at T1, but problems with fathers were higher among children with non-advanced cancer versus comparisons at T2. Openness declined for all fathers, while changes in problems varied by group for both parents. T1 communication predicted later adjustment only for children with advanced cancer. Communication plays an important role, particularly for children with advanced cancer. Additional research with families affected by life-limiting conditions is needed. © The Author 2017. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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

Prospective cohort study of clinical characteristics and management patterns for patients with non-small-cell lung cancer in the Russian Federation: EPICLIN-Lung.

PubMed

Tjulandin, S; Imyanitov, E; Moiseyenko, V; Ponomarenko, D; Gurina, L; Koroleva, I; Karaseva, V

2015-06-01

Lung cancer is a major cause of mortality in Russia. This study aimed to document the characteristics, clinical management, EGFR mutation status and outcomes of patients with non-small-cell lung cancer (NSCLC) throughout the Russian Federation to inform future management decisions. This non-interventional, prospective cohort study (clinicaltrials.gov NCT01069835) was conducted at 33 sites across the Russian Federation. Patients with confirmed NSCLC were enrolled and followed for up to 12 months or until death. Investigators collected information on patient and disease characteristics, diagnosis and treatment patterns, clinical outcomes and adverse events (AEs). A logistic regression model was used to evaluate characteristics affecting tumor EGFR mutation status. Data were analyzed from 838 patients. Most (78.4%) were male and Caucasian (98%), mean age was 58.7 years and 26.5% were never-smokers. Squamous-cell carcinoma (54.3%) was the most prevalent histology, followed by adenocarcinoma (31%). Most patients presented with advanced disease (23.7% with stage IIIA, 14.1% with stage IIIB, 25.4% with stage IV) and 10.1% of patients had EGFR-mutation-positive tumors. EGFR mutation was significantly associated with female gender, never smoking, age and adenocarcinoma histology. First- or second-line chemotherapy had been performed in 370 and 96 patients, respectively, and median progression-free survival was 35 and 19.4 weeks, respectively. For 813 patients, 194 AEs were reported at visit 1. A median of two AEs was reported for patients who had at least one AE. Study limitations include potential site selection bias, short observation period, small sample size and inclusion of fewer than average stage III-IV patients. This study contributes to a better understanding of prognostic and predictive factors of NSCLC in the Russian Federation, which will enable optimal treatment selection in future clinical practice. Epidemiology of EGFR mutations in this NSCLC cohort was

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

Isolation and Characterization of Circulating Tumor Cells in Squamous Cell Carcinoma of the Lung Using a Non-EpCAM-Based Capture Method.

PubMed

Bozzetti, Cecilia; Quaini, Federico; Squadrilli, Anna; Tiseo, Marcello; Frati, Caterina; Lagrasta, Costanza; Azzoni, Cinzia; Bottarelli, Lorena; Galetti, Maricla; Alama, Angela; Belletti, Silvana; Gatti, Rita; Passaro, Antonio; Gradilone, Angela; Cavazzoni, Andrea; Alfieri, Roberta; Petronini, Pier Giorgio; Bonelli, Mara; Falco, Angela; Carubbi, Cecilia; Pedrazzi, Giuseppe; Nizzoli, Rita; Naldi, Nadia; Pinto, Carmine; Ardizzoni, Andrea

2015-01-01

The exclusion of circulating tumor cells (CTCs) that have lost epithelial antigens during the epithelial-to-mesenchymal transition (EMT) process by using Epithelial Cell Adhesion Molecule (EpCAM) based capture methods is still a matter of debate. In this study, cells obtained after depletion procedure from blood samples of squamous cell lung cancer (SQCLC) patients were identified based on morphology and characterized with the combination of FISH assessment and immunophenotypic profile. Five mL blood samples, collected from 55 advanced SQCLC patients, were analyzed by a non-EpCAM-based capture method. After depletion of leukocytes and erythroid cells, the negative fraction was characterized by both FISH using a fibroblast growth factor receptor 1 (FGFR1) probe and by immunocytochemistry. Thirty healthy donors were also tested. Based on morphology (nuclear dimension ≥10 μm, shape and hypercromatic aspect) suspicious circulating cells clearly distinguishable from contaminant leukocytes were observed in 49/55 (89%) SQCLC patients. Thirty-four of the 44 (77%) samples evaluable for FGFR1 FISH showed ≥ 6 FGFR1 gene copy number on average per cell. Vimentin expression involved 43% (18/42) of pooled circulating SQCLC cells, whereas only 29% (14/48) were EpCAM positive. Confocal microscopy confirmed the localization of FGFR1 probe in suspicious circulating cells. Suspicious circulating elements were also observed in healthy donors and did not show any epithelial associated antigens. A significantly lower number of suspicious circulating cells in healthy donors compared to SQCLC patients was found. Among the heterogeneous cell population isolated by depletion procedure, the coexistence of cells with epithelial and/or mesenchymal phenotype suggests that EMT may participate to transendothelial invasion and migration of tumor cells in advanced SQCLC. The finding of cells with neither EpCAM or EMT phenotype, retrieved after non-EpCAM-based systems, underlines the presence

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.

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.

Assessing the extent of non-aggressive cancer in clinically detected stage I non-small cell lung cancer.

PubMed

Kale, Minal S; Sigel, Keith; Mhango, Grace; Wisnivesky, Juan P

2018-05-01

Overdiagnosis among clinically detected lung cancers likely consists of cases that are non-aggressive and slowly progressive and will never disseminate, cause symptoms or be a threat to a subject's survival, even if untreated. In this study, we estimate the prevalence of non-aggressive lung cancers from a large, population-based cancer registry. We identified individuals ≥65 years with histologically confirmed, untreated stage I non-small cell lung cancers (NSCLCs) from the Surveillance, Epidemiology, and End Results-Medicare registry. We estimated the rate of non-aggressive lung cancers by determining the point at which the cumulative lung cancer-specific survival curve no longer changed (ie, the slope approaches zero). At this point, there are no additional deaths due to progressive lung cancer observed among untreated patients after adjusting for deaths from competing risks (these long-term survivors can be considered 'non-aggressive cases). The overall rate of non-aggressive cancers among 2197 clinically detected cases of untreated stage I NSCLC was 2.4%, 95% CI: 1.0% to 3.8%. The rate of non-aggressive cancer was 1.9% (95% CI: 0.0% to 4.9%) for women and 2.4% (95% CI: 0.7% to 4.1%) for men (p=0.84). When stratifying by tumour size, non-aggressive cancer rates were 10.2% (95% CI: 0.0% to 29.3%), 2.1% (95% CI: 0.0% to 9.2%), 4.9% (95% CI: 0.0% to 10.3%), 1.8% (95% CI: 0.0% to 5.2%) and 0.0% (95% CI: 0.0% to 1.0%) for tumour sizes <15 mm, 15-24 mm, 25-34 mm, 35-44 mm and ≥45 mm, respectively. In comparison with the smallest tumour sizes (<15 mm), the rates of non-aggressive cancers were not statistically significantly different for tumour sizes 15-24 mm (p=0.36), 25-34 mm (p=0.57), 35-44 mm (p=0.38) and tumour sizes >45 mm (p=0.30). We found relatively low rates of non-aggressive cancers among clinically detected, stage I NSCLC regardless of sex or size. Our findings suggest that most clinically diagnosed early stage cancers should be treated with

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

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.

Hot spot mutations in Finnish non-small cell lung cancers.

PubMed

Mäki-Nevala, Satu; Sarhadi, Virinder Kaur; Rönty, Mikko; Kettunen, Eeva; Husgafvel-Pursiainen, Kirsti; Wolff, Henrik; Knuuttila, Aija; Knuutila, Sakari

2016-09-01

Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM). Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PIK3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure. Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

PD-L1 expression is associated with p16INK4A expression in non-oropharyngeal head and neck squamous cell carcinoma

PubMed Central

Chen, San-Chi; Chang, Peter Mu-Hsin; Wang, Hsiao-Jung; Tai, Shyh-Kuan; Chu, Pen-Yuan; Yang, Muh-Hwa

2018-01-01

PD-L1 expression is critical in helping tumor cells evade the immune system. However, the level of PD-L1 expression in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC) and its association with patient prognosis remains unclear. A retrospective clinicopathological analysis was performed on 106 patients with non-OPHNSCC diagnosed between 2007 and 2014. In the current study, tissue arrays from paraffin-embedded non-OPHNSCC samples obtained from patients were constructed, and PD-L1 and p16INK4A expression were determined using immunohistochemistry. Systemic inflammatory factors, including C-reactive protein, serum white blood cell, neutrophil, monocyte and lymphocyte counts were also analyzed. The current study demonstrated that PD-L1 was overexpressed in 32.1% (34/106) and p16INK4A in 20.8% (22/106) of patients. The expression of PD-L1 was associated with p16INK4A expression (P<0.01) but was not associated with levels of systemic inflammatory factors. Tumor stage was determined to be a significant prognostic value (stage I/II vs. III/IV, P=0.03), however, PD-L1, p16INK4A or other clinicopathological factors were not. The current study identified an association between PD-L1 and p16INK4A expression in non-OPHNSCC. This may facilitate the development of anti-PD1/PDL1 therapies to treat patients with head and neck cancer. PMID:29434933

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

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.

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.

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.

Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update.

PubMed

Hanna, Nasser; Johnson, David; Temin, Sarah; Baker, Sherman; Brahmer, Julie; Ellis, Peter M; Giaccone, Giuseppe; Hesketh, Paul J; Jaiyesimi, Ishmael; Leighl, Natasha B; Riely, Gregory J; Schiller, Joan H; Schneider, Bryan J; Smith, Thomas J; Tashbar, Joan; Biermann, William A; Masters, Gregory

2017-10-20

Purpose Provide evidence-based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC). Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of randomized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence-Based Care's update of a previous ASCO search. Results This guideline update reflects changes in evidence since the previous guideline update. Fourteen randomized controlled trials provide the evidence base; earlier phase trials also informed recommendation development. Recommendations New or revised recommendations include the following. Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma (without positive markers, eg, EGFR/ALK /ROS1), if the patient has high programmed death ligand 1 (PD-L1) expression, pembrolizumab should be used alone; if the patient has low PD-L1 expression, clinicians should offer standard chemotherapy. All other clinical scenarios follow 2015 recommendations. Regarding second-line treatment in patients who received first-line chemotherapy, without prior immune checkpoint therapy, if NSCLC tumor is positive for PD-L1 expression, clinicians should use single-agent nivolumab, pembrolizumab, or atezolizumab; if tumor has negative or unknown PD-L1 expression, clinicians should use nivolumab or atezolizumab. All immune checkpoint therapy is recommended alone plus in the absence of contraindications. For patients who received a prior first-line immune checkpoint inhibitor, clinicians should offer standard chemotherapy. For patients who cannot receive immune checkpoint inhibitor after chemotherapy, docetaxel is recommended; in patients with nonsquamous NSCLC, pemetrexed is recommended. In patients with a sensitizing EGFR mutation, disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy, and

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.

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

Incidence and clinical implication of tumor cavitation in patients with advanced non-small cell lung cancer induced by Endostar, an angiogenesis inhibitor.

PubMed

Huang, Chun; Wang, Xuan; Wang, Jing; Lin, Li; Liu, Zhujun; Xu, Wenjing; Wang, Liuchun; Xiao, Jianyu; Li, Kai

2014-09-01

Antiangiogenesis plays a key role in the treatment of non-small lung cancer (NSCLC). We observed the cavitation of lesions in patients with stage IIIB/IV NSCLC treated with Endostar and vinorelbine-cisplatin (NP) chemotherapy, and evaluated the imaging characteristics and clinical outcome of patients who developed tumor cavitation. Our study included 105 untreated NSCLC patients who received Endostar in combination with NP chemotherapy at the Tianjin Lung Cancer Center. Chest computed tomography (CT) was performed to evaluate the efficacy every two cycles. The number of activated circulating endothelial cells (aCECs) was measured by flow cytometry. Rates of tumor cavitation were documented and their clinical CT imaging data were analyzed. Tumor cavitation occurred in 11 of the 105 (10.5%) patients treated with Endostar and NP. The response rates were 37.2% (35/94) in patients without cavitation, 27.3% (3/11) evaluated by Response Evaluation Criteria in Solid Tumors, and 100.0% (11/11) if evaluated by an alternate method in patients who developed cavitation. Three of the 11 cases with cavitation had a centrally located tumor. No patients had hemoptysis or any other severe side effects. Compared with patients not developing cavitation, cavity formation resulted in a longer median survival time (13.6 vs. 11.8 months, P = 0.011) and an increase in the number of aCECs (244.4/10(5) vs. 23.3/10(5), P = 0.000). Intratumoral cavitation induced by Endostar is common in NSCLC patients, and is not correlated with squamous histology, tumor location or pulmonary hemorrhage. Cavitation might have a significant effect on the number of aCECs and overall prognosis.

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.

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

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

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.

The role of molecular pathology in non-small-cell lung carcinoma—now and in the future

PubMed Central

Brandao, G.D.A.; Brega, E.F.; Spatz, A.

2012-01-01

In recent years, better understanding of the molecular biology of non-small-cell lung carcinoma (nsclc) has led to a revolution in the work-up of these neoplasms. As a pathology diagnosis, “nsclc” without further attempt at subclassification is no longer accepted as a standard of care; separating squamous cell carcinoma from adenocarcinoma and large-cell carcinoma carries implications for prognosis and treatment decisions. Currently, detection of the presence in nsclc of mutations involving the epidermal growth factor receptor (EGFR) gene and fusion of the N-terminal portion of the protein encoded by EML4 (echinoderm microtubule-associated protein-like 4 gene) with the intracellular signaling portion of the receptor tyrosine kinase encoded by ALK (anaplastic lymphoma kinase gene)—that is, EML4–ALK—and variants has become routine in many centres because patients having tumours harbouring such alterations might benefit from tyrosine kinase inhibitors as part of their treatment regimen. The purpose of the present review is to highlight important aspects of the screening for molecular derangements in nsclc and to briefly discuss the emergence of possible future biomarkers. PMID:22787408

Adherence of non-O157 Shiga-toxin Escherichia coli to bovine recto-anal junction squamous epithelial cells appears to be mediated by mechanisms distinct from those used by O157

USDA-ARS?s Scientific Manuscript database

This study presents evidence that the pattern of adherence of clinically relevant non-O157 Shiga-toxin producing Escherichia coli (STEC) to bovine recto-anal junction squamous epithelial cells (RSE) is similar to that of O157, although the mechanisms of adherence appear to be distinct. Our results f...

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.

An Immunohistochemical Study of Anaplastic Lymphoma Kinase and Epidermal Growth Factor Receptor Mutation in Non-Small Cell Lung Carcinoma

PubMed Central

Verma, Sonal; Kumari, Malti; Mehrotra, Raj; Kushwaha, R A S; Goel, Madhumati; Kumar, Ashutosh; Kant, Surya

2017-01-01

Introduction Lung cancer is one of the leading causes of cancer related death. Targeted treatment for specific markers may help in reducing the cancer related morbidity and mortality. Aim To study expression of Anaplastic Lymphoma Kinase (ALK)and Epidermal Growth Factor Receptor (EGFR) mutations in patients of Non-Small Cell Lung Cancer NSCLC, that are the targets for specific ALK inhibitors and EGFR tyrosine kinase inhibitors. Materials and Methods Total 69 cases of histologically diagnosed NSCLC were examined retrospectively for immunohistochemical expression of EGFR and ALK, along with positive control of normal placental tissue and anaplastic large cell lymphoma respectively. Results Of the NSCLC, Squamous Cell Carcinoma (SCC) accounted for 71.0% and adenocarcinoma was 26.1%. ALK expression was seen in single case of 60-year-old female, non-smoker with adenocarcinoma histology. EGFR expression was seen in both SCC (59.18%) and adenocarcinoma in (77.78%) accounting for 63.77% of all cases. Both ALK and EGFR mutation were mutually exclusive. Conclusion EGFR expression was seen in 63.77% of cases, highlighting the importance of its use in routine analysis, for targeted therapy and better treatment results. Although, ALK expression was seen in 1.45% of all cases, it is an important biomarker in targeted cancer therapy. Also, the mutually exclusive expression of these two markers need further studies to develop a diagnostic algorithm for NSCLC patients. PMID:28892905

An Immunohistochemical Study of Anaplastic Lymphoma Kinase and Epidermal Growth Factor Receptor Mutation in Non-Small Cell Lung Carcinoma.

PubMed

Verma, Sonal; Kumar, Madhu; Kumari, Malti; Mehrotra, Raj; Kushwaha, R A S; Goel, Madhumati; Kumar, Ashutosh; Kant, Surya

2017-07-01

Lung cancer is one of the leading causes of cancer related death. Targeted treatment for specific markers may help in reducing the cancer related morbidity and mortality. To study expression of Anaplastic Lymphoma Kinase (ALK)and Epidermal Growth Factor Receptor (EGFR) mutations in patients of Non-Small Cell Lung Cancer NSCLC, that are the targets for specific ALK inhibitors and EGFR tyrosine kinase inhibitors. Total 69 cases of histologically diagnosed NSCLC were examined retrospectively for immunohistochemical expression of EGFR and ALK, along with positive control of normal placental tissue and anaplastic large cell lymphoma respectively. Of the NSCLC, Squamous Cell Carcinoma (SCC) accounted for 71.0% and adenocarcinoma was 26.1%. ALK expression was seen in single case of 60-year-old female, non-smoker with adenocarcinoma histology. EGFR expression was seen in both SCC (59.18%) and adenocarcinoma in (77.78%) accounting for 63.77% of all cases. Both ALK and EGFR mutation were mutually exclusive. EGFR expression was seen in 63.77% of cases, highlighting the importance of its use in routine analysis, for targeted therapy and better treatment results. Although, ALK expression was seen in 1.45% of all cases, it is an important biomarker in targeted cancer therapy. Also, the mutually exclusive expression of these two markers need further studies to develop a diagnostic algorithm for NSCLC patients.

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

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.

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.

Reevaluation and reclassification of resected lung carcinomas originally diagnosed as squamous cell carcinoma using immunohistochemical analysis

PubMed Central

Kadota, Kyuichi; Nitadori, Jun-ichi; Rekhtman, Natasha; Jones, David R.; Adusumilli, Prasad S.; Travis, William D.

2015-01-01

Currently, non-small cell lung carcinomas are primarily classified by light microscopy. However, recent studies have shown that poorly-differentiated tumors are more accurately classified by immunohistochemistry. In this study, we investigated the use of immunohistochemical analysis in reclassifying lung carcinomas that were originally diagnosed as squamous cell carcinoma. Tumor slides and blocks were available for histologic evaluation, and tissue microarrays were constructed from 480 patients with resected lung carcinomas originally diagnosed as squamous cell carcinoma between 1999 and 2009. Immunohistochemistry for p40, p63, thyroid transcription factor-1 (TTF-1; clone SPT24 and 8G7G3/1), Napsin A, Chromogranin A, Synaptophysin, and CD56 were performed. Staining intensity (weak, moderate, or strong) and distribution (focal or diffuse) were also recorded. Of all, 449 (93.5%) patients were confirmed as having squamous cell carcinomas; the cases were mostly diffusely positive for p40 and negative for TTF-1 (8G7G3/1). Twenty cases (4.2%) were reclassified as adenocarcinoma since they were positive for TTF-1 (8G7G3/1 or SPT24) with either no or focal p40 expression, and all of them were poorly-differentiated with squamoid morphology. In addition, 1 case was reclassified as adenosquamous carcinoma, 4 cases as large cell carcinoma, 4 cases as large cell neuroendocrine carcinoma, and 2 cases as small cell carcinoma. In poorly-differentiated non-small cell lung carcinomas, an accurate distinction between squamous cell carcinoma and adenocarcinoma cannot be reliably determined by morphology alone and requires immunohistochemical analysis, even in resected specimens. Our findings suggest that TTF-1 8G7G3/1 may be better suited as the primary antibody in differentiating adenocarcinoma from squamous cell carcinoma. PMID:25871623

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

Measuring non-recurrent congestion in small to medium sized urban areas.

DOT National Transportation Integrated Search

2013-05-01

Understanding the relative magnitudes of recurrent vs. non-recurrent congestion in an urban area is critical to the selection of proper countermeasures and the appropriate allocation of resources to address congestion problems. Small to medium sized ...

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.

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

Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants.

PubMed

Li, Yan; Zhang, Tongtong; Zhang, Jing; Li, Wenbin; Yuan, Pei; Xing, Puyuan; Zhang, Zhou; Chuai, Shannon; Li, Junling; Ying, Jianming

2018-04-01

Anaplastic lymphoma kinase (ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. Among 96 ALK-rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. The median Progression-free survival (PFS) of the 96 ALK-rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4-ALK variants and non EML4-ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4-ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4-ALK variants. Our results indicate prolonged PFS in patients with EML4-ALK variant 2. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

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

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.

Cigarette smoking and p16INK4α gene promoter hypermethylation in non-small cell lung carcinoma patients: a meta-analysis.

PubMed

Zhang, Bo; Zhu, Wei; Yang, Ping; Liu, Tao; Jiang, Mei; He, Zhi-Ni; Zhang, Shi-Xin; Chen, Wei-Qing; Chen, Wen

2011-01-01

Aberrant methylation of promoter DNA and transcriptional repression of specific tumor suppressor genes play an important role in carcinogenesis. Recently, many studies have investigated the association between cigarette smoking and p16(INK4α) gene hypermethylation in lung cancer, but could not reach a unanimous conclusion. Nineteen cross-sectional studies on the association between cigarette smoking and p16(INK4α) methylation in surgically resected tumor tissues from non-small cell lung carcinoma (NSCLC) patients were identified in PubMed database until June 2011. For each study, a 2×2 cross-table was extracted. In total, 2,037 smoker and 765 nonsmoker patients were pooled with a fixed-effects model weighting for the inverse of the variance. Overall, the frequency of p16(INK4α) hypermethylation was higher in NSCLC patients with smoking habits than that in non-smoking patients (OR = 2.25, 95% CI = 1.81-2.80). The positive association between cigarette smoking and p16(INK4α) hypermethylation was similar in adenocarcinoma and squamous-cell carcinoma. In the stratified analyses, the association was stronger in Asian patients and in the studies with larger sample sizes. Cigarette smoking is positively correlated to p16(INK4α) gene hypermethylation in NSCLC patients.

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.

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...

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

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

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.

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.

Advancements in Non-steroidal Antiandrogens as Potential Therapeutic Agents for the Treatment of Prostate Cancer.

PubMed

Kaur, Paranjeet; Khatik, Gopal L

2016-01-01

Prostate cancer (PCa) is a leading cause of death in men worldwide. The main reason for the progression of prostate cancer is identified as over activation of androgen receptor (AR) through androgens. Its development can be diagnosed by monitoring the prostate specific antigen (PSA). Treatment of PCa includes prostatectomy, radiotherapy, and chemotherapy, among them chemotherapy is normally employed in early and advanced prostate cancer. Chemotherapy mainly includes two classes of drugs which are steroidal and non-steroidal antiandrogens. The non-steroidal classes of compounds are preferred over steroidal because they are relatively safe, cost effective and diverse. Non-steroidal drugs are commonly used for the treatment of PCa, however these drugs are associated with serious side effects and acquired resistance. So researchers are working in the direction to develop better analogue which can address the issue related to resistant type of prostate cancer. This review discusses the advancement in the non-steroidal antiandrogens which offers a better potential in the treatment of prostate cancer.

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

Prior history of non-melanoma skin cancer is associated with increased mortality in patients with chronic lymphocytic leukemia

PubMed Central

Toro, Jorge R.; Blake, Patrick W.; Björkholm, Magnus; Kristinsson, Sigurdur Y.; Wang, Zhuoqiao; Landgren, Ola

2009-01-01

We investigated whether a previous diagnosis of non-melanoma skin cancer among chronic lymphocytic leukemia patients is a predictor of poor outcome. Using the Swedish Cancer Registry, we conducted a population-based study to evaluate the survival patterns among chronic lymphocytic leukemia patients with and without non-melanoma skin cancer. Cox proportional hazards regression models were used and Kaplan-Meier curves were constructed. Of a total of 12,041 chronic lymphocytic leukemia cases identified, 236 cases, including 111 squamous cell cancer, had a prior history of non-melanoma skin cancer. Chronic lymphocytic leukemia patients with a prior history of non-melanoma skin cancer had a 1.29-fold (95% CI 1.10–1.52; p=0.0024) increased risk of dying; and those with a history of squamous cell cancer had a further elevated 1.86-fold (95% CI 1.46–2.36; p<0.0001) risk of dying. Kaplan-Meier plots showed that patients with a history of non-melanoma skin cancer, particularly those with squamous cell cancer, had significantly poorer survival than chronic lymphocytic leukemia patients without non-melanoma skin cancer (p<0.0001; log-rank test). Non-melanoma skin cancer may be a novel clinical predictor of worse chronic lymphocytic leukemia outcome. PMID:19794092