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Sample records for dose escalated intensity

  1. Escalated median dose for pituitary macroadenomas using intensity-modulated radiation therapy

    SciTech Connect

    Robinson, D.; Murray, B.; Underwood, L.; Halls, S.; Roa, W

    2004-03-31

    Three-dimensional conformal radiotherapy (3D CRT) has become an established treatment for pituitary macroadenomas. This study is an investigation into the possible dosimetric advantages of intensity-modulated radiotherapy for such critically located tumors. Three consecutive patients with pituitary macroadenoma previously treated with 3D CRT were replanned with inverse-planned IMRT using Helax-TMS (V.6.0, Helax AB, Uppsala, Sweden. Fusion of computed tomography (CT) with postoperative magnetic resonance imaging (MRI) was performed within the planning system to define the gross tumor volume (GTV), planning target volume (PTV), and normal structures including the optic chiasm. Dose-volume histograms (DVHs) for the 3D CRT plans were then compared with those of the corresponding prospective IMRT plans. Both techniques maintained critical structure doses below tolerance levels while maintaining a minimum dose of 45 Gy to 100% of the PTV. While IMRT plans deliver consistently more heterogeneous dose distributions to the PTV, the median PTV dose is elevated in the IMRT plans compared with the 3D CRT plans. For critically located tumors like these pituitary macroadenomas, IMRT allows escalation of the median dose to the tumor without an accompanying loss in critical structure sparing or creating unacceptable cold spots within the PTV.

  2. Positron Emission Tomography-Guided, Focal-Dose Escalation Using Intensity-Modulated Radiotherapy for Head and Neck Cancer

    SciTech Connect

    Madani, Indira . E-mail: indira@krtkg1.ugent.be; Duthoy, Wim; Derie, Cristina R.N.; De Gersem, Werner Ir.; Boterberg, Tom; Saerens, Micky; Jacobs, Filip Ir.; Gregoire, Vincent; Lonneux, Max; Vakaet, Luc; Vanderstraeten, Barbara; Bauters, Wouter; Bonte, Katrien; Thierens, Hubert; Neve, Wilfried de

    2007-05-01

    Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography ({sup 18}F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was applied for the remaining 22 fractions of 2.16 Gy. Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted {sup 18}F-FDG-PET-delineated region. Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.

  3. Phase I dose-escalation study of helical intensity-modulated radiotherapy-based stereotactic body radiotherapy for hepatocellular carcinoma

    PubMed Central

    Kim, Jun Won; Seong, Jinsil; Lee, Ik Jae; Woo, Joong Yeol; Han, Kwang-Hyub

    2016-01-01

    Background Phase I trial was conducted to determine feasibility and toxicity of helical intensity-modulated radiotherapy (IMRT)-based stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC). Results Eighteen patients (22 lesions) were enrolled. With no DLT at 52 Gy (13 Gy/fraction), protocol was amended for further escalation to 60 Gy (15 Gy/fraction). Radiologic complete response rate was 88.9%. Two outfield intrahepatic, 2 distant, 4 concurrent local and outfield, and 1 concurrent local, outfield and distant failures (no local failure at dose levels 3–4) occurred. The worst toxicity was grade 3 hematologic in five patients, with no gastrointestinal toxicity > grade 1. At median follow-up of 28 months for living patients, 2-year local control, progression-free (PFS), and overall survival rates were 71.3%, 49.4% and 69.3%, respectively. Multi-segmental recurrences prior to SBRT was independent prognostic factor for PFS (p = 0.033). Materials and Methods Eligible patients had Child-Pugh's class A or B, unresectable HCC, ≤ 3 lesions, and cumulative tumor diameter ≤ 6 cm. Starting at 36 Gy in four fractions, dose was escalated with 2 Gy/fraction per dose-level. CTCAE v 3.0 ≥ grade 3 gastrointestinal toxicity and radiation induced liver disease defined dose-limiting toxicity (DLT). Conclusions Helical IMRT-based SBRT was tolerable and showed encouraging results. Confirmatory phase II trial is underway. PMID:27213593

  4. A dosimetric analysis of dose escalation using two intensity-modulated radiation therapy techniques in locally advanced pancreatic carcinoma

    SciTech Connect

    Brown, Michael W.; Ning, Holly; Arora, Barbara; Albert, Paul S.; Poggi, Matthew; Camphausen, Kevin; Citrin, Deborah . E-mail: citrind@mail.nih.gov

    2006-05-01

    Purpose: To perform an analysis of three-dimensional conformal radiation therapy (3D-CRT), sequential boost intensity-modulated radiation therapy (IMRTs), and integrated boost IMRT (IMRTi) for dose escalation in unresectable pancreatic carcinoma. Methods and Materials: Computed tomography images from 15 patients were used. Treatment plans were generated using 3D-CRT, IMRTs, and IMRTi for dose levels of 54, 59.4, and 64.8 Gy. Plans were analyzed for target coverage, doses to liver, kidneys, small bowel, and spinal cord. Results: Three-dimensional-CRT exceeded tolerance to small bowel in 1 of 15 (6.67%) patients at 54 Gy, and 4 of 15 (26.7%) patients at 59.4 and 64.8 Gy. 3D-CRT exceeded spinal cord tolerance in 1 of 15 patients (6.67%) at 59.4 Gy and liver constraints in 1 of 15 patients (6.67%) at 64.8 Gy; no IMRT plans exceeded tissue tolerance. Both IMRT techniques reduced the percentage of total kidney volume receiving 20 Gy (V20), the percentage of small bowel receiving 45 Gy (V45), and the percentage of liver receiving 35 Gy (V35). IMRTi appeared superior to IMRTs in reducing the total kidney V20 (p < 0.0001), right kidney V20 (p < 0.0001), and small bowel V45 (p = 0.02). Conclusions: Sequential boost IMRT and IMRTi improved the ability to achieve normal tissue dose goals compared with 3D-CRT. IMRTi allowed dose escalation to 64.8 Gy with acceptable normal tissue doses and superior dosimetry compared with 3D-CRT and IMRTs.

  5. Impact of Obesity on Outcomes After Definitive Dose Escalated Intensity Modulated Radiation Therapy For Localized Prostate Cancer

    PubMed Central

    Wang, Lora; Murphy, Colin; Ruth, Karen; Zaorsky, Nicholas; Smaldone, Marc; Sobczak, Mark; Kutikov, Alexander; Viterbo, Rosalia; Horwitz, Eric

    2015-01-01

    INTRODUCTION Previous publications have shown conflicting results regarding body mass index (BMI) and prostate cancer (CaP) outcomes after definitive radiotherapy prior to the dose escalation era. Our goal is to determine whether increasing BMI is associated with CaP outcomes in men with localized CaP treated with dose escalated radiotherapy. METHODS We identified patients with localized (T1b-T4N0M0) CaP treated with definitive intensity modulated radiation therapy (IMRT) and image guidance (IGRT) from 2001–2010. BMI was analyzed as a continuous variable. Adjusting for confounders, multivariable competing risk and Cox proportional hazards regression models were used to assess the association between BMI category and the risk of biochemical failure (BF), distant metastasis (DM), cause-specific mortality (CSM) and overall mortality (OM). RESULTS Of the 1,442 patients identified, there were 20% with BMI<25 kg/m2, 48% with BMI 25–29.9 kg/m2, 23% with BMI 30–34.9 kg/m2, 6% with 35–39.9 kg/m2, and 4% with BMI≥40 kg/m2. Median follow-up was 47.6 months (range 1–145) with median age of 68 years (range 36–89). Median dose was 78Gy (range 76–80) and 30% of patients received androgen deprivation therapy. Increasing BMI was inversely associated with age (p<0.001) and pre-treatment PSA (p=0.018). On multivariable analysis, increasing BMI was associated with increased risk of BF (HR=1.03[95% CI 1.00–1.07], p=0.042), DM (HR=1.07[1.02–1.11], p=0.004), CSM (HR=1.15[1.07–1.23], p<0.001), and OM (HR=1.05[1.02–1.08], p=0.004). CONCLUSION For CaP patients receiving dose-escalated IMRT with IGRT, increasing BMI appears to be associated with an increased risk of biochemical failure, distant metastases development, cause-specific and overall survival. PMID:26033633

  6. Role of Intensity-Modulated Radiotherapy in Reducing Toxicity in Dose Escalation for Localized Prostate Cancer

    SciTech Connect

    Al-Mamgani, Abrahim Heemsbergen, Wilma D.; Peeters, Stephanie T.H.; Lebesque, Joos V.

    2009-03-01

    Purpose: To compare the acute and late gastrointestinal (GI) and genitourinary (GU) toxicity in prostate cancer patients treated to a total dose of 78 Gy with either a three-conformal radiotherapy technique with a sequential boost (SEQ) or a simultaneous integrated boost using intensity-modulated radiotherapy (SIB-IMRT). Patients and Methods: A total of 78 prostate cancer patients participating in the randomized Dutch trial comparing 68 Gy and 78 Gy were the subject of this analysis. They were all treated at the same institution to a total dose of 78 Gy. The median follow-up was 76 and 56 months for the SEQ and SIB-IMRT groups, respectively. The primary endpoints were acute and late GI and GU toxicity. Results: A significantly lower incidence of acute Grade 2 or greater GI toxicity occurred in patients treated with SIB-IMRT compared with SEQ (20% vs. 61%, p = 0.001). For acute GU toxicity and late GI and GU toxicity, the incidence was lower after SIB-IMRT, but these differences were not statistically significant. No statistically significant difference were found in the 5-year freedom from biochemical failure rate (Phoenix definition) between the two groups (70% for the SIB-IMRT group vs. 61% for the SEQ group, p = 0.3). The same was true for the 5-year freedom from clinical failure rate (90% vs. 72%, p = 0.07). Conclusion: The results of our study have shown that SIB-IMRT reduced the toxicity without compromising the outcome in patients with localized prostate cancer treated to 78 Gy radiation.

  7. Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study

    SciTech Connect

    Vainshtein, Jeffrey M.; Schipper, Matthew; Zalupski, Mark M.; Lawrence, Theodore S.; Abrams, Ross; Francis, Isaac R.; Khan, Gazala; Leslie, William; Ben-Josef, Edgar

    2013-05-01

    Purpose: Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. Methods and Materials: Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. Results: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). Conclusions: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression

  8. Hypofractionated Boost to the Dominant Tumor Region With Intensity Modulated Stereotactic Radiotherapy for Prostate Cancer: A Sequential Dose Escalation Pilot Study

    SciTech Connect

    Miralbell, Raymond; Molla, Meritxell; Rouzaud, Michel; Hidalgo, Alberto; Toscas, Jose Ignacio; Lozano, Joan; Sanz, Sergi B.Sc.; Ares, Carmen; Jorcano, Sandra; Linero, Dolors; Escude, Lluis

    2010-09-01

    Purpose: To evaluate the feasibility, tolerability, and preliminary outcomes in patients with prostate cancer treated according to a hypofractionated dose escalation protocol to boost the dominant tumor-bearing region of the prostate. Methods and Materials: After conventional fractionated external radiotherapy to 64 to 64.4Gy, 50 patients with nonmetastatic prostate cancer were treated with an intensity-modulated radiotherapy hypofractionated boost under stereotactic conditions to a reduced prostate volume to the dominant tumor region. A rectal balloon inflated with 60cc of air was used for internal organ immobilization. Five, 8, and 8 patients were sequentially treated with two fractions of 5, 6, or 7Gy, respectively (normalized total dose in 2Gy/fraction [NTD{sub 2Gy}] < 100Gy, low-dose group), whereas 29 patients received two fractions of 8Gy each (NTD{sub 2Gy} > 100Gy, high-dose group). Androgen deprivation was given to 33 patients. Acute and late toxicities were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) scoring system. Results: Two patients presented with Grade 3 acute urinary toxicity. The 5-year probabilities of {>=}Grade 2 late urinary and late low gastrointestinal (GI) toxicity-free survival were 82.2% {+-} 7.4% and 72.2% {+-} 7.6%, respectively. The incidence and severity of acute or late toxicities were not correlated with low- vs. high-dose groups, pelvic irradiation, age, or treatment with or without androgen deprivation. The 5-year biochemical disease-free survival (b-DFS) and disease-specific survival were 98% {+-} 1.9% and 100%, respectively. Conclusion: Intensity-modulated radiotherapy hypofractionated boost dose escalation under stereotactic conditions was feasible, and showed excellent outcomes with acceptable long-term toxicity. This approach may well be considered an alternative to high-dose-rate brachytherapy.

  9. Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer

    PubMed Central

    2013-01-01

    Background As dose-escalation in prostate cancer radiotherapy improves cure rates, a major concern is rectal toxicity. We prospectively assessed an innovative approach of hydrogel injection between prostate and rectum to reduce the radiation dose to the rectum and thus side effects in dose-escalated prostate radiotherapy. Methods Acute toxicity and planning parameters were prospectively evaluated in patients with T1-2 N0 M0 prostate cancer receiving dose-escalated radiotherapy after injection of a hydrogel spacer. Before and after hydrogel injection, we performed MRI scans for anatomical assessment of rectal separation. Radiotherapy was planned and administered to 78 Gy in 39 fractions. Results From eleven patients scheduled for spacer injection the procedure could be performed in ten. In one patient hydrodissection of the Denonvillier space was not possible. Radiation treatment planning showed low rectal doses despite dose-escalation to the target. In accordance with this, acute rectal toxicity was mild without grade 2 events and there was complete resolution within four to twelve weeks. Conclusions This prospective study suggests that hydrogel injection is feasible and may prevent rectal toxicity in dose-escalated radiotherapy of prostate cancer. Further evaluation is necessary including the definition of patients who might benefit from this approach. Trial registration: German Clinical Trials Register DRKS00003273. PMID:23336502

  10. Dose-Escalated Intensity-Modulated Radiotherapy Is Feasible and May Improve Locoregional Control and Laryngeal Preservation in Laryngo-Hypopharyngeal Cancers

    SciTech Connect

    Miah, Aisha B.; Bhide, Shreerang A.; Guerrero-Urbano, M. Teresa; Clark, Catharine; Bidmead, A. Margaret; St Rose, Suzanne; Barbachano, Yolanda; A'Hern, Roger; Tanay, Mary; Hickey, Jennifer; Nicol, Robyn; Newbold, Kate L.; Harrington, Kevin J.; Nutting, Christopher M.

    2012-02-01

    Purpose: To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). Methods and Materials: A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and late toxicities and tumor control rates were recorded. Results: Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5-96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2. Conclusions: At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III

  11. Superiority of helical tomotherapy on liver sparing and dose escalation in hepatocellular carcinoma: a comparison study of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy

    PubMed Central

    Zhao, Qianqian; Wang, Renben; Zhu, Jian; Jin, Linzhi; Zhu, Kunli; Xu, Xiaoqing; Feng, Rui; Jiang, Shumei; Qi, Zhonghua; Yin, Yong

    2016-01-01

    Background and purpose To compare the difference of liver sparing and dose escalation between three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (HT) for hepatocellular carcinoma. Patients and methods Sixteen unresectable HCC patients were enrolled in this study. First, some evaluation factors of 3DCRT, IMRT, and HT plans were calculated with prescription dose at 50 Gy/25 fractions. Then, the doses were increased using HT or IMRT independently until either the plans reached 70 Gy or any normal tissue reached the dose limit according to quantitative analysis of normal tissue effects in the clinic criteria. Results The conformal index of 3DCRT was lower than that of IMRT (P<0.001) or HT (P<0.001), and the homogeneity index of 3DCRT was higher than that of IMRT (P<0.001) or HT (P<0.001). HT took the longest treatment time (P<0.001). For V50% (fraction of normal liver treated to at least 50% of the isocenter dose) of the normal liver, there was a significant difference: 3DCRT > IMRT > HT (P<0.001). HT had a lower Dmean (mean dose) and V20 (Vn, the percentage of organ volume receiving ≥n Gy) of liver compared with 3DCRT (P=0.005 and P=0.005, respectively) or IMRT (P=0.508 and P=0.007, respectively). Dmean of nontarget normal liver and V30 of liver were higher for 3DCRT than IMRT (P=0.005 and P=0.005, respectively) or HT (P=0.005 and P=0.005, respectively). Seven patients in IMRT (43.75%) and nine patients in HT (56.25%) reached the isodose 70 Gy, meeting the dose limit of the organs at risk. Conclusion HT may provide significantly better liver sparing and allow more patients to achieve higher prescription dose in HCC radiotherapy. PMID:27445485

  12. Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

    SciTech Connect

    Hoffman, Karen E. Voong, K. Ranh; Pugh, Thomas J.; Skinner, Heath; Levy, Lawrence B.; Takiar, Vinita; Choi, Seungtaek; Du, Weiliang; Frank, Steven J.; Johnson, Jennifer; Kanke, James; Kudchadker, Rajat J.; Lee, Andrew K.; Mahmood, Usama; McGuire, Sean E.; Kuban, Deborah A.

    2014-04-01

    Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. Results: 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this

  13. Increasing Use of Dose-Escalated External Beam Radiation Therapy for Men With Nonmetastatic Prostate Cancer

    SciTech Connect

    Swisher-McClure, Samuel; Mitra, Nandita; Woo, Kaitlin; Smaldone, Marc; Uzzo, Robert; Bekelman, Justin E.

    2014-05-01

    Purpose: To examine recent practice patterns, using a large national cancer registry, to understand the extent to which dose-escalated external beam radiation therapy (EBRT) has been incorporated into routine clinical practice for men with prostate cancer. Methods and Materials: We conducted a retrospective observational cohort study using the National Cancer Data Base, a nationwide oncology outcomes database in the United States. We identified 98,755 men diagnosed with nonmetastatic prostate cancer between 2006 and 2011 who received definitive EBRT and classified patients into National Comprehensive Cancer Network (NCCN) risk groups. We defined dose-escalated EBRT as total prescribed dose of ≥75.6 Gy. Using multivariable logistic regression, we examined the association of patient, clinical, and demographic characteristics with the use of dose-escalated EBRT. Results: Overall, 81.6% of men received dose-escalated EBRT during the study period. The use of dose-escalated EBRT did not vary substantially by NCCN risk group. Use of dose-escalated EBRT increased from 70.7% of patients receiving treatment in 2006 to 89.8% of patients receiving treatment in 2011. On multivariable analysis, year of diagnosis and use of intensity modulated radiation therapy were significantly associated with receipt of dose-escalated EBRT. Conclusions: Our study results indicate that dose-escalated EBRT has been widely adopted by radiation oncologists treating prostate cancer in the United States. The proportion of patients receiving dose-escalated EBRT increased nearly 20% between 2006 and 2011. We observed high utilization rates of dose-escalated EBRT within all disease risk groups. Adoption of intensity modulated radiation therapy was strongly associated with use of dose-escalated treatment.

  14. A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

    SciTech Connect

    Ben-Josef, Edgar; Schipper, Mathew; Francis, Isaac R.; Hadley, Scott; Ten-Haken, Randall; Lawrence, Theodore; Normolle, Daniel; Simeone, Diane M.; Sonnenday, Christopher; Abrams, Ross; Leslie, William; Khan, Gazala; Zalupski, Mark M.

    2012-12-01

    Purpose: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). Methods and Materials: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of {>=}1500/mm{sup 3}, platelets {>=}100,000/mm{sup 3}, creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase {<=}2.5 Multiplication-Sign upper limit of normal. FDR-G (1000 mg/m{sup 2}/100 min intravenously) was given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) {>=}3, neutropenic fever, or deterioration in performance status to {>=}3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. Results: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. Conclusions: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local

  15. Individualized Tamoxifen Dose Escalation: Confirmation of Feasibility, Question of Utility.

    PubMed

    Hertz, Daniel L; Rae, James M

    2016-07-01

    Tamoxifen may require metabolic activation to endoxifen for efficacy in treating hormone receptor-positive breast cancer. Dose escalation in patients with low endoxifen concentrations could enhance treatment efficacy. This approach is clinically feasible, and successfully increases endoxifen concentrations; however, it is unknown whether patients benefit from individualized tamoxifen dose escalation. Clin Cancer Res; 22(13); 3121-3. ©2016 AACRSee related article by Fox et al., p. 3164.

  16. Image guided dose escalated prostate radiotherapy: still room to improve

    PubMed Central

    Martin, Jarad M; Bayley, Andrew; Bristow, Robert; Chung, Peter; Gospodarowicz, Mary; Menard, Cynthia; Milosevic, Michael; Rosewall, Tara; Warde, Padraig R; Catton, Charles N

    2009-01-01

    Background Prostate radiotherapy (RT) dose escalation has been reported to result in improved biochemical control at the cost of greater late toxicity. We report on the application of 79.8 Gy in 42 fractions of prostate image guided RT (IGRT). The primary objective was to assess 5-year biochemical control and potential prognostic factors by the Phoenix definition. Secondary endpoints included acute and late toxicity by the Radiotherapy Oncology Group (RTOG) scoring scales. Methods From October/2001 and June/2003, 259 men were treated with at least 2-years follow-up. 59 patients had low, 163 intermediate and 37 high risk disease. 43 had adjuvant hormonal therapy (HT), mostly for high- or multiple risk factor intermediate-risk disease (n = 25). They received either 3-dimensional conformal RT (3DCRT, n = 226) or intensity modulated RT (IMRT) including daily on-line IGRT with intraprostatic fiducial markers. Results Median follow-up was 67.8 months (range 24.4-84.7). There was no severe (grade 3-4) acute toxicity, and grade 2 acute gastrointestinal (GI) toxicity was unusual (10.1%). The 5-year incidence of grade 2-3 late GI and genitourinary (GU) toxicity was 13.7% and 12.1%, with corresponding grade 3 figures of 3.5% and 2.0% respectively. HT had an association with an increased risk of grade 2-3 late GI toxicity (11% v 21%, p = 0.018). Using the Phoenix definition for biochemical failure, the 5 year-bNED is 88.4%, 76.5% and 77.9% for low, intermediate and high risk patients respectively. On univariate analysis, T-category and Gleason grade correlated with Phoenix bNED (p = 0.006 and 0.039 respectively). Hormonal therapy was not a significant prognostic factor on uni- or multi-variate analysis. Men with positive prostate biopsies following RT had a lower chance of bNED at 5 years (34.4% v 64.3%; p = 0.147). Conclusion IGRT to 79.8 Gy results in favourable rates of late toxicity compared with published non-IGRT treated cohorts. Future avenues of investigation for

  17. Rotation to methadone after opioid dose escalation: How should individualization of dosing occur?

    PubMed

    Zimmermann, Camilla; Seccareccia, Dori; Booth, Christopher M; Cottrell, Wayne

    2005-01-01

    Methadone is a synthetic opioid agonist and N-methyl-D-aspartate (NMDA) receptor antagonist that is being increasingly used in pain management, particularly for pain that is resistant to conventional opioids. We describe two patients with neurotoxic side effects on escalating doses of parenteral hydromorphone with uncontrolled cancer pain who were successfully converted to oral methadone at a dose much smaller than predicted. The phenomenon of increasing pain despite opioid dose escalation is discussed and the rationale for the use of methadone in this situation is described. While methadone is useful for patients with unremitting pain on another opioid, existing conversion regimens do not specifically take into account the setting of dose escalation. Clinical guidelines for rotation to methadone after dose escalation of the previous opioid are needed to avoid toxicity including respiratory depression. A possible conversion method for rotation to methadone for patients with escalating pain and opioid use is suggested.

  18. COSMIC: A Regimen of Intensity Modulated Radiation Therapy Plus Dose-Escalated, Raster-Scanned Carbon Ion Boost for Malignant Salivary Gland Tumors: Results of the Prospective Phase 2 Trial

    SciTech Connect

    Jensen, Alexandra D.; Nikoghosyan, Anna V.; Lossner, Karen; Haberer, Thomas; Jäkel, Oliver; Münter, Marc W.; Debus, Jürgen

    2015-09-01

    Purpose: To investigate the effect of intensity modulated radiation therapy (IMRT) and dose-escalated carbon ion (C12) therapy in adenoid cystic carcinoma (ACC) and other malignant salivary gland tumors (MSGTs) of the head and neck. Patients and Methods: COSMIC (combined treatment of malignant salivary gland tumors with intensity modulated radiation therapy and carbon ions) is a prospective phase 2 trial of 24 Gy(RBE) C12 followed by 50 Gy IMRT in patients with pathologically confirmed MSGT. The primary endpoint is mucositis Common Terminology Criteria grade 3; the secondary endpoints are locoregional control (LC), progression-free survival (PFS), overall survival (OS), and toxicity. Toxicity was scored according to the Common Terminology Criteria for Adverse Events version 3; treatment response was scored according to Response Evaluation Criteria in Solid Tumors 1.1. Results: Between July 2010 and August 2011, 54 patients were accrued, and 53 were available for evaluation. The median follow-up time was 42 months; patients with microscopically incomplete resections (R1, n=20), gross residual disease (R2, n=17), and inoperable disease (n=16) were included. Eighty-nine percent of patients had ACC, and 57% had T4 tumors. The most common primary sites were paranasal sinus (34%), submandibular gland, and palate. At the completion of radiation therapy, 26% of patients experienced grade 3 mucositis, and 20 patients reported adverse events of the ear (38%). The most common observed late effects were grade 1 xerostomia (49%), hearing impairment (25%, 2% ipsilateral hearing loss), and adverse events of the eye (20%), but no visual impairment or loss of vision. Grade 1 central nervous system necrosis occurred in 6%, and 1 grade 4 ICA hemorrhage without neurologic sequelae. The best response was 54% (complete response/partial remission). At 3 years, the LC, PFS, and OS were 81.9%, 57.9%, and 78.4%, respectively. No difference was found regarding resection status. The

  19. Misonidazole with dexamethasone rescue: an escalating dose toxicity study

    SciTech Connect

    Tanasichuk, H.; Urtasun, R.C.; Fulton, D.S.; Raleigh, J.

    1984-09-01

    Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, the authors reported a preliminary study suggestive that Dexamethasone (DEXA) does have a protective effect against peripheral neuropathies (PN) resulting from toxicity of misonidazole. The authors are presently investigating the use of DEXA, with escalating doses of MISO in an attempt to modify its neurotoxicity. To date, 16 patients have been registered to receive total doses of MISO given in 9 equally divided doses over 3 weeks. DEXA is given 3 days prior to the first dose and continues for the duration of therapy. All patients receive palliative radiation. No toxicity was seen at the total dose of 13.5 gm/M/sub 2/. One grade I PN occurred in the first four patients receiving 15.5 gm/M/sub 2/. Six additional patients were entered at this dose level and no further incidence of PN was observed.

  20. A Phase I Study of Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed by Dose Escalation of Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33+ Acute Myeloid Leukemia.

    PubMed

    Zahler, Stacey; Bhatia, Monica; Ricci, Angela; Roy, Sumith; Morris, Erin; Harrison, Lauren; van de Ven, Carmella; Fabricatore, Sandra; Wolownik, Karen; Cooney-Qualter, Erin; Baxter-Lowe, Lee Ann; Luisi, Paul; Militano, Olga; Kletzel, Morris; Cairo, Mitchell S

    2016-04-01

    Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33+ relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33+ AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m2 × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m2). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m2 per dose), 5 at dose level 2 (6 mg/m2 per dose), 3 at dose level 3 (7.5 mg/m2 per dose), and 3 at dose level 4 (9 mg/m2 per dose). Three of 14 patients received only 1 dose of GO after alloHSCT. One patient experienced grade

  1. Positron Emission Tomography for Pre-Clinical Sub-Volume Dose Escalation

    NASA Astrophysics Data System (ADS)

    Bass, Christopher Paul

    registering small animal PET/CT data sets in less than 5 minutes with an average registration error of .3 mm. The methods used in chapter 3 allowed for the comparison of the spatial distributions of multiple PET tracers imaged at different times. A comparison of FDG and FLT showed that both are positively correlated but that tumor morphology does significantly affect the correlation between the two tracers. An overlap analysis of the high intensity PET regions of FDG and FLT showed that FLT offers additional spatial information to that seen with FDG. In chapter 4 the SARRP allowed for the delivery of planned PET-guided selective dose escalations to a pre-clinical tumor model. This will facilitate future research validating the use of PET for clinical selective dose escalation.

  2. Steepness of the radiation dose-response curve for dose-per-fraction escalation keeping the number of fractions fixed.

    PubMed

    Bentzen, Søren M

    2005-01-01

    Clinically, there is growing interest in strategies for intensifying radiation therapy by escalating the dose per fraction. This paper considers the steepness of the dose-response curve in this case. The steepness of a radiation dose-response curve is most conveniently quantified by the normalized dose-response gradient, gamma. Under the assumption of a linear-quadratic dose-effect model, a simple analytical relationship is derived between the gamma-value for a dose-response curve generated by varying the total dose while keeping the number of fractions constant, i.e. escalating the dose per fraction, and the gamma-value for a dose-response curve generated by varying the total dose while keeping the dose per fraction constant. This formulation is compared with clinical dose-response data from the literature and shown to be in good agreement with the observations. Some implications of this formulation for non-uniform dose distributions delivered using 3D conformal radiotherapy or intensity modulated radiotherapy (IMRT) are briefly discussed.

  3. The Impact of Dose Escalation on Secondary Cancer Risk After Radiotherapy of Prostate Cancer

    SciTech Connect

    Schneider, Uwe . E-mail: uwe.schneider@psi.ch; Lomax, Antony; Besserer, Juergen; Pemler, Peter; Lombriser, Norbert; Kaser-Hotz, Barbara D.V.M.

    2007-07-01

    Purpose: To estimate secondary cancer risk due to dose escalation in patients treated for prostatic carcinoma with three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated RT (IMRT), and spot-scanned proton RT. Methods and Materials: The organ equivalent dose (OED) concept with a linear-exponential, a plateau, and a linear dose-response curve was applied to dose distributions of 23 patients who received RT of prostate cancer. Conformal RT was used in 7 patients, 8 patients received IMRT with 6- and 15-MV photons, and 8 patients were treated with spot-scanned protons. We applied target doses ranging from 70 Gy to 100 Gy. Cancer risk was estimated as a function of target dose and tumor control probability. Results: At a 100-Gy target dose the secondary cancer risk relative to the 3D treatment plan at 70 Gy was +18.4% (15.0% for a plateau model, 22.3% for a linear model) for the 6-MV IMRT plan, +25.3% (17.0%, 14.1%) for the 15-MV IMRT plan, and -40.7% (-41.3%, -40.0%) for the spot-scanned protons. The increasing risk of developing a radiation-associated malignancy after RT with increasing dose was balanced by the enhanced cure rates at a larger dose. Conclusions: Cancer risk after dose escalation for prostate RT is expected to be equal to or lower than for conventional 3D treatment at 70 Gy, independent of treatment modality or dose-response model. Spot-scanned protons are the treatment of choice for dose escalation because this therapy can halve the risk of secondary cancers.

  4. Dose escalation studies with caspofungin against Candida glabrata.

    PubMed

    Domán, Marianna; Kovács, Renátó; Perlin, David S; Kardos, Gábor; Gesztelyi, Rudolf; Juhász, Béla; Bozó, Aliz; Majoros, László

    2015-09-01

    Echinocandins are recommended as first-line agents against invasive fungal infections caused by Candida glabrata, which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against C. glabrata. To address this possibility, we performed in vitro and in vivo experiments with caspofungin against four WT C. glabrata clinical isolates, a drug-susceptible ATCC 90030 reference strain and two echinocandin-resistant strains with known FKS mutations. MIC values for the clinical isolates in RPMI 1640 were ≤ 0.03 mg l(-1 ) but increased to 0.125-0.25 mg l(-1 )in RPMI 1640+50% serum. In RPMI 1640+50% serum, the replication of C. glabrata was weaker than in RPMI 1640.Caspofungin in RPMI 1640 at 1 and 4 mg l(-1) showed a fungicidal effect within 7 h against three of the four clinical isolates but was only fungistatic at 16 and 32 mg l(-1) (paradoxically decreased killing activity). In RPMI 1640+50% serum, caspofungin at ≥ 1 mg l(-1) was rapidly fungicidal (within 3.31 h) against three of the four isolates. In a profoundly neutropenic murine model, all caspofungin doses (1, 2, 3, 5 and 20 mg kg(-1) daily) decreased the fungal tissue burdens significantly (P < 0.05-0.001) without statistical differences between doses, but the mean fungal tissue burdens never fell below 105 cells (g tissue)(-1). The echinocandin-resistant strains were highly virulent in animal models and all doses were ineffective. These results confirm the clinical experience that caspofungin dose escalation does not improve efficacy.

  5. Radiation Dose Escalation in Stage III Non-Small-Cell Lung Cancer

    PubMed Central

    Terakedis, Breanne; Sause, William

    2011-01-01

    For patients with stage III non-small-cell lung cancer with unresectable or inoperable tumors, definitive chemoradiotherapy is often utilized. Historically, local control and overall survival rates have been poor. In an effort to improve local control, new chemotherapeutic agents in combination with higher doses of radiotherapy have been investigated. Early dose escalation trials date back to the 1980s, and the feasibility and efficacy of dose escalation for patients with inoperable stage III lung cancer continue to be topics of investigation. Herein, we review the evolution of chemotherapy as it relates to treatment of unresectable stage III lung cancer, and we outline the early and the more recent dose escalation studies. While dose escalation appears to provide a modest benefit in terms of preventing local failure and improving overall survival, advances in diagnostic imaging and radiotherapy treatment have possibly resulted in selection of a more favorable patient population. These variables make statements regarding the benefit of dose escalation challenging. PMID:22645713

  6. Preliminary results of radiation dose escalation for locally advanced nasopharyngeal carcinoma

    SciTech Connect

    Kwong, Dora L.W. . E-mail: dlwkwong@hkucc.hku.hk; Sham, Jonathan S.T.; Leung, Lucullus H.T.; Cheng, Ashley C.K.; Ng, W.M.; Kwong, Philip W.K.; Lui, W.M.; Yau, C.C.; Wu, P.M.; Wei, William; Au, Gordon

    2006-02-01

    Purpose: To study the safety and efficacy of dose escalation in tumor for locally advanced nasopharyngeal carcinoma (NPC). Methods and Materials: From September 2000 to June 2004, 50 patients with T3-T4 NPC were treated with intensity-modulated radiotherapy (IMRT). Fourteen patients had Stage III and 36 patients had Stage IVA-IVB disease. The prescribed dose was 76 Gy to gross tumor volume (GTV), 70 Gy to planning target volume (PTV), and 72 Gy to enlarged neck nodes (GTVn). All doses were given in 35 fractions over 7 weeks. Thirty-four patients also had concurrent cisplatin and induction or adjuvant PF (cisplatin and 5-fluorouracil). Results: The average mean dose achieved in GTV, GTVn, and PTV were 79.5 Gy, 75.3 Gy, and 74.6 Gy, respectively. The median follow-up was 25 months, with 4 recurrences: 2 locoregional and 2 distant failures. All patients with recurrence had IMRT alone without chemotherapy. The 2-year locoregional control rate, distant metastases-free and disease-free survivals were 95.7%, 94.2%, and 93.1%, respectively. One treatment-related death caused by adjuvant chemotherapy occurred. The 2-year overall survival was 92.1%. Conclusions: Dose escalation to 76 Gy in tumor is feasible with T3-T4 NPC and can be combined with chemotherapy. Initial results showed good local control and survival.

  7. Strategy for stochastic dose-rate induced enhanced elimination of malignant tumour without dose escalation.

    PubMed

    Paul, Subhadip; Roy, Prasun Kumar

    2016-09-01

    The efficacy of radiation therapy, a primary modality of cancer treatment, depends in general upon the total radiation dose administered to the tumour during the course of therapy. Nevertheless, the delivered radiation also irradiates normal tissues and dose escalation procedure often increases the elimination of normal tissue as well. In this article, we have developed theoretical frameworks under the premise of linear-quadratic-linear (LQL) model using stochastic differential equation and Jensen's inequality for exploring the possibility of attending to the two therapeutic performance objectives in contraposition-increasing the elimination of prostate tumour cells and enhancing the relative sparing of normal tissue in fractionated radiation therapy, within a prescribed limit of total radiation dose. Our study predicts that stochastic temporal modulation in radiation dose-rate appreciably enhances prostate tumour cell elimination, without needing dose escalation in radiation therapy. However, constant higher dose-rate can also enhance the elimination of tumour cells. In this context, we have shown that the sparing of normal tissue with stochastic dose-rate is considerably more than the sparing of normal tissue with the equivalent constant higher dose-rate. Further, by contrasting the stochastic dose-rate effects under LQL and linear-quadratic (LQ) models, we have also shown that the LQ model over-estimates stochastic dose-rate effect in tumour and under-estimates the stochastic dose-rate effect in normal tissue. Our study indicates the possibility of utilizing stochastic modulation of radiation dose-rate for designing enhanced radiation therapy protocol for cancer.

  8. Esophageal Cancer Dose Escalation Using a Simultaneous Integrated Boost Technique

    SciTech Connect

    Welsh, James; Palmer, Matthew B.; Ajani, Jaffer A.; Liao Zhongxing; Swisher, Steven G.; Hofstetter, Wayne L.; Allen, Pamela K.; Settle, Steven H.; Gomez, Daniel; Likhacheva, Anna; Cox, James D.; Komaki, Ritsuko

    2012-01-01

    Purpose: We previously showed that 75% of radiation therapy (RT) failures in patients with unresectable esophageal cancer are in the gross tumor volume (GTV). We performed a planning study to evaluate if a simultaneous integrated boost (SIB) technique could selectively deliver a boost dose of radiation to the GTV in patients with esophageal cancer. Methods and Materials: Treatment plans were generated using four different approaches (two-dimensional conformal radiotherapy [2D-CRT] to 50.4 Gy, 2D-CRT to 64.8 Gy, intensity-modulated RT [IMRT] to 50.4 Gy, and SIB-IMRT to 64.8 Gy) and optimized for 10 patients with distal esophageal cancer. All plans were constructed to deliver the target dose in 28 fractions using heterogeneity corrections. Isodose distributions were evaluated for target coverage and normal tissue exposure. Results: The 50.4 Gy IMRT plan was associated with significant reductions in mean cardiac, pulmonary, and hepatic doses relative to the 50.4 Gy 2D-CRT plan. The 64.8 Gy SIB-IMRT plan produced a 28% increase in GTV dose and comparable normal tissue doses as the 50.4 Gy IMRT plan; compared with the 50.4 Gy 2D-CRT plan, the 64.8 Gy SIB-IMRT produced significant dose reductions to all critical structures (heart, lung, liver, and spinal cord). Conclusions: The use of SIB-IMRT allowed us to selectively increase the dose to the GTV, the area at highest risk of failure, while simultaneously reducing the dose to the normal heart, lung, and liver. Clinical implications warrant systematic evaluation.

  9. The Role of Age on Dose Limiting Toxicities (DLTs) in Phase I Dose-escalation Trials

    PubMed Central

    Schwandt, A; Harris, P. J.; Hunsberger, S.; Deleporte, A.; Smith, G. L.; Vulih, D.; Anderson, B. D.; Ivy, S. P.

    2016-01-01

    Purpose Elderly oncology patients are not enrolled in early phase trials in proportion to the numbers of geriatric patients with cancer. There may be concern that elderly patients will not tolerate investigational agents as well as younger patients resulting in a disproportionate number of dose-limiting toxicities (DLTs). Recent single-institution studies provide conflicting data on the relationship between age and DLT. Experimental Design We retrospectively reviewed data about patients treated on single-agent, dose-escalation, phase I clinical trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Patients’ dose levels were described as percentage of maximum tolerated dose (%MTD), the highest dose level at which <33% of patients had a DLT, or recommended phase II dose (RP2D). Mixed-effect logistic regression models were used to analyze relationships between the probability of a DLT and age and other explanatory variables. Results Increasing dose, increasing age, and worsening performance status (PS) were significantly related to an increased probability of a DLT in this model (p<0.05). There was no association between dose level administered and age (p=0.57). Conclusions This analysis of phase I dose-escalation trials involving over 500 patients older than 70 years of age, is the largest reported. As age and dose level increased and PS worsened, the probability of a DLT increased. While increasing age was associated with occurrence of DLT, this risk remained within accepted thresholds of risk for phase I trials. There was no evidence of age bias on enrollment of patients on low or high dose levels. PMID:25028396

  10. Dose-Escalation Study for Cardiac Radiosurgery in a Porcine Model

    SciTech Connect

    Blanck, Oliver; Bode, Frank; Gebhard, Maximilian; Hunold, Peter; Brandt, Sebastian; Bruder, Ralf; Grossherr, Martin; Vonthein, Reinhard; Rades, Dirk; Dunst, Juergen

    2014-07-01

    Purpose: To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. Methods and Materials: Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm{sup 3}). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. Results: Transmural scarring of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. Conclusions: Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.

  11. Dose escalation in permanent brachytherapy for prostate cancer: dosimetric and biological considerations

    NASA Astrophysics Data System (ADS)

    Li, X. Allen; Wang, Jian Z.; Stewart, Robert D.; Di Biase, Steven J.

    2003-09-01

    No prospective dose escalation study for prostate brachytherapy (PB) with permanent implants has been reported. In this work, we have performed a dosimetric and biological analysis to explore the implications of dose escalation in PB using 125I and 103Pd implants. The concept of equivalent uniform dose (EUD), proposed originally for external-beam radiotherapy (EBRT), is applied to low dose rate brachytherapy. For a given 125I or 103Pd PB, the EUD for tumour that corresponds to a dose distribution delivered by EBRT is calculated based on the linear quadratic model. The EUD calculation is based on the dose volume histogram (DVH) obtained retrospectively from representative actual patient data. Tumour control probabilities (TCPs) are also determined in order to compare the relative effectiveness of different dose levels. The EUD for normal tissue is computed using the Lyman model. A commercial inverse treatment planning algorithm is used to investigate the feasibility of escalating the dose to prostate with acceptable dose increases in the rectum and urethra. The dosimetric calculation is performed for five representative patients with different prostate sizes. A series of PB dose levels are considered for each patient using 125I and 103Pd seeds. It is found that the PB prescribed doses (minimum peripheral dose) that give an equivalent EBRT dose of 64.8, 70.2, 75.6 and 81 Gy with a fraction size of 1.8 Gy are 129, 139, 150 and 161 Gy for 125I and 103, 112, 122 and 132 Gy for 103Pd implants, respectively. Estimates of the EUD and TCP for a series of possible prescribed dose levels (e.g., 145, 160, 170 and 180 Gy for 125I and 125, 135, 145 and 155 for 103Pd implants) are tabulated. The EUD calculation was found to depend strongly on DVHs and radiobiological parameters. The dosimetric calculations suggest that the dose to prostate can be escalated without a substantial increase in both rectal and urethral dose. For example, increasing the PB prescribed dose from 145 to

  12. Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

    PubMed

    Triplett, Brandon M; Kuttab, Hani I; Kang, Guolian; Leung, Wing

    2015-12-01

    Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD.

  13. Biological equivalent dose studies for dose escalation in the stereotactic synchrotron radiation therapy clinical trials

    SciTech Connect

    Prezado, Y.; Fois, G.; Edouard, M.; Nemoz, C.; Renier, M.; Requardt, H.; Esteve, F.; Adam, JF.; Elleaume, H.; Bravin, A.

    2009-03-15

    Synchrotron radiation is an innovative tool for the treatment of brain tumors. In the stereotactic synchrotron radiation therapy (SSRT) technique a radiation dose enhancement specific to the tumor is obtained. The tumor is loaded with a high atomic number (Z) element and it is irradiated in stereotactic conditions from several entrance angles. The aim of this work was to assess dosimetric properties of the SSRT for preparing clinical trials at the European Synchrotron Radiation Facility (ESRF). To estimate the possible risks, the doses received by the tumor and healthy tissues in the future clinical conditions have been calculated by using Monte Carlo simulations (PENELOPE code). The dose enhancement factors have been determined for different iodine concentrations in the tumor, several tumor positions, tumor sizes, and different beam sizes. A scheme for the dose escalation in the various phases of the clinical trials has been proposed. The biological equivalent doses and the normalized total doses received by the skull have been calculated in order to assure that the tolerance values are not reached.

  14. Dose-Escalated Robotic SBRT for Stage I–II Prostate Cancer

    PubMed Central

    Meier, Robert

    2015-01-01

    Stereotactic body radiotherapy (SBRT) is the precise external delivery of very high-dose radiotherapy to targets in the body, with treatment completed in one to five fractions. SBRT should be an ideal approach for organ-confined prostate cancer because (I) dose-escalation should yield improved rates of cancer control; (II) the unique radiobiology of prostate cancer favors hypofractionation; and (III) the conformal nature of SBRT minimizes high-dose radiation delivery to immediately adjacent organs, potentially reducing complications. This approach is also more convenient for patients, and is cheaper than intensity-modulated radiotherapy (IMRT). Several external beam platforms are capable of delivering SBRT for early-stage prostate cancer, although most of the mature reported series have employed a robotic non-coplanar platform (i.e., CyberKnife). Several large studies report 5-year biochemical relapse rates which compare favorably to IMRT. Rates of late GU toxicity are similar to those seen with IMRT, and rates of late rectal toxicity may be less than with IMRT and low-dose rate brachytherapy. Patient-reported quality of life (QOL) outcomes appear similar to IMRT in the urinary domain. Bowel QOL may be less adversely affected by SBRT than with other radiation modalities. After 5 years of follow-up, SBRT delivered on a robotic platform is yielding outcomes at least as favorable as IMRT, and may be considered appropriate therapy for stage I–II prostate cancer. PMID:25905037

  15. Dose-Escalated Robotic SBRT for Stage I-II Prostate Cancer.

    PubMed

    Meier, Robert

    2015-01-01

    Stereotactic body radiotherapy (SBRT) is the precise external delivery of very high-dose radiotherapy to targets in the body, with treatment completed in one to five fractions. SBRT should be an ideal approach for organ-confined prostate cancer because (I) dose-escalation should yield improved rates of cancer control; (II) the unique radiobiology of prostate cancer favors hypofractionation; and (III) the conformal nature of SBRT minimizes high-dose radiation delivery to immediately adjacent organs, potentially reducing complications. This approach is also more convenient for patients, and is cheaper than intensity-modulated radiotherapy (IMRT). Several external beam platforms are capable of delivering SBRT for early-stage prostate cancer, although most of the mature reported series have employed a robotic non-coplanar platform (i.e., CyberKnife). Several large studies report 5-year biochemical relapse rates which compare favorably to IMRT. Rates of late GU toxicity are similar to those seen with IMRT, and rates of late rectal toxicity may be less than with IMRT and low-dose rate brachytherapy. Patient-reported quality of life (QOL) outcomes appear similar to IMRT in the urinary domain. Bowel QOL may be less adversely affected by SBRT than with other radiation modalities. After 5 years of follow-up, SBRT delivered on a robotic platform is yielding outcomes at least as favorable as IMRT, and may be considered appropriate therapy for stage I-II prostate cancer.

  16. Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation

    PubMed Central

    Krishnan, Sunil; Chadha, Awalpreet S.; Suh, Yelin; Chen, Hsiang-Chun; Rao, Arvind; Das, Prajnan; Minsky, Bruce D.; Mahmood, Usama; Delclos, Marc E.; Sawakuchi, Gabriel O.; Beddar, Sam; Katz, Matthew H.; Fleming, Jason B.; Javle, Milind M.; Varadhachary, Gauri R.; Wolff, Robert A.; Crane, Christopher H.

    2016-01-01

    Purpose To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. Methods and Materials A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume was treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. Results Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P = .03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local-regional RFS (10.2 vs 6.2 months, P = .05) as compared with those receiving BED ≤70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. Conclusion Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS. PMID:26972648

  17. Anuvasan Basti in escalating dose is an alternative for Snehapana before Vamana and Virechana: Trends from a pilot study

    PubMed Central

    Kadus, Priyadarshani Arvind; Vedpathak, Surendra M.

    2014-01-01

    Oral administration of medicated fats (oil or ghee) is termed as Snehapana. It is an essential step before Vamana (therapeutic emesis) and Virechana (therapeutic purgation). Ayurveda physicians often experience a poor compliance in 10-15% patients for oral administration of medicated fats especially in escalating doses. Incomplete Snehapana sometimes creates a problem for a physician to prepare the patient for these processes. These inconveniences made us think about effective alternatives to counter drawbacks and improve acceptance of Snehapana. The present study was planned to assess the efficacy of Anuvasana Basti (oil enema) in escalating doses as an alternative for Snehapana. Anuvasana Basti of medicated sesame oil with rock salt was administered in 10 patients for three to seven days till they showed signs and symptoms of complete Snehana. The symptoms of Snehana like semisolid or loose stools, feeling exhausted without much exertion, lightness of body and oiliness of skin were observed. Though the Snehana symptoms varied in intensity, they were similar as they are produced after oral administration of fats. This trend suggests Anuvasana Basti in escalating dose is an alternative for Snehapana before administration of Shodhana therapy like Vamana or Virechana. PMID:25624700

  18. Dose escalation pharmacokinetics of intranasal scopolamine gel formulation.

    PubMed

    Wu, Lei; Boyd, Jason L; Daniels, Vernie; Wang, Zuwei; Chow, Diana S-L; Putcha, Lakshmi

    2015-02-01

    Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness.

  19. Prostate Dose Escalation by Innovative Inverse Planning-Driven IMRT

    DTIC Science & Technology

    2005-11-01

    hypothetical phantom case and a prostate case. Compared with the conventional inverse planning technique, we found that, for the same target dose coverage...reduces the dosimetric inconsistency between the CBCT-based and CT-based dose calculation down to less than 1% in both phantom and patient studies. Our...calculation down to less than 1% in both phantom and patient studies. While the true solution to the hurdle lies in the effective removal of motion

  20. A product of independent beta probabilities dose escalation design for dual-agent phase I trials.

    PubMed

    Mander, Adrian P; Sweeting, Michael J

    2015-04-15

    Dual-agent trials are now increasingly common in oncology research, and many proposed dose-escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single-agent phase I trials, where a 3 + 3 rule-based design is often still used. To expedite this process, new dose-escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve-free (nonparametric) design for a dual-agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose-escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R, Stata and Excel are available for implementation.

  1. Dose-escalation designs in oncology: ADEPT and the CRM.

    PubMed

    Shu, Jianfen; O'Quigley, John

    2008-11-20

    The ADEPT software package is not a statistical method in its own right as implied by Gerke and Siedentop (Statist. Med. 2008; DOI: 10.1002/sim.3037). ADEPT implements two-parameter CRM models as described in O'Quigley et al. (Biometrics 1990; 46(1):33-48). All of the basic ideas (use of a two-parameter logistic model, use of a two-dimensional prior for the unknown slope and intercept parameters, sequential estimation and subsequent patient allocation based on minimization of some loss function, flexibility to use cohorts instead of one by one inclusion) are strictly identical. The only, and quite trivial, difference arises in the setting of the prior. O'Quigley et al. (Biometrics 1990; 46(1):33-48) used priors having an analytic expression whereas Whitehead and Brunier (Statist. Med. 1995; 14:33-48) use pseudo-data to play the role of the prior. The question of interest is whether two-parameter CRM works as well, or better, than the one-parameter CRM recommended in O'Quigley et al. (Biometrics 1990; 46(1):33-48). Gerke and Siedentop argue that it does. The published literature suggests otherwise. The conclusions of Gerke and Siedentop stem from three highly particular, and somewhat contrived, situations. Unlike one-parameter CRM (Biometrika 1996; 83:395-405; J. Statist. Plann. Inference 2006; 136:1765-1780; Biometrika 2005; 92:863-873), no statistical properties appear to have been studied for two-parameter CRM. In particular, for two-parameter CRM, the parameter estimates are inconsistent. This ought to be a source of major concern to those proposing its use. Worse still, for finite samples the behavior of estimates can be quite wild despite having incorporated the kind of dampening priors discussed by Gerke and Siedentop. An example in which we illustrate this behavior describes a single patient included at level 1 of 6 levels and experiencing a dose limiting toxicity. The subsequent recommendation is to experiment at level 6! Such problematic behavior is not

  2. A Phase I Dose-Escalation Study (ISIDE-BT-1) of Accelerated IMRT With Temozolomide in Patients With Glioblastoma

    SciTech Connect

    Morganti, Alessio G.; Balducci, Mario; Salvati, Maurizio; Esposito, Vincenzo; Romanelli, Pantaleo; Ferro, Marica; Calista, Franco; Digesu, Cinzia; Macchia, Gabriella; Ianiri, Massimo; Deodato, Francesco; Cilla, Savino; Piermattei, Angelo M.P.; Valentini, Vincenzo; Cellini, Numa; Cantore, Gian Paolo

    2010-05-01

    Purpose: To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma. Methods and Materials: A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150-200 mg/day, Days 1-5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed +- enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade >=3 or any hematological toxicity rated as >=4 by Radiation Therapy Oncology Group (RTOG) criteria. Results: Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8-40 months). No patient experienced DLT. Grade 1-2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted. Conclusion: Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg.

  3. Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

    SciTech Connect

    Wong, Jeffrey Y.C.; Forman, Stephen; Somlo, George; Liu An; Schultheiss, Timothy; Radany, Eric; Palmer, Joycelynne; Stein, Anthony

    2013-01-01

    Purpose: We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens. Methods and Materials: Trial 1 consisted of TMI on Days -10 to -6, etoposide (VP16) on Day -5 (60 mg/kg), and cyclophosphamide (CY) on Day -3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days -12 to -8 (800 {mu}M min), TMI on Days -8 to -4, and VP16 on Day -3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily. Results: Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials. Conclusions: TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to

  4. Dose Escalated Liver Stereotactic Body Radiation Therapy at the Mean Respiratory Position

    SciTech Connect

    Velec, Michael; Moseley, Joanne L.; Dawson, Laura A.; Brock, Kristy K.

    2014-08-01

    Purpose: The dosimetric impact of dose probability based planning target volume (PTV) margins for liver cancer patients receiving stereotactic body radiation therapy (SBRT) was compared with standard PTV based on the internal target volume (ITV). Plan robustness was evaluated by accumulating the treatment dose to ensure delivery of the intended plan. Methods and Materials: Twenty patients planned on exhale CT for 27 to 50 Gy in 6 fractions using an ITV-based PTV and treated free-breathing were retrospectively evaluated. Isotoxic, dose escalated plans were created on midposition computed tomography (CT), representing the mean breathing position, using a dose probability PTV. The delivered doses were accumulated using biomechanical deformable registration of the daily cone beam CT based on liver targeting at the exhale or mean breathing position, for the exhale and midposition CT plans, respectively. Results: The dose probability PTVs were on average 38% smaller than the ITV-based PTV, enabling an average ± standard deviation increase in the planned dose to 95% of the PTV of 4.0 ± 2.8 Gy (9 ± 5%) on the midposition CT (P<.01). For both plans, the delivered minimum gross tumor volume (GTV) doses were greater than the planned nominal prescribed dose in all 20 patients and greater than the planned dose to 95% of the PTV in 18 (90%) patients. Nine patients (45%) had 1 or more GTVs with a delivered minimum dose more than 5 Gy higher with the midposition CT plan using dose probability PTV, compared with the delivered dose with the exhale CT plan using ITV-based PTV. Conclusions: For isotoxic liver SBRT planned and delivered at the mean respiratory, reduced dose probability PTV enables a mean escalation of 4 Gy (9%) in 6 fractions over ITV-based PTV. This may potentially improve local control without increasing the risk of tumor underdosing.

  5. Decision Regret in Men Undergoing Dose-Escalated Radiation Therapy for Prostate Cancer

    SciTech Connect

    Steer, Anna N.; Aherne, Noel J.; Gorzynska, Karen; Hoffman, Matthew; Last, Andrew; Hill, Jacques; Shakespeare, Thomas P.

    2013-07-15

    Purpose: Decision regret (DR) is a negative emotion associated with medical treatment decisions, and it is an important patient-centered outcome after therapy for localized prostate cancer. DR has been found to occur in up to 53% of patients treated for localized prostate cancer, and it may vary depending on treatment modality. DR after modern dose-escalated radiation therapy (DE-RT) has not been investigated previously, to our knowledge. Our primary aim was to evaluate DR in a cohort of patients treated with DE-RT. Methods and Materials: We surveyed 257 consecutive patients with localized prostate cancer who had previously received DE-RT, by means of a validated questionnaire. Results: There were 220 responses (85.6% response rate). Image-guided intensity modulated radiation therapy was given in 85.0% of patients and 3-dimensional conformal radiation therapy in 15.0%. Doses received included 73.8 Gy (34.5% patients), 74 Gy (53.6%), and 76 Gy (10.9%). Neoadjuvant androgen deprivation (AD) was given in 51.8% of patients and both neoadjuvant and adjuvant AD in 34.5%. The median follow-up time was 23 months (range, 12-67 months). In all, 3.8% of patients expressed DR for their choice of treatment. When asked whether they would choose DE-RT or AD again, only 0.5% probably or definitely would not choose DE-RT again, compared with 8.4% for AD (P<.01). Conclusion: Few patients treated with modern DE-RT express DR, with regret appearing to be lower than in previously published reports of patients treated with radical prostatectomy or older radiation therapy techniques. Patients experienced more regret with the AD component of treatment than with the radiation therapy component, with implications for informed consent. Further research should investigate regret associated with individual components of modern therapy, including AD, radiation therapy and surgery.

  6. Successful Within-patient Dose Escalation of Olipudase Alfa in Acid Sphingomyelinase Deficiency

    PubMed Central

    Wasserstein, Melissa P.; Jones, Simon A.; Soran, Handrean; Diaz, George A.; Lippa, Natalie; Thurberg, Beth L.; Culm-Merdek, Kerry; Shamiyeh, Elias; Inguilizian, Haig; Cox, Gerald F.; Puga, Ana Cristina

    2015-01-01

    Background Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy. Methods Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks. Results All patients successfully reached 3.0 mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4 hours across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed. Conclusions This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD. PMID:26049896

  7. A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Monjazeb, Arta M.; Ayala, Deandra; Jensen, Courtney; Case, L. Douglas; Bourland, J. Daniel; Ellis, Thomas L.; McMullen, Kevin P.; Chan, Michael D.; Tatter, Stephen B.; Lesser, Glen J.; Shaw, Edward G.

    2012-02-01

    Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. Results: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

  8. Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding

    PubMed Central

    Rogatko, André; Cook-Wiens, Galen; Tighiouart, Mourad; Piantadosi, Steven

    2016-01-01

    The standard 3 + 3 or “modified Fibonacci” up-and-down (MF-UD) method of dose escalation is by far the most used design in dose-finding cancer trials. However, MF-UD has always shown inferior performance when compared with its competitors regarding number of patients treated at optimal doses. A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. In June 2012, the U S Food and Drug Administration (FDA) rejected the proposal to use Escalation with Overdose Control (EWOC), an established dose-finding method which has been extensively used in FDA-approved first in human trials and imposed a variation of the MF-UD, known as accelerated titration (AT) design. This event motivated us to perform an extensive simulation study comparing the operating characteristics of AT and EWOC. We show that the AT design has poor operating characteristics relative to three versions of EWOC under several practical scenarios. From the clinical investigator's perspective, lower bias and mean square error make EWOC designs preferable than AT designs without compromising safety. From a patient's perspective, uniformly higher proportion of patients receiving doses within an optimal range of the true MTD makes EWOC designs preferable than AT designs. PMID:27156869

  9. Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer

    SciTech Connect

    Warren, Samantha; Partridge, Mike; Carrington, Rhys; Hurt, Chris; Crosby, Thomas; Hawkins, Maria A.

    2014-10-01

    Purpose: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm{sup 3}. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA{sub 62.5}) was compared to a standard dose plan of 50 Gy/25 fractions (RA{sub 50}). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA{sub 50}) to 56.3% (RA{sub 62.5}), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA{sub 50}) versus 5.6% (RA{sub 62.5}) P<.001 and median lung NTCP 6.5% (RA{sub 50}) versus 7.5% (RA{sub 62.5}) P<.001. Conclusions: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.

  10. Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

    SciTech Connect

    Castle, Katherine O.; Hoffman, Karen E.; Levy, Lawrence B.; Lee, Andrew K.; Choi, Seungtaek; Nguyen, Quynh N.; Frank, Steven J.; Pugh, Thomas J.; McGuire, Sean E.; Kuban, Deborah A.

    2013-03-01

    Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease

  11. New-onset depression following stable, slow, and rapid rate of prescription opioid dose escalation.

    PubMed

    Salas, Joanne; Scherrer, Jeffrey F; Schneider, Frank David; Sullivan, Mark D; Bucholz, Kathleen K; Burroughs, Thomas; Copeland, Laurel A; Ahmedani, Brian K; Lustman, Patrick J

    2017-02-01

    Recent studies suggest that longer durations of opioid use, independent of maximum morphine equivalent dose (MED) achieved, is associated with increased risk of new-onset depression (NOD). Conversely, other studies, not accounting for duration, found that higher MED increased probability of depressive symptoms. To determine whether rate of MED increase is associated with NOD, a retrospective cohort analysis of Veterans Health Administration data (2000-2012) was conducted. Eligible patients were new, chronic (>90 days) opioid users, aged 18 to 80, and without depression diagnoses for 2 years before start of follow-up (n = 7051). Mixed regression models of MED across follow-up defined 4 rate of dose change categories: stable, decrease, slow increase, and rapid increase. Cox proportional hazard models assessed the relationship of rate of dose change and NOD, controlling for pain, duration of use, maximum MED, and other confounders using inverse probability of treatment-weighted propensity scores. Incidence rate for NOD was 14.1/1000PY (person-years) in stable rate, 13.0/1000PY in decreasing, 19.3/1000PY in slow increasing, and 27.5/1000PY in rapid increasing dose. Compared with stable rate, risk of NOD increased incrementally for slow (hazard ratio = 1.22; 95% confidence interval: 1.05-1.42) and rapid (hazard ratio = 1.58; 95% confidence interval: 1.30-1.93) rate of dose increase. Faster rates of MED escalation contribute to NOD, independent of maximum dose, pain, and total opioid duration. Dose escalation may be a proxy for loss of control or undetected abuse known to be associated with depression. Clinicians should avoid rapid dose increase when possible and discuss risk of depression with patients if dose increase is warranted for pain.

  12. SU-E-T-622: Identification and Improvement of Patients Eligible for Dose Escalation with Matched Plans

    SciTech Connect

    Bush, K; Holcombe, C; Kapp, D; Buyyounouski, M; Hancock, S; Xing, L; Atwood, T; King, M

    2014-06-15

    Purpose: Radiation-therapy dose-escalation beyond 80Gy may improve tumor control rates for patients with localized prostate cancer. Since toxicity remains a concern, treatment planners must achieve dose-escalation while still adhering to dose-constraints for surrounding structures. Patientmatching is a machine-learning technique that identifies prior patients that dosimetrically match DVH parameters of target volumes and critical structures prior to actual treatment planning. We evaluated the feasibility of patient-matching in (1)identifying candidates for safe dose-escalation; and (2)improving DVH parameters for critical structures in actual dose-escalated plans. Methods: We analyzed DVH parameters from 319 historical treatment plans to determine which plans could achieve dose-escalation (8640cGy) without exceeding Zelefsky dose-constraints (rectal and bladder V47Gy<53%, and V75.6Gy<30%, max-point dose to rectum of 8550cGy, max dose to PTV< 9504cGy). We then estimated the percentage of cases that could achieve safe dose-escalation using software that enables patient matching (QuickMatch, Siris Medical, Mountain View, CA). We then replanned a case that had violated DVH constraints with DVH parameters from patient matching, in order to determine whether this previously unacceptable plan could be made eligible with this automated technique. Results: Patient-matching improved the percentage of patients eligible for dose-escalation from 40% to 63% (p=4.7e-4, t-test). Using a commercial optimizer augmented with patient-matching, we demonstrated a case where patient-matching improved the toxicity-profile such that dose-escalation would have been possible; this plan was rapidly achieved using patientmatching software. In this patient, all lower-dose constraints were met with both the denovo and patient-matching plan. In the patient-matching plan, maximum dose to the rectum was 8385cGy, while the denovo plan failed to meet the maximum rectal constraint at 8571c

  13. Acute quetiapine dose-dependently exacerbates anhedonia induced by withdrawal from escalating doses of d-amphetamine.

    PubMed

    Zhornitsky, Simon; Potvin, Stéphane; Stip, Emmanuel; Rompré, Pierre-Paul

    2010-10-01

    Recent clinical studies show that the atypical antipsychotic medication, quetiapine, may be beneficial in the treatment of substance abuse by alleviating the withdrawal-negative affect stage of addiction. Since the effect of quetiapine on central reward function is largely unknown we studied its effects on brain stimulation reward in animals under withdrawal from escalating doses of d-amphetamine. Male Sprague-Dawley rats were trained to produce an operant response to receive a short train of electrical stimulation to the lateral hypothalamus. Measures of reward threshold were determined with the curve-shift method in different groups of rats before, and during four days after treatment with escalating doses (1 to 10mg/kg, i.p.) of d-amphetamine or its vehicle. At 24h of withdrawal, the effects of two doses of quetiapine (2 and 10mg/kg i.p.) were tested. Animals treated with d-amphetamine showed a 25% reward deficit at 24h of withdrawal, an effect that decreased progressively over the next three days. Quetiapine attenuated reward in the vehicle-control animals, and amplified the anhedonia at the moderate, but not the low, dose in the animals under withdrawal. These results show that acute treatment with clinically relevant doses of quetiapine for the treatment of schizophrenia may exacerbate anhedonia induced by amphetamine withdrawal. Further research should investigate whether repeated treatment with quetiapine has the ability to reverse amphetamine withdrawal-induced anhedonia.

  14. Dose Escalation of Whole-Brain Radiotherapy for Brain Metastases From Melanoma

    SciTech Connect

    Rades, Dirk; Heisterkamp, Christine; Huttenlocher, Stefan; Bohlen, Guenther; Dunst, Juergen; Haatanen, Tiina; Schild, Steven E.

    2010-06-01

    Purpose: The majority of patients with brain metastases from melanoma receive whole-brain radiotherapy (WBRT). However, the results are poor. Hypofractionation regimens failed to improve the outcome of these patients. This study investigates a potential benefit from escalation of the WBRT dose beyond the 'standard' regimen 30 Gy in 10 fractions (10x3 Gy). Methods and Materials: Data from 51 melanoma patients receiving WBRT alone were retrospectively analyzed. A dosage of 10x3 Gy (n = 33) was compared with higher doses including 40 Gy/20 fractions (n = 11) and 45 Gy/15 fractions (n = 7) for survival (OS) and local (intracerebral) control (LC). Additional potential prognostic factors were evaluated: age, gender, performance status, number of metastases, extracerebral metastases, and recursive partitioning analysis (RPA) class. Results: At 6 months, OS rates were 27% after 10x3 Gy and 50% after higher doses (p = 0.009). The OS rates at 12 months were 4% and 20%. On multivariate analysis, higher WBRT doses (p = 0.010), fewer than four brain metastases (p = 0.012), no extracerebral metastases (p = 0.006), and RPA class 1 (p = 0.005) were associated with improved OS. The LC rates at 6 months were 23% after 10x3 Gy and 50% after higher doses (p = 0.021). The LC rates at 12 months were 0% and 13%. On multivariate analysis, higher WBRT doses (p = 0.020) and fewer than brain metastases (p = 0.002) were associated with better LC. Conclusions: Given the limitations of a retrospective study, the findings suggest that patients with brain metastases from melanoma receiving WBRT alone may benefit from dose escalation beyond 10x3 Gy. The hypothesis generated by this study must be confirmed in a randomized trial stratifying for significant prognostic factors.

  15. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.

    PubMed

    Dooley, K E; Bliven-Sizemore, E E; Weiner, M; Lu, Y; Nuermberger, E L; Hubbard, W C; Fuchs, E J; Melia, M T; Burman, W J; Dorman, S E

    2012-05-01

    Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AU C0–24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.

  16. Safety and Pharmacokinetics of Escalating Daily Doses of the Antituberculosis Drug Rifapentine in Healthy Volunteers

    PubMed Central

    Dooley, KE; Bliven-Sizemore, EE; Weiner, M; Lu, Y; Nuermberger, EL; Hubbard, WC; Fuchs, EJ; Melia, MT; Burman, WJ; Dorman, SE

    2013-01-01

    Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high as a prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RPT concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AUC0–24) and maximum concentration (Cmax) were similar in the 15- and 20-mg/kg cohorts. Although RPT pharmacokinetics (PK) appeared to be time-dependent, accumulation occurred with daily dosing. The mean AUC0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01). Changes in the oral clearance of MDZ did not vary by RPT dose. In conclusion, RPT was tolerated at doses as high as 20 mg/kg/day, its PK were less than dose-proportional, and its CYP3A induction was robust. PMID:22472995

  17. Impact of dose escalation and adaptive radiotherapy for cervical cancers on tumour shrinkage—a modelling study

    NASA Astrophysics Data System (ADS)

    Røthe Arnesen, Marius; Paulsen Hellebust, Taran; Malinen, Eirik

    2017-03-01

    Tumour shrinkage occurs during fractionated radiotherapy and is regulated by radiation induced cellular damage, repopulation of viable cells and clearance of dead cells. In some cases additional tumour shrinkage during external beam therapy may be beneficial, particularly for locally advanced cervical cancer where a small tumour volume may simplify and improve brachytherapy. In the current work, a mathematical tumour model is utilized to investigate how local dose escalation affects tumour shrinkage, focusing on implications for brachytherapy. The iterative two-compartment model is based upon linear-quadratic radiation response, a doubling time for viable cells and a half-time for clearance of dead cells. The model was individually fitted to clinical tumour volume data from fractionated radiotherapy of 25 cervical cancer patients. Three different fractionation patterns for dose escalation, all with an additional dose of 12.2 Gy, were simulated and compared to standard fractionation in terms of tumour shrinkage. An adaptive strategy where dose escalation was initiated after one week of treatment was also considered. For 22 out of 25 patients, a good model fit was achieved to the observed tumour shrinkage. A large degree of inter-patient variation was seen in predicted volume reduction following dose escalation. For the 10 best responding patients, a mean tumour volume reduction of 34  ±  3% (relative to standard treatment) was estimated at the time of brachytherapy. Timing of initiating dose escalation had a larger impact than the number of fractions applied. In conclusion, the model was found useful in evaluating the impact from dose escalation on tumour shrinkage. The results indicate that dose escalation could be conducted from the start of external beam radiotherapy in order to obtain additional tumour shrinkage before brachytherapy.

  18. Caspofungin dose escalation for invasive candidiasis due to resistant Candida albicans.

    PubMed

    Wiederhold, Nathan P; Najvar, Laura K; Bocanegra, Rosie A; Kirkpatrick, William R; Patterson, Thomas F

    2011-07-01

    Previous in vivo studies have reported caspofungin dose escalation to be effective against Candida glabrata with reduced susceptibility. We hypothesized that higher doses of caspofungin would be effective against invasive candidiasis caused by the more virulent species Candida albicans, including isolates resistant to this echinocandin. Immunocompetent mice were inoculated with one of three C. albicans isolates, including one susceptible and two resistant isolates with different FKS1 hot spot 1 point mutations. Mice received daily caspofungin treatment for 7 days and were then followed off therapy for 2 weeks to assess survival. Kidney tissue and blood were collected, and fungal burden and serum (1 → 3)-β-D-glucan were measured. Significant differences in virulence were observed among the three C. albicans isolates, which translated into differences in responses to caspofungin. The most virulent of the resistant isolates studied (isolate 43001; Fks1p F641S) did not respond to caspofungin doses of up to 10 mg/kg of body weight, as there were no differences in survival (survival range, 0 to 12% with treatment), tissue burden, or (1 → 3)-β-D-glucan concentration compared to those for untreated controls. Higher doses of caspofungin did improve survival against the second resistant isolate (53264; Fks1p S645P) that demonstrated reduced virulence (5 and 10 mg/kg; 80% survival). In contrast, caspofungin doses as low as 1 mg/kg improved survival (85 to 95%) and reduced tissue burden and (1 → 3)-β-D-glucan concentration against the susceptible isolate (ATCC 90028). These data suggest that caspofungin dose escalation for invasive candidiasis may not be consistently effective against resistant C. albicans isolates, and this may be associated with the virulence of the strain.

  19. Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

    SciTech Connect

    Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd; Tran, David D.; Linette, Gerry; Jalalizadeh, Rohan; Dacey, Ralph; Rich, Keith M.; Chicoine, Michael R.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H.; Huang, Jiayi

    2014-11-15

    Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.

  20. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects.

    PubMed

    Guzzo, Cynthia A; Furtek, Christine I; Porras, Arturo G; Chen, Cong; Tipping, Robert; Clineschmidt, Coleen M; Sciberras, David G; Hsieh, John Y K; Lasseter, Kenneth C

    2002-10-01

    Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.

  1. Dose Escalation for Metastatic Spinal Cord Compression in Patients With Relatively Radioresistant Tumors

    SciTech Connect

    Rades, Dirk; Freundt, Katja; Meyners, Thekla; Bajrovic, Amira; Basic, Hiba; Karstens, Johann H.; Adamietz, Irenaeus A.; Wildfang, Ingeborg; Rudat, Volker; Schild, Steven E.; Dunst, Juergen

    2011-08-01

    Purpose: Radiotherapy alone is the most common treatment for metastatic spinal cord compression (MSCC) from relatively radioresistant tumors such as renal cell carcinoma, colorectal cancer, and malignant melanoma. However, the results of the 'standard' regimen 30 Gy/10 fractions need to be improved with respect to functional outcome. This study investigated whether a dose escalation beyond 30 Gy can improve treatment outcomes. Methods and Materials: A total of 91 patients receiving 30 Gy/10 fractions were retrospectively compared to 115 patients receiving higher doses (37.5 Gy/15 fractions, 40 Gy/20 fractions) for motor function and local control of MSCC. Ten further potential prognostic factors were evaluated: age, gender, tumor type, performance status, number of involved vertebrae, visceral or other bone metastases, interval from tumor diagnosis to radiotherapy, pretreatment ambulatory status, and time developing motor deficits before radiotherapy. Results: Motor function improved in 18% of patients after 30 Gy and in 22% after higher doses (p = 0.81). On multivariate analysis, functional outcome was associated with visceral metastases (p = 0.030), interval from tumor diagnosis to radiotherapy (p = 0.010), and time developing motor deficits (p < 0.001). The 1-year local control rates were 76% after 30 Gy and 80% after higher doses, respectively (p = 0.64). On multivariate analysis, local control was significantly associated with visceral metastases (p = 0.029) and number of involved vertebrae (p = 0.043). Conclusions: Given the limitations of a retrospective study, escalation of the radiation dose beyond 30 Gy/10 fractions did not significantly improve motor function and local control of MSCC in patients with relatively radioresistant tumors.

  2. Escalation of radiation dose beyond 30 Gy in 10 fractions for metastatic spinal cord compression

    SciTech Connect

    Rades, Dirk . E-mail: Rades.Dirk@gmx.net; Karstens, Johann H.; Hoskin, Peter J.; Rudat, Volker; Veninga, Theo; Schild, Steven E.; Dunst, Juergen

    2007-02-01

    Purpose: In many centers worldwide, radiotherapy for metastatic spinal cord compression (MSCC) is performed with 30 Gy in 10 fractions. This study investigated the potential benefit of dose escalation. Methods and Materials: Data from 922 patients with carcinomas causing MSCC were retrospectively evaluated. The outcome of 345 patients treated with 10 fractions of 3 Gy in 2 weeks was compared with the outcomes of 577 patients treated with 37.5 Gy in 15 fractions within 3 weeks or 40 Gy in 20 fractions within 4 weeks. Additionally, 10 potential prognostic factors were investigated: age, gender, performance status, tumor type, interval between cancer diagnosis and MSCC, number of involved vertebrae, other bone and visceral metastases, ambulatory status, and the interval to the development of motor deficits before radiotherapy. Results: Motor function improved in 19% of patients after 30 Gy in 10 fractions and in 22% after greater doses (p = 0.31). The local control (p = 0.28) and survival (p = 0.85) rates were not significantly different with doses >30 Gy. Better functional outcome was associated with the absence of visceral metastases, an interval between tumor diagnosis and MSCC of >12 months, ambulatory status, and an interval to the development of motor deficits of >7 days. Improved local control was significantly associated with no visceral metastases, improved survival with favorable histologic features (breast or prostate cancer), no visceral metastases, ambulatory status, an interval between cancer diagnosis and MSCC of >12 months, and an interval to the development of motor deficits of >7days. Conclusion: Escalation of the radiation dose to >30 Gy in 10 fractions did not improve the outcomes in terms of motor function, local control, or survival but did increase the treatment time for these frequently debilitated patients. Therefore, doses >30 Gy in 10 fractions are not recommended.

  3. Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

    PubMed Central

    Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

    2016-01-01

    Aim Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. PMID:27274277

  4. Dose-escalation study of octanoic acid in patients with essential tremor

    PubMed Central

    Voller, Bernhard; Lines, Emily; McCrossin, Gayle; Tinaz, Sule; Lungu, Codrin; Grimes, George; Starling, Judith; Potti, Gopal; Haubenberger, Dietrich

    2016-01-01

    BACKGROUND. Recently, 1-octanol has been shown to have efficacy in treating patients with essential tremor (ET). The primary metabolite of 1-octanol is octanoic acid (OA), which is now thought to be the active substance that mediates tremor suppression. Our aim was to describe the maximum tolerated dose (MTD) of oral OA in patients with ET and assess the pharmacokinetics (PK) and pharmacodynamics (PD) profile of OA. METHODS. The MTD was studied using an open-label, single-ascending 3 + 3 dose–escalation design. Predefined single doses ranged from 8 to 128 mg/kg, with grade 2 adverse events (AEs) defined as dose-limiting toxicity. Tremor was assessed using accelerometry, digital spiral analysis, and a standard clinical rating scale at baseline and up to 600 minutes after intake. Safety assessments and PK sampling were also performed. RESULTS. Dose-limiting toxicity was not reached. The most frequent AE was mild abdominal discomfort. Exposure (AUC) increased linearly with the dose. Secondary efficacy measures suggested a dose-dependent reduction of tremor. Accordingly, a single unified PK/PD model with an effect compartment and sigmoid maximum effect (Emax) response could be built that accounted well for the time profiles of plasma concentrations as well as effects on tremor severity across the 5 dose levels. CONCLUSION. Although our trial did not reach an MTD, a dose-dependent effect was demonstrated in the PK/PD model as well as in secondary efficacy outcomes. Future studies are needed to explore the safety in higher dose ranges and to confirm dose-dependent efficacy in a placebo-controlled design. TRIAL REGISTRATION. Clinicaltrials.gov NCT01468948 FUNDING. NINDS Intramural Research Program; TG Therapeutics Inc. PMID:26927672

  5. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects.

    PubMed

    Dvorchik, Barry H; Brazier, David; DeBruin, Michael F; Arbeit, Robert D

    2003-04-01

    The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight ( approximately 20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life ( approximately 9 h), volume of distribution ( approximately 0.1 liters/kg), systemic clearance ( approximately 8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h ( approximately 54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.

  6. Escalating dose pretreatment induces pharmacodynamic and not pharmacokinetic tolerance to a subsequent high-dose methamphetamine binge.

    PubMed

    O'Neil, Meghan L; Kuczenski, Ronald; Segal, David S; Cho, Arthur K; Lacan, Goran; Melega, William P

    2006-11-01

    A major feature of human methamphetamine (METH) abuse is the gradual dose escalation that precedes high-dose exposure. The period of escalating doses (EDs) is likely associated with development of tolerance to aspects of METH's pharmacologic and toxic effects but the relative contributions of pharmacokinetic and pharmacodynamic factors have not been well defined. In our prior studies in rats, we showed that pretreatment with an ED-METH regimen (0.1-4.0 mg/kg over 14 days) attenuated the toxicity of a subsequently administered high-dose METH binge (4 x 6 mg/kg at 2 h interval) that itself produced behavioral stereotypy, increases in core temperature, and decreases in DA system phenotypic markers in caudate-putamen (CP). Using those ED-METH and binge protocols in the present studies, pharmacokinetic and pharmacodynamic parameters that may have contributed to the apparent neuroprotection afforded by ED-METH were assessed. The ED-METH regimen itself reduced [(3)H]WIN35,428 (WIN) binding to the dopamine transporter (DAT) by 15% in CP, but did not affect DA content. During the METH binge, ED-METH pretreated animals showed attenuated increases in core temperature while concurrent microdialysis studies in CP showed a reduced DA response despite unaltered extracellular levels of METH. At 1 h after the binge, concentrations of METH and its metabolite amphetamine in brain and plasma were unaffected by the ED-METH. The results show that ED-METH pretreatment produces reductions in DAT binding and the DA response during a subsequent METH binge by altering pharmacodynamic and not pharmacokinetic parameters.

  7. Iranian Low-dose Escalating Prophylaxis Regimen in Children with Severe Hemophilia A and B.

    PubMed

    Eshghi, Peyman; Sadeghi, Elham; Tara, S Zahra; Habibpanah, Behnaz; Hantooshzadeh, Razieh

    2017-01-01

    Establishing an appropriate prophylaxis regimen for children with hemophilia is a critical challenge in developing countries. Barriers including availability and affordability, catheter-related complications, and inhibitor development risks have led to the introduction of new tailored prophylaxis regimens in different countries. This study emphasizes on the benefits of the Iranian low-dose escalating prophylaxis regimen in a Hemophilia Comprehensive Care Center in Iran. Referred patients with hemophilia less than 15 years of age, who were subject to prophylaxis regimen, are studied retrospectively. A once-weekly prophylaxis regimen of 25 IU/kg was started for the patients primarily. Their prophylaxis regimen was changed to 25 IU/kg twice a week and then 3 times a week when they experienced 3 joint bleedings, 4 soft tissue bleedings, or a 1 life-threatening bleed without a specific trauma history. Overall, 25 patients with severe hemophilia and at least 6-month history of on-demand (OD) treatment were studied. A mean of 1754 IU/kg/yr of coagulation factors, used for OD and prophylaxis purposes, was sufficient to decrease the mean annual bleeding rate (ABR) to 1.86 after prophylaxis. It also reduced the mean hospitalization days and the mean number of target joints to 0.24 and 0.16, respectively. Overall, 19 (76%) patients were continuing their once-weekly regimen at the end of the follow-up. None of the patients needed 3-times-a-week regimen or central venous catheterization and none developed inhibitors in the follow-up. Benefits of the Iranian low-dose escalating prophylaxis regimen prove equal to some of the previous 3-times-a-week prophylaxis regimens in reducing the ABR and hospitalizations.

  8. Chemoradiation of Hepatic Malignancies: Prospective, Phase 1 Study of Full-Dose Capecitabine With Escalating Doses of Yttrium-90 Radioembolization

    SciTech Connect

    Hickey, Ryan; Mulcahy, Mary F.; Lewandowski, Robert J.; Gates, Vanessa L.; Vouche, Michael; Habib, Ali; Kircher, Sheetal; Newman, Steven; Nimeiri, Halla; Benson, Al B.; Salem, Riad

    2014-04-01

    Purpose: Radiosensitizing chemotherapy improves the outcomes in comparison with radiation alone for gastrointestinal cancers. The delivery of radiation therapy with yttrium90 ({sup 90}Y) radioembolization, in combination with the radiosensitizing chemotherapeutic agent capecitabine, provides the opportunity to enhance the effects of radiation on hepatic malignancies. This phase 1 study sought to determine the maximum tolerated dose (MTD) of {sup 90}Y plus capecitabine in patients with cholangiocarcinoma or liver metastases confined to the liver. Methods and Materials: Patients were given initial treatment at full-dose capecitabine during days 1 to 14 of a 21-day cycle. At days 1 to 7 of the second cycle, whole-liver {sup 90}Y was given at the test dose, after which time capecitabine was continued. Dose-limiting toxicity (DLT) was determined 6 weeks after {sup 90}Y infusion. If a DLT was not observed, the {sup 90}Y dose was escalated. The planned dose cohorts were 110, 130, 150, and 170 Gy. The primary endpoint was to determine the MTD of {sup 90}Y with full-dose capecitabine. Results: Sixteen patients were treated according to the study protocol. Two patients experienced DLTs. Nine patients required capecitabine dose reduction as a result of toxicities attributable to capecitabine alone. The criteria for establishing {sup 90}Y MTD were not met, indicating an MTD of >170 Gy. Conclusion: The MTD of {sup 90}Y delivered in conjunction with capecitabine in the setting of intrahepatic cholangiocarcinoma or metastatic disease confined to the liver exceeds 170 Gy. This is the highest {sup 90}Y dose reported to date and has important implications on combined therapy with the radiosensitizing oral chemotherapeutic capecitabine. Further studies are under way.

  9. Potential for dose-escalation and reduction of risk in pancreatic cancer using IMRT optimization with lexicographic ordering and gEUD-based cost functions

    SciTech Connect

    Spalding, Aaron C.; Jee, Kyung-Wook; Vineberg, Karen; Jablonowski, Marla; Fraass, Benedick A.; Pan, Charlie C.; Lawrence, Theodore S.; Ten Haken, Randall K.; Ben-Josef, Edgar

    2007-02-15

    Radiotherapy for pancreatic cancer is limited by the tolerance of local organs at risk (OARs) and frequent overlap of the planning target volume (PTV) and OAR volumes. Using lexicographic ordering (LO), a hierarchical optimization technique, with generalized equivalent uniform dose (gEUD) cost functions, we studied the potential of intensity modulated radiation therapy (IMRT) to increase the dose to pancreatic tumors and to areas of vascular involvement that preclude surgical resection [surgical boost volume (SBV)]. We compared 15 forward planned three-dimensional conformal (3DCRT) and IMRT treatment plans for locally advanced unresectable pancreatic cancer. We created IMRT plans optimized using LO with gEUD-based cost functions that account for the contribution of each part of the resulting inhomogeneous dose distribution. LO-IMRT plans allowed substantial PTV dose escalation compared with 3DCRT; median increase from 52 Gy to 66 Gy (a=-5,p<0.005) and median increase from 50 Gy to 59 Gy (a=-15,p<0.005). LO-IMRT also allowed increases to 85 Gy in the SBV, regardless of a value, along with significant dose reductions in OARs. We conclude that LO-IMRT with gEUD cost functions could allow dose escalation in pancreas tumors with concomitant reduction in doses to organs at risk as compared with traditional 3DCRT.

  10. Escalating doses of transdermal nicotine in heavy smokers: effects on smoking behavior and craving.

    PubMed

    Selby, Peter; Andriash, Katherine; Zawertailo, Laurie; Persad, Desmond; Zack, Martin; Busto, Usoa E

    2013-10-01

    Fixed-dose nicotine replacement therapy (NRT) is efficacious for smoking cessation in the general population of smokers. However, it is less effective in populations with psychiatric comorbidities and/or severe tobacco dependence where the percent nicotine replacement is suboptimal. The objective of this pilot study was to determine the effectiveness of nicotine patch dose titration in response to continued smoking in heavily dependent smokers with psychiatric comorbidity. In a single-arm, open-label study adult smokers (mean cigarettes per day, 25.4 ± 13.4; range, 14-43; n = 12) willing to quit were treated with escalating doses of transdermal nicotine and brief counseling intervention if they continued to smoke over a 9-week treatment period. Plasma nicotine and cotinine, along with expired carbon monoxide levels, and the subjective effects of smoking, urge to smoke, demand elasticity, and mood symptoms were also assessed. The mean NRT dose was 32.7 (SD, 16.4) mg/d (range, 7-56 mg/d). Smokers reported significant reductions in both cigarettes per day (mean decrease, 18.4 ± 11.5) confirmed by expired carbon monoxide (mean decrease, 13.5 ± 13.0) with no significant changes in plasma nicotine concentrations during the course of NRT dose titration. There were significant effects on the subjective effects of smoking and measures of smoking behavior. Most commonly reported adverse events were respiratory infections, skin irritation at patch site, nausea, and sleep disturbances, which were generally mild and transient. Titrating doses of NRT to effect with brief intervention hold promise as an effective clinical strategy to assist heavily dependent psychiatrically ill smokers to change their smoking behavior.

  11. Target localization and toxicity in dose-escalated prostate radiotherapy with image-guided approach using daily planar kilovoltage imaging.

    PubMed

    Nath, S K; Sandhu, A P; Sethi, R A; Jensen, L G; Rosario, M D; Kane, C J; Parsons, J K; Millard, F E; Jiang, S B; Rice, R K; Pawlicki, T; Mundt, A J

    2011-02-01

    Dose escalation with intensity-modulated radiation therapy (IMRT) for carcinoma of the prostate has augmented the need for accurate prostate localization prior to dose delivery. Daily planar kilovoltage (kV) imaging is a low-dose image-guidance technique that is prevalent among radiation oncologists. However, clinical outcomes evaluating the benefit of daily kV imaging are lacking. The purpose of this study was to report our clinical experience, including prostate motion and gastrointestinal (GI) and genitourinary (GU) toxicities, using this modality. A retrospective analysis of 100 patients treated consecutively between December 2005 and March 2008 with definitive external beam IMRT for T1c-T4 disease were included in this analysis. Prescription doses ranged from 74-78 Gy (median, 76) in 2 Gy fractions and were delivered following daily prostate localization using on-board kV imaging (OBI) to localize gold seed fiducial markers within the prostate. Acute and late toxicities were graded as per the NCI CTCAEv3.0. The median follow-up was 22 months. The magnitude and direction of prostate displacement and daily shifts in three axes are reported. Of note, 9.1% and 12.9% of prostate displacements were ≥ 5 mm in the anterior-posterior and superior-inferior directions, respectively. Acute grade 2 GI and GU events occurred in 11% and 39% of patients, respectively, however no grade 3 or higher acute GI or GU events were observed. Regarding late toxicity, 2% and 17% of patients developed grade 2 toxicities, and similarly no grade 3 or higher events had occurred by last follow-up. Thus, kV imaging detected a substantial amount of inter-fractional displacement and may help reduce toxicity profiles, especially high grade events, by improving the accuracy of dose delivery.

  12. Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2016-02-18

    Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

  13. Dose Escalation and Dosimetry of First in Human Alpha Radioimmunotherapy with 212Pb-TCMC-trastuzumab

    PubMed Central

    Meredith, Ruby; Torgue, Julien; Shen, Sui; Fisher, Darrell R.; Banaga, Eileen; Bunch, Patty; Morgan, Desiree; Fan, Jinda; Straughn, J. Michael

    2015-01-01

    Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity and tumor response of intraperitoneal (IP) 212Pb-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyantobenzl)-1, 4, 7, 10-tetraaza-1, 4, 7, 10=tetra (2-carbamoylmethl) cyclododecane) in patients with HER-2 expressing malignancy. Methods In a standard 3+3 Phase 1 design for dose escalation, 212Pb-TCMC-trastuzumab was delivered IP less than 4 hours after giving 4mg/kg IV trastuzumab to patients with peritoneal carcinomatosis who had failed standard therapies. Results Five dosage levels (7.4, 9.6, 12.6, 16.3, 21.1 MBq/m2) showed minimal toxicity at >1 year for the first group and >4 months for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow = 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n=3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion and no specific uptake in major organs was observed in 24 hours. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24h (decay corrected to injection time) and 500 Bq/mL (decay corrected to collection time). Non-decay corrected cumulative urinary excretion was ≤6% in 24h (2.3 half lives). Dose rate measurements performed at 1m from the patient registered less than 5μSv/hr (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Anti-drug antibody assays performed on serum from the first 4 cohorts were all negative. Conclusions Five dose levels of IP 212Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent related toxicity, consistent with the dosimetry calculations. PMID:25157044

  14. A Randomized Phase 1 Dose Escalation Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Trabodenoson in Healthy Adult Volunteers

    PubMed Central

    Laties, Alan; Rich, Cadmus C.; Stoltz, Randall; Humbert, Vernon; Brickman, Chaim; McVicar, William

    2016-01-01

    Abstract Purpose: To investigate the safety, tolerability, and pharmacokinetics of trabodenoson, a highly selective adenosine mimetic targeting the adenosine A1 receptor. Methods: In Part 1, 60 healthy adult volunteers were randomized to 14 days of twice-daily topical monocular application of placebo or trabodenoson (200, 400, 800, 1,600, 2,400, or 3,200 μg). In Part 2, 10 subjects were randomized to placebo or 8 escalating doses of bilateral trabodenoson (total daily doses: 1,800–6,400 μg). Results: The incidence of treatment-related adverse events in Part 1 was similar in the trabodenoson (27.8%) and placebo (25.0%) groups. Most were mild in intensity. The most common adverse events (AEs) for trabodenoson and placebo were headache (25.0% vs. 33%, respectively) and eye pain (11.1% vs. 4.2%, respectively). Ocular AEs were infrequent (16.7% and 17.9%, respectively), were self-limited, lasted <24 h, and were typically mild in intensity. The most common ocular AE was eye pain (9.5% and 3.6%, respectively), with a single observation of ocular hyperemia (200 μg trabodenoson). Trabodenoson was rapidly absorbed [median time to maximum concentration (tmax): ∼0.08 to 0.27 h] and eliminated (t½: 0.48–2.0 h), with no evidence of drug accumulation. Systemic exposure to topical trabodenoson was dose related but not dose proportional, with a plateau effect at doses ≥2,400 mg per eye. No clinically significant treatment-related systemic AEs were observed, and increasing systemic exposure had no effect on heart rate or blood pressure. Conclusions: Ocular doses of trabodenoson up to 3,200 μg per eye were safe and well tolerated in the eye and resulted in no detectable systemic effects in healthy adult volunteers. PMID:27046445

  15. Image-guided adaptive radiation therapy (IGART): Radiobiological and dose escalation considerations for localized carcinoma of the prostate

    SciTech Connect

    Song, William; Schaly, Bryan; Bauman, Glenn; Battista, Jerry; Van Dyk, Jake

    2005-07-15

    The goal of this work was to evaluate the efficacy of various image-guided adaptive radiation therapy (IGART) techniques to deliver and escalate dose to the prostate in the presence of geometric uncertainties. Five prostate patients with 15-16 treatment CT studies each were retrospectively analyzed. All patients were planned with an 18 MV, six-field conformal technique with a 10 mm margin size and an initial prescription of 70 Gy in 35 fractions. The adaptive strategy employed in this work for patient-specific dose escalation was to increase the prescription dose in 2 Gy-per-fraction increments until the rectum normal tissue complication probability (NTCP) reached a level equal to that of the nominal plan NTCP (i.e., iso-NTCP dose escalation). The various target localization techniques simulated were: (1) daily laser-guided alignment to skin tattoo marks that represents treatment without image-guidance, (2) alignment to bony landmarks with daily portal images, and (3) alignment to the clinical target volume (CTV) with daily CT images. Techniques (1) and (3) were resimulated with a reduced margin size of 5 mm to investigate further dose escalation. When delivering the original clinical prescription dose of 70 Gy in 35 fractions, the 'CTV registration' technique yielded the highest tumor control probability (TCP) most frequently, followed by the 'bone registration' and 'tattoo registration' techniques. However, the differences in TCP among the three techniques were minor when the margin size was 10 mm ({<=}1.1%). Reducing the margin size to 5 mm significantly degraded the TCP values of the 'tattoo registration' technique in two of the five patients, where a large difference was found compared to the other techniques ({<=}11.8%). The 'CTV registration' technique, however, did maintain similar TCP values compared to their 10 mm margin counterpart. In terms of normal tissue sparing, the technique producing the lowest NTCP varied from patient to patient. Reducing the

  16. Parameters Favorable to Intraprostatic Radiation Dose Escalation in Men With Localized Prostate Cancer

    SciTech Connect

    Housri, Nadine; Ning, Holly; Ondos, John; Choyke, Peter; Camphausen, Kevin; Citrin, Deborah; Arora, Barbara; Shankavaram, Uma; Kaushal, Aradhana

    2011-06-01

    Purpose: To identify , within the framework of a current Phase I trial, whether factors related to intraprostatic cancer lesions (IPLs) or individual patients predict the feasibility of high-dose intraprostatic irradiation. Methods and Materials: Endorectal coil MRI scans of the prostate from 42 men were evaluated for dominant IPLs. The IPLs, prostate, and critical normal tissues were contoured. Intensity-modulated radiotherapy plans were generated with the goal of delivering 75.6 Gy in 1.8-Gy fractions to the prostate, with IPLs receiving a simultaneous integrated boost of 3.6 Gy per fraction to a total dose of 151.2 Gy, 200% of the prescribed dose and the highest dose cohort in our trial. Rectal and bladder dose constraints were consistent with those outlined in current Radiation Therapy Oncology Group protocols. Results: Dominant IPLs were identified in 24 patients (57.1%). Simultaneous integrated boosts (SIB) to 200% of the prescribed dose were achieved in 12 of the 24 patients without violating dose constraints. Both the distance between the IPL and rectum and the hip-to-hip patient width on planning CT scans were associated with the feasibility to plan an SIB (p = 0.002 and p = 0.0137, respectively). Conclusions: On the basis of this small cohort, the distance between an intraprostatic lesion and the rectum most strongly predicted the ability to plan high-dose radiation to a dominant intraprostatic lesion. High-dose SIB planning seems possible for select intraprostatic lesions.

  17. Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.

    PubMed

    Schmeichel, Brooke E; Barbier, Estelle; Misra, Kaushik K; Contet, Candice; Schlosburg, Joel E; Grigoriadis, Dimitri; Williams, John P; Karlsson, Camilla; Pitcairn, Caleb; Heilig, Markus; Koob, George F; Vendruscolo, Leandro F

    2015-03-13

    The hypocretin/orexin (HCRT) system has been associated with both positive and negative drug reinforcement, implicating HCRT receptor 1 (HCRT-R1) signaling in drug-related behaviors for all major drug classes, including opioids. However, to date there are limited studies investigating the role of HCRT receptor 2 (HCRT-R2) signaling in compulsive-like drug seeking. Escalation of drug intake with extended access has been suggested to model the transition from controlled drug use to compulsive-like drug seeking/taking. The current study examined the effects of a HCRT-R2 antagonist, NBI-80713, on heroin self-administration in rats allowed short- (1 h; ShA) or long- (12 h; LgA) access to intravenous heroin self-administration. Results indicate that systemically administered NBI-80713 dose-dependently decreased heroin self-administration in LgA, but not in ShA, animals. Quantitative PCR analyses showed an increase in Hcrtr2 mRNA levels in the central amygdala, a stress-related brain region, of LgA rats. These observations suggest a functional role for HCRT-R2 signaling in compulsive-like heroin self-administration associated with extended access and indicate HCRT-R2 antagonism as a potential pharmacological target for the treatment of heroin dependence.

  18. Long-Term Response and Possible Cure of Patients With B-Cell Malignancies With Dose-Escalated Rituximab

    PubMed Central

    Jacobs, Lauren M.; Wiernik, Peter H.; Dutcher, Janice P.; Muxi, Pablo

    2017-01-01

    Rituximab (R), a chimeric monoclonal antibody targeting CD20 antigen on B-cells, has become a standard of care in the treatment of B-cell malignancies, most often in conjunction with cytotoxic chemotherapy. Activity has been demonstrated in many subtypes of B-cell lymphoma, including diffuse large cell lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), lymphocyte-predominant Hodgkin lymphoma, and Waldenström macroglobulinemia (WM). Additionally, dose escalation of R as a single agent has demonstrated improved activity in previously treated/poor prognosis CLL. We present 4 cases of B-cell malignancy (2 CLL variants/MCL, 1 FL, 1 WM) who received dose-escalated R as a single agent and achieved complete response (3 patients) and stable disease/partial response (1 patient) of 6.5+ to 15+ years duration. They have been off treatment for 6.5+ to 15+ years. Toxicity was minimal, with initial infusion reactions similar to those observed with standard dose infusions. There were no serious treatment-related adverse events or infections. Dose escalated R as a single agent may possibly be curative for some patients with B-cell malignancies, unlike the standard empiric dose of 375 mg/m2, and deserves further study. PMID:28203581

  19. Postradiotherapy PSA nadirs fail to support dose escalation study in patients with pretreatment PSA values < 10 ng/ml.

    PubMed

    Herold, D; Hanks, G; Movsas, B; Hanlon, A

    1997-01-01

    With three-dimensional conformal therapy, doses > 75 Gy have been delivered to the prostate with acceptable levels of morbidity; however, higher doses do appear to increase late gastrointestinal (GI) and genitourinary (GU) morbidity. Because patients with pretreatment prostate-specific antigen (PSA) values < 10 ng/ml can achieve 3-year actuarial bNED control rates of 90% after treatment with external beam radiotherapy to doses < 71 Gy, one might question the need for further dose escalation in this population. In this report, we examined the relationship between dose and PSA nadir for 90 patients with pretreatment PSA values < 10 ng/ml entered into a dose escalation study from March 1987 to October 1992. We wanted to see if nadir response data would predict a different outcome from our 3-year bNED control reports. All patients were treated with external beam radiotherapy to ICRU reporting point doses of 6,598 cGy to 7,895 cGy (median of 7,068 cGy). Minimum follow-up was 36 months (median, 47 months). Seven hundred thirty-nine posttreatment PSA nadir values were analyzed, yielding an average of 8.2 values per patient. Estimates of rates of bNED control and time to reach a posttreatment PSA of 1.0 ng/ml were calculated using the Kaplan-Meier product limit method. The log-rank test was used to evaluate differences in rates according to dose levels. Linear regression and Cox proportional hazard modeling were used to relate dose to bNED control on a continuum. Escalating doses from 66 to 79 Gy failed to increase the percentage of patients achieving nadir values < 1 ng/ml and similarly failed to increase the 3-year actuarial bNED control. Linear regression (P = .81) and the chi-square test of association (P = .23) supported the lack of a dose effect on nadir continuously and categorically, respectively, and the Cox regression model supported the conclusion that dose on a continuum has no effect on bNED control (P = .34). Furthermore, time to reach a posttreatment PSA

  20. Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study

    PubMed Central

    Kaplovitch, Eric; Gomes, Tara; Camacho, Ximena; Dhalla, Irfan A.; Mamdani, Muhammad M.; Juurlink, David N.

    2015-01-01

    Background The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. Methods and Findings We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Conclusions Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated. PMID:26291716

  1. Optimizing Collimator Margins for Isotoxically Dose-Escalated Conformal Radiation Therapy of Non-Small Cell Lung Cancer

    SciTech Connect

    Warren, Samantha; Panettieri, Vanessa; Panakis, Niki; Bates, Nicholas; Lester, Jason F.; Jain, Pooja; Landau, David B.; Nahum, Alan E.; Mayles, W. Philip M.; Fenwick, John D.

    2014-04-01

    Purpose: Isotoxic dose escalation schedules such as IDEAL-CRT [isotoxic dose escalation and acceleration in lung cancer chemoradiation therapy] (ISRCTN12155469) individualize doses prescribed to lung tumors, generating a fixed modeled risk of radiation pneumonitis. Because the beam penumbra is broadened in lung, the choice of collimator margin is an important element of the optimization of isotoxic conformal radiation therapy for lung cancer. Methods and Materials: Twelve patients with stage I-III non-small cell lung cancer (NSCLC) were replanned retrospectively using a range of collimator margins. For each plan, the prescribed dose was calculated according to the IDEAL-CRT isotoxic prescription method, and the absolute dose (D{sub 99}) delivered to 99% of the planning target volume (PTV) was determined. Results: Reducing the multileaf collimator margin from the widely used 7 mm to a value of 2 mm produced gains of 2.1 to 15.6 Gy in absolute PTV D{sub 99}, with a mean gain ± 1 standard error of the mean of 6.2 ± 1.1 Gy (2-sided P<.001). Conclusions: For NSCLC patients treated with conformal radiation therapy and an isotoxic dose prescription, absolute doses in the PTV may be increased by using smaller collimator margins, reductions in relative coverage being offset by increases in prescribed dose.

  2. Effects of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in the male rat.

    PubMed

    Barr, A M; Fiorino, D F; Phillips, A G

    1999-11-01

    The present study sought to determine the effect of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in male rats. Tests were conducted every 5 days until stable levels of sexual behavior were obtained. With repeated testing, male rats displayed an increase in their exploration of the testing chambers prior to the introduction of an estrous female. Half of the male rats were then subjected to a 4-day escalating dose schedule of d-amphetamine administration (1-12 mg/kg), while half received vehicle. Twelve hours after the final drug injection, subjects were tested for sexual behavior. Withdrawal from the drug was associated with decrements in several motivational components of sexual behavior, including decreased anticipatory locomotor and increased postejaculatory intervals, while consummatory measures remained largely unaffected. This pattern of sexual deficits resembles those seen in human depressive disorders, and therefore, provides additional support for the use of psychostimulant withdrawal as a rodent model of depression.

  3. Update of Dutch Multicenter Dose-Escalation Trial of Radiotherapy for Localized Prostate Cancer

    SciTech Connect

    Al-Mamgani, Abrahim Putten, Wim L.J. van; Heemsbergen, Wilma D.; Leenders, Geert J.L.H. van; Slot, Annerie; Dielwart, Michel F.H.; Incrocci, Luca; Lebesque, Joos V.

    2008-11-15

    Purpose: To update the analysis of the Dutch dose-escalation trial of radiotherapy for prostate cancer. Patients and Methods: A total of 669 patients with localized prostate cancer were randomly assigned to receive 68 or 78 Gy. The patients were stratified by age, institution, use of neoadjuvant or adjuvant hormonal therapy, and treatment group. The primary endpoint was freedom from failure (FFF), with failure defined as clinical or biochemical failure. Two definitions of biochemical failure were used: the American Society for Therapeutic Radiology and Oncology definition (three consecutive increases in prostate-specific antigen level) and the Phoenix definition (nadir plus 2 {mu}g/L). The secondary endpoints were freedom from clinical failure, overall survival, and genitourinary and gastrointestinal toxicity. Results: After a median follow-up of 70 months, the FFF using the American Society for Therapeutic Radiology and Oncology definition was significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 54% vs. 47%, respectively; p = 0.04). The FFF using the Phoenix definition was also significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 56% vs. 45%, respectively; p = 0.03). However, no differences in freedom from clinical failure or overall survival were observed. The incidence of late Grade 2 or greater genitourinary toxicity was similar in both arms (40% and 41% at 7 years; p = 0.6). However, the cumulative incidence of late Grade 2 or greater gastrointestinal toxicity was increased in the 78-Gy arm compared with the 68-Gy arm (35% vs. 25% at 7 years; p = 0.04). Conclusion: The results of our study have shown a statistically significant improvement in FFF in prostate cancer patients treated with 78 Gy but with a greater rate of late gastrointestinal toxicity.

  4. Dose Escalation for Prostate Cancer Using the Three-Dimensional Conformal Dynamic Arc Technique: Analysis of 542 Consecutive Patients

    SciTech Connect

    Jereczek-Fossa, Barbara A. Vavassori, Andrea; Fodor, Cristiana; Santoro, Luigi; Zerini, Dario; Cattani, Federica; Garibaldi, Cristina; Cambria, Raffaella; Fodor, Andrei; Boboc, Genoveva Ionela; Vitolo, Viviana; Ivaldi, Giovanni Battista; Musi, Gennaro; De Cobelli, Ottavio; Orecchia, Roberto

    2008-07-01

    Purpose: To present the results of dose escalation using three-dimensional conformal dynamic arc radiotherapy (3D-ART) for prostate cancer. Methods and Materials: Five hundred and forty two T1-T3N0M0 prostate cancer patients were treated with 3D-ART. Dose escalation (from 76 Gy/38 fractions to 80 Gy/40 fractions) was introduced in September 2003; 32% of patients received 80 Gy. In 366 patients, androgen deprivation was added to 3D-ART. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median follow-up was 25 months. Results: Acute toxicity included rectal (G1-2 28.9%; G3 0.5%) and urinary events (G1-2 57.9%; G3-4 2.4%). Late toxicity included rectal (G1-2 15.8%; G3-4 3.1%) and urinary events (G1-2 26.9%; G3-4 1.6%). Two-year failure-free survival and overall survival rates were 94.1% and 97.9%, respectively. Poor prognostic group (GS, iPSA, T), transurethral prostate resection, and dose >76 Gy showed significant association to high risk of progression in multivariate analysis (p = 0.014, p = 0.045, and p 0.04, respectively). The negative effect of dose >76 Gy was not observed (p 0.10), when the analysis was limited to 353 patients treated after September 2003 (when dose escalation was introduced). Higher dose was not associated with higher late toxicity. Conclusions: Three-dimensional-ART is a feasible modality allowing for dose escalation (no increase in toxicity has been observed with higher doses). However, the dose increase from 76 to 80 Gy was not associated with better tumor outcome. Further investigation is warranted for better understanding of the dose effect for prostate cancer.

  5. SU-E-T-183: Feasibility of Extreme Dose Escalation for Glioblastoma Multiforme Using 4π Radiotherapy

    SciTech Connect

    Nguyen, D; Rwigema, J; Yu, V; Kaprealian, T; Kupelian, P; Selch, M; Low, D; Sheng, K

    2014-06-01

    Purpose: GBM recurrence primarily occurs inside or near the high-dose radiation field of original tumor site requiring greater than 100 Gy to significantly improve local control. We utilize 4π non-coplanar radiotherapy to test the feasibility of planning target volume (PTV) margin expansions or extreme dose escalations without incurring additional radiation toxicities. Methods: 11 GBM patients treated with VMAT to a prescription dose of 59.4 Gy or 60 Gy were replanned with 4π. Original VMAT plans were created with 2 to 4 coplanar or non-coplanar arcs using 3 mm hi-res MLC. The 4π optimization, using 5 mm MLC, selected and inverse optimized 30 beams from a candidate pool of 1162 beams evenly distributed through 4π steradians. 4π plans were first compared to clinical plans using the same prescription dose. Two more studies were then performed to respectively escalate the GTV and PTV doses to 100 Gy, followed by a fourth plan expanding the PTV by 5 mm and maintaining the prescription dose. Results: The standard 4π plan significantly reduced (p<0.01) max and mean doses to critical structures by a range of 47.0–98.4% and 61.0–99.2%, respectively. The high dose PTV/high dose GTV/expanded PTV studies showed a reduction (p<0.05) or unchanged* (p>0.05) maximum dose of 72.1%/86.7%/77.1% (chiasm), 7.2%*/27.7%*/30.7% (brainstem), 39.8%*/84.2%/51.9%* (spinal cord), 69.0%/87.0%/66.9% (L eye), 76.2%/88.1%/84.1% (R eye), 95.0%/98.6%/97.5% (L lens), 93.9%/98.8%/97.6% (R lens), 74.3%/88.5%/72.4% (L optical nerve), 80.4%/91.3%/75.7% (R optical nerve), 64.8%/84.2%/44.9%* (L cochlea), and 85.2%/93.0%/78.0% (R cochlea), respectively. V30 and V36 for both brain and (brain - PTV) were reduced for all cases except the high dose PTV plan. PTV dose coverage increased for all 4π plans. Conclusion: Extreme dose escalation or further margin expansion is achievable using 4π, maintaining or reducing OAR doses. This study indicates that clinical trials employing 4π delivery using

  6. A Phase I clinical and pharmacology study using amifostine as a radioprotector in dose-escalated whole liver radiation therapy

    PubMed Central

    Feng, Mary; Smith, David E.; Normolle, Daniel P.; Knol, James A.; Pan, Charlie C.; Ben-Josef, Edgar; Lu, Zheng; Feng, Meihua R.; Chen, Jun; Ensminger, William; Lawrence, Theodore S.

    2011-01-01

    PURPOSE Diffuse intrahepatic tumors are difficult to control. Whole liver radiotherapy has been limited by toxicity, most notably radiation-induced liver disease (RILD). Amifostine is a prodrug free-radical scavenger that selectively protects normal tissues and, in a preclinical model of intrahepatic cancer, systemic amifostine reduced normal liver radiation damage without compromising tumor effect.(1) We hypothesized that amifostine would permit escalation of whole liver radiation dose to potentially control microscopic disease. We also aimed to characterize the pharmacokinetics of amifostine and its active metabolite WR-1065 to optimize timing of radiotherapy. METHODS AND MATERIALS We conducted a radiation dose escalation trial for patients with diffuse, intrahepatic cancer treated with whole liver radiation and intravenous amifostine. Radiation dose was assigned using the Time-to-Event Continual Reassessment Method. A companion pharmacokinetic study was performed. RESULTS 23 patients were treated, with a maximum dose of 40 Gy. Using a logistical regression model, compared to our previously treated patients, amifostine increased liver tolerance by 3.3 ± 1.1 Gy (p=0.007) (approximately 10%) with similar response rates. Peak concentrations of WR-1065 were 25 μM with an elimination half life of 1.5 hours; these levels are consistent with radioprotective effects of amifostine in patients. CONCLUSION These findings demonstrate for the first time that amifostine is a normal liver radioprotector. They further suggest that it may be useful to combine amifostine with fractionated or stereotactic body radiation therapy for patients with focal intrahepatic cancer. PMID:22440042

  7. Phase I dose-escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors

    PubMed Central

    Brennan, R. C.; Furman, W.; Mao, S.; Wu, J.; Turner, D. C.; Stewart, C. F.; Santana, V.; McGregor, L. M.

    2015-01-01

    Purpose This phase I study endeavored to estimate the maximum tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors. Methods Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150mg/m2/day) on days 1-12 of a 21-day course. The Escalation with Overdose Control (EWOC) method guided irinotecan dose escalation (7 dose levels, range 5mg/m2/day to 40mg/m2/day). Results Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in 10 patients. Diagnoses included osteosarcoma (N=5), neuroblastoma (N=3), sarcoma (N=3), and others (N=5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N=2 and hypophosphatemia, N=1) at dose levels two (10mg/m2) and four (20mg/m2). One patient experienced grade 3 diarrhea (40mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35mg/m2). Of eleven patients receiving at least two courses of therapy, three had stable disease (SD) lasting two to four courses and one patient maintained a complete response through 18 courses. Conclusions The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure. PMID:25257509

  8. Dose escalation in brachytherapy for cervical cancer: impact on (or increased need for) MRI-guided plan optimisation

    PubMed Central

    Paton, A M; Chalmers, K E; Coomber, H; Cameron, A L

    2012-01-01

    Objective The aim of this study was to assess the impact of dose escalation on the proportion of patients requiring MR image-guided optimisation rather than standard Manchester-based CT-guided planning, and the level of escalation achievable. Methods 30 patients with cervical cancer treated with external beam radiotherapy and image-guided brachytherapy (IGBT) had MR images acquired at the first fraction of IGBT. Gross tumour volume and high-risk clinical target volume (HR CTV) were contoured and treatment plans retrospectively produced for a range of total 2-Gy equivalent (EQD2) prescription doses from 66 Gyα/β=10 to 90 Gyα/β=10 (HR CTV D90). Standard Manchester system-style plans were produced, prescribed to point A and then optimised where necessary with the aim of delivering at least the prescription dose to the HR CTV D90 while respecting organ-at-risk (OAR) tolerances. Results Increasing the total EQD2 from 66 Gyα/β=10 to 90 Gyα/β=10 increased the number of plans requiring optimisation from 13.3% to 90%. After optimisation, the number of plans achieving the prescription dose ranged from 93.3% (66 Gyα/β=10) to 63.3% (90 Gyα/β=10) with the mean±standard deviation for HR CTV D90 EQD2 from 78.4±12.4 Gyα/β=10 (66 Gyα/β=10) to 94.1±19.9 Gyα/β=10 (90 Gyα/β=10). Conclusion As doses are escalated, the need for non-standard optimised planning increases, while benefits in terms of increased target doses actually achieved diminish. The maximum achievable target dose is ultimately limited by proximity of OARs. Advances in knowledge This work represents a guide for other centres in determining the highest practicable prescription doses while considering patient throughput and maintaining acceptable OAR doses. PMID:23175490

  9. Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control.

    PubMed

    Tighiouart, Mourad; Piantadosi, Steven; Rogatko, André

    2014-09-28

    We present a Bayesian adaptive design for dose finding of a combination of two drugs in cancer phase I clinical trials. The goal is to estimate the maximum tolerated dose (MTD) as a curve in the two-dimensional Cartesian plane. We use a logistic model to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity. The model is re-parameterized in terms of parameters clinicians can easily interpret. Trial design proceeds using univariate escalation with overdose control, where at each stage of the trial, we seek a dose of one agent using the current posterior distribution of the MTD of this agent given the current dose of the other agent. At the end of the trial, an estimate of the MTD curve is proposed as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial design and percent of dose recommendation at dose combination neighborhoods around the true MTD curve. We also examine the performance of the approach under model misspecifications for the true dose-toxicity relationship.

  10. Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study

    PubMed Central

    Gutzmer, R; Rivoltini, L; Levchenko, E; Testori, A; Utikal, J; Ascierto, P A; Demidov, L; Grob, J J; Ridolfi, R; Schadendorf, D; Queirolo, P; Santoro, A; Loquai, C; Dreno, B; Hauschild, A; Schultz, E; Lesimple, T P; Vanhoutte, N; Salaun, B; Gillet, M; Jarnjak, S; De Sousa Alves, P M; Louahed, J; Brichard, V G; Lehmann, F F

    2016-01-01

    Purpose The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients and methods Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. Results 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. Conclusions The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. Trial registration number NCT01149343, Results. PMID:27843625

  11. Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer

    SciTech Connect

    Gomez, Daniel R.; Gillin, Michael; Liao, Zhongxing; Wei, Caimiao; Lin, Steven H.; Swanick, Cameron; Alvarado, Tina; Komaki, Ritsuko; Cox, James D.; Chang, Joe Y.

    2013-07-15

    Background: Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control. Methods and Materials: Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectiveness [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment. Results: The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT. Conclusion: Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC.

  12. Dose Escalation and Quality of Life in Patients With Localized Prostate Cancer Treated With Radiotherapy: Long-Term Results of the Dutch Randomized Dose-Escalation Trial (CKTO 96-10 Trial)

    SciTech Connect

    Al-Mamgani, Abrahim; Putten, Wim L.J. van; Wielen, Gerard J. van der; Levendag, Peter C.; Incrocci, Luca

    2011-03-15

    Purpose: To assess the impact of dose escalation of radiotherapy on quality of life (QoL) in prostate cancer patients. Patients and Methods: Three hundred prostate cancer patients participating in the Dutch randomized trial (CKTO 69-10) comparing 68 Gy with 78 Gy were the subject of this analysis. These patients filled out the SF-36 QoL questionnaire before radiotherapy (baseline) and 6, 12, 24, and 36 months thereafter. Changes in QoL over time of {>=}10 points were considered clinically relevant. Repeated-measures regression analyses were applied to estimate and test the QoL changes over time, the differences between the two arms, and for association with a number of covariates. Results: At 3-year follow-up, the summary score physical health was 73.2 for the 68-Gy arm vs. 71.6 for the 78-Gy arm (p = 0.81), and the summary score mental health was 76.7 for the 68-Gy arm vs. 76.1 for the 78-Gy arm (p = 0.97). Statistically significant (p < 0.01) deterioration in QoL scores over time was registered in both arms in six scales. The deterioration over time was more pronounced in the high-dose arm for most scales. However, clinically relevant deterioration (>10 points) was seen for only two scales. None of the tested covariates were significantly correlated with QoL scores. Conclusion: Dose escalation did not result in significant deterioration of QoL in prostate cancer patients. In both randomization arms, statistically significant decreases in QoL scores over time were seen in six scales. The deterioration of QoL was more pronounced in the physical than in the mental health domain and in some scales more in the high- than in the low-dose arm, but the differences between arms were not statistically significant.

  13. Phase I, multicenter, open-label, dose-escalation study of sonidegib in Asian patients with advanced solid tumors.

    PubMed

    Minami, Hironobu; Ando, Yuichi; Ma, Brigette Buig Yue; Hsiang Lee, Jih-; Momota, Hiroyuki; Fujiwara, Yutaka; Li, Leung; Fukino, Koichi; Ito, Koji; Tajima, Takeshi; Mori, Asuka; Lin, Chia-Chi

    2016-10-01

    Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose-limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, two-group, parallel, dose-escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with Clinicaltrials.gov: NCT01208831.).

  14. Intensity Modulated Radiation Therapy With Dose Painting to Treat Rhabdomyosarcoma

    SciTech Connect

    Yang, Joanna C.; Dharmarajan, Kavita V.; Wexler, Leonard H.; La Quaglia, Michael P.; Happersett, Laura; Wolden, Suzanne L.

    2012-11-01

    Purpose: To examine local control and patterns of failure in rhabdomyosarcoma patients treated with intensity modulated radiation therapy (RT) with dose painting (DP-IMRT). Patients and Methods: A total of 41 patients underwent DP-IMRT with chemotherapy for definitive treatment. Nineteen also underwent surgery with or without intraoperative RT. Fifty-six percent had alveolar histologic features. The median interval from beginning chemotherapy to RT was 17 weeks (range, 4-25). Very young children who underwent second-look procedures with or without intraoperative RT received reduced doses of 24-36 Gy in 1.4-1.8-Gy fractions. Young adults received 50.4 Gy to the primary tumor and lower doses of 36 Gy in 1.8-Gy fractions to at-risk lymph node chains. Results: With 22 months of median follow-up, the actuarial local control rate was 90%. Patients aged {<=}7 years who received reduced overall and fractional doses had 100% local control, and young adults had 79% (P=.07) local control. Three local failures were identified in young adults whose primary target volumes had received 50.4 Gy in 1.8-Gy fractions. Conclusions: DP-IMRT with lower fractional and cumulative doses is feasible for very young children after second-look procedures with or without intraoperative RT. DP-IMRT is also feasible in adolescents and young adults with aggressive disease who would benefit from prophylactic RT to high-risk lymph node chains, although dose escalation might be warranted for improved local control. With limited follow-up, it appears that DP-IMRT produces local control rates comparable to those of sequential IMRT in patients with rhabdomyosarcoma.

  15. A Phase I Clinical and Pharmacology Study Using Amifostine as a Radioprotector in Dose-escalated Whole Liver Radiation Therapy

    SciTech Connect

    Feng, Mary; Smith, David E.; Normolle, Daniel P.; Knol, James A.; Pan, Charlie C.; Ben-Josef, Edgar; Lu Zheng; Feng, Meihua R.; Chen Jun; Ensminger, William; Lawrence, Theodore S.

    2012-08-01

    Purpose: Diffuse intrahepatic tumors are difficult to control. Whole-liver radiotherapy has been limited by toxicity, most notably radiation-induced liver disease. Amifostine is a prodrug free-radical scavenger that selectively protects normal tissues and, in a preclinical model of intrahepatic cancer, systemic amifostine reduced normal liver radiation damage without compromising tumor effect. We hypothesized that amifostine would permit escalation of whole-liver radiation dose to potentially control microscopic disease. We also aimed to characterize the pharmacokinetics of amifostine and its active metabolite WR-1065 to optimize timing of radiotherapy. Methods and Materials: We conducted a radiation dose-escalation trial for patients with diffuse, intrahepatic cancer treated with whole-liver radiation and intravenous amifostine. Radiation dose was assigned using the time-to-event continual reassessment method. A companion pharmacokinetic study was performed. Results: Twenty-three patients were treated, with a maximum dose of 40 Gy. Using a logistical regression model, compared with our previously treated patients, amifostine increased liver tolerance by 3.3 {+-} 1.1 Gy (p = 0.007) (approximately 10%) with similar response rates. Peak concentrations of WR-1065 were 25 {mu}M with an elimination half-life of 1.5 h; these levels are consistent with radioprotective effects of amifostine in patients. Conclusion: These findings demonstrate for the first time that amifostine is a normal liver radioprotector. They further suggest that it may be useful to combine amifostine with fractionated or stereotactic body radiation therapy for patients with focal intrahepatic cancer.

  16. Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

    PubMed Central

    Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

    2016-01-01

    Background Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. PMID:27073327

  17. SU-E-T-500: Dose Escalation Strategy for Lung Cancer Patients Using a Biologically- Guided Target Definition

    SciTech Connect

    Shusharina, N; Khan, F; Choi, N; Sharp, G

    2014-06-01

    Purpose: Dose escalation strategy for lung cancer patients can lead to late symptoms such as pneumonitis and cardiac injury. We propose a strategy to increase radiation dose for improving local tumor control while simultaneously striving to minimize the injury of organs at risk (OAR). Our strategy is based on defining a small, biologically-guided target volume for receiving additional radiation dose. Methods: 106 patients with lung cancer treated with radiotherapy were selected for patients diagnosed with stage II and III disease. Previous research has shown that 50% of the maximum SUV threshold in FDG-PET imaging is appropriate for delineation of the most aggressive part of a tumor. After PET- and CT-derived targets were contoured, an IMRT treatment plan was designed to deliver 60 Gy to the GTV as delineated on a 4D CT (Plan 1). A second plan was designed with additional dose of 18 Gy to the PET-derived volume (Plan 2). A composite plan was generated by the addition of Plan 1 and Plan 2. Results: Plan 1 was compared to the composite plan and increases in OAR dose were assessed. For seven patients on average, lung V5 was increased by 1.4% and V20 by 4.2% for ipsilateral lung and by 13.5% and 7% for contralateral lung. For total lung, V5 and V20 were increased by 4.5% and 4.8% respectively. Mean lung dose was increased by 9.7% for the total lung. The maximum dose to the spinal cord increased by 16% on average. For the heart, V20 increased by 4.2% and V40 by 5.2%. Conclusion: It seems feasible that an additional 18 Gy of radiation dose can be delivered to FDG PET-derived subvolume of the CT-based GTV of the primary tumor without significant increase in total dose to the critical organs such as lungs, spinal cord and heart.

  18. Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

    SciTech Connect

    Prokic, Vesna; Wiedenmann, Nicole; Fels, Franziska; Schmucker, Marianne; Nieder, Carsten; Grosu, Anca-Ligia

    2013-01-01

    Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 {+-} 0.62 Gy and 6.29 {+-} 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 {+-} 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 {+-} 0.7 Gy and 32.7 {+-} 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 {+-} 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.

  19. Results of the Phase I Dose-Escalating Study of Motexafin Gadolinium With Standard Radiotherapy in Patients With Glioblastoma Multiforme

    SciTech Connect

    Ford, Judith M. Seiferheld, Wendy; Alger, Jeffrey R.; Wu, Genevieve; Endicott, Thyra J.; Mehta, Minesh; Curran, Walter; Phan, See-Chun

    2007-11-01

    Purpose: Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. This Phase I trial studied the safety and tolerability of a 2-6-week course (10-22 doses) of MGd with radiotherapy for glioblastoma multiforme. Methods and Materials: A total of 33 glioblastoma multiforme patients received one of seven MGd regimens starting at 10 doses of 4 mg/kg/d MGd and escalating to 22 doses of 5.3 mg/kg/d MGd (5 or 10 daily doses then three times per week). The National Cancer Institute Cancer Therapy Evaluation Program toxicity and stopping rules were applied. Results: The maximal tolerated dose was 5.0 mg/kg/d MGd (5 d/wk for 2 weeks, then three times per week) for 22 doses. The dose-limiting toxicity was reversible transaminase elevation. Adverse reactions included rash/pruritus (45%), chills/fever (30%), and self-limiting vesiculobullous rash of the thumb and fingers (42%). The median survival of 17.6 months prompted a case-matched analysis. In the case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31) compared with the matched Radiation Therapy Oncology Group database patients with a median survival of 11.8 months (hazard ratio, 0.43; 95% confidence interval, 0.20-0.94). Conclusion: The maximal tolerated dose of MGd with radiotherapy for glioblastoma multiforme in this study was 5 mg/kg/d for 22 doses (daily for 2 weeks, then three times weekly). The baseline survival calculations suggest progression to Phase II trials is appropriate, with the addition of MGd to radiotherapy with concurrent and adjuvant temozolomide.

  20. Perineural Invasion Predicts Increased Recurrence, Metastasis, and Death From Prostate Cancer Following Treatment With Dose-Escalated Radiation Therapy

    SciTech Connect

    Feng, Felix Y.; Qian Yushen; Stenmark, Matthew H.; Halverson, Schuyler; Blas, Kevin; Vance, Sean; Sandler, Howard M.; Hamstra, Daniel A.

    2011-11-15

    Purpose: To assess the prognostic value of perineural invasion (PNI) for patients treated with dose-escalated external-beam radiation therapy for prostate cancer. Methods and Materials: Outcomes were analyzed for 651 men treated for prostate cancer with EBRT to a minimum dose {>=}75 Gy. We assessed the impact of PNI as well as pretreatment and treatment-related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival. Results: PNI was present in 34% of specimens at biopsy and was significantly associated with higher Gleason score (GS), T stage, and prostate-specific antigen level. On univariate and multivariate analysis, the presence of PNI was associated with worse FFBF (hazard ratio = 1.7, p <0.006), FFM (hazard ratio = 1.8, p <0.03), and CSS (HR = 1.4, p <0.05) compared with absence of PNI; there was no difference in overall survival. Seven-year rates of FFBF, FFM, and CCS were 64% vs. 80%, 84% vs. 92%, and 91% vs. 95% for those patients with and without PNI, respectively. On recursive partitioning analysis, PNI predicted for worse FFM and CSS in patients with GS 8-10, with FFM of 67% vs. 89% (p <0.02), and CSS of 69% vs. 91%, (p <0.04) at 7 years for those with and without PNI, respectively. Conclusions: The presence of PNI in the prostate biopsy predicts worse clinical outcome for patients treated with dose-escalated external-beam radiation therapy. Particularly in patients with GS 8-10 disease, the presence of PNI suggests an increased risk of metastasis and prostate cancer death.

  1. A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer.

    PubMed

    Mayer, Erica L; Scheulen, M E; Beckman, J; Richly, H; Duarte, A; Cotreau, M M; Strahs, A L; Agarwal, S; Steelman, L; Winer, E P; Dickler, M N

    2013-07-01

    Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.

  2. Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine.

    PubMed

    Pabst, Thomas; Vellenga, Edo; van Putten, Wim; Schouten, Harry C; Graux, Carlos; Vekemans, Marie-Christiane; Biemond, Bart; Sonneveld, Peter; Passweg, Jakob; Verdonck, Leo; Legdeur, Marie-Cecile; Theobald, Matthias; Jacky, Emanuel; Bargetzi, Mario; Maertens, Johan; Ossenkoppele, Gert Jan; Löwenberg, Bob

    2012-06-07

    The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.

  3. Use of radiation protraction to escalate biologically effective dose to the treatment target

    SciTech Connect

    Kuperman, V. Y.; Spradlin, G. S.

    2011-12-15

    Purpose: The aim of this study is to evaluate how simultaneously increasing fraction time and dose per fraction affect biologically effective dose for the target (BED{sub tar}) while biologically effective dose for the normal tissue (BED{sub nt}) is fixed. Methods: In this investigation, BED{sub tar} and BED{sub nt} were studied by assuming mono-exponential repair of sublethal damage with tissue dependent repair half-time. Results: Our results demonstrate that under certain conditions simultaneously increasing fraction time and dose per fraction result in increased BED{sub tar} while BED{sub nt} is fixed. The dependence of biologically effective dose on fraction time is influenced by the dose rate. In this investigation we analytically determined time-varying dose rate R-tilde which minimizes BED. Changes in BED with fraction time were compared for constant dose rate and for R-tilde. Conclusions: A number of recent experimental and theoretical studies have demonstrated that slow delivery of radiation (known as radiation protraction) leads to reduced therapeutic effect because of increased repair of sublethal damage. In contrast, our analysis shows that under certain conditions simultaneously increasing fraction time and dose per fraction are radiobiologically advantageous.

  4. An escalating dose study to assess the safety, tolerability and immunogenicity of a Herpes Simplex Virus DNA vaccine, COR-1

    PubMed Central

    Dutton, Julie L.; Woo, Wai-Ping; Chandra, Janin; Xu, Yan; Li, Bo; Finlayson, Neil; Griffin, Paul; Frazer, Ian H.

    2016-01-01

    ABSTRACT This paper describes a single site, open-label Phase I clinical trial evaluating the safety, tolerability and immunogenicity in healthy volunteers of a herpes simplex polynucleotide vaccine that has previously been shown to enhance immunogenicity and protect against lethal herpes simplex virus type 2 (HSV-2) challenge in mice. Five escalating doses of the vaccine, COR-1, were given by intradermal injection to HSV-1 and 2 seronegative healthy individuals. COR-1 was found to be safe and well-tolerated; the only vaccine-related adverse events were mild. While vaccine-induced antibody responses were not detectable, cell-mediated immune responses to HSV-specific peptide groups were identified in 19 of the 20 subjects who completed the study, and local inflammation at the immunisation site was observed. This study indicates COR-1 has potential to be used as a therapeutic vaccine for HSV-2 infection. PMID:27580249

  5. Phase I trial of escalating-dose cisplatin with 5-fluorouracil and concurrent radiotherapy in Chinese patients with esophageal cancer.

    PubMed

    Lin, Qiang; Gao, Xian-Shu; Qiao, Xue-Ying; Zhou, Zhi-Guo; Zhang, Ping; Chen, Kun; Zhao, Yan-Nan; Asaumi, Junichi

    2008-02-01

    We defined the maximum-tolerated dose (MTD) of chemoradiotherapy (cisplatin (CDDP) with 5-fluorouracil (5-FU) and concurrent chemoradiotherapy) for Chinese patients with esophageal cancer. Twenty-one previously untreated patients with primary esophageal cancer were entered into this study. Escalating doses of CDDP with 5-FU were administered in a modified Fibonacci sequence, with concurrent conventional fractionation radiotherapy (CFR) of 60 Gy or 50 Gy. The starting doses were CDDP 37.5 mg/m2 on day 1, and 5-FU 500 mg/m2 on days 1-5, respectively. The regimen was repeated 4 times every 28 days. If no dose-limiting toxicity (DLT) was observed, the next dose level was applied. The procedures were repeated until DLT appeared. The MTD was declared to be 1 dose level below the level at which DLT appeared. DLT was grade 3 radiation-induced esophagitis at a dose level of CDDP 60 mg/m2 with 5-FU 700 mg/m2 and concurrent 60 Gy CFR. MTD was defined as CDDP 52.5 mg/m2 with 5-FU 700 mg/m2 and concurrent 50 Gy CFR. The MTD of CDDP with 5-FU and in concurrent chemoradiotherapy for Chinese patients with esophageal cancer is CDDP 52.5 mg/m2 on day 1 and 5FU 700 mg/m2 on days 1-5, repeated 4 times every 28 days, and concurrent 50 Gy CFR. Further evaluation of this regimen in a prospective phase II trial is ongoing.

  6. Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

    PubMed

    Gonzales, Nicole R; Shah, Jharna; Sangha, Navdeep; Sosa, Lenis; Martinez, Rebecca; Shen, Loren; Kasam, Mallikarjunarao; Morales, Miriam M; Hossain, M Monir; Barreto, Andrew D; Savitz, Sean I; Lopez, George; Misra, Vivek; Wu, Tzu-Ching; El Khoury, Ramy; Sarraj, Amrou; Sahota, Preeti; Hicks, William; Acosta, Indrani; Sline, M Rick; Rahbar, Mohammad H; Zhao, Xiurong; Aronowski, Jaroslaw; Grotta, James C

    2013-07-01

    RATIONALE : Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. AIMS : The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. STUDY DESIGN : This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. OUTCOMES : The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

  7. Gut hormone release and appetite regulation in healthy non-obese participants following oligofructose intake. A dose-escalation study.

    PubMed

    Pedersen, Camilla; Lefevre, Solenne; Peters, Véronique; Patterson, Michael; Ghatei, Mohammad A; Morgan, Linda M; Frost, Gary S

    2013-07-01

    Prevention of weight gain in adults is a major public health target. Animal experiments have consistently demonstrated a relationship between fermentable carbohydrate intake, such as oligofructose, anorectic gut hormones, and appetite suppression and body weight control. This study was designed to determine the dose of oligofructose which would augment the release of anorectic gut hormones and reduce appetite consistently in non-obese humans. Twelve non-obese participants were recruited for a 5-week dose-escalation study. Following a 9-14-day run-in, participants increased their daily oligofructose intake every week from 15, 25, 35, 45, to 55 g daily. Subjective appetite and side effects were monitored daily. Three-day food diaries were completed every week. Appetite study sessions explored the acute effects of 0, 15, 35, and 55 g oligofructose on appetite-related hormones, glycaemia, subjective appetite, and energy intake. In the home environment, oligofructose suppressed hunger, but did not affect energy intake. Oligofructose dose-dependently increased peptide YY, decreased pancreatic polypeptide and tended to decrease ghrelin, but did not significantly affect appetite profile, energy intake, glucose, insulin, or glucagon-like peptide 1 concentrations during appetite study sessions. In conclusion, oligofructose supplementation at ≥ 35 g/day increased peptide YY and suppressed pancreatic polypeptide and hunger; however, energy intake did not change significantly.

  8. Dose De-Escalation With Gamma Knife Radiosurgery in the Treatment of Choroidal Melanoma

    SciTech Connect

    Schirmer, Clemens M.; Chan, Michael; Mignano, John; Duker, Jay; Melhus, Christopher S.; Williams, Lloyd B.; Wu, Julian K.; Yao, Kevin C.

    2009-09-01

    Purpose: Single-fraction targeted radiation therapy delivered by the Leksell Gamma Knife system is a minimally invasive treatment option for choroidal melanoma that has been used as an alternative to enucleation, proton beam therapy, or brachytherapy. Previously reported Gamma Knife series involved the treatment of choroidal melanomas with a dose of 40 to 50 Gy at the tumor margin. We report our institutional experience using a significantly lower dose. Methods and Materials: Fourteen patients with choroidal melanoma were treated with the Leksell Gamma Knife at our institution over a 7-year period. The treatment and clinical data were analyzed in a retrospective fashion after a mean follow-up of 32.2 months. Results: The mean dose to the tumor margin was 22.2 {+-} 2.4 Gy (range, 20- 25 Gy). Mean treated tumor volume was 1.1 {+-} 1.2 cc. Local control was achieved in 13 cases (93%). In 1 patient both intraocular spread and distant metastatic disease developed after treatment. Visual function of the affected eye was preserved in 5 patients (36%) at latest follow-up, in 9 patients (64%) visual loss ensued. Mild to moderate radiation toxicity developed in 8 patients. Conclusions: Choroidal melanoma can be safely and effectively treated using Leksell Gamma Knife stereotactic radiosurgery with a marginal dose of less than 25 Gy.

  9. Dose escalation study of carbon ion radiotherapy for locally advanced carcinoma of the uterine cervix

    SciTech Connect

    Kato, Shingo . E-mail: s.kato@nirs.go.jp; Ohno, Tatsuya; Tsujii, Hirohiko; Nakano, Takashi; Mizoe, Jun-etsu; Kamada, Tadashi; Miyamoto, Tadaaki; Tsuji, Hiroshi; Kato, Hirotoshi; Yamada, Shigeru; Kandatsu, Susumu; Yoshikawa, Kyosan; Ezawa, Hidefumi; Suzuki, Michiya

    2006-06-01

    Purpose: To evaluate the toxicity and efficacy of carbon ion radiotherapy (CIRT) for locally advanced cervical cancer by two phase I/II clinical trials. Methods and Materials: Between June 1995 and January 2000, 44 patients were treated with CIRT. Thirty patients had Stage IIIB disease, and 14 patients had Stage IVA disease. Median tumor size was 6.5 cm (range, 4.2-11.0 cm). The treatment consisted of 16 fractions of whole pelvic irradiation and 8 fractions of local boost. In the first study, the total dose ranged from 52.8 to 72.0 gray equivalents (GyE) (2.2-3.0 GyE per fraction). In the second study, the whole pelvic dose was fixed at 44.8 GyE, and an additional 24.0 or 28.0 GyE was given to the cervical tumor (total dose, 68.8 or 72.8 GyE). Results: No patient developed severe acute toxicity. In contrast, 8 patients developed major late gastrointestinal complications. The doses resulting in major complications were {>=}60 GyE. All patients with major complications were surgically salvaged. The 5-year local control rate for patients in the first and second studies was 45% and 79%, respectively. When treated with {>=}62.4 GyE, the local control was favorable even for the patients with stage IVA disease (69%) or for those with tumors {>=}6.0 cm (64%). Conclusions: In CIRT for advanced cervical cancer, the dose to the intestines should be limited to <60 GyE to avoid major complications. Although the number of patients in this study was small, the results support continued investigation to confirm therapeutic efficacy.

  10. Dose escalation study of proton beam therapy with concurrent chemotherapy for stage III non-small cell lung cancer.

    PubMed

    Harada, Hideyuki; Fuji, Hiroshi; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Yamashita, Haruo; Asakura, Hirofumi; Nishimura, Tetsuo; Takahashi, Toshiaki; Murayama, Shigeyuki

    2016-07-01

    The purpose of this study is to determine the recommended dose (RD) of proton beam therapy (PBT) for inoperable stage III non-small cell lung cancer (NSCLC). We tested two prescribed doses of PBT: 66 Gy (relative biological effectiveness [RBE]) in 33 fractions and 74 Gy (RBE) in 37 fractions in arms 1 and 2, respectively. The planning target volume (PTV) included the primary tumor and metastatic lymph nodes with adequate margins. Concurrent chemotherapy included intravenous cisplatin (60 mg/m(2) , day 1) and oral S-1 (80, 100 or 120 mg based on body surface area, days 1-14), repeated as four cycles every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 3 or severe toxicities related to PBT during days 1-90. Each dose level was performed in three patients, and then escalated to the next level if no DLT occurred. When one patient developed a DLT, three additional patients were enrolled. Overall, nine patients (five men, four women; median age, 72 years) were enrolled, including six in arm 1 and three in arm 2. The median follow-up time was 43 months, and the median progression-free survival was 15 months. In arm 1, grade 3 infection occurred in one of six patients, but no other DLT was reported. Similarly, no DLT occurred in arm 2. However, one patient in arm 2 developed grade 3 esophageal fistula at 9 months after the initiation of PBT. Therefore, we determined that 66 Gy (RBE) is the RD from a clinical viewpoints. (Clinical trial registration no. UMIN000005585).

  11. What does a modified-Fibonacci dose-escalation actually correspond to?

    PubMed Central

    2012-01-01

    Background In most phase I oncology trials, it is often stated that the dose increments follow a “modified-Fibonacci sequence”. This term, however, is vague. Methods To better characterize this sequence, we reviewed 81 phase I trials based on this concept. Results Out of 198 phase I oncology trials, 81 (41%) are based on modified-Fibonacci series. Actual incremental ratios varied in a large range from 0.80 to 2.08. The median of actual increments was about 2.00, 1.50, 1.33, 1.33, 1.33, 1.33, 1.30, 1.35…. The “modified Fibonacci-sequence” gathers heterogeneous variation of the genuine sequence, which does not tend to a constant number at higher dose-levels. Conclusion This confusing term should be avoided. PMID:22824322

  12. Impact of conventional fractionated RT to pelvic lymph nodes and dose-escalated hypofractionated RT to prostate gland using IMRT treatment delivery in high-risk prostate cancer

    NASA Astrophysics Data System (ADS)

    Pervez, Nadeem

    Prostate cancer is the most common cancer among Canadian men. The standard treatment in high-risk category is radical radiation, with androgen suppression treatment (AST). Significant disease progression is reported despite this approach. Radiation dose escalation has been shown to improve disease-free survival; however, it results in higher toxicities. Hypofractionated radiation schedules (larger dose each fraction in shorter overall treatment time) are expected to deliver higher biological doses. A hypofractionated scheme was used in this study to escalate radiation doses with AST. Treatment was well tolerated acutely. Early results of self-administered quality of life reported by patients shows a decrease in QOL which is comparable to other treatment schedules. Significant positional variation of the prostate was observed during treatment. Therefore, we suggest daily target verification to avoid a target miss. Initial late effects are reasonable and early treatment outcomes are promising. Longer follow-up is required for full outcomes assessments.

  13. Crossover versus parallel designs: dose-escalation design comparisons for first-in-human studies.

    PubMed

    Yan, Zhiwu; Hosmane, Balakrishna; Locke, Charles

    2013-01-01

    We study the statistical efficiency for rising-dose designs in the context of first-in-human studies. Specifically, we identify a class of crossover designs that are appealing in terms of both subject safety and statistical efficiency and, for a three-period, two-panel design in such a class, we compare its A-efficiency relative to the corresponding parallel designs and optimal/efficient crossover designs, respectively, under various plausible models. In the meantime, we also evaluate the impact of inclusion of baseline measurements as a covariate in the statistical analysis, for both crossover and parallel studies.

  14. A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

    PubMed

    Brown, Jennifer R; Messmer, Bradley; Werner, Lillian; Davids, Matthew S; Mikler, Evgeny; Supko, Jeffrey G; Fisher, David C; LaCasce, Ann S; Armand, Philippe; Jacobsen, Eric; Dalton, Virginia; Tesar, Bethany; Fernandes, Stacey M; McDonough, Sean; Ritz, Jerome; Rassenti, Laura; Kipps, Thomas J; Neuberg, Donna; Freedman, Arnold S

    2013-06-01

    This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80% of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab, and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance. We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252).

  15. Phase I dose escalation study of high dose carfilzomib monotherapy for Japanese patients with relapsed or refractory multiple myeloma.

    PubMed

    Iida, Shinsuke; Tobinai, Kensei; Taniwaki, Masafumi; Shumiya, Yoshihisa; Nakamura, Toru; Chou, Takaaki

    2016-11-01

    We conducted a multicenter, open-label Phase I study of single-agent carfilzomib in Japanese patients with relapsed or refractory multiple myeloma. The primary endpoints were tolerability and safety. Carfilzomib was administrated for 30 min on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. In cycle 1, doses for days 1 and 2 were 20 mg/m(2), followed by 45 or 56 mg/m(2). Three and four subjects were enrolled in the 20/45 mg/m(2) cohort and 20/56 mg/m(2) cohort. No dose-limiting toxicity was observed, and the tolerability of carfilzomib was confirmed. Pyrexia, hypertension, nausea and vomiting were considered as noteworthy adverse events (AE) when carfilzomib was administered at high doses. Moreover, pyrexia, blood creatinine increased, and body weight gain were observed as acute dose effects. These findings suggest that addition of dexamethasone is important to alleviate acute dose effect. The overall response rates of the 20/45 mg/m(2) and 20/56 mg/m(2) cohort were 66.7 % (two out of three) and 50 % (two out of four), respectively. Carfilzomib administrated at up to 20/56 mg/m(2) was well tolerated and seemed active in Japanese patients with relapsed or refractory multiple myeloma.

  16. Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial

    SciTech Connect

    Westover, Kenneth D.; Loo, Billy W.; Gerber, David E.; Iyengar, Puneeth; Choy, Hak; Diehn, Maximilian; Hughes, Randy; Schiller, Joan; Dowell, Jonathan; Wardak, Zabi; Sher, David; Christie, Alana; Xie, Xian-Jin; Corona, Irma; Sharma, Akanksha; Wadsworth, Margaret E.; Timmerman, Robert

    2015-09-01

    Purpose: Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. Methods and Materials: Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. Results: Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59). Conclusions: Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long

  17. Yohimbine treatment of organic erectile dysfunction in a dose-escalation trial.

    PubMed

    Guay, A T; Spark, R F; Jacobson, J; Murray, F T; Geisser, M E

    2002-02-01

    Yohimbine has had questionable effects in men with organic erectile dysfunction. We conducted this study to better define the population of men responsive to yohimbine, because tobacco was thought to affect a regimen of yohimbine more than other risk factors. We measured nocturnal penile tumescence with the RigiScan monitor, hormone profiles, answers to the Florida Sexual Health Questionnaire, and clinical responses at baseline and after two different doses of yohimbine in 18 nonsmoking men with erectile dysfunction. Of the 18 men, nine (50%) were successful in completing intercourse in more than 75% of attempts. The yohimbine responders were men with less severe erectile dysfunction as manifested by improved increased rigidity on RigiScan testing, higher Florida Sexual Health Questionnaire scores, and slightly higher levels of serum testosterone. Yohimbine is an effective therapy to treat organic erectile dysfunction in some men with erectile dysfunction.

  18. Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis.

    PubMed

    Vincenzi, Bruno; Nannini, Margherita; Fumagalli, Elena; Bronte, Giuseppe; Frezza, Anna Maria; De Lisi, Delia; Spalato Ceruso, Mariella; Santini, Daniele; Badalamenti, Giuseppe; Pantaleo, Maria Abbondanza; Russo, Antonio; Dei Tos, Angelo Paolo; Casali, Paolo; Tonini, Giuseppe

    2016-10-25

    We retrospectively reviewed data from 123 patients (KIT exon 11 mutated) who received sunitinib or dose-escalated imatinib as second line.All patients progressed on imatinib (400 mg/die) and received a second line treatment with imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 off or 37.5 mg/day). Deletion versus other KIT 11 mutation was recorded, correlated with clinical benefits.64% received imatinib, 36% sunitinib. KIT exon 11 mutation was available in 94 patients. With a median follow-up of 61 months, median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7-10.9) and 5 months (95% CI 3.6-6.7) respectively (P = 0.012). No difference was found in overall survival (OS) (P = 0.883). In imatinib arm, KIT exon 11 deletions was associated with a shorter TTP (7 vs 17 months; P = 0.02), with a trend in OS (54 vs 71 months P = 0.063). No difference was found in patients treated with sunitinib (P = 0.370).A second line with sunitinib was associated with an improved TTP in KIT exon 11 mutated patients progressing on imatinib 400 mg/die. Deletions in exon 11 seemed to be correlated with worse outcome in patients receiving imatinib-based second line.

  19. [F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure

    SciTech Connect

    Douglas, James G. . E-mail: drjay@u.washington.edu; Stelzer, Keith J.; Mankoff, David A.; Tralins, Kevin S.; Krohn, Kenneth A.; Muzi, Mark; Silbergeld, Daniel L.; Rostomily, Robert C.; Scharnhorst, Jeffrey B.S.; Spence, Alexander M.

    2006-03-01

    Purpose: [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brain tumors has been shown to identify areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme may lead to improved disease control. Based on these premises, we initiated a prospective study of FDG-PET for the treatment planning of radiation dose escalation for the treatment of glioblastoma multiforme. Methods and Materials: Forty patients were enrolled. Patients were treated with standard conformal fractionated radiotherapy with volumes defined by MRI imaging. When patients reached a dose of 45-50.4 Gy, they underwent FDG-PET imaging for boost target delineation, for an additional 20 Gy (2 Gy per fraction) to a total dose of 79.4 Gy (n = 30). Results: The estimated 1-year and 2-year overall survival (OS) for the entire group was 70% and 17%, respectively, with a median overall survival of 70 weeks. The estimated 1-year and 2-year progression-free survival (PFS) was 18% and 3%, respectively, with a median of 24 weeks. No significant improvements in OS or PFS were observed for the study group in comparison to institutional historical controls. Conclusions: Radiation dose escalation to 79.4 Gy based on FDG-PET imaging demonstrated no improvement in OS or PFS. This study establishes the feasibility of integrating PET metabolic imaging into radiotherapy treatment planning.

  20. Potential of Adaptive Radiotherapy to Escalate the Radiation Dose in Combined Radiochemotherapy for Locally Advanced Non-Small Cell Lung Cancer

    SciTech Connect

    Guckenberger, Matthias; Wilbert, Juergen; Richter, Anne; Baier, Kurt; Flentje, Michael

    2011-03-01

    Purpose: To evaluate the potential of adaptive radiotherapy (ART) for advanced-stage non-small cell lung cancer (NSCLC) in terms of lung sparing and dose escalation. Methods and Materials: In 13 patients with locally advanced NSCLC, weekly CT images were acquired during radio- (n = 1) or radiochemotherapy (n = 12) for simulation of ART. Three-dimensional (3D) conformal treatment plans were generated: conventionally fractionated doses of 66 Gy were prescribed to the planning target volume without elective lymph node irradiation (Plan{sub 3}D). Using a surface-based algorithm of deformable image registration, accumulated doses were calculated in the CT images acquired during the treatment course (Plan{sub 4}D). Field sizes were adapted to tumor shrinkage once in week 3 or 5 and twice in weeks 3 and 5. Results: A continuous tumor regression of 1.2% per day resulted in a residual gross tumor volume (GTV) of 49% {+-} 15% after six weeks of treatment. No systematic differences between Plan{sub 3}D and Plan{sub 4}D were observed regarding doses to the GTV, lung, and spinal cord. Plan adaptation to tumor shrinkage resulted in significantly decreased lung doses without compromising GTV coverage: single-plan adaptation in Week 3 or 5 and twice-plan adaptation in Weeks 3 and 5 reduced the mean lung dose by 5.0% {+-} 4.4%, 5.6% {+-} 2.9% and 7.9% {+-} 4.8%, respectively. This lung sparing with twice ART allowed an iso-mean lung dose escalation of the GTV dose from 66.8 Gy {+-} 0.8 Gy to 73.6 Gy {+-} 3.8 Gy. Conclusions: Adaptation of radiotherapy to continuous tumor shrinkage during the treatment course reduced doses to the lung, allowed significant dose escalation and has the potential of increased local control.

  1. A Phase 1 Dose-Escalation Study of ASP2409, a Selective T-Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy.

    PubMed

    Zhang, Wenhui; Kernstock, Robert M; Karrer, Erik E; Cohen, Stanley B; Chindalore, Vishala L; Kivitz, Alan J; Blahunka, Paul C; Delgado-Herrera, Leticia; Zeiher, Bernhardt G; Samberg, Nancy L; Garg, Jay P

    2016-07-01

    ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either ASP2409 or placebo in a sequential manner. Escalation to higher dose levels occurred in the absence of dose-limiting toxicity. A total of 57 patients completed the study. ASP2409 showed nonlinear PK over the dose range of 0.01 to 3.0 mg/kg following a single intravenous administration, indicating target-mediated drug disposition. Area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased at a greater than dose-proportional rate. The half-life of ASP2409 increased dose dependently and ranged from 1.57 to 6.68 days. ASP2409 showed a dose-dependent increase in the extent and duration of CD86 receptor occupancy. There were no clinically relevant safety issues up to a single dose of 3.0 mg/kg. No maximum tolerated dose was reached. The incidence and duration of antidrug antibodies did not correlate with adverse events. ClinicalTrials.gov identifier: NCT02171143.

  2. Phase I dose escalation trial of the novel proteasome inhibitor carfilzomib in patients with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma.

    PubMed

    Awan, Farrukh T; Flynn, Joseph M; Jones, Jeffrey A; Andritsos, Leslie A; Maddocks, Kami J; Sass, Ellen J; Lucas, Margaret S; Chase, Weihong; Waymer, Sharon; Ling, Yonghua; Jiang, Yao; Phelps, Mitch A; Byrd, John C; Lucas, David M; Woyach, Jennifer A

    2015-01-01

    The proteasome complex degrades proteins involved in a variety of cellular processes and is a powerful therapeutic target in several malignancies. Carfilzomib is a potent proteasome inhibitor which induces rapid chronic lymphocytic leukemia (CLL) cell apoptosis in vitro. We conducted a phase I dose-escalation trial to determine the safety and tolerability of carfilzomib in relapsed/refractory CLL or small lymphocytic lymphoma (SLL). Nineteen patients were treated with carfilzomib initially at 20 mg/m(2), then escalated in four cohorts (27, 36, 45 and 56 mg/m(2)) on days 1, 2, 8, 9, 15 and 16 of 28-day cycles. Therapy was generally well tolerated, and no dose limiting toxicities were observed. The most common hematologic toxicities were thrombocytopenia and neutropenia. All patients evaluable for response had stable disease, including patients with del17p13 and fludarabine-resistant disease. This trial shows acceptable tolerability and limited preliminary efficacy of carfilzomib in CLL and SLL.

  3. Phase III pilot study of dose escalation using conformal radiotherapy in prostate cancer: PSA control and side effects

    PubMed Central

    Dearnaley, D P; Hall, E; Lawrence, D; Huddart, R A; Eeles, R; Nutting, C M; Gadd, J; Warrington, A; Bidmead, M; Horwich, A

    2005-01-01

    Radical radiotherapy is a standard form of management of localised prostate cancer. Conformal treatment planning spares adjacent normal tissues reducing treatment-related side effects and may permit safe dose escalation. We have tested the effects on tumour control and side effects of escalating radiotherapy dose and investigated the appropriate target volume margin. After an initial 3–6 month period of androgen suppression, 126 men were randomised and treated with radiotherapy using a 2 by 2 factorial trial design. The initial radiotherapy tumour target volume included the prostate and base of seminal vesicles (SV) or complete SV depending on SV involvement risk. Treatments were randomised to deliver a dose of 64 Gy with either a 1.0 or 1.5 cm margin around the tumour volume (1.0 and 1.5 cm margin groups) and also to treat either with or without a 10 Gy boost to the prostate alone with no additional margin (64 and 74 Gy groups). Tumour control was monitored by prostate-specific antigen (PSA) testing and clinical examination with additional tests as appropriate. Acute and late side effects of treatment were measured using the Radiation Treatment and Oncology Groups (RTOG) and LENT SOM systems. The results showed that freedom from PSA failure was higher in the 74 Gy group compared to the 64 Gy group, but this did not reach conventional levels of statistical significance with 5-year actuarial control rates of 71% (95% CI 58–81%) in the 74 Gy group vs 59% (95% CI 45–70%) in the 64 Gy group. There were 23 failures in the 74Gy group and 33 in the 64 Gy group (Hazard ratio 0.64, 95% CI 0.38–1.10, P=0.10). No difference in disease control was seen between the 1.0 and 1.5 cm margin groups (5-year actuarial control rates 67%, 95% CI 53–77% vs 63%, 95% CI 50–74%) with 28 events in each group (Hazard ratio 0.97, 95% CI 0.50–1.86, P=0.94). Acute side effects were generally mild and 18 weeks after treatment, only four and five of the 126 men

  4. Late Gastrointestinal Toxicity After Dose-Escalated Conformal Radiotherapy for Early Prostate Cancer: Results From the UK Medical Research Council RT01 Trial (ISRCTN47772397)

    SciTech Connect

    Syndikus, Isabel; Morgan, Rachel C.; Sydes, Matthew R.; Graham, John D.; Dearnaley, David P.

    2010-07-01

    Purpose: In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects. Methods and Materials: The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Management (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires. Results: In the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade {>=}2) was 1.55 (95% CI, 1.17-2.04); for diarrhea (LENT/SOM grade {>=}2), the HR was 1.79 (95% CI, 1.10-2.94); and for proctitis (RTOG grade {>=}2), the HR was 1.64 (95% CI, 1.20-2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively. Conclusions: There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up.

  5. Evaluating changes in tumor volume using magnetic resonance imaging during the course of radiotherapy treatment of high-grade gliomas: Implications for conformal dose-escalation studies

    SciTech Connect

    Tsien, Christina . E-mail: ctsien@umich.edu; Gomez-Hassan, Diana; Haken, Randall K. ten; Tatro, Daniel C.; Junck, L.; Chenevert, T.L.; Lawrence, T.

    2005-06-01

    tumors had tumor progression, based on MRI obtained during Week 3 of radiotherapy. Median increase in GTV (Week 3) was 11.7 cc (range, 9.8-21.3). Retrospective DVH analysis of PTV (Pre-Rx) and PTV (Week 3) demonstrated a decrease in V{sub 95%}(PTV volume receiving 95% of the prescribed dose) in those 3 cases. Conclusions: Routine MR imaging during radiotherapy may be essential in ensuring tumor coverage if highly conformal radiotherapy techniques such as stereotactic boost and intensity-modulated radiotherapy are used in dose-escalation trials that utilize smaller treatment margins.

  6. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor

    PubMed Central

    Bendell, Johanna C; Javle, Milind; Bekaii-Saab, Tanios S; Finn, Richard S; Wainberg, Zev A; Laheru, Daniel A; Weekes, Colin D; Tan, Benjamin R; Khan, Gazala N; Zalupski, Mark M; Infante, Jeffrey R; Jones, Suzanne; Papadopoulos, Kyriakos P; Tolcher, Anthony W; Chavira, Renae E; Christy-Bittel, Janna L; Barrett, Emma; Patnaik, Amita

    2017-01-01

    Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population. PMID:28152546

  7. Using Generalized Equivalent Uniform Dose Atlases to Combine and Analyze Prospective Dosimetric and Radiation Pneumonitis Data From 2 Non-Small Cell Lung Cancer Dose Escalation Protocols

    SciTech Connect

    Liu Fan; Yorke, Ellen D.; Belderbos, Jose S.A.; Borst, Gerben R.; Rosenzweig, Kenneth E.; Lebesque, Joos V.; Jackson, Andrew

    2013-01-01

    Purpose: To demonstrate the use of generalized equivalent uniform dose (gEUD) atlas for data pooling in radiation pneumonitis (RP) modeling, to determine the dependence of RP on gEUD, to study the consistency between data sets, and to verify the increased statistical power of the combination. Methods and Materials: Patients enrolled in prospective phase I/II dose escalation studies of radiation therapy of non-small cell lung cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) (78 pts) and the Netherlands Cancer Institute (NKI) (86 pts) were included; 10 (13%) and 14 (17%) experienced RP requiring steroids (RPS) within 6 months after treatment. gEUD was calculated from dose-volume histograms. Atlases for each data set were created using 1-Gy steps from exact gEUDs and RPS data. The Lyman-Kutcher-Burman model was fit to the atlas and exact gEUD data. Heterogeneity and inconsistency statistics for the fitted parameters were computed. gEUD maps of the probability of RPS rate {>=}20% were plotted. Results: The 2 data sets were homogeneous and consistent. The best fit values of the volume effect parameter a were small, with upper 95% confidence limit around 1.0 in the joint data. The likelihood profiles around the best fit a values were flat in all cases, making determination of the best fit a weak. All confidence intervals (CIs) were narrower in the joint than in the individual data sets. The minimum P value for correlations of gEUD with RPS in the joint data was .002, compared with P=.01 and .05 for MSKCC and NKI data sets, respectively. gEUD maps showed that at small a, RPS risk increases with gEUD. Conclusions: The atlas can be used to combine gEUD and RPS information from different institutions and model gEUD dependence of RPS. RPS has a large volume effect with the mean dose model barely included in the 95% CI. Data pooling increased statistical power.

  8. Differential regulation of 5-HT2A receptor mRNA expression following withdrawal from a chronic escalating dose regimen of D-amphetamine.

    PubMed

    Horner, Kristen A; Gilbert, Yamiece E; Noble, Erika S

    2011-05-16

    Several lines of evidence indicate that psychostimulant withdrawal can induce negative emotional symptoms, such as anhedonia and dysphoria, which may be due in part, to dysfunction of the serotonin (5-HT) system, including alterations in 5-HT receptors. For example, changes in 5-HT(2A) receptor function in prefrontal cortex (PFC) have been reported in association with psychostimulant withdrawal. However, it is not known if alterations in 5-HT(2A) receptor mRNA expression occur in the PFC or other limbic-associated areas following withdrawal from chronic psychostimulant treatment. The goal of the current study was to determine the effects of chronic, escalating doses of D-amphetamine (D-AMPH) and withdrawal on the expression of 5-HT(2A) receptors in the cortex, caudate putamen, NAc and hippocampus of rat brain. Animals were treated three times a day for 4 days with escalating doses of D-AMPH (1-10 mg/kg). Twenty-four hours after the final dose of D-AMPH, animals were sacrificed and the tissue processed for in situ hybridization histochemistry. Chronic, escalating doses of D-AMPH, followed by a 24 h withdrawal period, significantly decreased 5-HT(2A) receptor mRNA expression in the prefrontal, motor and cingulate cortices, while 5-HT(2A) receptor mRNA expression in the NAc, caudal CPu and hippocampus were significantly increased. These data indicate that region-specific changes in 5-HT(2A) receptor mRNA expression occur in limbic system and associated areas following chronic D-AMPH treatment, supporting the notion that alterations in the 5-HT system may contribute to the negative emotional aspects of psychostimulant withdrawal.

  9. Phase 1, Open-Label, Dose Escalation, Safety, and Pharmacokinetics Study of ME-344 as a Single Agent in Patients With Refractory Solid Tumors

    PubMed Central

    Bendell, Johanna C; Patel, Manish R; Infante, Jeffrey R; Kurkjian, Carla D; Jones, Suzanne F; Pant, Shubham; Burris, Howard A; Moreno, Ofir; Esquibel, Vanessa; Levin, Wendy; Moore, Kathleen N

    2015-01-01

    Background The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. Methods Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. Results A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥31 weeks]). Conclusions The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy. The

  10. PSA Response to Neoadjuvant Androgen Deprivation Therapy Is a Strong Independent Predictor of Survival in High-Risk Prostate Cancer in the Dose-Escalated Radiation Therapy Era

    SciTech Connect

    McGuire, Sean E.; Lee, Andrew K.; Cerne, Jasmina Z.; Munsell, Mark F.; Levy, Lawrence B.; Kudchadker, Rajat J.; Choi, Seungtaek L.; Nguyen, Quynh N.; Hoffman, Karen E.; Pugh, Thomas J.; Frank, Steven J.; Corn, Paul G.; Logothetis, Christopher J.; Kuban, Deborah A.

    2013-01-01

    Purpose: The aim of the study was to evaluate the prognostic value of prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer. Methods and Materials: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specific mortality (PCSM) and overall survival (OS) were examined. Results: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs {>=}0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL. Conclusions: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level {>=}0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level {>=}0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation.

  11. Optimization of collimator parameters to reduce rectal dose in intensity-modulated prostate treatment planning

    SciTech Connect

    Chapek, Julie . E-mail: Julie.chapek@hci.utah.edu; Tobler, Matt; Toy, Beau J.; Lee, Christopher M.; Leavitt, Dennis D.

    2005-01-01

    The inability to avoid rectal wall irradiation has been a limiting factor in prostate cancer treatment planning. Treatment planners must not only consider the maximum dose that the rectum receives throughout a course of treatment, but also the dose that any volume of the rectum receives. As treatment planning techniques have evolved and prescription doses have escalated, limitations of rectal dose have remained an area of focus. External pelvic immobilization devices have been incorporated to aid in daily reproducibility and lessen concern for daily patient motion. Internal immobilization devices (such as the intrarectal balloon) and visualization techniques (including daily ultrasound or placement of fiducial markers) have been utilized to reduce the uncertainty of intrafractional prostate positional variation, thus allowing for minimization of treatment volumes. Despite these efforts, prostate volumes continue to abut portions of the rectum, and the necessary volume expansions continue to include portions of the anterior rectal wall within high-dose regions. The addition of collimator parameter optimization (both collimator angle and primary jaw settings) to intensity-modulated radiotherapy (IMRT) allows greater rectal sparing compared to the use of IMRT alone. We use multiple patient examples to illustrate the positive effects seen when utilizing collimator parameter optimization in conjunction with IMRT to further reduce rectal doses.

  12. Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD.

    PubMed

    Moorthy, Ganesh; Sallee, Floyd; Gabbita, Prasad; Zemlan, Frank; Sallans, Larry; Desai, Pankaj B

    2015-10-01

    Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.

  13. Time-dependent changes in skeletal response to teriparatide: Escalating versus constant dose teriparatide (PTH 1–34) in osteoporotic women

    PubMed Central

    Yu, Elaine W.; Neer, Robert M.; Lee, Hang; Wyland, Jason J.; de la Paz, Amanda V.; Davis, Melissa C.; Okazaki, Makoto; Finkelstein, Joel S.

    2010-01-01

    Once-daily injections of teriparatide initially increase biochemical markers of bone formation and resorption, but markers peak after 6–12 months and then decline despite continued treatment. We sought to determine whether increasing teriparatide doses in a stepwise fashion could prolong skeletal responsiveness. We randomized 52 postmenopausal women with low spine and/or hip bone mineral density (BMD) to either a constant or an escalating subcutaneous teriparatide dose (30 mcg daily for 18 months or 20 mcg daily for 6 months, then 30 mcg daily for 6 months, then 40 mcg daily for 6 months). Serum procollagen I N-terminal propeptide, osteocalcin, and C-terminal telopeptide of type I collagen were assessed frequently. BMD of the spine, hip, radius, and total body was measured every 6 months. Acute changes in urinary cyclic AMP in response to teriparatide were examined in a subset of women in the constant dose group. All bone markers differed significantly between the two treatment groups. During the final six months, bone markers declined in the constant dose group but remained stable or increased in the escalating dose group (all markers, p<0.017). Nonetheless, mean area under the curve did not differ between treatments for any bone marker, and BMD increases were equivalent in both treatment groups. Acute renal response to teriparatide, as assessed by urinary cyclic AMP, did not change over 18 months of teriparatide administration. In conclusion, stepwise increases in teriparatide prevented the decline in bone turnover markers that is observed with chronic administration without altering BMD increases. The time-dependent waning of the response to teriparatide appears to be bone-specific. PMID:21111078

  14. Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers

    SciTech Connect

    Horton, Janet K.; Blitzblau, Rachel C.; Yoo, Sua; Geradts, Joseph; Chang, Zheng; Baker, Jay A.; Georgiade, Gregory S.; Chen, Wei; Siamakpour-Reihani, Sharareh; Wang, Chunhao; Broadwater, Gloria; Groth, Jeff; Palta, Manisha; Dewhirst, Mark; Barry, William T.; Duffy, Eileen A.; and others

    2015-07-15

    Purpose: Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. Methods and Materials: Women aged ≥55 years with clinically node-negative, estrogen receptor–positive, and/or progesterone receptor–positive HER2−, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. Results: No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. Conclusions: Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should

  15. A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors.

    PubMed

    Dittrich, Christian; Fridrik, Michael A; Koenigsberg, Robert; Lee, Chooi; Goeldner, Rainer-Georg; Hilbert, James; Greil, Richard

    2015-04-01

    Purpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4-130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48%). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20%), neutropenia, alopecia (16% each), anemia, dry skin, and nausea (12% each). Treatment-related grade ≥3 AEs were neutropenia (12%), anemia (8%), and febrile neutropenia (4%); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients' solid tumors.

  16. Phase I Three-Dimensional Conformal Radiation Dose Escalation Study in Newly Diagnosed Glioblastoma: Radiation Therapy Oncology Group Trial 98-03

    SciTech Connect

    Tsien, Christina Moughan, Jennifer; Michalski, Jeff M.; Gilbert, Mark R.; Purdy, James; Simpson, Joseph; Kresel, John J.; Curran, Walter J.; Diaz, Aidnag; Mehta, Minesh P.

    2009-03-01

    Purpose: To evaluate in a Phase I trial the feasibility and toxicity of dose-escalated three-dimensional conformal radiotherapy (3D-CRT) concurrent with chemotherapy in patients with primary supratentorial glioblastoma (GBM). Methods and Materials: A total of 209 patients were enrolled. All received 46 Gy in 2-Gy fractions to the first planning target volume (PTV{sub 1}), defined as the gross tumor volume (GTV) plus 1.8 cm. A subsequent boost was given to PTV{sub 2}, defined as GTV plus 0.3 cm. Patients were stratified into two groups (Group 1: PTV{sub 2} <75 cm{sup 3}; Group 2: PTV{sub 2} {>=}75 cm{sup 3}). Four RT dose levels were evaluated: 66, 72, 78, and 84 Gy. Carmustine 80 mg/m{sup 2} was given during RT, then every 8 weeks for 6 cycles. Pretreatment characteristics were well balanced. Results: Acute and late Grade 3/4 RT-related toxicities were no more frequent at higher RT dose or with larger tumors. There were no dose-limiting toxicities (acute Grade {>=}3 irreversible central nervous system toxicities) observed on any dose level in either group. On the basis of the absence of dose-limiting toxicities, dose was escalated to 84 Gy in both groups. Late RT necrosis was noted at 66 Gy (1 patient), 72 Gy (2 patients), 78 Gy (2 patients), and 84 Gy (3 patients) in Group 1. In Group 2, late RT necrosis was noted at 78 Gy (1 patient) and 84 Gy (2 patients). Median time to RT necrosis was 8.8 months (range, 5.1-12.5 months). Median survival in Group 1 was 11.6-19.3 months. Median survival in Group 2 was 8.2-13.9 months. Conclusions: Our study shows the feasibility of delivering higher than standard (60 Gy) RT dose with concurrent chemotherapy for primary GBM, with an acceptable risk of late central nervous system toxicity.

  17. A Phase I Dose-Escalation Study of Fractionated Stereotactic Radiosurgery in Combination With Gefitinib in Patients With Recurrent Malignant Gliomas

    SciTech Connect

    Schwer, Amanda L.; Damek, Denise M.; Kavanagh, Brian D.; Gaspar, Laurie E.; Lillehei, Kevin; Stuhr, Kelly; Chen Changhu

    2008-03-15

    Purpose: To determine the maximum tolerated dose (MTD) of fractionated stereotactic radiosurgery (SRS) with gefitinib in patients with recurrent malignant gliomas. Methods and Materials: A Phase I clinical trial was performed. Eligible patients had pathologically proved recurrent anaplastic astrocytoma or glioblastoma. Patients started gefitinib (250 mg/day) 7 days before SRS and continued for 1 year or until disease progression. SRS was delivered in three fractions over 3 days. The planning target volume (PTV) was the T1-weighted MRI postcontrast enhancing lesion + 2 mm. The first cohort received an SRS dose of 18 Gy, and subsequent cohorts received higher doses up to the maximum dose of 36 Gy. Dose-limiting toxicity (DLT) was any Grade 3 toxicity. The MTD was exceeded if 2 of 6 patients in a cohort experienced DLT. Results: Characteristics of the 15 patients enrolled were: 9 men, 6 women; median age, 47 years (range, 23-65 years); 11 glioblastoma, 4 AA; median prior RT dose, 60 Gy (range, 54-61.2 Gy); median interval since RT, 12 months (range, 3-57 months); median PTV, 41 cc (range, 12-151 cc). Median follow-up time was 7 months (range, 2-28 months). Median time on gefitinib was 5 months (range, 2-12 months). No patient experienced a DLT, and the SRS dose was escalated from 18 to 36 Gy. Grade 1-2 gefitinib-related dermatitis and diarrhea were common (10 and 7 patients, respectively). Conclusion: Fractionated SRS to a dose of 36 Gy in three fractions is well tolerated with gefitinib at daily dose of 250 mg. Further studies of SRS and novel molecular targeted agents are warranted in this challenging clinical setting.

  18. Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer

    SciTech Connect

    Kim, D.W. Nathan; Cho, L. Chinsoo; Straka, Christopher; Christie, Alana; Lotan, Yair; Pistenmaa, David; Kavanagh, Brian D.; Nanda, Akash; Kueplian, Patrick; Brindle, Jeffrey; Cooley, Susan; Perkins, Alida; Raben, David; Xie, Xian-Jin; Timmerman, Robert D.

    2014-07-01

    Purpose: To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury. Methods and Materials: Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer. Results: At the highest dose level, 6.6% of patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm{sup 3} (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010). Conclusion: Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.

  19. A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis

    PubMed Central

    Verstovsek, S; Talpaz, M; Ritchie, E; Wadleigh, M; Odenike, O; Jamieson, C; Stein, B; Uno, T; Mesa, R A

    2017-01-01

    NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK–signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ⩾50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1–2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion. PMID:27479177

  20. Does Hormone Therapy Reduce Disease Recurrence in Prostate Cancer Patients Receiving Dose-Escalated Radiation Therapy? An Analysis of Radiation Therapy Oncology Group 94-06

    SciTech Connect

    Valicenti, Richard K.; Bae, Kwounghwa; Michalski, Jeff; Sandler, Howard; Shipley, William; Lin, Alex; Cox, James

    2011-04-01

    Purpose: The purpose of this study was to evaluate the effect on freedom from biochemical failure (bNED) or disease-free survival (DFS) by adding hormone therapy (HT) to dose-escalated radiation therapy (HDRT). Methods and Materials: We used 883 analyzable prostate cancer patients who enrolled on Radiation Therapy Oncology Group (RTOG) 94-06, a Phase I/II dose escalation trial, and whose mean planning target volume dose exceeded 73.8 Gy (mean, 78.5 Gy; maximum, 84.3 Gy). We defined biochemical failure according to the Phoenix definition. Results: A total of 259 men started HT 2 to 3 months before HDRT, but not longer than 6 months, and 66 men with high-risk prostate cancer received HT for a longer duration. At 5 years, the biochemical failure rates after HDRT alone were 12%, 18%, and 29% for low-, intermediate-, and high-risk patients, respectively (p < 0.0001). Cox proportional hazards regression analysis adjusted for covariates revealed that pretreatment PSA level was a significant factor, whereas risk group, Gleason score, T-stage, and age were not. When the patients were stratified by risk groups, the Cox proportion hazards regression model (after adjusting for pretreatment PSA, biopsy Gleason score, and T stage) did not reveal a significant effect on bNED or DFS by adding HT to HDRT Conclusion: The addition of HT did not significantly improve bNED survival or DFS in all prostate cancer patients receiving HDRT, but did approach significance in high-risk patient subgroup. The result of this study is hypothesis generating and requires testing in a prospective randomized trial.

  1. Long-Term Failure Patterns and Survival in a Randomized Dose-Escalation Trial for Prostate Cancer. Who Dies of Disease?

    SciTech Connect

    Kuban, Deborah A.; Levy, Lawrence B.; Cheung, M. Rex; Lee, Andrew K.; Choi, Seungtaek; Frank, Steven; Pollack, Alan

    2011-04-01

    Purpose: To report long-term failure patterns and survival in a randomized radiotherapy dose escalation trial for prostate cancer. Materials and Methods: A total of 301 patients with Stage T1b-T3 prostate cancer treated to 70 Gy versus 78 Gy now have a median follow-up of 9 years. Failure patterns and survival were compared between dose levels. The cumulative incidence of death from prostate cancer versus other causes was examined and regression analysis was used to establish predictive factors. Results: Patients with pretreatment prostate-specific antigen (PSA) >10 ng/mL or high-risk disease had higher biochemical and clinical failures rates when treated to 70 Gy. These patients also had a significantly higher risk of dying of prostate cancer. Patients <70 years old at treatment died of prostate cancer nearly three times more frequently than of other causes when they were radiated to 70 Gy, whereas those treated to 78 Gy died of other causes more frequently. Patients age 70 or older treated to 70 Gy died of prostate cancer as often as other causes, and those receiving 78 Gy never died of prostate cancer within 10 years of follow-up. In regression analysis, factors predicting for death from prostate cancer were pretreatment PSA >10.5 ng/mL, Gleason score 9 and 10, recurrence within 2.6 years of radiation, and doubling time of <3.6 months at the time of recurrence. Conclusions: Moderate dose escalation (78 Gy) decreases biochemical and clinical failure as well as prostate cancer death in patients with pretreatment PSA >10 ng/mL or high-risk disease.

  2. A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia

    PubMed Central

    Schliemann, Christoph; Gerss, Joachim; Wiebe, Stefanie; Mikesch, Jan-Henrik; Knoblauch, Nicola; Sauer, Tim; Angenendt, Linus; Kewitz, Tobias; Urban, Marc; Butterfass-Bahloul, Trude; Edemir, Sabine; Vehring, Kerstin; Müller-Tidow, Carsten

    2016-01-01

    Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28-day cycles. Dose-limiting toxicity (DLT) was defined as non-hematological severe adverse reaction CTC grade ≥ 4 with possible or definite relationship to nintedanib. Between April 2012 and October 2013, 13 patients (median age 73 [range: 62–86] years) were enrolled. One patient did not receive study medication and was replaced. Nine (69%) patients had relapsed or refractory disease and 6 (46%) patients had unfavorable cytogenetics. The most frequently reported treatment-related adverse events (AE) were gastrointestinal events. Twelve SAEs irrespective of relatedness were reported. Two SUSARs were observed, one fatal hypercalcemia and one fatal gastrointestinal infection. Two patients (17%) with relapsed AML achieved a complete remission (one CR, one CRi) and bone marrow blast reductions without fulfilling PR criteria were observed in 3 patients (25%). One-year overall survival was 33%. Nintedanib combined with LDAC shows an adequate safety profile and survival data are promising in a difficult-to-treat patient population. Continuation of this trial with a phase II recommended dose of 2 x 200 mg nintedanib in a randomized, placebo-controlled phase II study is planned. The trial is registered to EudraCT as 2011-001086-41. Trial Registration: ClinicalTrials.gov NCT01488344 PMID:27716819

  3. Interfractional Dose Variations in Intensity-Modulated Radiotherapy With Breath-Hold for Pancreatic Cancer

    SciTech Connect

    Nakamura, Mitsuhiro; Shibuya, Keiko; Nakamura, Akira; Shiinoki, Takehiro; Matsuo, Yukinori; Nakata, Manabu; Sawada, Akira; Mizowaki, Takashi; Hiraoka, Masahiro

    2012-04-01

    negligible range in achieving dose escalation with intensity-modulated RT combined with BH at EE.

  4. A Systematic Review of the Definitions, Determinants, and Clinical Outcomes of Antimicrobial De-escalation in the Intensive Care Unit.

    PubMed

    Tabah, Alexis; Cotta, Menino Osbert; Garnacho-Montero, Jose; Schouten, Jeroen; Roberts, Jason A; Lipman, Jeffrey; Tacey, Mark; Timsit, Jean-François; Leone, Marc; Zahar, Jean Ralph; De Waele, Jan J

    2016-04-15

    Antimicrobial de-escalation (ADE) is a strategy to reduce the spectrum of antimicrobials and aims to prevent the emergence of bacterial resistance. We present a systematic review describing the definitions, determinants and outcomes associated with ADE. We included 2 randomized controlled trials and 12 cohort studies. There was considerable variability in the definition of ADE. It was more frequently performed in patients with broad-spectrum and/or appropriate antimicrobial therapy (P= .05 to .002), when more agents were used (P= .002), and in the absence of multidrug-resistant pathogens (P< .05). Where investigated, lower or improving severity scores were consistently associated with ADE (P= .04 to <.001). The pooled effect of ADE on mortality is protective (relative risk, 0.68; 95% confidence interval, .52-.88). Because the determinants of ADE are markers of clinical improvement and/or of lower risk of treatment failure this effect on mortality cannot be retained as evidence. None of the studies were designed to investigate the effect of ADE on antimicrobial resistance.

  5. Impact of peptide transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PepT1 knockout mice.

    PubMed

    Yang, Bei; Hu, Yongjun; Smith, David E

    2013-10-01

    The primary objective of this study was to determine the in vivo absorption properties of valacyclovir, including the potential for saturable proton-coupled oligopeptide transporter 1 (PepT1)-mediated intestinal uptake, after escalating oral doses of prodrug within the clinical dose range. A secondary aim was to characterize the role of PepT1 on the tissue distribution of its active metabolite, acyclovir. [³H]Valacyclovir was administered to wild-type (WT) and PepT1 knockout (KO) mice by oral gavage at doses of 10, 25, 50, and 100 nmol/g. Serial blood samples were collected over 180 minutes, and tissue distribution studies were performed 20 minutes after a 25-nmol/g oral dose of valacyclovir. We found that the C(max) and area under the curve (AUC)₀₋₁₈₀ of acyclovir were 4- to 6-fold and 2- to 3-fold lower, respectively, in KO mice for all four oral doses of valacyclovir. The time to peak concentration of acyclovir was 3- to 10-fold longer in KO compared with WT mice. There was dose proportionality in the C(max) and AUC₀₋₁₈₀ of acyclovir in WT and KO mice over the valacyclovir oral dose range of 10-100 nmol/g (i.e., linear absorption kinetics). No differences were observed in the peripheral tissue distribution of acyclovir once these tissues were adjusted for differences in perfusing drug concentrations in the systemic circulation. In contrast, some differences were observed between genotypes in the concentrations of acyclovir in the distal intestine. Collectively, the findings demonstrate a critical role of intestinal PepT1 in improving the rate and extent of oral absorption for valacyclovir. Moreover, this study provides definitive evidence for the rational development of a PepT1-targeted prodrug strategy.

  6. Investigational Aurora A kinase inhibitor alisertib (MLN8237) as an enteric-coated tablet formulation in non-hematologic malignancies: Phase 1 dose-escalation study

    PubMed Central

    Falchook, Gerald; Kurzrock, Razelle; Gouw, Launce; Hong, David; McGregor, Kimberly A.; Zhou, Xiaofei; Shi, Hongliang; Fingert, Howard; Sharma, Sunil

    2014-01-01

    Background This phase 1b study evaluated an enteric-coated tablet (ECT) formulation of the investigational Aurora A kinase inhibitor, alisertib (MLN8237). Methods Patients with advanced, non-hematologic malignancies received oral alisertib ECT for 7 days BID followed by 14 days treatment-free (21-day cycles; 3+3 dose escalation schema). Objectives were to assess safety, pharmacokinetics, and antitumor activity, and to define a recommended phase 2 dose (RP2D) of alisertib. Results 24 patients were treated. Median age was 57 years. Patients received a median of 2 cycles (range 1–12). The RP2D was determined as 50 mg BID for 7 days (21-day cycles). A cycle 1 dose-limiting toxicity of grade 4 febrile neutropenia was observed in 1 of 13 patients at RP2D. The most common drug-related adverse event (AE) was neutropenia (50%). At doses ≥40 mg BID, 7 patients had drug-related AEs that were serious but largely reversible/manageable by dose reduction and supportive care, including 3 with febrile neutropenia. Pharmacokinetic data were available in 24 patients. Following administration of alisertib ECT, the plasma peak concentration of alisertib was achieved at ~3 h; systemic exposure increased with increasing dose over 10–60 mg BID. Mean t½ was ~21 h following multiple dosing. Renal clearance was negligible. Nine patients achieved stable disease (3.98*, 5.59, 1.28*, 2.56, 5.45*, 3.48, 3.15, 8.31, and 6.93* months; *censored). Conclusions Alisertib ECT was generally well tolerated in adults with advanced, non-hematologic malignancies. The RP2D is 50 mg BID for 7 days and is being evaluated in ongoing phase 2 studies. PMID:24879333

  7. A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies

    PubMed Central

    2013-01-01

    Background Dinaciclib, a small-molecule, cyclin-dependent kinase inhibitor, inhibits cell cycle progression and proliferation in various tumor cell lines in vitro. We conducted an open-label, dose-escalation study to determine the safety, tolerability, and bioactivity of dinaciclib in adults with advanced malignancies. Methods Dinaciclib was administered starting at a dose of 0.33 mg/m2, as a 2-hour intravenous infusion once weekly for 3 weeks (on days 1, 8, and 15 of a 28-day cycle), to determine the maximum administered dose (MAD), dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and safety and tolerability. Pharmacodynamics of dinaciclib were assessed using an ex vivo phytohemagglutinin lymphocyte stimulation assay and immunohistochemistry staining for retinoblastoma protein phosphorylation in skin biopsies. Evidence of antitumor activity was assessed by sequential computed tomography imaging after every 2 treatment cycles. Results Forty-eight subjects with solid tumors were treated. The MAD was found to be 14 mg/m2 and the RP2D was determined to be 12 mg/m2; DLTs at the MAD included orthostatic hypotension and elevated uric acid. Forty-seven (98%) subjects reported adverse events (AEs) across all dose levels; the most common AEs were nausea, anemia, decreased appetite, and fatigue. Dinaciclib administered at the RP2D significantly inhibited lymphocyte proliferation, demonstrating a pharmacodynamic effect. Ten subjects treated at a variety of doses achieved prolonged stable disease for at least 4 treatment cycles. Conclusions Dinaciclib administered every week for 3 weeks (on days 1, 8, and 15 of a 28-day cycle) was generally safe and well tolerated. Initial bioactivity and observed disease stabilization support further evaluation of dinaciclib as a treatment option for patients with advanced solid malignancies. Trial registration ClinicalTrials.gov # NCT00871663 PMID:24131779

  8. Differential regulation of prodynophin, c-fos, and serotonin transporter mRNA following withdrawal from a chronic, escalating dose regimen of D-amphetamine.

    PubMed

    Horner, Kristen A; Noble, Erika S; Lauterbach, Edward C

    2009-04-01

    Several lines of evidence suggest that D-amphetamine (D-AMPH) withdrawal induces a syndrome with symptoms similar to major depressive disorder (MDD). Upregulation of dynorphin (DYN) may underlie the symptoms of MDD and contribute to the negative emotional symptoms associated with psychostimulant withdrawal. Changes in the serotonin transporter (SERT) have also been reported in MDD, and changes in the immediate early gene c-fos have been observed in the context of psychostimulant withdrawal. This study examined the effects of chronic, escalating doses of D-AMPH followed by 24 h of withdrawal on the expression of prodynorphin (PD) and c-fos mRNA in limbic regions of the brain, caudate putamen (CPu), and brainstem and SERT mRNA expression in the dorsal raphe nucleus (DRN). Male Sprague-Dawley rats were treated three times a day for 4 days with escalating doses of D-AMPH (1-10 mg/kg) and sacrificed 24 h after the last injection. Following 24 h of withdrawal, there was an increase in PD and c-fos mRNA expression in the CPu and nucleus accumbens (NAc), and a decrease in PD and c-fos expression in hippocampus and amygdala. SERT mRNA expression was decreased in the DRN, and PD mRNA expression was increased in the adjacent ventrolateral periaqueductal gray (VLPAG) following D-AMPH withdrawal. These data indicate that region-specific changes in PD and c-fos expression occur after withdrawal, while SERT mRNA expression is suppressed, similar to what has been reported in MDD. Alterations in PD, c-fos, and SERT expression could contribute to the depression-like syndrome associated with psychostimulant withdrawal.

  9. Stereotactic Body Radiotherapy for Recurrent Squamous Cell Carcinoma of the Head and Neck: Results of a Phase I Dose-Escalation Trial

    SciTech Connect

    Heron, Dwight E.; Ferris, Robert L.; Karamouzis, Michalis; Andrade, Regiane S.; Deeb, Erin L.; Burton, Steven; Gooding, William E.; Branstetter, Barton F.; Mountz, James M.; Johnson, Jonas T.; Argiris, Athanassios; Grandis, Jennifer R.; Lai, Stephen Y.

    2009-12-01

    Purpose: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) in previously irradiated patients with squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods: In this Phase I dose-escalation clinical trial, 25 patients were treated in five dose tiers up to 44 Gy, administered in 5 fractions over a 2-week course. Response was assessed according to the Response Evaluation Criteria in Solid Tumors and [{sup 18}F]-fluorodeoxyglucose standardized uptake value change on positron emission tomography-computed tomography (PET-CT). Results: No Grade 3/4 or dose-limiting toxicities occurred. Four patients had Grade 1/2 acute toxicities. Four objective responses were observed, for a response rate of 17% (95% confidence interval 2%-33%). The maximum duration of response was 4 months. Twelve patients had stable disease. Median time to disease progression was 4 months, and median overall survival was 6 months. Self-reported quality of life was not significantly affected by treatment. Fluorodeoxyglucose PET was a more sensitive early-measure response to treatment than CT volume changes. Conclusion: Reirradiation up to 44 Gy using SBRT is well tolerated in the acute setting and warrants further evaluation in combination with conventional and targeted therapies.

  10. SU-E-T-69: A Radiobiological Investigation of Dose Escalation in Lower Oesophageal Tumours with a Focus On Gastric Toxicity

    SciTech Connect

    Carrington, R; Staffurth, J; Spezi, E; Crosby, T; Warren, S; Partridge, M; Hawkins, M

    2015-06-15

    The incidence of lower third oesophageal tumours is increasing in most Western populations. With the role of radiotherapy dose escalation being identified as a research priority in improving outcomes, it is important to quantify the increased toxicity that this may pose to sites such as the lower oesophagus. This study therefore aims to investigate the feasibility of lower oesophageal dose escalation with a focus on stomach tissue toxicity.The original 3D-conformal plans (50Gy3D) from 10 patients in the SCOPE1 trial were reviewed and compared to two RapidArc plans created retrospectively to represent the treatment arms of the forthcoming SCOPE2 trial: 50GyRA and 60GyRA (50Gy to PTV1 with a simultaneously integrated boost of 60Gy to PTV2). The stomach was contoured as stomach wall and dose constraints set according to QUANTEC. Normal tissue complication probability (NTCP) was estimated for the stomach wall for an endpoint of gastric bleeding. There was a mean increase of 5.93% in NTCP from 50Gy3D to 60GyRA and a mean increase of 8.15% in NTCP from the 50GyRA to 60GyRA. With NTCP modelling restricted to volumes outside PTV2, there was a mean decrease of 0.92% in NTCP from the 50Gy3D to 60GyRA, and a mean increase of 2.25% from 50GyRA to 60GyRA. There was a strong correlation between the NTCP and Stomach Wall/PTV1 overlap volume for all plans (R=0.80, 0.77 and 0.77 for 60GyRA, 50GyRA and 50Gy3D respectively). There was also a strong correlation between NTCP and the Stomach Wall/PTV2 overlap volume for 60GyRA (R= 0.82).Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach within the boost volume. It is recommended that stomach toxicity be closely monitored prospectively when treating patients with lower oesophageal tumours in the forthcoming SCOPE 2 trial. Rhys Carrington received a PhD studentship grant from Cancer Research Wales. Grant number: 2445; Dr Warren and

  11. SU-C-BRA-01: 18F-NaF PET/CT-Directed Dose Escalation in Stereotactic Body Radiotherapy for Spine Oligometastases From Prostate Cancer

    SciTech Connect

    Wu, L; Zhang, W; Li, M; Peng, X; Xie, L; Lin, Z; Kwee, S; Wang, H; Kuang, Y

    2015-06-15

    Purpose: To investigate the technical feasibility of SBRT dose painting using {sup 18}F-NaF positron emission tomography (PET) scans guidance in patients with spine oligometastases from prostate cancer. Methods: As a proof of concept, six patients with 14 spine oligometastatic lesions from prostate cancer who had {sup 18}F-NaF PET/CT scan prior to treatment were retrospectively included. GTV{sub reg} was delineated according to the regular tumor boundary shown on PET and/or CT images; and GTV{sub MATV} was contoured based on a net metabolically active tumor volume (MATV) defined by 60% of the SUV{sub max} values on {sup 18}F-NaF PET images. The PTVs (PTV{sub reg} and PTV{sub MATV}) were defined as respective GTVs (plus involved entire vertebral body for PTV{sub reg}) with a 3-mm isotropic expansion margin. Three 1-fraction SBRT plans using VMAT technique along with 10 MV FFF beams (Plan{sub 24Gy}, Plan{sub 24–27Gy}, and Plan{sub 24–30Gy}) were generated for each patient. All plans included a dose of 24 Gy prescribed to PTV{sub reg}. The Plan{sub 24–27Gy} and Plan{sub 24–30Gy} also included a simultaneous boost dose of 27 Gy or 30 Gy prescribed to the PTV{sub MATV}, respectively. The feasibility of 18F-NaF PET-guided SBRT dose escalation was evaluated by its ability to achieve the prescription dose objectives while adhering to organ-at-risk (OAR) dose constraints. The normal tissue complication probabilities (NTCP) calculated by radiological models were also compared between the plans. Results: In all 33 SBRT plans generated, the planning objectives and dose constraints were met without exception. Plan{sub 24–27Gy} and Plan{sub 24–30Gy} had a significantly higher dose in PTV{sub MATV} than Plan{sub 24Gy} (p < 0.05), respectively, while maintaining a similar OAR sparing profile and NTCP values. Conclusion: Using VMAT with FFF beams to incorporate a simultaneous {sup 18}F-NaF PET-guided radiation boost dose up to 30 Gy into a SBRT plan is technically

  12. Effects of short-term abstinence from escalating doses of D-amphetamine on drug and sucrose-evoked dopamine efflux in the rat nucleus accumbens.

    PubMed

    Vacca, Giada; Ahn, Soyon; Phillips, Anthony G

    2007-04-01

    Abstinence from high doses of psychostimulant drugs, in both humans and rodents, is linked to adverse psychological effects including anhedonia, a core symptom of major depression, manifested behaviorally as decreased responding for rewarding stimuli. The present study used brain microdialysis in freely moving rats to examine the effect of D-amphetamine (D-amph) withdrawal on changes in extracellular dopamine (DA) levels in the nucleus accumbens (NAc) evoked by D-amph or behavior related to sucrose consumption. D-amph was administered intraperitoneally (i.p.) according to an escalating dose (ED) schedule (from 1 to 10 mg/kg, 3 doses/day). We first confirmed the development of tolerance by monitoring DA efflux in the NAc in response to 5 and 10 mg/kg doses of D-amph administered during the ED schedule of drug administration and again in response to the 5 mg/kg dose of D-amph 72 h following the last 10 mg/kg D-amph injection. In a separate study, DA efflux in the NAc was first shown to be increased significantly during both preparatory and consummatory phases of responding for a 4% sucrose solution. Withdrawal from the ED schedule of D-amph caused a selective attenuation of DA efflux only during the preparatory phase of the sucrose test. These results provided convincing evidence of neurochemical adaptation within the mesocorticolimbic DA pathway during and following the administration of an ED schedule of D-amph as well as suppressed neurochemical responses to a psychostimulant drug and cues associated with a natural reward after withdrawal from drug treatment. Accordingly, these findings support the hypothesis that downregulation of mesocorticolimbic DA function maintained during D-amph withdrawal may account for the selective disruption of motivated behavior reported in studies employing psychostimulant drug withdrawal as a model of depression in rodents.

  13. Aphasia treatment: intensity, dose parameters, and script training.

    PubMed

    Cherney, Leora R

    2012-10-01

    Studies of aphasia treatment have shown that intensive speech-language therapy is associated with significant improvements. However, there is no standard definition of intensity and the simplistic notion that "more is better" is not necessarily supported by the research. First, current evidence regarding intensity and aphasia treatment was briefly summarized. Second, studies that directly compare conditions of higher- and lower-intensity treatment for aphasia were reviewed with regard to the inclusion of parameters that contribute to a definition of intensity. In addition to five parameters proposed by Warren, Fey, and Yoder (2007) and highlighted by Baker (2012) , total number of sessions was also often documented. The review illustrated the complexity of quantifying the dose of comprehensive treatments that target multiple modalities and utilize a variety of different strategies. Third, data from a study reporting a relationship between intensive computer-based script training and outcomes in aphasia were examined. Results serve to illustrate Baker's contention that intensity alone is insufficient without also considering the active ingredients of the teaching episode. Information about dose, therapeutic inputs, and client acts can lead to better optimization of an intervention.

  14. A Phase I Dose Escalation Study Demonstrates Quercetin Safety and Explores Potential for Bioflavonoid Antivirals in Patients with Chronic Hepatitis C.

    PubMed

    Lu, Nu T; Crespi, Catherine M; Liu, Natalie M; Vu, James Q; Ahmadieh, Yasaman; Wu, Sheng; Lin, Sherry; McClune, Amy; Durazo, Francisco; Saab, Sammy; Han, Steven; Neiman, David C; Beaven, Simon; French, Samuel W

    2016-01-01

    The hepatitis C virus (HCV) infects more than 180 million people worldwide, with long-term consequences including liver failure and hepatocellular carcinoma. Quercetin bioflavonoids can decrease HCV production in tissue culture, in part through inhibition of heat shock proteins. If quercetin demonstrates safety and antiviral activity in patients, then it could be developed into an inexpensive HCV treatment for third world countries or other affected populations that lack financial means to cover the cost of mainstream antivirals. A phase 1 dose escalation study was performed to evaluate the safety of quercetin in 30 untreated patients with chronic HCV infection and to preliminarily characterize quercetin's potential in suppressing viral load and/or liver injury. Quercetin displayed safety in all trial participants. Additionally, 8 patients showed a "clinically meaningful" 0.41-log viral load decrease. There was a positive correlation (r = 0.41, p = 0.03) indicating a tendency for HCV decrease in patients with a lower ratio of plasma quercetin relative to dose. No significant changes in aspartate transaminase and alanine transaminase were detected. In conclusion, quercetin exhibited safety (up to 5 g daily) and there was a potential for antiviral activity in some hepatitis C patients.

  15. An improved Francisella tularensis Live Vaccine Strain (LVS) is well tolerated and highly immunogenic when administered to rabbits in escalating doses using various immunization routes

    PubMed Central

    Pasetti, Marcela F.; Cuberos, Lilian; Horn, Thomas L.; Shearer, Jeffry D.; Matthews, Stephen J.; House, Robert V.; Sztein, Marcelo B.

    2008-01-01

    Tularemia is a severe disease for which there is no licensed vaccine. An attenuated F. tularensis live vaccine strain (LVS) was protective when administered to humans but safety concerns precluded its licensure and use in large scale immunization. An improved F. tularensis LVS preparation was produced under current Good Manufacturing Practice (cGMP) guidelines for evaluation in clinical trials. Preclinical safety, tolerability and immunogenicity were investigated in rabbits that received LVS in escalating doses (1x105 to 1x109 CFU) by the intradermal, subcutaneous or percutaneous (scarification) route. This improved LVS formulation was well tolerated at all doses; no death or adverse clinical signs were observed and necropsies showed no signs of pathology. No live organisms were detected in liver or spleen. Transient local reactogenicity was observed after scarification injection. Erythema and edema developed after intradermal injection in the highest dose cohorts. High levels of F. tularensis-specific IgM, IgG and IgA developed early after immunization, in a dose-dependent fashion. Scarification elicited higher levels of IgA. Antibodies elicited by LVS also recognized F. tularensis Schu-S4 antigens and there was a significant correlation between antibody titers measured against both LVS and Schu-S4. The ELISA titers also correlated closely with those measured by microagglutination. This is the first report describing comprehensive toxicological and immunological studies of F. tularensis LVS in rabbits. This animal model, which closely resembles human disease, proved adequate to assess safety and immunogenicity of F. tularensis vaccine candidates. This new LVS vaccine preparation is being evaluated in human clinical studies. PMID:18308432

  16. TU-F-CAMPUS-T-05: Dose Escalation to Biological Tumor Volumes of Prostate Cancer Patients Using Gold Nanoparticles

    SciTech Connect

    Jermoumi, M; Ngwa, W; Sajo, E; Houari, K

    2015-06-15

    Purpose: Studies have shown that radiation boosting could help reduce prostate cancer (PCa) recurrence. Biological tumor volumes (BTV) are a high priority for such radiation boosting. The purpose of this study is to investigate the potential of radiation boosting of real patient BTVs using gold nanoparticles (GNP) released from gold-loaded brachytherapy spacers (GBS) during brachytherapy. Methods: The BTVs of 12 patients having prostate adenocarcinoma identified with positron emission tomography (PET) and CT scanner using C-11 labeled tracer [11C]acetate were investigated. The initial GNP concentration and time to achieve a dose enhancement effect (DEF) of 2 was simulated using the freely downloadable software RAID APP. The investigations were carried out for low dose rate (LDR) brachytherapy sources (BTS) described in AAPM Task Group report 43: Cs-131, I-125, and Pd-103. In first case, we used 7 mg/g and 18 mg/g of GNP initial concentrations to estimate the time needed for released GNP to achieve a DEF of 2 for the different BTS, and compare with clinically relevant treatment times. In second case, we calculated the initial concentration of GNPs needed to achieve a DEF of 2 during the time the BTS would typically deliver 50%, 70% and 90% of the total dose. Results: For an initial concentration of 18 mg/g, when using Cs-131, and Pd-103, a DEF of 2 could only be achieved for BTV of 3.3 cm3 and 1 cm3 respectively. Meanwhile a DEF of 2 could be achieved for all 12 BTVs when using I-125. To achieve a DEF of 2 for all patients using Cs-131 and Pd-103, much higher initial concentrations would have to be used than have been typically employed in pre-clinical studies. Conclusion: The I-125 is the most viable BTS that can be employed with GBS to guide dose painting treatment planning for localized PCa.

  17. TEAMS: Toxicity- and Efficacy-based Dose Insertion Design with Adaptive Model Selection for Phase I/II Dose-Escalation Trials in Oncology

    PubMed Central

    Guo, Wentian; Ni, Yang; Ji, Yuan

    2015-01-01

    Summary In many oncology clinical trials it is necessary to insert new candidate doses when the prespecified doses are poorly elicited. Formal statistical designs with dose insertion are lacking. We propose a dose insertion design for phase I/II clinical trials in oncology based on both efficacy and toxicity outcomes. We also implement Bayesian model selection during the course of the trial so that better models can be adaptively chosen to achieve more accurate inference. The new design, TEAMS, achieves great operating characteristics in extensive simulation studies due to its ability to adaptively insert new doses as well as perform model selection. As a result, appropriate doses are inserted when necessary and desirable doses are selected with higher probabilities at the end of the trial. PMID:26528377

  18. Allogeneic marrow transplantation following cyclophosphamide and escalating doses of hyperfractionated total body irradiation in patients with advanced lymphoid malignancies: A phase I/II trial

    SciTech Connect

    Demirer, T.; Petersen, F.B.; Appelbaum, F.R.

    1995-07-15

    The purpose of this investigation was to define the maximum tolerated dose (MTD) of unshielded total body irradiation (TBI) delivered from dual {sup 60}C sources at an exposure rate of 0.08 Gy/min and given in thrice daily fractions of 1.2 Gy in patients with advanced lymphoid malignancies. Forty-four patients with a median age of 28 (range 6-48) years were entered into a Phase I/II study. All patients received cyclophosphamide (Cy), 120 mg/kg administered over 2 days before TBI. Marrow from human leukocyte antigen (HLA) identical siblings was infused following the last dose of TBI. An escalation-deescalation schema designed to not exceed an incidence of 25% of Grade 3-4 regimen-related toxicities (RRTs) was used. The first dose level tested was 13.2 Gy followed by 14.4 Gy. None of the four patients at the dose level of 13.2 Gy developed Grade 3-4 RRT. Two of the first eight patients receiving 14.4 Gy developed Grade 3-4 RRT, establishing this as the MTD. An additional 32 patients were evaluated at the 14.4 Gy level to confirm these initial observations. Of 40 patients receiving 14.4 Gy, 13 (32.5%) developed Grade 3-4 RRTs; 46% in adults and 12% in children. The primary dose limiting toxicity was Grade 3-4 hepatic toxicity, which occurred in 12.5% of patients. Noninfectious Grade 3-4 interstitial pneumonia syndrome occurred in 5% of patients. The actuarial probabilities of event-free survival, relapse, and nonrelapse mortality at 2 years were 0.10, 0.81, and 0.47, respectively, for patients who received 14.4 Gy of TBI. The outcome for patients receiving 14.4 Gy of TBI was not different from previous studies of other CY and TBI regimens in patients with advanced lymphoid malignancies. These data showed that the incidence of Grade 3-4 RRTs in adults was greater than the 25% maximum set as the goal of this study, suggesting that 13.2 Gy is a more appropriate dose of TBI for adults, while 14.4 Gy is an appropriate dose for children. 36 refs., 1 fig., 3 tabs.

  19. The Percent of Positive Biopsy Cores Improves Prediction of Prostate Cancer-Specific Death in Patients Treated With Dose-Escalated Radiotherapy

    SciTech Connect

    Qian Yushen; Feng, Felix Y.; Halverson, Schuyler; Blas, Kevin; Sandler, Howard M.; Hamstra, Daniel A.

    2011-11-01

    Purpose: To examine the prognostic utility of the percentage of positive cores (PPC) at the time of prostate biopsy for patients treated with dose-escalated external beam radiation therapy. Methods and Materials: We performed a retrospective analysis of patients treated at University of Michigan Medical Center to at least 75 Gy. Patients were stratified according to PPC by quartile, and freedom from biochemical failure (nadir + 2 ng/mL), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) were assessed by log-rank test. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal cut point for PPC stratification. Finally, Cox proportional hazards multivariate regression was used to assess the impact of PPC on clinical outcome when adjusting for National Comprehensive Cancer Network (NCCN) risk group and androgen deprivation therapy. Results: PPC information was available for 651 patients. Increasing-risk features including T stage, prostate-specific antigen, Gleason score, and NCCN risk group were all directly correlated with increasing PPC. On log-rank evaluation, all clinical endpoints, except for OS, were associated with PPC by quartile, with worse clinical outcomes as PPC increased, with the greatest impact seen in the highest quartile (>66.7% of cores positive). ROC curve analysis confirmed that a cut point using two-thirds positive cores was most closely associated with CSS (p = 0.002; area under ROC curve, 0.71). On univariate analysis, stratifying patients according to PPC less than or equal to 66.7% vs. PPC greater than 66.7% was prognostic for freedom from biochemical failure (p = 0.0001), FFM (p = 0.0002), and CSS (p = 0.0003) and marginally prognostic for OS (p = 0.055). On multivariate analysis, after adjustment for NCCN risk group and androgen deprivation therapy use, PPC greater than 66.7% increased the risk for biochemical failure (p = 0.0001; hazard ratio [HR], 2.1 [95% confidence

  20. Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study

    SciTech Connect

    Roach, Mack . E-mail: roach@radonc17.ucsf.edu; Winter, Kathryn; Michalski, Jeffrey M.; Cox, James D.; Purdy, James A.; Bosch, Walter; Lin Xiao; Shipley, William S.

    2004-12-01

    Purpose: To assess the relationship between the dose to the bulb of the penis and the risk of impotence in men treated on Radiation Therapy Oncology Group (RTOG) 9406. Methods and materials: Men enrolled on a Phase I/II dose-escalation study, RTOG 9406, who were reported to be potent at entry and evaluable (n = 158) were selected for inclusion. Follow-up evaluations were scheduled every 3, 4, and 6 months for the first, second, and the third through fifth years, then annually. At each follow-up visit an assessment of potency status was made. Penile structures were defined by a single observer blinded to the potency status, using Web-based, on-line software. The dosimetry for penile structures was calculated at the Quality Assurance Center at Washington University and provided to RTOG Statistical Headquarters to determine whether there was a relationship between dose and impotence. Results: Patients whose median penile dose was {>=}52.5 Gy had a greater risk of impotence compared with those receiving <52.5 Gy (p = 0.039). In a multivariate analysis neither age, the dose to the prostate, nor the use of hormonal therapy correlated with the risk of impotence. Conclusions: Dose to the bulb of the penis seems to be associated with the risk of radiation-induced impotence.

  1. Escalating polypharmacy.

    PubMed

    Gorard, D A

    2006-11-01

    New drug treatments, new indications for older drug treatments, lower thresholds for treating risk factors in preventative medicine, and an ageing population acquiring multiple pathologies all contribute to the development of polypharmacy. Longitudinal studies document the rise in prescribed medications, particularly in the elderly. The potential dangers of adverse drug reactions and interactions, poor adherence and confusion associated with ever-increasing polypharmacy are likely to worsen. Strategies to reduce prescribing will obviously decrease the dangers of polypharmacy. These include more considered prescribing when contemplating additions to patients' already lengthy prescription lists, and external reviews of medicine lists by a doctor or pharmacist. Despite such strategies, polypharmacy seems inevitable and considerations must be given to simplifying patients' multiple drug administrations using single-daily-dose regimens, fixed-dose combination pills, calendar-blister packaging and pill organizers.

  2. A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

    PubMed

    Kutlar, Abdullah; Reid, Marvin E; Inati, Adlette; Taher, Ali T; Abboud, Miguel R; El-Beshlawy, Amal; Buchanan, George R; Smith, Hedy; Ataga, Kenneth I; Perrine, Susan P; Ghalie, Richard G

    2013-11-01

    2,2-Dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/β(0) thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases ≥4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases ≥1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. .

  3. A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors.

    PubMed

    Deutsch, Eric; Cohen-Jonathan Moyal, Elizabeth; Gregorc, Vanesa; Zucali, Paolo Andrea; Menard, Jean; Soria, Jean-Charles; Kloos, Ioana; Hsu, Jeff; Luan, Ying; Liu, Emily; Vezan, Remus; Graef, Thorsten; Rivera, Sofia

    2016-12-24

    Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions.

  4. Causes of Mortality After Dose-Escalated Radiation Therapy and Androgen Deprivation for High-Risk Prostate Cancer

    SciTech Connect

    Tendulkar, Rahul D.; Hunter, Grant K.; Reddy, Chandana A.; Stephans, Kevin L.; Ciezki, Jay P.; Abdel-Wahab, May; Stephenson, Andrew J.; Klein, Eric A.; Mahadevan, Arul; Kupelian, Patrick A.

    2013-09-01

    Purpose: Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. Methods and Materials: A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (≥74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. Results: The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ≥1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ≥1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). Conclusions: Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not.

  5. Safety and Reactogenicity of an MSP-1 Malaria Vaccine Candidate: A Randomized Phase Ib Dose-Escalation Trial in Kenyan Children

    PubMed Central

    Withers, Mark R; McKinney, Denise; Ogutu, Bernhards R; Waitumbi, John N; Milman, Jessica B; Apollo, Odika J; Allen, Otieno G; Tucker, Kathryn; Soisson, Lorraine A; Diggs, Carter; Leach, Amanda; Wittes, Janet; Dubovsky, Filip; Stewart, V. Ann; Remich, Shon A; Cohen, Joe; Ballou, W. Ripley; Holland, Carolyn A; Lyon, Jeffrey A; Angov, Evelina; Stoute, José A; Martin, Samuel K; Heppner, D. Gray

    2006-01-01

    Objective: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. Design: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. Setting: The study was conducted in a rural population in Kombewa Division, western Kenya. Participants: Subjects were 135 children, aged 12–47 mo. Interventions: Subjects received 10, 25, or 50 μg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 μL, respectively, of AS02A, or they received a comparator (Imovax® rabies vaccine). Outcome Measures: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Results: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 μg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 μg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F3,1047 = 10.78, or F3, 995 = 11.22, p < 0.001); however, the comparison of 25 μg and 50 μg recipients indicated no significant difference (F1,1047 = 0.05; p = 0.82). Conclusions

  6. Intensity-modulated radiation therapy.

    PubMed

    Goffman, Thomas E; Glatstein, Eli

    2002-07-01

    Intensity-modulated radiation therapy (IMRT) is an increasingly popular technical means of tightly focusing the radiation dose around a cancer. As with stereotactic radiotherapy, IMRT uses multiple fields and angles to converge on the target. The potential for total dose escalation and for escalation of daily fraction size to the gross cancer is exciting. The excitement, however, has greatly overshadowed a range of radiobiological and clinical concerns.

  7. A Dose Escalation and Pharmacodynamic Study of Triapine and Radiation in Patients With Locally Advanced Pancreas Cancer

    SciTech Connect

    Martin, Ludmila Katherine; Grecula, John; Jia, Guang; Wei Lai; Yang Xiangyu; Otterson, Gregory A.; Wu Xin; Harper, Erica; Kefauver, Cheryl; Zhou Bingsen; Yen Yun; Bloomston, Mark; Knopp, Michael; Ivy, S. Percy; Grever, Michael; Bekaii-Saab, Tanios

    2012-11-15

    Purpose: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). Methods and Materials: We evaluated 3 dosage levels of triapine (24 mg/m{sup 2}, 48 mg/m{sup 2}, 72 mg/m{sup 2}) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. Results: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. Conclusion: The combination of triapine at 72 mg/m{sup 2} 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.

  8. Treatment of active lupus nephritis with the novel immunosuppressant 15-deoxyspergualin: an open-label dose escalation study

    PubMed Central

    2011-01-01

    Introduction As the immunosuppressive potency of 15-deoxyspergualin (DSG) has been shown in the therapy of renal transplant rejection and Wegener's granulomatosis, the intention of this study was to evaluate the safety of DSG in the therapy of lupus nephritis (LN). Methods Patients with histologically proven active LN after prior treatment with at least one immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of one week. These cycles were repeated to a maximum of nine times. Doses of oral corticosteroids were gradually reduced to 7.5 mg/day or lower by cycle 4. Response was measured according to a predefined decision pattern. The dose of DSG was adjusted depending on the efficacy and side effects. Results A total of 21 patients were included in this phase-I/II study. After the first DSG injection, one patient was excluded from the study due to renal failure. Five patients dropped out due to adverse events or serious adverse events including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia. Eleven out of 20 patients achieved partial (4) or complete responses (7), 8 were judged as treatment failures and 1 patient was not assessable. Twelve patients completed all nine cycles; in those patients, proteinuria decreased from 5.88 g/day to 3.37 g/day (P = 0.028), Selena-SLEDAI (Safety of Estrogens in Lupus Erythematosus - National Assessment - systemic lupus erythematosus disease activity index) decreased from 17.6 to 11.7. In 13 out of 20 patients, proteinuria decreased by at least 50%; in 7 patients to less than 1 g/day. Conclusions Although the number of patients was small, we could demonstrate that DSG provides a tolerably safe treatment for LN. The improvement in proteinuria encourages larger controlled trials. Trial registration ClinicalTrials.gov: NCT00709722 PMID:21356124

  9. Monte Carlo dose verification for intensity-modulated arc therapy

    NASA Astrophysics Data System (ADS)

    Li, X. Allen; Ma, Lijun; Naqvi, Shahid; Shih, Rompin; Yu, Cedric

    2001-09-01

    Intensity-modulated arc therapy (IMAT), a technique which combines beam rotation and dynamic multileaf collimation, has been implemented in our clinic. Dosimetric errors can be created by the inability of the planning system to accurately account for the effects of tissue inhomogeneities and physical characteristics of the multileaf collimator (MLC). The objective of this study is to explore the use of Monte Carlo (MC) simulation for IMAT dose verification. The BEAM/DOSXYZ Monte Carlo system was implemented to perform dose verification for the IMAT treatment. The implementation includes the simulation of the linac head/MLC (Elekta SL20), the conversion of patient CT images and beam arrangement for 3D dose calculation, the calculation of gantry rotation and leaf motion by a series of static beams and the development of software to automate the entire MC process. The MC calculations were verified by measurements for conventional beam settings. The agreement was within 2%. The IMAT dose distributions generated by a commercial forward planning system (RenderPlan, Elekta) were compared with those calculated by the MC package. For the cases studied, discrepancies of over 10% were found between the MC and the RenderPlan dose calculations. These discrepancies were due in part to the inaccurate dose calculation of the RenderPlan system. The computation time for the IMAT MC calculation was in the range of 20-80 min on 15 Pentium-III computers. The MC method was also useful in verifying the beam apertures used in the IMAT treatments.

  10. DVC1-0101 to Treat Peripheral Arterial Disease: A Phase I/IIa Open-label Dose-escalation Clinical Trial

    PubMed Central

    Yonemitsu, Yoshikazu; Matsumoto, Takuya; Itoh, Hiroyuki; Okazaki, Jin; Uchiyama, Makiko; Yoshida, Kumi; Onimaru, Mitsuho; Onohara, Toshihiro; Inoguchi, Hiroyuki; Kyuragi, Ryoichi; Shimokawa, Mototsugu; Ban, Hiroshi; Tanaka, Michiko; Inoue, Makoto; Shu, Tsugumine; Hasegawa, Mamoru; Nakanishi, Yoichi; Maehara, Yoshihiko

    2013-01-01

    We here report the results of a Phase I/IIa open-label four dose-escalation clinical study assessing the safety, tolerability, and possible therapeutic efficacy of a single intramuscular administration of DVC1-0101, a new gene transfer vector based on a nontransmissible recombinant Sendai virus (rSeV) expressing the human fibroblast growth factor-2 (FGF-2) gene (rSeV/dF-hFGF2), in patients with peripheral arterial disease (PAD). Gene transfer was done in 12 limbs of 12 patients with rest pain, and three of them had ischemic ulcer(s). No cardiovascular or other serious adverse events (SAEs) caused by gene transfer were detected in the patients over a 6-month follow-up. No infectious viral particles, as assessed by hemagglutination activity, were detected in any patient during the study. No representative elevation of proinflammatory cytokines or plasma FGF-2 was seen. Significant and continuous improvements in Rutherford category, absolute claudication distance (ACD), and rest pain were observed (P < 0.05 to 0.01). To the best of our knowledge, this is the first clinical trial of the use of a gene transfer vector based on rSeV. The single intramuscular administration of DVC1-0101 to PAD patients was safe and well tolerated, and resulted in significant improvements of limb function. Larger pivotal studies are warranted as a next step. PMID:23319060

  11. WE-G-BRB-02: The Role of Program Project Grants in Study of 3D Conformal Therapy, Dose Escalation and Motion Management

    SciTech Connect

    Fraass, B.

    2015-06-15

    Over the past 20 years the NIH has funded individual grants, program projects grants, and clinical trials which have been instrumental in advancing patient care. The ways that each grant mechanism lends itself to the different phases of translating research into clinical practice will be described. Major technological innovations, such as IMRT and proton therapy, have been advanced with R01-type and P01-type funding and will be discussed. Similarly, the role of program project grants in identifying and addressing key hypotheses on the potential of 3D conformal therapy, normal tissue-guided dose escalation and motion management will be described. An overview will be provided regarding how these technological innovations have been applied to multi-institutional NIH-sponsored trials. Finally, the panel will discuss regarding which research questions should be funded by the NIH to inspire the next advances in radiation therapy. Learning Objectives: Understand the different funding mechanisms of the NIH Learn about research advances that have led to innovation in delivery Review achievements due to NIH-funded program project grants in radiotherapy over the past 20 years Understand example advances achieved with multi-institutional clinical trials NIH.

  12. Individual vulnerability to escalated aggressive behavior by a low dose of alcohol: decreased serotonin receptor mRNA in the prefrontal cortex of male mice.

    PubMed

    Chiavegatto, S; Quadros, I M H; Ambar, G; Miczek, K A

    2010-02-01

    Low to moderate doses of alcohol consumption induce heightened aggressive behavior in some, but not all individuals. Individual vulnerability for this nonadaptive behavior may be determined by an interaction of genetic and environmental factors with the sensitivity of alcohol's effects on brain and behavior. We used a previously established protocol for alcohol oral self-administration and characterized alcohol-heightened aggressive (AHA) mice as compared with alcohol non-heightened (ANA) counterparts. A week later, we quantified mRNA steady state levels of several candidate genes in the serotonin [5-hydroxytryptamine (5-HT)] system in different brain areas. We report a regionally selective and significant reduction of all 5-HT receptor subtype transcripts, except for 5-HT(3), in the prefrontal cortex of AHA mice. Comparable gene expression profile was previously observed in aggressive mice induced by social isolation or by an anabolic androgenic steroid. Additional change in the 5-HT(1B) receptor transcripts was seen in the amygdala and hypothalamus of AHA mice. In both these areas, 5-HT(1B) mRNA was elevated when compared with ANA mice. In the hypothalamus, AHA mice also showed increased transcripts for 5-HT(2A) receptor. In the midbrain, 5-HT synthetic enzyme, 5-HT transporter and 5-HT receptors mRNA levels were similar between groups. Our results emphasize a role for postsynaptic over presynaptic 5-HT receptors in mice which showed escalated aggression after the consumption of a moderate dose of alcohol. This gene expression profile of 5-HT neurotransmission components in the brain of mice may suggest a vulnerability trait for alcohol-heightened aggression.

  13. Phase II dose escalation study of image-guided adaptive radiotherapy for prostate cancer: Use of dose-volume constraints to achieve rectal isotoxicity

    SciTech Connect

    Vargas, Carlos; Yan Di; Kestin, Larry L.; Krauss, Daniel; Lockman, David M.; Brabbins, Donald S.; Martinez, Alvaro A. . E-mail: amartinez@beaumont.edu

    2005-09-01

    Purpose: In our Phase II prostate cancer Adaptive Radiation Therapy (ART) study, the highest possible dose was selected on the basis of normal tissue tolerance constraints. We analyzed rectal toxicity rates in different dose levels and treatment groups to determine whether equivalent toxicity rates were achieved as hypothesized when the protocol was started. Methods and Materials: From 1999 to 2002, 331 patients with clinical stage T1 to T3, node-negative prostate cancer were prospectively treated with three-dimensional conformal adaptive RT. A patient-specific confidence-limited planning target volume was constructed on the basis of 5 CT scans and 4 sets of electronic portal images after the first 4 days of treatment. For each case, the rectum (rectal solid) was contoured in its entirety. The rectal wall was defined by use of a 3-mm wall thickness (median volume: 29.8 cc). The prescribed dose level was chosen using the following rectal wall dose constraints: (1) Less than 30% of the rectal wall volume can receive more than 75.6 Gy. (2) Less than 5% of the rectal wall can receive more than 82 Gy. Low-risk patients (PSA < 10, Stage {<=} T2a, Gleason score < 7) were treated to the prostate alone (Group 1). All other patients, intermediate and high risk, where treated to the prostate and seminal vesicles (Group 2). The risk of chronic toxicity (NCI Common Toxicity Criteria 2.0) was assessed for the different dose levels prescribed. HIC approval was acquired for all patients. Median follow-up was 1.6 years. Results: Grade 2 chronic rectal toxicity was experienced by 34 patients (10%) (9% experienced rectal bleeding, 6% experienced proctitis, 3% experienced diarrhea, and 1% experienced rectal pain) at a median interval of 1.1 year. Nine patients (3%) experienced grade 3 or higher chronic rectal toxicity (1 Grade 4) at a median interval of 1.2 years. The 2-year rates of Grade 2 or higher and Grade 3 or higher chronic rectal toxicity were 17% and 3%, respectively. No

  14. A comparative study of reduced dose alemtuzumab in matched unrelated donor and related donor reduced intensity transplants.

    PubMed

    Jardine, Laura; Publicover, Amy; Bigley, Venetia; Hale, Geoff; Pearce, Kim; Dickinson, Anne; Jackson, Graham; Collin, Matthew

    2015-03-01

    In vivo T cell depletion with 100 mg alemtuzumab prevents graft-versus-host disease (GVHD) in reduced intensity conditioned transplants but is associated with delayed immune reconstitution, a higher risk of infection and relapse. De-escalation studies have shown that a reduced dose of 30 mg is as effective as 100 mg in preventing GVHD in matched related donor (MRD) transplants. Dose reduction in matched unrelated donor (MUD) transplants is feasible but the comparative efficacy of alemtuzumab in this setting is not known and opinions vary widely concerning the optimal level of GVHD prophylaxis that should be achieved. Through retrospective analysis we made an objective comparison of MUD transplants receiving an empirically reduced dose of 60 mg, with MRD transplants receiving a 30 mg dose. We observed proportionate levels of alemtuzumab according to dose but an inverse relationship with body surface area particularly in MRD transplants. MUD transplants experienced more acute and chronic GVHD, higher T cell chimerism, more sustained use of ciclosporin and less need for donor lymphocyte infusion than MRD transplants. Thus, doubling the dose of alemtuzumab to 60 mg did not provide equivalent prevention of GVHD after MUD transplant although there was no difference in non-relapse mortality or survival compared with MRD transplants.

  15. Is Intermediate Radiation Dose Escalation With Concurrent Chemotherapy for Stage III Non–Small-Cell Lung Cancer Beneficial? A Multi-Institutional Propensity Score Matched Analysis

    SciTech Connect

    Rodrigues, George; Oberije, Cary; Senan, Suresh; Tsujino, Kayoko; Wiersma, Terry; Moreno-Jimenez, Marta; Kim, Tae Hyun; Marks, Lawrence B.; Rengan, Ramesh; De Petris, Luigi; Ramella, Sara; DeRuyck, Kim; De Dios, Núria Rodriguez; Warner, Andrew; Bradley, Jeffrey D.; Palma, David A.

    2015-01-01

    Purpose: The clinical benefits and risks of dose escalation (DE) for stage III non–small-cell lung cancer (NSCLC) remain uncertain despite the results from Radiation Therapy Oncology Group (RTOG) protocol 0617. There is significant heterogeneity of practice, with many clinicians prescribing intermediate dose levels between the 0617 study arms of 60 and 74 Gy. This study investigated whether this strategy is associated with any survival benefits/risks by analyzing a large multi-institutional database. Methods and Materials: An individual patient database of stage III NSCLC patients treated with radical intent concurrent chemoradiation therapy was created (13 institutions, n=1274 patients). Patients were divided into 2 groups based on tumor Biological Effective Dose at 10 Gy (BED 10): those receiving standard dose (SD; n=552), consisting of 72Gy ≤ BED 10 ≤ 76.8 Gy (eg 60-64 Gy/30-32 fractions [fr]), and those receiving intermediate dose (ID; n=497), consisting of 76.8Gy < BED 10 < 100.8 Gy (eg >64 Gy/32 fr and <74 Gy/37 fr), with lower-dose patients (n=225) excluded from consideration. Patients were then matched using propensity scores, leading to 2 matched groups of 196 patients. Outcomes were compared using various statistics including interquartile range (IQR), Kaplan-Meier curves, and adjusted Cox regression analysis. Results: Matched groups were found to be balanced except for N stage (more N3 disease in SD), median treatment year (SD in 2003; ID in 2007), platinum and taxane chemotherapy (SD in 28%; ID in 39%), and median follow-up (SD were 89 months; ID were 40 months). Median dose fractionation was 60 Gy/30 fr in SD (BED 10 IQR: 72.0-75.5 Gy) and 66 Gy/33 fr (BED 10 IQR: 78.6-79.2 Gy) in ID. Survival curves for SD and ID matched cohorts were statistically similar (P=.27); however, a nonstatistically significant trend toward better survival for ID was observed after 15 months (median survival SD: 19.3 months; ID: 21.0

  16. Retrospective Evaluation Reveals That Long-term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

    SciTech Connect

    Feng, Felix Y.; Blas, Kevin; Olson, Karin; Stenmark, Matthew; Sandler, Howard; Hamstra, Daniel A.

    2013-05-01

    Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. Results: The median follow-up time was 64 months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.

  17. The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke

    PubMed Central

    Elkind, Mitchell S. V.; Sacco, Ralph L.; MacArthur, Robert B.; Fink, Daniel J.; Peerschke, Ellinor; Andrews, Howard; Neils, Greg; Stillman, Josh; Corporan, Tania; Leifer, Dana; Cheung, Ken

    2014-01-01

    There is growing experimental and clinical evidence that by reducing downstream products of the mevalonate pathway other than cholesterol, HMG-CoA reductase inhibitors (‘statins’) have beneficial effects on endothelial function, coronary and cerebral blood flow, inflammation, and hemostasis. Statins have been shown in rodent models of acute ischemic stroke to reduce neuronal injury and infarct size in a dose-dependent fashion. The objective of this early phase trial will be to determine the maximal-tolerated dose of lovastatin for short-term acute stroke therapy. In this multicenter phase 1B dose-escalation and dose-finding study, 33 patients with acute ischemic stroke will be administered lovastatin in increasing doses from one to 10 mg/kg daily for 3 days beginning within 24 hours after symptom onset. The primary safety outcomewill be occurrence of myotoxicity or hepatotoxicity, defined by clinical and laboratory criteria, and the study is designed to determine the highest dose of lovastatin that can be administered with <10% risk of myotoxicity or hepatotoxicity. The statistical design of the study utilizes an adaptive design, the Continual Reassessment Method, which is novel to stroke trials, to find the optimal dosage. The dose–toxicity model is calibrated such that the method will eventually select a dose that causes 7–13% dose-limiting toxicity (within 3% of target). A sample size of 33 will ensure that estimates of any binary variables will have a 95% confidence interval of width ≤0·34, and enable us to detect any unexpected toxicity that occurs at 5% rate (in a non-dose-dependent fashion) with probability 0·82. The probability of choosing a dose for further trials with 25% or higher likelihood of toxicity is no more than 23%. The presently described trial represents a new approach for treatment of acute ischemic stroke, as well as a novel way of conducting a phase I trial, evaluating safety and determining an optimal dose of a potential

  18. Radiation Dose to Newborns in Neonatal Intensive Care Units

    PubMed Central

    Bahreyni Toossi, Mohammad Taghi; Malekzadeh, Malakeh

    2012-01-01

    Background With the increase of X-ray use for medical diagnostic purposes, knowing the given doses is necessary in patients for comparison with reference levels. The concept of reference doses or diagnostic reference levels (DRLs) has been developed as a practical aid in the optimization of patient protection in diagnostic radiology. Objectives To assess the radiation doses to neonates from diagnostic radiography (chest and abdomen). This study has been carried out in the neonatal intensive care unit of a province in Iran. Patients and Methods Entrance surface dose (ESD) was measured directly with thermoluminescent dosimeters (TLDs). The population included 195 neonates admitted for a diagnostic radiography, in eight NICUs of different hospital types. Results The mean ESD for chest and abdomen examinations were 76.3 µGy and 61.5 µGy, respectively. DRLs for neonate in NICUs of the province were 88 µGy for chest and 98 µGy for abdomen examinations that were slightly higher than other studies. Risk of death due to radiation cancer incidence of abdomens examination was equal to 1.88 × 10 -6 for male and 4.43 × 10 -6 for female. For chest X-ray, it was equal to 2.54 × 10 -6 for male and 1.17 × 10 -5 for female patients. Conclusion DRLs for neonates in our province were slightly higher than values reported by other studies such as European national diagnostic reference levels and the NRPB reference dose. The main reason was related to using a high mAs and a low kVp applied in most departments and also a low focus film distance (FFD). Probably lack of collimation also affected some exams in the NICUs. PMID:23329980

  19. Phase II Trial of Radiation Dose Escalation With Conformal External Beam Radiotherapy and High-Dose-Rate Brachytherapy Combined With Long-Term Androgen Suppression in Unfavorable Prostate Cancer: Feasibility Report

    SciTech Connect

    Valero, Jeanette; Cambeiro, Mauricio; Galan, Carlos; Teijeira, Mercedes; Romero, Pilar; Zudaire, Javier; Moreno, Marta; Ciervide, Raquel; Aristu, Jose Javier; Martinez-Monge, Rafael

    2010-02-01

    Purpose: To determine the feasibility of combined long-term luteinizing hormone-releasing hormone agonist-based androgen suppressive therapy (AST) and dose escalation with high-dose-rate (HDR) brachytherapy for high-risk (HRPC) or very-high-risk prostate cancer (VHRPC). Methods and Materials: Between January 2001 and October 2006, 134 patients (median age, 70 years) with either National Comprehensive Cancer Network criteria-defined HRPC (n = 47, 35.1%) or VHRPC (n = 87, 64.9%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen level of 14.6 ng/mL, a median clinical stage of T2c, and a median Gleason score of 7. Three-dimensional conformal radiotherapy (54 Gy in 30 fractions) was followed by HDR brachytherapy (19 Gy in 4 b.i.d. treatments). Androgen suppressive therapy started 0-3 months before three-dimensional conformal radiotherapy and continued for 2 years. Results: One implant was repositioned with a new procedure (0.7%). Five patients (3.7%) discontinued AST at a median of 13 months (range, 6-18 months) because of disease progression (n = 1), hot flashes (n = 2), fatigue (n = 1), and impotence (n = 1). After a median follow-up of 37.4 months (range, 24-90 months), the highest Radiation Therapy Oncology Group-defined late urinary toxicities were Grade 0 in 47.8%, Grade 1 in 38.1%, Grade 2 in 7.5%, and Grade 3 in 6.7% of patients. Maximal late gastrointestinal toxicities were Grade 0 in 73.1%, Grade 1 in 16.4%, Grade 2 in 7.5%, and Grade 3 in 2.9% of patients. There were no Grade 4 or 5 events. Conclusions: Intermediate-term results show that dose escalation with HDR brachytherapy combined with long-term AST is feasible and has a toxicity profile similar to that reported by previous HDR brachytherapy studies.

  20. Escalator design features evaluation

    NASA Technical Reports Server (NTRS)

    Zimmerman, W. F.; Deshpande, G. K.

    1982-01-01

    Escalators are available with design features such as dual speed (90 and 120 fpm), mat operation and flat steps. These design features were evaluated based on the impact of each on capital and operating costs, traffic flow, and safety. A human factors engineering model was developed to analyze the need for flat steps at various speeds. Mat operation of escalators was found to be cost effective in terms of energy savings. Dual speed operation of escalators with the higher speed used during peak hours allows for efficient operation. A minimum number of flat steps required as a function of escalator speed was developed to ensure safety for the elderly.

  1. Intensity-modulated radiosurgery: improving dose gradients and maximum dose using post inverse-optimization interactive dose shaping.

    PubMed

    Fuss, Martin; Salter, Bill J

    2007-06-01

    Intensity-modulated radiosurgery (IMRS) for brain metastases and arterio-venous malformations (AVM) using a serial tomotherapy system (Nomos Corp., Cranberry Township, PA) has been delivered in >150 cases over the last 5 years. A new software tool provided within the Corvus inverse planning software (ActiveRx) allows for post inverse planning re-optimization and individualization of the dose distribution. We analyzed this tool with respect to increasing the steepness of the dose gradient and in-target dose inhomogeneity while maintaining conformity. Fifteen clinically delivered IMRS plans for solitary brain metastases provided the basis for this analysis. The clinical IMRS plans were copied and the ActiveRx module was opened. The toolset in ActiveRx includes a hot spot eraser, a pencil tool to redefine isodose lines and a drag and drop tool, allowing reshaping of existing isodose lines. To assess changes in the steepness of the dose gradient and dose homogeneity, the 100%, 90%, 50% and 25% isodose volume, the volume of the target, maximum dose and mean dose to the target were recorded. We also recorded total monitor units and calculated treatment delivery times. Target volumes ranged from 0.6 to 14.1 cm(3) (mean/median 3.9/1.8 cm(3)). Mean RTOG conformity index (CI) of plans clinically delivered was 1.23+/-0.31; mean homogeneity index (HI) was 115+/-5%. After using the ActiveRx tool-set, the mean CI was slightly improved to 1.14+/-0.1, with an associated increase in HI to 141+/-10%. The average, respective Ian Paddick CI for the 100%, 90% 50% and 25% isodose lines were 0.79 vs. 0.83, 0.44 vs. 0.59, 0.12 vs. 0.19, and 0.04 vs. 0.07, representing significant improvements after using ActiveRx post-optimization. Total MU were reduced by a mean of 12.3% using ActiveRx, shortening estimated treatment delivery times by 3.2 minutes on average. A post inverse planning optimization tool for IMRS plans allowed for statistically significant improvements in the steepness of the

  2. Dose-Escalated Radiotherapy for High-Risk Prostate Cancer: Outcomes in Modern Era With Short-Term Androgen Deprivation Therapy

    SciTech Connect

    Liauw, Stanley L.; Stadler, Walter M.; Correa, David B.S.; Weichselbaum, Ralph R.; Jani, Ashesh B.

    2010-05-01

    Purpose: Randomized data have supported the use of long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) for men with high-risk prostate cancer. The present study reviewed the outcomes of intermediate- and high-risk men treated with RT and short-term ADT. Materials and Methods: A total of 184 men with any single risk factor of prostate-specific antigen >=10 ng/mL, clinical Stage T2b or greater, or Gleason score >=7 were treated with primary external beam RT for nonmetastatic adenocarcinoma of the prostate. The median radiation dose was 74 Gy; 55% were treated with intensity-modulated RT. All patients received ADT for 1 to 6 months (median, 4), consisting of a gonadotropin-releasing hormone analog. Univariate and multivariable analyses were performed for risk factors, including T stage, Gleason score, radiation dose, and prostate-specific antigen level. Results: With a median follow-up of 51 months, the 4-year freedom from biochemical failure (FFBF) using the nadir plus 2 ng/mL definition was 83% for all patients. Clinical Stage T3 disease was the only variable tested associated with FFBF on univariate (4-year FFBF rate, 46% vs. 87% for Stage T1-T2c disease; p = .0303) and multivariable analysis (hazard ratio, 3.9; p = .0016). On a subset analysis of high-risk patients (National Comprehensive Cancer Network criteria), those with clinical Stage T3 disease (4-year FFBF rate, 46% vs. 80%; p = .0303) and a radiation dose <74 Gy (4-year FFBF rate, 64% vs. 80%) had a poorer outcome on univariate analysis. However, clinical Stage T3 disease and radiation dose were not significant on multivariable analysis, although a statistical multivariable trend was seen for both (p = .0650 and p = .0597, respectively). Conclusion: Short-term ADT and RT might be acceptable for men with intermediate- and high-risk prostate cancer, especially for clinically localized disease treated with doses of >=74 Gy.

  3. Comparison of the efficacy and safety of intensive-dose and standard-dose statin treatment for stroke prevention

    PubMed Central

    Wang, Juan; Chen, Dan; Li, Da-Bing; Yu, Xin; Shi, Guo-Bing

    2016-01-01

    Abstract Background: Previous study indicated that high-dose statin treatment might increase the risk of hemorrhagic stroke and adverse reactions. We aim to compare the efficacy and safety of intensive-dose and standard-dose statin treatment for preventing stroke in high-risk patients. Methods: A thorough search was performed of multiple databases for publications from 1990 to June 2015. We selected the randomized clinical trials comparing standard-dose statin with placebo and intensive-dose statin with standard-dose statin or placebo for the prevention of stroke events in patients. Duplicate independent data extraction and bias assessments were performed. Data were pooled using a fixed-effects model or a random-effects model if significant heterogeneity was present. Results: For the all stroke incidences, intensive-dose statin treatment compared with placebo treatment and standard-dose statin treatment compared with placebo treatment showed a significant 21% reduction in relative risk (RR) (RR 0.79, 95% confidence interval (CI) [0.71, 0.87], P < 0.00001) and an 18% reduction in RR (RR 0.82, 95% CI [0.73, 0.93], P = 0.002) in the subgroup without renal transplant recipients and patients undergoing regular hemodialysis separately. For the fatal stroke incidences, intensive-dose statin treatment compared with standard dose or placebo was effective reducing fatal stroke (RR 0.61, 95% CI [0.39, 0.96], P = 0.03) and the RR was 1.01 (95% CI [0.85, 1.20], P = 0.90) in standard-dose statin treatment compared with placebo. Conclusion: The results of this meta-analysis suggest that intensive-dose statin treatment might be more favorable for reducing the incidences of all strokes than standard-dose statin treatment, especially for patients older than 65 years in reducing the incidences of all stroke incidences. PMID:27684837

  4. A Phase I Clinical Study of a Live Attenuated Bordetella pertussis Vaccine - BPZE1; A Single Centre, Double-Blind, Placebo-Controlled, Dose-Escalating Study of BPZE1 Given Intranasally to Healthy Adult Male Volunteers

    PubMed Central

    Thorstensson, Rigmor; Trollfors, Birger; Al-Tawil, Nabil; Jahnmatz, Maja; Bergström, Jakob; Ljungman, Margaretha; Törner, Anna; Wehlin, Lena; Van Broekhoven, Annie; Bosman, Fons; Debrie, Anne-Sophie; Mielcarek, Nathalie; Locht, Camille

    2014-01-01

    Background Acellular pertussis vaccines do not control pertussis. A new approach to offer protection to infants is necessary. BPZE1, a genetically modified Bordetella pertussis strain, was developed as a live attenuated nasal pertussis vaccine by genetically eliminating or detoxifying 3 toxins. Methods We performed a double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally for the first time to human volunteers, the first trial of a live attenuated bacterial vaccine specifically designed for the respiratory tract. 12 subjects per dose group received 103, 105 or 107 colony-forming units as droplets with half of the dose in each nostril. 12 controls received the diluent. Local and systemic safety and immune responses were assessed during 6 months, and nasopharyngeal colonization with BPZE1 was determined with repeated cultures during the first 4 weeks after vaccination. Results Colonization was seen in one subject in the low dose, one in the medium dose and five in the high dose group. Significant increases in immune responses against pertussis antigens were seen in all colonized subjects. There was one serious adverse event not related to the vaccine. Other adverse events were trivial and occurred with similar frequency in the placebo and vaccine groups. Conclusions BPZE1 is safe in healthy adults and able to transiently colonize the nasopharynx. It induces immune responses in all colonized individuals. BPZE1 can thus undergo further clinical development, including dose optimization and trials in younger age groups. Trial Registration ClinicalTrials.gov NCT01188512 PMID:24421886

  5. NT-07PHASE 1-2 DOSE-ESCALATION STUDY OF VB-111, AN ANTI-ANGIOGENIC GENE THERAPY, AS MONOTHERAPY AND IN COMBINATION WITH BEVACIZUMAB, IN PATIENTS WITH RECURRENT GLIOBLASTOMA

    PubMed Central

    Brenner, Andrew; Cohen, Yael; Vredenburgh, James; Peters, Katherine; Blumenthal, Deborah; Bokstein, Felix; Breitbart, Eyal; Bangio, Livnat; Sher, Naamit; Harats, Dror; Wen, Patrick

    2014-01-01

    BACKGROUND: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. Safety and efficacy of VB-111 alone and in combination with bevacizumab (BEV) were evaluated for patients with recurrent Glioblastoma (rGBM) in this phase 1-2 dose-escalation study. METHODS: VB-111 was administered as a single intravenous infusion at escalating doses from 1x1012 to 1x1013 viral particles (VPs), followed by repeat doses of 3x1012 or 1x1013 every 2 months. The protocol was amended to add-on BEV 10mg/Kg every 2 weeks upon further progression. Assessments included safety, pharmacokinetics, tumor response (RANO criteria) and overall survival (OS). RESULTS: Forty-six patients at 4 recruiting medical centers in the US and Israel received up to 13 repeat doses of VB-111. Of these 30 received the high dose (1x1013). There were 22 related adverse events, 19 CTCAE grade 1-2. The median OS was 360 [range: 70-574] and 266 days [range: 28-664] for patients receiving at least one high dose vs. subjects who received lower doses, respectively (p NS). Progression free survival was 63 vs. 55 days for patients who received high vs. lower doses, respectively (p = 0.01). Median follow-up was 232 days. Six patients had a partial response and/or prolonged disease stability (≥180 days). Tumor growth rates showed a statistically significant dose response. Eleven patients received combination therapy of VB-111 with BEV after progression on VB-111 alone. Median time to second progression was 93 days. VB-111 was safe and well tolerated both as monotherapy and combined therapy. CONCLUSIONS: VB-111 was safe and well tolerated as monotherapy and in combination with BEV in patients with recurrent glioblastoma. Encouraging tumor growth attenuation and responses were seen. Overall survival was about 3 months longer

  6. Dose reconstruction for intensity-modulated radiation therapy using a non-iterative method and portal dose image

    NASA Astrophysics Data System (ADS)

    Yeo, Inhwan Jason; Jung, Jae Won; Chew, Meng; Kim, Jong Oh; Wang, Brian; Di Biase, Steven; Zhu, Yunping; Lee, Dohyung

    2009-09-01

    A straightforward and accurate method was developed to verify the delivery of intensity-modulated radiation therapy (IMRT) and to reconstruct the dose in a patient. The method is based on a computational algorithm that linearly describes the physical relationship between beamlets and dose-scoring voxels in a patient and the dose image from an electronic portal imaging device (EPID). The relationship is expressed in the form of dose response functions (responses) that are quantified using Monte Carlo (MC) particle transport techniques. From the dose information measured by the EPID the received patient dose is reconstructed by inversely solving the algorithm. The unique and novel non-iterative feature of this algorithm sets it apart from many existing dose reconstruction methods in the literature. This study presents the algorithm in detail and validates it experimentally for open and IMRT fields. Responses were first calculated for each beamlet of the selected fields by MC simulation. In-phantom and exit film dosimetry were performed on a flat phantom. Using the calculated responses and the algorithm, the exit film dose was used to inversely reconstruct the in-phantom dose, which was then compared with the measured in-phantom dose. The dose comparison in the phantom for all irradiated fields showed a pass rate of higher than 90% dose points given the criteria of dose difference of 3% and distance to agreement of 3 mm.

  7. A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.

    PubMed

    Grilley-Olson, J E; Bedard, P L; Fasolo, A; Cornfeld, M; Cartee, L; Razak, A R Abdul; Stayner, L-A; Wu, Y; Greenwood, R; Singh, R; Lee, C B; Bendell, J; Burris, H A; Del Conte, G; Sessa, C; Infante, J R

    2016-12-01

    Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

  8. Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: results of a dose de-escalation trial.

    PubMed

    Horan, John T; Haight, Ann; Dioguardi, Jacqueline Lagerlof; Brown, Clark; Grizzle, Audrey; Shelman, Chiani; Kanter, Julie; Hale, Greg; Nieder, Michael; Benton, Melody; Kasow, Kimberly A; Abraham, Allistair; Chiang, Kuang-Yueh

    2015-05-01

    High-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day +28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200 mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted.

  9. Phase I North Central Cancer Treatment Group Trial-N9923 of escalating doses of twice-daily thoracic radiation therapy with amifostine and with alternating chemotherapy in limited stage small-cell lung cancer

    SciTech Connect

    Garces, Yolanda I. . E-mail: garces.yolanda@Mayo.edu; Okuno, Scott H.; Schild, Steven E.; Mandrekar, Sumithra J.; Bot, Brian M.; Martens, John M.; Wender, Donald B.; Soori, Gamini S.; Moore, Dennis F.; Kozelsky, Timothy F.; Jett, James R.

    2007-03-15

    Purpose: The primary goal was to identify the maximum tolerable dose (MTD) of thoracic radiation therapy (TRT) that can be given with chemotherapy and amifostine for patients with limited-stage small-cell lung cancer (LSCLC). Methods and Materials: Treatment began with two cycles of topotecan (1 mg/m{sup 2}) Days 1 to 5 and paclitaxel (175 mg/m{sup 2}) Day 5 (every 3 weeks) given before and after TRT. The TRT began at 6 weeks. The TRT was given in 120 cGy fractions b.i.d. and the dose escalation (from 4,800 cGy, dose level 1, to 6,600 cGy, dose level 4) followed the standard 'cohorts of 3' design. The etoposide (E) (50 mg/day) and cisplatin (C) (3 mg/m{sup 2}) were given i.v. before the morning TRT and amifostine (500 mg/day) was given before the afternoon RT. This was followed by prophylactic cranial irradiation (PCI). The dose-limiting toxicities (DLTs) were defined as Grade {>=}4 hematologic, febrile neutropenia, esophagitis, or other nonhematologic toxicity, Grade {>=}3 dyspnea, or Grade {>=}2 pneumonitis. Results: Fifteen patients were evaluable for the Phase I portion of the trial. No DLTs were seen at dose levels 1 and 2. Two patients on dose level 4 experienced DLTs: 1 patient had a Grade 4 pneumonitis, dyspnea, fatigue, hypokalemia, and anorexia, and 1 patient had a Grade 5 hypoxia attributable to TRT. One of 6 patients on dose level 3 had a DLT, Grade 3 esophagitis. The Grade {>=}3 toxicities seen in at least 10% of patients during TRT were esophagitis (53%), leukopenia (33%), dehydration (20%), neutropenia (13%), and fatigue (13%). The median survival was 14.5 months. Conclusion: The MTD of b.i.d. TRT was 6000 cGy (120 cGy b.i.d.) with EP and amifostine.

  10. Phase I, Dose-Escalation, 2-Part Trial of Poly(ADP-Ribose) Polymerase Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.

    PubMed

    de Bono, Johann; Ramanathan, Ramesh K; Mina, Lida; Chugh, Rashmi; Glaspy, John; Rafii, Saeed; Kaye, Stan; Sachdev, Jasgit; Heymach, John; Smith, David C; Henshaw, Joshua W; Herriott, Ashleigh; Patterson, Miranda; Curtin, Nicola J; Byers, Lauren Averett; Wainberg, Zev A

    2017-02-27

    Talazoparib inhibits poly(ADP-ribose) polymerase (PARP) catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this 2-part, phase I, first-in-human trial. Antitumor activity, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7/14 (50%) and 5/12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.

  11. Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects.

    PubMed

    Stone, Nimalie D; Dunaway, Shelia B; Flexner, Charles; Tierney, Camlin; Calandra, Gary B; Becker, Stephen; Cao, Ying-Jun; Wiggins, Ilene P; Conley, Jeanne; MacFarland, Ron T; Park, Jeong-Gun; Lalama, Christina; Snyder, Sally; Kallungal, Beatrice; Klingman, Karin L; Hendrix, Craig W

    2007-07-01

    AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < or = 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an E(max) model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.

  12. Multiple-dose escalation, safety, and tolerability study of wood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medication, in healthy subjects.

    PubMed

    Kuge, Tomoo; Shibata, Takashi; Willett, Michael S

    2003-03-01

    Seirogan, an herbal medicine containing wood creosote (CAS 8021-39-4), a mixture of simple phenolic compounds, has been marketed for the past century in Asia for the treatment of acute diarrhea and associated symptoms, such as abdominal discomfort and cramping. The present study was designed to assess the safety and tolerability of an anticipated acute antidiarrheal dosing regimen. Sixty healthy males were randomized into five groups of 12 subjects each (9 wood creosote; 3 placebo) to receive 45-, 90-, 135-, 180-, and 225-mg tablets every 2 hours for five doses. Serial sitting and standing vital signs, ECG rhythm strips, and continuous telemetry monitoring were obtained predose and for 24 hours after the first dose. Clinical laboratory tests and 12-lead resting ECGs were obtained predose and 24 hours postdose. Of the subjects, 27% (12/45) receiving wood creosote and 27% (4/15) receiving placebo reported adverse events. The most common adverse events were altered taste and somnolence, reported more often with 180- and 225-mg doses. Wood creosote had no clinically significant effects on vital signs, ECG intervals or interpretations, or clinical laboratory tests. No clinically significant or serious dysrhythmias were reported on continuous telemetry monitoring. It was concluded that oral doses of wood creosote 45 to 225 mg every 2 hours for up to five doses were safe and well tolerated in 45 healthy subjects. Wood creosote doses ranging from 45 to 135 mg per dose, which are commonly administered antidiarrheal doses in Asia, were associated with minimal side effects.

  13. Pharmacodynamics of non-break weekly paclitaxel (Taxol) and pharmacokinetics of Cremophor-EL vehicle: results of a dose-escalation study.

    PubMed

    Briasoulis, Evangelos; Karavasilis, Vasilis; Tzamakou, Eleftheria; Haidou, Constantina; Piperidou, Christina; Pavlidis, Nicholas

    2002-06-01

    We characterized the toxicity and determined the maximum tolerated dose of non-break weekly paclitaxel (Taxol) in chemotherapy-naive cancer patients, and studied pharmacokinetics of the formulation vehicle Cremophor-EL with this schedule. Twenty-three patients with primary refractory solid tumors received weekly paclitaxel at the dose range of 70-200 mg/m2. As dose-limiting toxicity we defined granulocytopenia grade > or =2 causing a treatment delay for more than 2 weeks, or febrile neutropenia or grade >2 organ-specific toxicity. Plasma kinetics of Cremophor-EL were analyzed over the first five courses of treatment. Non-break weekly paclitaxel was feasible at doses up to 110 mg/m2, while granulocytopenia precluded scheduled administration of doses > or =130 mg/m2. Clinically relevant peripheral neurotoxicity tended to occur at around 1500 mg/m2 cumulative dosage at weekly doses > or =110 mg/m2. Detectable Cremophor-EL levels were found in all pre-dose samples, but there was no evidence of accumulation up to the sixth course. Our results, discussed in the light of an overview of published data, suggest that chronic weekly administration of paclitaxel is feasible and with a lack of significant accumulation of Cremophor-EL levels at doses up to 90 mg/m2.

  14. Clinical Application of High-Dose, Image-Guided Intensity-Modulated Radiotherapy in High-Risk Prostate Cancer

    SciTech Connect

    Bayley, Andrew; Rosewall, Tara; Craig, Tim; Bristow, Rob; Chung, Peter; Gospodarowicz, Mary; Menard, Cynthia; Milosevic, Michael; Warde, Padraig; Catton, Charles

    2010-06-01

    Purpose: To report the feasibility and early toxicity of dose-escalated image-guided IMRT to the pelvic lymph nodes (LN), prostate (P), and seminal vesicles (SV). Methods and Materials: A total of 103 high-risk prostate cancer patients received two-phase, dose-escalated, image-guided IMRT with 3 years of androgen deprivation therapy. Clinical target volumes (CTVs) were delineated using computed tomography/magnetic resonance co-registration and included the prostate, portions of the SV, and the LN. Planning target volume margins (PTV) used were as follows: P (10 mm, 7 mm posteriorly), SV (10 mm), and LN (5 mm). Organs at risk (OaR) were the rectal and bladder walls, femoral heads, and large and small bowel. The IMRT was planned with an intended dose of 55.1 Gy in 29 fractions to all CTVs (Phase 1), with P+SV consecutive boost of 24.7 Gy in 13 fractions. Daily online image guidance was performed using bony landmarks and intraprostatic markers. Feasibility criteria included delivery of intended doses in 80% of patients, 95% of CTV displacements incorporated within PTV during Phase 1, and acute toxicity rate comparable to that of lower-dose pelvic techniques. Results: A total of 91 patients (88%) received the total prescription dose. All patients received at least 72 Gy. In Phase 1, 63 patients (61%) received the intended 55.1 Gy, whereas 87% of patients received at least 50 Gy. Dose reductions were caused by small bowel and rectal wall constraints. All CTVs received the planned dose in >95% of treatment fractions. There were no Radiation Therapy Oncology Group acute toxicities greater than Grade 3, although there were five incidences equivalent to Grade 3 within a median follow-up of 23 months. Conclusion: These results suggest that dose escalation to the PLN+P+SV using IMRT is feasible, with acceptable rates of acute toxicity.

  15. A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of 2 and 4 Weeks of Twice-Daily Ocular Trabodenoson in Adults with Ocular Hypertension or Primary Open-Angle Glaucoma

    PubMed Central

    Sall, Kenneth N.; DuBiner, Harvey; Slomowitz, Natanya; McVicar, William; Rich, Cadmus C.; Baumgartner, Rudolf A.

    2016-01-01

    Abstract Purpose: To evaluate the safety and ocular hypotensive efficacy of 4 trabodenoson doses administered twice daily over 14 or 28 days in subjects with ocular hypertension or primary open-angle glaucoma (POAG). Methods: In this multicenter, randomized, double-masked, placebo-controlled, dose-escalation Phase 2 study, patients received unilateral topical twice-daily trabodenoson (50, 100, or 200 mcg) or placebo for 14 days, or 500 mcg trabodenoson or placebo for 28 days. Ocular and systemic safety and tolerability were assessed by examinations, clinical and laboratory studies. Intraocular pressure (IOP) was assessed using Goldmann tonometry. Results: Trabodenoson was well tolerated; no clinically meaningful ocular or systemic side effects were identified. Trabodenoson produced a dose-dependent IOP reduction. IOP reductions in the 500 mcg group were significantly greater than placebo at all time points at Day 28. Mean IOP reductions from diurnal baseline ranged from −3.5 to −5.0 mmHg with a mean change of −4.1 mmHg in the 500 mcg group compared −1.0 to −2.5 mmHg with a mean change of −1.6 mmHg for the placebo group, and the Day 28 drop was significantly greater than at Day 14 (P = 0.0163) indicating improvement in IOP lowering with longer treatment time. IOP remained significantly reduced 24 h after the final 500 mcg dose (P = 0.048). Conclusion: Twice-daily ocular doses of trabodenoson, from 50 to 500 mcg, were well tolerated and showed a dose-related decrease in IOP that was statistically significant and clinically relevant at 500 mcg in patients with ocular hypertension or POAG. PMID:27002298

  16. High dose intensity combination chemotherapy for advanced epithelial ovarian carcinoma: results of a pilot study.

    PubMed Central

    Sweetenham, J. W.; McKendrick, J. J.; Jones, D. H.; Whitehouse, J. M.; Williams, C. J.

    1990-01-01

    Retrospective studies have recently demonstrated a significant correlation between dose intensity of chemotherapy and response rates and survival in various diseases including epithelial ovarian carcinoma. As part of a proposed randomised trial to assess the effect of dose intensity on outcome in ovarian carcinoma, a pilot study has been undertaken to determine the toxicity and efficacy of the high intensity therapy. Nineteen patients with advanced ovarian carcinoma received initial treatment with cisplatin 120 mg m-2 i.v. day 1, and cyclophosphamide 1,000 mg-2 i.v. day 1, given at 21-day intervals for six cycles. The average relative dose intensity of this therapy is 1.14 when compared with the CHAP regimen. Severe toxicity was experienced by most patients. The median received average relative dose intensity was 0.90, with only one patient receiving treatment to the proposed intensity. Randomised studies of the effect of dose intensity in ovarian carcinoma are essential, but an initial step must be to assess whether the proposed high dose treatment can be delivered. PMID:2155645

  17. A weekly regimen with dose escalation of doxorubicin for patients with advanced Hodgkin's lymphoma: results of a phase II study of the Groupe d'Etudes des Lymphomes de l'Adulte (GELA).

    PubMed

    Fermé, Christophe; Brice, Pauline; Michallet, Anne-Sophie; Lederlin, Pierre; Diviné, Marine; Casasnovas, Olivier; Devidas, Alain; Anglaret, Bruno; Cazals-Hatem, Dominique; Mounier, Nicolas

    2007-04-01

    This multicenter phase II study assessed the feasibility and efficacy of a weekly chemotherapy regimen with a moderately escalated dose of doxorubicin administered over 16 weeks, followed by radiation therapy (RT) to bulky sites. From July 1996 to February 1998, 44 untreated patients with stage IIIB-IV Hodgkin's lymphoma (HL), and 0 - 2 risk factors described by the Memorial Sloan-Kettering Cancer Center, were treated. Chemotherapy was a combination of increased-dose doxorubicin with conventional doses of cyclophosphamide, vinblastine, prednisone, vindesine, bleomycin, and etoposide. Patients received four cycles of the weekly regimen for 16 weeks. Forty-one patients received the planned four cycles of chemotherapy, and RT was delivered to 36 patients. The incidence of WHO grade 3 - 4 neutropenia was 90%. A total of 39 patients achieved a complete remission (88.6%). The median follow-up was 95 months. The 7-years freedom from treatment failure and overall survival estimates were 57% (95% confidence interval (CI), 41% - 70%), and 93% (95% CI, 80 - 98%), respectively. The relapse rate was related to the short duration of chemotherapy, and the failure to prevent relapses with consolidation RT. In this study population the 16-week regimen and RT to bulky sites were not sufficient for disease control.

  18. A prospective, single-blind, multicenter, dose escalation study of intracoronary iNOS lipoplex (CAR-MP583) gene therapy for the prevention of restenosis in patients with de novo or restenotic coronary artery lesion (REGENT I extension).

    PubMed

    von der Leyen, Heiko E; Mügge, Andreas; Hanefeld, Christoph; Hamm, Christian W; Rau, Mathias; Rupprecht, Hans J; Zeiher, Andreas M; Fichtlscherer, Stephan

    2011-08-01

    Neointimal hyperplasia causing recurrent stenosis is a limitation of the clinical utility of percutaneous transluminal coronary interventions (PCI). Nitric oxide (NO) inhibits smooth muscle cell proliferation, platelet activation, and inflammatory responses, all of which have been implicated in the pathogenesis of restenosis. In animals, neointimal proliferation after balloon injury has been shown to be effectively reduced by gene transfer of the inducible NO synthase (iNOS). The primary objective of this first multicenter, prospective, single-blind, dose escalation study was to obtain safety and tolerability information of the iNOS lipoplex (CAR-MP583) gene therapy for reducing restenosis following PCI. Local coronary intramural CAR-MP583 delivery was achieved using the Infiltrator balloon catheter. A total of 30 patients were treated in the study (six patients, 0.5 μg; six patients, 2.0 μg; six patients, 5.0 μg; and 12 patients, 10 μg). There were no complications related to local application of CAR-MP583. In one patient, PCI procedure-related transient vessel occlusion occurred with consecutive troponin elevation. There were no signs of inflammatory responses or hepatic or renal toxicity. No dose relationship was seen with regard to adverse events across the dose groups. Thus, coronary intramural lipoplex-enhanced iNOS gene therapy during PCI is feasible and appears to be safe. These initial clinical results are encouraging to support further clinical research, in particular in conjunction with new local drug delivery technologies.

  19. Phase I dose-escalation study of the thioxanthone SR271425 administered intravenously once every 3 weeks in patients with advanced malignancies

    PubMed Central

    Goncalves, Priscila H.; High, Francine; Juniewicz, Paul; Shackleton, Gareth; Li, Jing; Boerner, Scott

    2013-01-01

    Summary This study was performed to determine the dose limiting toxicity (DLT), the recommended phase II dose and the pharmacokinetic profile for SR271425, given over 1 h every 3 weeks. The initial starting dose of SR271425 was 17 mg/m2. Patient selection was based on common phase I criteria as well as additional cardiac criteria. Thirty-eight patients were accrued to 16 dose levels from 17 to 1,320 mg/m2. Patient characteristics included 24 males and 14 females ages 35–78 with an Eastern Cooperative Oncology Group performance status of 0 (ten patients), 1 (27) and 2 (1). Tumor types were typical for a phase I study. The maximum administered dose was 1,320 mg/m2 with two DLTs, both QTc grade 3 prolongation. No drug related hematological toxicity was noted. Grade 1 toxicities included rash, flushing, pruritus, weight loss, diarrhea, hypertension and fatigue. Grade 2 toxicities included yellow discoloration of the skin, nausea and vomiting. QTc prolongation and hyperbilirubinemia were the only grade 3 toxicities noted. No confirmed tumor response was observed; however, two patients had prolonged stable disease. Both Cend and area under the plasma concentration– time curve increased in a dose related manner. Plasma drug concentrations declined in a biphasic manner with a mean terminal elimination half-life (t1/2) of 7.1 h (±1.3). There was no change in clearance or volume of distribution over the dose range studied. Due to cardiac toxicity occurring with both the parent compound, SR233377, as well as this analog, this series of agents was abandoned from further clinical development. PMID:18449472

  20. An Exploratory Dose-Escalating Study Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous Atacicept in Patients with Systemic Lupus Erythematosus

    PubMed Central

    Pena-Rossi, C; Nasonov, E; Stanislav, M; Yakusevich, V; Ershova, O; Lomareva, N; Saunders, H; Hill, J; Nestorov, I

    2009-01-01

    Atacicept, a recombinant fusion protein containing the extracellular, ligand-binding portion of the transmembrane activator and calcium modulator and cyclophilin-ligand interactor receptor, and the Fc portion of human immunoglobulin (Ig) G, is designed to block the activity of B-lymphocyte stimulator and a proliferation-inducing ligand, and may have utility as a treatment for B-cellmediated diseases, such as systemic lupus erythematosus (SLE). This Phase Ib study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of intravenous (i.v.) atacicept in patients with mild-to-moderate SLE. Patients (n = 24) were randomised (5:1) to receive atacicept (single dose: 3, 9 or 18 mg/kg; or multiple dose: 2 × 9 mg/kg) or matching placebo. Patients were followed for 6 weeks after dosing (9 weeks in the 2 × 9 mg/kg cohort). Local tolerability of atacicept was comparable with that of placebo, with only mild injection-site reactions reported with atacicept. Atacicept i.v. was generally well tolerated, both systemically and locally, in patients with mild-to-moderate SLE. Atacicept displayed non-linear PK, which was predictable across doses and between single and repeat doses. The biological activity of atacicept was demonstrated by its marked effect in reducing B-cells and Ig levels in patients with SLE. This supports the utility of this therapeutic approach in the treatment of autoimmune diseases, such as SLE. PMID:19395457

  1. Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy

    PubMed Central

    Park, Haeseong; Garrido-Laguna, Ignacio; Naing, Aung; Fu, Siqing; Falchook, Gerald S.; Piha-Paul, Sarina A.; Wheler, Jennifer J.; Hong, David S.; Tsimberidou, Apostolia M.; Subbiah, Vivek; Zinner, Ralph G.; Kaseb, Ahmed O.; Patel, Shreyaskumar; Fanale, Michelle A.; Velez-Bravo, Vivianne M.; Meric-Bernstam, Funda; Kurzrock, Razelle; Janku, Filip

    2016-01-01

    Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (−78%) and perivascular epithelioid tumor (−54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma. PMID:27589687

  2. Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies

    PubMed Central

    Puzanov, Igor; LoRusso, Patricia M.; Cohen, Roger B.; Morris, John C.; Olowokure, Olugbenga O.; Yin, Jian Y.; Doroumian, Séverine; Shen, Liji; Olszanski, Anthony J.

    2015-01-01

    Taxane–gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15–20 mg/m2) before (part 1a) or after (part 1b) gemcitabine (700–1000 mg/m2) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m2 cabazitaxel plus 1000 mg/m2 gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3–4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation. PMID:26020806

  3. Phase Ib Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Patients with Barrett’s Esophagus

    PubMed Central

    Joe, Andrew K.; Schnoll-Sussman, Felice; Bresalier, Robert S.; Abrams, Julian A.; Hibshoosh, Hanina; Cheung, Ken; Friedman, Richard A.; Yang, Chung S.; Milne, Ginger L.; Liu, Diane D.; Lee, J. Jack; Abdul, Kazeem; Bigg, Michelle; Foreman, Jessica; Su, Tao; Wang, Xiaomei; Ahmed, Aqeel; Neugut, Alfred I.; Akpa, Esther; Lippman, Scott M.; Perloff, Marjorie; Brown, Powel H.; Lightdale, Charles J.

    2015-01-01

    This study was conducted to determine the safety and efficacy of the green-tea derived Polyphenon E (Poly E) in patients with Barrett’s Esophagus (BE). Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200 mg, 400 mg, or 600 mg). Endoscopic evaluation, including biopsies, was performed before and after treatment. The primary objective was to demonstrate safety; secondary objectives investigated catechin accumulation and effects in clinical specimens. Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached. The recommended phase 2 dose was 600 mg BID. The most common treatment-related adverse events (AEs) in Poly E-treated subjects were grade 1–2 nausea, grade 1 belching, and grade 1 LDH elevation. No treatment-related AEs were reported in placebo-treated subjects, aside from grade 1 laboratory abnormalities. Pill counts and subject diaries were not consistently collected, and compliance was difficult to determine. However, based on an intention-to-treat analysis there was a significant relationship between Poly E dose and esophageal EGCG level – mean changes (pmol/g) of 0.79 (placebo), 6.06 (200 mg), 35.67 (400 mg), and 34.95 (600 mg); p=0.005. There was a possible relationship between Poly E dose and urine PGE-M concentration. In conclusion, Poly E was well-tolerated, and treatment with Poly E (400 mg and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa. PMID:26471236

  4. A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors.

    PubMed

    Adjei, Alex A; LoRusso, Patricia; Ribas, Antoni; Sosman, Jeffrey A; Pavlick, Anna; Dy, Grace K; Zhou, Xiaofei; Gangolli, Esha; Kneissl, Michelle; Faucette, Stephanie; Neuwirth, Rachel; Bózon, Viviana

    2017-02-01

    Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned.

  5. Exploring the dose-response relationship between resistance exercise intensity and cognitive function.

    PubMed

    Chang, Yu-Kai; Etnier, Jennifer L

    2009-10-01

    The purpose of this study was to explore the dose-response relationship between resistance exercise intensity and cognitive performance. Sixty-eight participants were randomly assigned into control, 40%, 70%, or 100% of 10-repetition maximal resistance exercise groups. Participants were tested on Day 1 (baseline) and on Day 2 (measures were taken relative to performance of the treatment). Heart rate, ratings of perceived exertion, self-reported arousal, and affect were assessed on both days. Cognitive performance was assessed on Day 1 and before and following treatment on Day 2. Results from regression analyses indicated that there is a significant linear effect of exercise intensity on information processing speed, and a significant quadratic trend for exercise intensity on executive function. Thus, there is a dose-response relationship between the intensity of resistance exercise and cognitive performance such that high-intensity exercise benefits speed of processing, but moderate intensity exercise is most beneficial for executive function.

  6. Radiochromic film based transit dosimetry for verification of dose delivery with intensity modulated radiotherapy

    SciTech Connect

    Chung, Kwangzoo; Lee, Kiho; Shin, Dongho; Kyung Lim, Young; Byeong Lee, Se; Yoon, Myonggeun; Son, Jaeman; Yong Park, Sung

    2013-02-15

    Purpose: To evaluate the transit dose based patient specific quality assurance (QA) of intensity modulated radiation therapy (IMRT) for verification of the accuracy of dose delivered to the patient. Methods: Five IMRT plans were selected and utilized to irradiate a homogeneous plastic water phantom and an inhomogeneous anthropomorphic phantom. The transit dose distribution was measured with radiochromic film and was compared with the computed dose map on the same plane using a gamma index with a 3% dose and a 3 mm distance-to-dose agreement tolerance limit. Results: While the average gamma index for comparisons of dose distributions was less than one for 98.9% of all pixels from the transit dose with the homogeneous phantom, the passing rate was reduced to 95.0% for the transit dose with the inhomogeneous phantom. Transit doses due to a 5 mm setup error may cause up to a 50% failure rate of the gamma index. Conclusions: Transit dose based IMRT QA may be superior to the traditional QA method since the former can show whether the inhomogeneity correction algorithm from TPS is accurate. In addition, transit dose based IMRT QA can be used to verify the accuracy of the dose delivered to the patient during treatment by revealing significant increases in the failure rate of the gamma index resulting from errors in patient positioning during treatment.

  7. Acute and Late Toxicity After Dose Escalation to 82 GyE Using Conformal Proton Radiation for Localized Prostate Cancer: Initial Report of American College of Radiology Phase II Study 03-12

    SciTech Connect

    Coen, John J.; Bae, Kyounghwa; Zietman, Anthony L.; Patel, Baldev; Shipley, William U.; Slater, Jerry D.; Rossi, Carl J.

    2011-11-15

    Purpose: Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation. Methods and Materials: From 2003-2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. The study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%. Results: The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%. Conclusions: Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation.

  8. Pharmacokinetics and Dose Escalation of the Heat Shock Protein Inhibitor 17-AAG in Combination with Bortezomib in Relapsed or Refractory Acute Myeloid Leukemia

    PubMed Central

    Walker, Alison R.; Klisovic, Rebecca; Johnston, Jeffrey S.; Jiang, Yao; Geyer, Susan; Kefauver, Cheryl; Binkley, Philip; Byrd, John C.; Grever, Michael R.; Garzon, Ramiro; Phelps, Mitch A.; Marcucci, Guido; Blum, Kristie A.; Blum, William

    2013-01-01

    This phase I study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) in combination with bortezomib, and to provide pharmacokinetic data in relapsed or refractory acute myeloid leukemia (AML). Eleven patients were enrolled. The MTD was 17-AAG 150mg/m2 and bortezomib 0.7mg/m2. Hepatic toxicity and cardiac toxicity were dose limiting. Co-administration on day 4 led to a decrease in clearance (p=0.005) and increase in AUC (p=.032) of 17-amino-17-demethoxygeldanamycin (17-AG) not observed when 17-AAG was administered alone. Pharmacokinetic parameters of patients who developed toxicities and those who did not were not different. The combination of 17-AAG and bortezomib led to toxicity without measurable response in patients with relapsed or refractory AML. Pharmacokinetic data provide insight for studies of related agents in AML; next generation HSP90 inhibitors are appealing for further development in this area. PMID:23256542

  9. Prolongation of Total Treatment Time Because of Infrequently Missed Days of Treatment Is Not Associated With Inferior Biochemical Outcome After Dose-Escalated Radiation Therapy for Prostate Cancer

    SciTech Connect

    Liauw, Stanley L.; Liauw, Sun H.

    2011-11-01

    Purpose: Prolongation of treatment time with radiation therapy (RT) is associated with inferior disease control for many rapidly proliferating tumors, but it is uncertain whether the same effect is seen in prostate cancer. Methods and Materials: 596 patients underwent with curative-intent RT for adenocarcinoma of the prostate. By National Comprehensive Cancer Network criteria, men were classified as having low-risk (30%), medium-risk (40%), or high-risk (30%) disease. The median RT dose was 72 Gy. Androgen-deprivation therapy (ADT) was used in 45%. The idealized treatment time was defined as the total elapsed time (including weekends) to complete treatment if started on a Monday. Missed days of treatment, defined as the number of days beyond the idealized treatment time, was recorded for all patients. Missed days were added to the end of therapy resulting in a longer treatment time. Analysis was conducted for missed days and other standard prognostic variables against freedom from biochemical failure (FFBF). Results: The median number of missed days was 2 (range, -3 to 22). With a median follow-up of 51 months, men with 5 or more missed days had similar 4-year FFBF rates (79% vs. 83% in men with <5 missed days, p = 0.0809), especially in the subset of men receiving 74 Gy or greater (89% for both groups, p = 0.8008). Analysis of missed days was performed for the subsets of dose, ADT, and risk category. Men without ADT had a lower FFBF rate with more missed days (p = 0.0030), but this association was not seen in men treated to a dose of 74 Gy or greater (p = 0.7425). On multivariate analysis, dose (p = 0.0010), T stage (p = 0.0145), and prostate-specific antigen level (p < 0.0001) were associated with FFBF, but Gleason score (p = 0.1351) and missed days (p = 0.3767) were not. Conclusions: Slight prolongation of treatment time (e.g., {<=}7 days) was not associated with inferior FFBF, especially in men receiving an RT dose of 74 Gy or greater.

  10. Initial Results of a Phase I Dose-Escalation Trial of Concurrent and Maintenance Erlotinib and Reirradiation for Recurrent and New Primary Head-and-Neck Cancer

    SciTech Connect

    Rusthoven, Kyle E.; Feigenberg, Steven J.; Raben, David; Kane, Madeleine; Song, John I.; Nicolaou, Nicos; Mehra, Ranee; Burtness, Barbara; Ridge, John; Swing, Robyn; Lango, Miriam; Cohen, Roger; Jimeno, Antonio; Chen Changhu

    2010-11-15

    Purpose: To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC). Methods and Materials: Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinib started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days. Results: Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis. Conclusions: Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible.

  11. A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients

    PubMed Central

    Fava, M; Johe, K; Ereshefsky, L; Gertsik, L G; English, B A; Bilello, J A; Thurmond, L M; Johnstone, J; Dickerson, B C; Makris, N; Hoeppner, B B; Flynn, M; Mischoulon, D; Kinrys, G; Freeman, M P

    2016-01-01

    We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4–20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions—Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort. PMID:26643541

  12. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: A Phase I/II dose-escalation study

    SciTech Connect

    Tsuji, Hiroshi . E-mail: h_tsuji@nirs.go.jp; Ishikawa, Hitoshi; Yanagi, Takeshi; Hirasawa, Naoki; Kamada, Tadashi; Mizoe, Jun-Etsu; Kanai, Tatsuaki; Tsujii, Hirohiko; Ohnishi, Yoshitaka

    2007-03-01

    Purpose: To evaluate the applicability of carbon ion beams for the treatment of choroidal melanoma with regard to normal tissue morbidity and local tumor control. Methods and Materials: Between January 2001 and February 2006, 59 patients with locally advanced or unfavorably located choroidal melanoma were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy at the National Institute of Radiologic Sciences. The primary endpoint of this study was normal tissue morbidity, and secondary endpoints were local tumor control and patient survival. Of the 59 subjects enrolled, 57 were followed >6 months and analyzed. Results: Twenty-three patients (40%) developed neovascular glaucoma, and three underwent enucleation for eye pain due to elevated intraocular pressure. Incidence of neovascular glaucoma was dependent on tumor size and site. Five patients had died at analysis, three of distant metastasis and two of concurrent disease. All but one patient, who developed marginal recurrence, were controlled locally. Six patients developed distant metastasis, five in the liver and one in the lung. Three-year overall survival, disease-free survival, and local control rates were 88.2%, 84.8%, and 97.4%, respectively. No apparent dose-response relationship was observed in either tumor control or normal tissue morbidity at the dose range applied. Conclusion: Carbon-ion radiotherapy can be applied to choroidal melanoma with an acceptable morbidity and sufficient antitumor effect, even with tumors of unfavorable size or site.

  13. Phase 1/2 open-label dose-escalation study of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with painful diabetic peripheral neuropathy.

    PubMed

    Ajroud-Driss, Senda; Christiansen, Mark; Allen, Jeffrey A; Kessler, John A

    2013-06-01

    This study aimed to evaluate the safety and preliminary efficacy of intramuscular injections of plasmid DNA (VM202) expressing two isoforms of hepatocyte growth factor (HGF) in subjects with painful diabetic peripheral neuropathy (PDPN). Twelve patients in three cohorts (4, 8, and 16 mg) received two sets of VM202 injections separated by two weeks. Safety and tolerability were evaluated and the visual analog scale (VAS), the short form McGill questionnaire (SF-MPQ), and the brief pain inventory for patients with diabetic peripheral neuropathy (BPI-DPN) measured pain level throughout 12 months after treatment. No serious adverse events (AEs) were observed. The mean VAS was reduced from baseline by 47.2% (P = 0.002) at 6 months and by 44.1% (P = 0.005) at 12 months after treatment. The VAS scores for the 4, 8, and 16 mg dose cohorts at 6 months follow-up decreased in a dose-responsive manner, by 21% (P = 0.971), 53% (P = 0.014), and 62% (P = 0.001), respectively. The results with the BPI-DPN and SF-MPQ showed patterns similar to the VAS scores. In conclusion, VM202 treatment appeared to be safe, well tolerated, and sufficient to provide long term symptomatic relief and improvement in the quality of life in patients with PDPN.

  14. Preventing and Responding to Student Escalation: Combining De-Escalation Strategies and Function-Based Support

    ERIC Educational Resources Information Center

    Martel, Chelsea; Cavanaugh, Brian

    2016-01-01

    Preventing and responding to intense problem behavior in schools has garnered increased attention. With recent attention focused on the restraint and seclusion of students with disabilities, educators are in need of effective ways to respond to student escalations that result in severe, disruptive problem behavior. By combining the research-based…

  15. Safety and immunogenicity of a mutagenized, live attenuated Rift Valley fever vaccine, MP-12, in a Phase 1 dose escalation and route comparison study in humans.

    PubMed

    Pittman, Phillip R; McClain, David; Quinn, Xiaofei; Coonan, Kevin M; Mangiafico, Joseph; Makuch, Richard S; Morrill, John; Peters, Clarence J

    2016-01-20

    Rift Valley fever (RVF) poses a risk as a potential agent in bioterrorism or agroterrorism. A live attenuated RVF vaccine (RVF MP-12) has been shown to be safe and protective in animals and showed promise in two initial clinical trials. In the present study, healthy adult human volunteers (N=56) received a single injection of (a) RVF MP-12, administered subcutaneously (SQ) at a concentration of 10(4.7) plaque-forming units (pfu) (SQ Group); (b) RVF MP-12, administered intramuscularly (IM) at 10(3.4)pfu (IM Group 1); (c) RVF MP-12, administered IM at 10(4.4)pfu (IM Group 2); or (d) saline (Placebo Group). The vaccine was well tolerated by volunteers in all dose and route groups. Infrequent and minor adverse events were seen among recipients of both placebo and RVF MP-12. One subject had viremia detectable by direct plaque assay, and six subjects from IM Group 2 had transient low-titer viremia detectable only by nucleic acid amplification. Of the 43 vaccine recipients, 40 (93%) achieved neutralizing antibodies (measured as an 80% plaque reduction neutralization titer [PRNT80]) as well as RVF-specific IgM and IgG. The highest peak geometric mean PRNT80 titers were observed in IM Group 2. Of 34 RVF MP-12 recipients available for testing 1 year following inoculation, 28 (82%) remained seropositive (PRNT80≥1:20); this included 20 of 23 vaccinees (87%) from IM Group 2. The live attenuated RVF MP-12 vaccine was safe and immunogenic at the doses and routes studied. Given the need for an effective vaccine against RVF virus, further evaluation in humans is warranted.

  16. Incorporation of gantry angle correction for 3D dose prediction in intensity-modulated radiation therapy

    PubMed Central

    Sumida, Iori; Yamaguchi, Hajime; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yamada, Yuji; Yagi, Masashi; Ogawa, Kazuhiko

    2015-01-01

    Pretreatment dose verification with beam-by-beam analysis for intensity-modulated radiation therapy (IMRT) is commonly performed with a gantry angle of 0° using a 2D diode detector array. Any changes in multileaf collimator (MLC) position between the actual treatment gantry angle and 0° may result in deviations from the planned dose. We evaluated the effects of MLC positioning errors between the actual treatment gantry angles and nominal gantry angles. A gantry angle correction (GAC) factor was generated by performing a non-gap test at various gantry angles using an electronic portal imaging device (EPID). To convert pixel intensity to dose at the MLC abutment positions, a non-gap test was performed using an EPID and a film at 0° gantry angle. We then assessed the correlations between pixel intensities and doses. Beam-by-beam analyses for 15 prostate IMRT cases as patient-specific quality assurance were performed with a 2D diode detector array at 0° gantry angle to determine the relative dose error for each beam. The resulting relative dose error with or without GAC was added back to the original dose grid for each beam. We compared the predicted dose distributions with or without GAC for film measurements to validate GAC effects. A gamma pass rate with a tolerance of 2%/2 mm was used to evaluate these dose distributions. The gamma pass rate with GAC was higher than that without GAC (P = 0.01). The predicted dose distribution improved with GAC, although the dosimetric effect to a patient was minimal. PMID:25742866

  17. Incorporation of gantry angle correction for 3D dose prediction in intensity-modulated radiation therapy.

    PubMed

    Sumida, Iori; Yamaguchi, Hajime; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yamada, Yuji; Yagi, Masashi; Ogawa, Kazuhiko

    2015-05-01

    Pretreatment dose verification with beam-by-beam analysis for intensity-modulated radiation therapy (IMRT) is commonly performed with a gantry angle of 0° using a 2D diode detector array. Any changes in multileaf collimator (MLC) position between the actual treatment gantry angle and 0° may result in deviations from the planned dose. We evaluated the effects of MLC positioning errors between the actual treatment gantry angles and nominal gantry angles. A gantry angle correction (GAC) factor was generated by performing a non-gap test at various gantry angles using an electronic portal imaging device (EPID). To convert pixel intensity to dose at the MLC abutment positions, a non-gap test was performed using an EPID and a film at 0° gantry angle. We then assessed the correlations between pixel intensities and doses. Beam-by-beam analyses for 15 prostate IMRT cases as patient-specific quality assurance were performed with a 2D diode detector array at 0° gantry angle to determine the relative dose error for each beam. The resulting relative dose error with or without GAC was added back to the original dose grid for each beam. We compared the predicted dose distributions with or without GAC for film measurements to validate GAC effects. A gamma pass rate with a tolerance of 2%/2 mm was used to evaluate these dose distributions. The gamma pass rate with GAC was higher than that without GAC (P = 0.01). The predicted dose distribution improved with GAC, although the dosimetric effect to a patient was minimal.

  18. 70 Gy Versus 80 Gy in Localized Prostate Cancer: 5-Year Results of GETUG 06 Randomized Trial;Prostate cancer; Dose escalation; Conformal radiotherapy; Randomized trial

    SciTech Connect

    Beckendorf, Veronique; Guerif, Stephane; Le Prise, Elisabeth; Cosset, Jean-Marc; Bougnoux, Agnes; Chauvet, Bruno; Salem, Naji; Chapet, Olivier; Bourdain, Sylvain; Bachaud, Jean-Marc; Maingon, Philippe; Hannoun-Levi, Jean-Michel; Malissard, Luc; Simon, Jean-Marc; Pommier, Pascal; Hay, Men; Dubray, Bernard; Lagrange, Jean-Leon; Luporsi, Elisabeth; Bey, Pierre

    2011-07-15

    Purpose: To perform a randomized trial comparing 70 and 80 Gy radiotherapy for prostate cancer. Patients and Methods: A total of 306 patients with localized prostate cancer were randomized. No androgen deprivation was allowed. The primary endpoint was biochemical relapse according to the modified 1997-American Society for Therapeutic Radiology and Oncology and Phoenix definitions. Toxicity was graded using the Radiation Therapy Oncology Group 1991 criteria and the late effects on normal tissues-subjective, objective, management, analytic scales (LENT-SOMA) scales. The patients' quality of life was scored using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item cancer-specific and 25-item prostate-specific modules. Results: The median follow-up was 61 months. According to the 1997-American Society for Therapeutic Radiology and Oncology definition, the 5-year biochemical relapse rate was 39% and 28% in the 70- and 80-Gy arms, respectively (p = .036). Using the Phoenix definition, the 5-year biochemical relapse rate was 32% and 23.5%, respectively (p = .09). The subgroup analysis showed a better biochemical outcome for the higher dose group with an initial prostate-specific antigen level >15 ng/mL. At the last follow-up date, 26 patients had died, 10 of their disease and none of toxicity, with no differences between the two arms. According to the Radiation Therapy Oncology Group scale, the Grade 2 or greater rectal toxicity rate was 14% and 19.5% for the 70- and 80-Gy arms (p = .22), respectively. The Grade 2 or greater urinary toxicity was 10% at 70 Gy and 17.5% at 80 Gy (p = .046). Similar results were observed using the LENT-SOMA scale. Bladder toxicity was more frequent at 80 Gy than at 70 Gy (p = .039). The quality-of-life questionnaire results before and 5 years after treatment were available for 103 patients with no differences found between the 70- and 80-Gy arms. Conclusion: High-dose radiotherapy provided a

  19. A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic

    PubMed Central

    Buda, Jeffrey J; Carroll, F I; Kosten, Thomas R; Swearingen, Dennis; Walters, Bradford B

    2015-01-01

    Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1–6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect. PMID:25628006

  20. Quality assurance for radiotherapy in prostate cancer: Point dose measurements in intensity modulated fields with large dose gradients

    SciTech Connect

    Escude, Lluis . E-mail: lluis.escude@gmx.net; Linero, Dolors; Molla, Meritxell; Miralbell, Raymond

    2006-11-15

    Purpose: We aimed to evaluate an optimization algorithm designed to find the most favorable points to position an ionization chamber (IC) for quality assurance dose measurements of patients treated for prostate cancer with intensity-modulated radiotherapy (IMRT) and fields up to 10 cm x 10 cm. Methods and Materials: Three cylindrical ICs (PTW, Freiburg, Germany) were used with volumes of 0.6 cc, 0.125 cc, and 0.015 cc. Dose measurements were made in a plastic phantom (PMMA) at 287 optimized points. An algorithm was designed to search for points with the lowest dose gradient. Measurements were made also at 39 nonoptimized points. Results were normalized to a reference homogeneous field introducing a dose ratio factor, which allowed us to compare measured vs. calculated values as percentile dose ratio factor deviations {delta}F (%). A tolerance range of {delta}F (%) of {+-}3% was considered. Results: Half of the {delta}F (%) values obtained at nonoptimized points were outside the acceptable range. Values at optimized points were widely spread for the largest IC (i.e., 60% of the results outside the tolerance range), whereas for the two small-volume ICs, only 14.6% of the results were outside the tolerance interval. No differences were observed when comparing the two small ICs. Conclusions: The presented optimization algorithm is a useful tool to determine the best IC in-field position for optimal dose measurement conditions. A good agreement between calculated and measured doses can be obtained by positioning small volume chambers at carefully selected points in the field. Large chambers may be unreliable even in optimized points for IMRT fields {<=}10 cm x 10 cm.

  1. Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome

    PubMed Central

    Raza, Azra; Galili, Naomi; Callander, Natalie; Ochoa, Leonel; Piro, Lawrence; Emanuel, Peter; Williams, Stephanie; Burris, Howard; Faderl, Stefan; Estrov, Zeev; Curtin, Peter; Larson, Richard A; Keck, James G; Jones, Marsha; Meng, Lisa; Brown, Gail L

    2009-01-01

    Background Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle. Results 54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed. Conclusion Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development. Trial Registration Clinicaltrials.gov: NCT00035867 PMID:19439093

  2. SU-E-T-802: Verification of Implanted Cardiac Pacemaker Doses in Intensity-Modulated Radiation Therapy: Dose Prediction Accuracy and Reduction Effect of a Lead Sheet

    SciTech Connect

    Lee, J; Chung, J

    2015-06-15

    Purpose: To verify delivered doses on the implanted cardiac pacemaker, predicted doses with and without dose reduction method were verified using the MOSFET detectors in terms of beam delivery and dose calculation techniques in intensity-modulated radiation therapy (IMRT). Methods: The pacemaker doses for a patient with a tongue cancer were predicted according to the beam delivery methods [step-and-shoot (SS) and sliding window (SW)], intensity levels for dose optimization, and dose calculation algorithms. Dosimetric effects on the pacemaker were calculated three dose engines: pencil-beam convolution (PBC), analytical anisotropic algorithm (AAA), and Acuros-XB. A lead shield of 2 mm thickness was designed for minimizing irradiated doses to the pacemaker. Dose variations affected by the heterogeneous material properties of the pacemaker and effectiveness of the lead shield were predicted by the Acuros-XB. Dose prediction accuracy and the feasibility of the dose reduction strategy were verified based on the measured skin doses right above the pacemaker using mosfet detectors during the radiation treatment. Results: The Acuros-XB showed underestimated skin doses and overestimated doses by the lead-shield effect, even though the lower dose disagreement was observed. It led to improved dose prediction with higher intensity level of dose optimization in IMRT. The dedicated tertiary lead sheet effectively achieved reduction of pacemaker dose up to 60%. Conclusion: The current SS technique could deliver lower scattered doses than recommendation criteria, however, use of the lead sheet contributed to reduce scattered doses.Thin lead plate can be a useful tertiary shielder and it could not acuse malfunction or electrical damage of the implanted pacemaker in IMRT. It is required to estimate more accurate scattered doses of the patient with medical device to design proper dose reduction strategy.

  3. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer

    PubMed Central

    Scholz, Mark; Yep, Sabrina; Chancey, Micah; Kelly, Colleen; Chau, Ken; Turner, Jeffrey; Lam, Richard; Drake, Charles G

    2017-01-01

    Background Sipuleucel-T (SIP-T), which functions by stimulating cancer-specific dendritic cells, prolongs survival in men with prostate cancer. Ipilimumab (IPI) achieved a borderline survival advantage in a large randomized trial. SIP-T and IPI are potentially synergistic. Patients and Methods Nine men with progressive metastatic castrate-resistant prostate cancer (mCRPC) were treated prospectively with SIP-T followed immediately by IPI with one of the following doses of IPI: 1 mg/kg at 1 week after SIP-T; 1 mg/kg at 1 and 4 weeks after SIP-T; or 1 mg/kg at 1, 4, and 7 weeks after SIP-T. Three patients were evaluated at each level. Cancer-specific immunoglobulins directed at granulocyte-macrophage-colony-stimulating factor/prostatic acid phosphatase (PAP) fusion protein (PA2024) and PAP were measured prior to SIP-T, after SIP-T, 1 week after IPI, every other month for 5 months, then every 3 months for an additional 12 months. Results Adverse events of SIP-T were consistent with previous reports. IPI only caused a transient grade 1 rash in one patient. Median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively. Eight men had bone metastases and one had lymph node metastasis. Statistically significant increases in serum immunoglobulin G (IgG) and IgG-IgM specific for PA2024 and PAP occurred after SIP-T. An additional statistically significant increase in the aforementioned immunoglobulins – above the levels achieved by SIP-T – occurred after IPI. Median clinical follow-up was 36 months (range: 26–40). Three patients died from progressive disease after 9, 18, and 20 months. Out of the remaining six patients, five of them needed further treatment that included abiraterone acetate, enzalutamide, radium-223 dichloride, and spot radiation. One patient had an undetectable PSA, who did not receive any other treatment except spot radiation. Median PSA at last follow-up for the surviving patients was 3.8 (range: 0.6

  4. [Intensity-modulated radiotherapy for head and neck cancer. Dose constraint for salivary gland and mandible].

    PubMed

    Pointreau, Y; Lizée, T; Bensadoun, R-J; Boisselier, P; Racadot, S; Thariat, J; Graff, P

    2016-10-01

    Intensity-modulated radiation therapy (IMRT) is the gold standard for head and neck irradiation. It allows better protection to the organs at risk such as salivary glands and mandible, and can reduce the frequency of xerostomia, trismus and osteoradionecrosis. At the time of treatment planning, the mean dose to a single parotid gland should be kept below 26Gy, the mean dose to a single submandibular gland below 39Gy, the mean dose to the mandible below 60 to 65Gy and the D2% to a single temporomandibular joint below 65Gy. These dose constraints could be further improved with data extracted from cohorts of patients receiving IMRT exclusively. The dose administered to the target volumes should not be lessened to spare the salivary glands or mandible.

  5. Intensity-modulated arc therapy to improve radiation dose delivery in the treatment of abdominal neuroblastoma.

    PubMed

    Gains, Jennifer E; Stacey, Christopher; Rosenberg, Ivan; Mandeville, Henry C; Chang, Yen-Ch'ing; D'Souza, Derek; Moroz, Veronica; Wheatley, Keith; Gaze, Mark N

    2013-03-01

    The standard European radiotherapy technique for children with neuroblastoma is a conventional parallel opposed pair. This frequently results in compromise on planning target volume coverage to stay within normal tissue tolerances. This study investigates the use of an intensity-modulated arc therapy (IMAT) technique to improve dose distribution and allow better protocol compliance. Among 20 previously treated patients, ten had received the full prescribed dose with conventional planning (protocol compliant) and ten had a compromise on planning target volume coverage (protocol noncompliant). All patients were replanned with IMAT. Dosimetric parameters of the conventional radiotherapy and IMAT were compared. The dose received by 98% of the planning target volume, homogeneity and conformity indices were all improved with IMAT (p < 0.001). IMAT would have enabled delivery of the full protocol dose in eight out of ten protocol-noncompliant patients. IMAT may improve outcomes through improved protocol compliance and better dose distributions.

  6. Dose to the intracranial arteries in stereotactic and intensity-modulated radiotherapy for skull base tumors

    SciTech Connect

    Nieder, Carsten . E-mail: cnied@hotmail.com; Grosu, Anca L.; Stark, Sybille; Wiedenmann, Nicole; Busch, Raymonde; Kneschaurek, Peter; Molls, Michael

    2006-03-15

    Purpose: To examine retrospectively the maximum dose to the large skull base/intracranial arteries in fractionated stereotactic radiotherapy (FSRT) and intensity-modulated radiotherapy (IMRT), because of the potential risk of perfusion disturbances. Methods and Materials: Overall, 56 patients with tumors adjacent to at least one major artery were analyzed. Our strategy was to perform FSRT with these criteria: 1.8 Gy per fraction, planning target volume (PTV) enclosed by the 95% isodose, maximum dose 107%. Dose limits were applied to established organs at risk, but not the vessels. If FSRT planning failed to meet any of these criteria, IMRT was planned with the same objectives. Results: In 31 patients (median PTV, 23 cm{sup 3}), the FSRT plan fulfilled all criteria. No artery received a dose {>=}105%. Twenty-five patients (median PTV, 39 cm{sup 3}) needed IMRT planning. In 11 of 25 patients (median PTV, 85 cm{sup 3}), no plan satisfying all our criteria could be calculated. Only in this group, moderately increased maximum vessel doses were observed (106-110%, n = 7, median PTV, 121 cm{sup 3}). The median PTV dose gradient was 29% (significantly different from the 14 patients with satisfactory IMRT plans). Three of the four patients in this group had paranasal sinus tumors. Conclusion: The doses to the major arteries should be calculated in IMRT planning for critical tumor locations if a dose gradient >13% within the PTV can not be avoided because the PTV is large or includes air cavities.

  7. In vivo verification of superficial dose for head and neck treatments using intensity-modulated techniques

    SciTech Connect

    Qi Zhenyu; Deng Xiaowu; Huang Shaomin; Zhang Li; He Zhichun; Allen Li, X.; Kwan, Ian; Lerch, Michael; Cutajar, Dean; Metcalfe, Peter; Rosenfeld, Anatoly

    2009-01-15

    Skin dose is one of the key issues for clinical dosimetry in radiation therapy. Currently planning computer systems are unable to accurately predict dose in the buildup region, leaving ambiguity as to the dose levels actually received by the patient's skin during radiotherapy. This is one of the prime reasons why in vivo measurements are necessary to estimate the dose in the buildup region. A newly developed metal-oxide-semiconductor-field-effect-transistor (MOSFET) detector designed specifically for dose measurements in rapidly changing dose gradients was introduced for accurate in vivo skin dosimetry. The feasibility of this detector for skin dose measurements was verified in comparison with plane parallel ionization chamber and radiochromic films. The accuracy of a commercial treatment planning system (TPS) in skin dose calculations for intensity-modulated radiation therapy treatment of nasopharyngeal carcinoma was evaluated using MOSFET detectors in an anthropomorphic phantom as well as on the patients. Results show that this newly developed MOSFET detector can provide a minimal but highly reproducible intrinsic buildup of 7 mg cm{sup -2} corresponding to the requirements of personal surface dose equivalent Hp (0.07). The reproducibility of the MOSFET response, in high sensitivity mode, is found to be better than 2% at the phantom surface for the doses normally delivered to the patients. The MOSFET detector agrees well with the Attix chamber and the EBT Gafchromic registered film in terms of surface and buildup region dose measurements, even for oblique incident beams. While the dose difference between MOSFET measurements and TPS calculations is within measurement uncertainty for the depths equal to or greater than 0.5 cm, an overestimation of up to 8.5% was found for the surface dose calculations in the anthropomorphic phantom study. In vivo skin dose measurements reveal that the dose difference between the MOSFET results and the TPS calculations was on

  8. Dose Escalation Versus Standard in Laryngopharyngeal Cancers

    ClinicalTrials.gov

    2016-05-02

    Malignant Neoplasm of Oropharynx Stage III; Malignant Neoplasm of Larynx Stage III; Malignant Neoplasm of Hypopharynx Stage III; Malignant Neoplasm of Oropharynx Stage IVa; Malignant Neoplasm of Oropharynx Stage IVb; Malignant Neoplasm of Larynx Stage IV; Malignant Neoplasm of Hypopharynx Stage IVa; Malignant Neoplasm of Hypopharynx Stage IVb

  9. Evaluation of Dose Distribution in Intensity Modulated Radiosurgery for Lung Cancer under Condition of Respiratory Motion

    PubMed Central

    Yoon, Mee Sun; Jeong, Jae-Uk; Nam, Taek-Keun; Ahn, Sung-Ja; Chung, Woong-Ki; Song, Ju-Young

    2016-01-01

    The dose of a real tumor target volume and surrounding organs at risk (OARs) under the effect of respiratory motion was calculated for a lung tumor plan, based on the target volume covering the whole tumor motion range for intensity modulated radiosurgery (IMRS). Two types of IMRS plans based on simulated respiratory motion were designed using humanoid and dynamic phantoms. Delivery quality assurance (DQA) was performed using ArcCHECK and MapCHECK2 for several moving conditions of the tumor and the real dose inside the humanoid phantom was evaluated using the 3DVH program. This evaluated dose in the tumor target and OAR using the 3DVH program was higher than the calculated dose in the plan, and a greater difference was seen for the RapidArc treatment than for the standard intensity modulated radiation therapy (IMRT) with fixed gantry angle beams. The results of this study show that for IMRS plans based on target volume, including the whole tumor motion range, tighter constraints of the OAR should be considered in the optimization process. The method devised in this study can be applied effectively to analyze the dose distribution in the real volume of tumor target and OARs in IMRT plans targeting the whole tumor motion range. PMID:27648949

  10. A method to dynamically balance intensity modulated radiotherapy dose between organs-at-risk.

    PubMed

    Das, Shiva K

    2009-05-01

    The IMRT treatment planning process typically follows a path that is based on the manner in which the planner interactively adjusts the target and organ-at-risk (OAR) constraints and priorities. The time-intensive nature of this process restricts the planner from fully understanding the dose tradeoff between structures, making it unlikely that the resulting plan fully exploits the extent to which dose can be redistributed between anatomical structures. Multiobjective Pareto optimization has been used in the past to enable the planner to more thoroughly explore alternatives in dose trade-off by combining pre-generated Pareto optimal solutions in real time, thereby potentially tailoring a plan more exactly to requirements. However, generating the Pareto optimal solutions can be nonintuitive and computationally time intensive. The author presents an intuitive and fast non-Pareto approach for generating optimization sequences (prior to planning), which can then be rapidly combined by the planner in real time to yield a satisfactory plan. Each optimization sequence incrementally reduces dose to one OAR at a time, starting from the optimization solution where dose to all OARs are reduced with equal priority, until user-specified target coverage limits are violated. The sequences are computationally efficient to generate, since the optimization at each position along a sequence is initiated from the end result of the previous position in the sequence. The pre-generated optimization sequences require no user interaction. In real time, a planner can more or less instantaneously visualize a treatment plan by combining the dose distributions corresponding to user-selected positions along each of the optimization sequences (target coverage is intrinsically maintained in the combination). Interactively varying the selected positions along each of the sequences enables the planner to rapidly understand the nature of dose trade-off between structures and, thereby, arrive at a

  11. A method to dynamically balance intensity modulated radiotherapy dose between organs-at-risk

    SciTech Connect

    Das, Shiva K.

    2009-05-15

    The IMRT treatment planning process typically follows a path that is based on the manner in which the planner interactively adjusts the target and organ-at-risk (OAR) constraints and priorities. The time-intensive nature of this process restricts the planner from fully understanding the dose trade-off between structures, making it unlikely that the resulting plan fully exploits the extent to which dose can be redistributed between anatomical structures. Multiobjective Pareto optimization has been used in the past to enable the planner to more thoroughly explore alternatives in dose trade-off by combining pre-generated Pareto optimal solutions in real time, thereby potentially tailoring a plan more exactly to requirements. However, generating the Pareto optimal solutions can be nonintuitive and computationally time intensive. The author presents an intuitive and fast non-Pareto approach for generating optimization sequences (prior to planning), which can then be rapidly combined by the planner in real time to yield a satisfactory plan. Each optimization sequence incrementally reduces dose to one OAR at a time, starting from the optimization solution where dose to all OARs are reduced with equal priority, until user-specified target coverage limits are violated. The sequences are computationally efficient to generate, since the optimization at each position along a sequence is initiated from the end result of the previous position in the sequence. The pre-generated optimization sequences require no user interaction. In real time, a planner can more or less instantaneously visualize a treatment plan by combining the dose distributions corresponding to user-selected positions along each of the optimization sequences (target coverage is intrinsically maintained in the combination). Interactively varying the selected positions along each of the sequences enables the planner to rapidly understand the nature of dose trade-off between structures and, thereby, arrive at a

  12. Radiation Dose Measurement for High-Intensity Laser Interactions with Solid Targets at SLAC

    SciTech Connect

    Liang, Taiee

    2015-09-25

    A systematic study of photon and neutron radiation doses generated in high-intensity laser-solid interactions is underway at SLAC National Accelerator Laboratory. We found that these laser-solid experiments are being performed using a 25 TW (up to 1 J in 40 fs) femtosecond pulsed Ti:sapphire laser at the Linac Coherent Light Source’s (LCLS) Matter in Extreme Conditions (MEC) facility. Additionally, radiation measurements were performed with passive and active detectors deployed at various locations inside and outside the target chamber. Results from radiation dose measurements for laser-solid experiments at SLAC MEC in 2014 with peak intensity between 1018 to 7.1x1019 W/cm2 are presented.

  13. Dose estimation and shielding calculation for X-ray hazard at high intensity laser facilities

    NASA Astrophysics Data System (ADS)

    Qiu, Rui; Zhang, Hui; Yang, Bo; James, C. Liu; Sayed, H. Rokni; Michael, B. Woods; Li, Jun-Li

    2014-12-01

    An ionizing radiation hazard produced from the interaction between high intensity lasers and solid targets has been observed. Laser-plasma interactions create “hot” electrons, which generate bremsstrahlung X-rays when they interact with ions in the target. However, up to now only limited studies have been conducted on this laser-induced radiological protection issue. In this paper, the physical process and characteristics of the interaction between high intensity lasers and solid targets are analyzed. The parameters of the radiation sources are discussed, including the energy conversion efficiency from laser to hot electrons, hot electron energy spectrum and electron temperature, and the bremsstrahlung X-ray energy spectrum produced by hot electrons. Based on this information, the X-ray dose generated with high-Z targets for laser intensities between 1014 and 1020 W/cm2 is estimated. The shielding effects of common shielding items such as the glass view port, aluminum chamber wall and concrete wall are also studied using the FLUKA Monte Carlo code. This study provides a reference for the dose estimation and the shielding design of high intensity laser facilities.

  14. Continuous dose-intense temozolomide and cisplatin in recurrent glioblastoma patients

    PubMed Central

    Wang, Yu; Kong, Xiangyi; Guo, Yi; Wang, Renzhi; Ma, Wenbin

    2017-01-01

    Abstract In glioblastoma multiforme (GBM), both temozolomide (TMZ) and cisplatin are very active at various toxic levels. Previous studies demonstrated that cisplatin with the standard regimen of TMZ is active in patients suffering from recurrent GBM, generating a moderate level of toxicity. Also, continuous dose-intense TMZ is a helpful therapy for patients with recurrent GBM. We have conducted a research to evaluate the security and effectiveness of cisplatin with constant dose-intense TMZ for reduplicative GBM. The time to progression (TTP) and progression-free survival (PFS) at 6 months (PFS-6) was the major end point. Toxicity, overall survival, and response are the secondary end points. GBM patients who suffered from progression or relapse after surgery, radiotherapy, and chemotherapy were qualified. Cisplatin 40, 30, and 30 mg were given on days 1, 2, and 3 before the corresponding TMZ doses, respectively. Without interruption, TMZ was given at a dose of 50 mg/m2 on everyday basis (dose-intense) until development or progression of unacceptable side effects. A cycle was defined as 28 days. Response Assessment in Neuro-Oncology criteria were utilized to evaluate the response. Twenty-seven patients in total (median Karnofsky performance status—80, ranging from 60 to 100; average age—56 years, ranging from 24 to 78 years) were accrued in the research. PFS-12 was 11.1% (95% confidence interval [CI], −0.7% to 22.9%), and PFS-6 was 37% (95% CI, 18.8%–55.2%). Twenty-three weeks was the median TTP (95% CI, 17–29 weeks). In the 27 evaluative patients, 6 partial responses were observed with an overall response rate of 22.2% (95% CI, 6.5%–37.9%), while no complete response was obtained. Toxicity was mostly of grades 1 to 2 amongst 116 therapy cycles. Hematological and gastroenterological toxicities were the major limiting side effect found in the research. One patient has received leukopenia World Health Organization grade 4 at cycle 5 during her

  15. Continuous dose-intense temozolomide and cisplatin in recurrent glioblastoma patients.

    PubMed

    Wang, Yu; Kong, Xiangyi; Guo, Yi; Wang, Renzhi; Ma, Wenbin

    2017-03-01

    In glioblastoma multiforme (GBM), both temozolomide (TMZ) and cisplatin are very active at various toxic levels. Previous studies demonstrated that cisplatin with the standard regimen of TMZ is active in patients suffering from recurrent GBM, generating a moderate level of toxicity. Also, continuous dose-intense TMZ is a helpful therapy for patients with recurrent GBM. We have conducted a research to evaluate the security and effectiveness of cisplatin with constant dose-intense TMZ for reduplicative GBM. The time to progression (TTP) and progression-free survival (PFS) at 6 months (PFS-6) was the major end point. Toxicity, overall survival, and response are the secondary end points. GBM patients who suffered from progression or relapse after surgery, radiotherapy, and chemotherapy were qualified. Cisplatin 40, 30, and 30 mg were given on days 1, 2, and 3 before the corresponding TMZ doses, respectively. Without interruption, TMZ was given at a dose of 50 mg/m on everyday basis (dose-intense) until development or progression of unacceptable side effects. A cycle was defined as 28 days. Response Assessment in Neuro-Oncology criteria were utilized to evaluate the response. Twenty-seven patients in total (median Karnofsky performance status-80, ranging from 60 to 100; average age-56 years, ranging from 24 to 78 years) were accrued in the research. PFS-12 was 11.1% (95% confidence interval [CI], -0.7% to 22.9%), and PFS-6 was 37% (95% CI, 18.8%-55.2%). Twenty-three weeks was the median TTP (95% CI, 17-29 weeks). In the 27 evaluative patients, 6 partial responses were observed with an overall response rate of 22.2% (95% CI, 6.5%-37.9%), while no complete response was obtained. Toxicity was mostly of grades 1 to 2 amongst 116 therapy cycles. Hematological and gastroenterological toxicities were the major limiting side effect found in the research. One patient has received leukopenia World Health Organization grade 4 at cycle 5 during her treatment. Eight percent of

  16. Intensive combined modality therapy including low-dose TBI in high-risk Ewing's sarcoma patients

    SciTech Connect

    Kinsella, T.J.; Glaubiger, D.; Diesseroth, A.; Makuch, R.; Waller, B.; Pizzo, P.; Glatstein, E.

    1983-12-01

    Twenty-four high-risk Ewing's sarcoma patients were treated on an intensive combined modality protocol including low-dose fractionated total body irradiaiton (TBI) and autologous bone marrow infusion (ABMI). Twenty patients (83%) achieved a complete clinical response to the primary and/or metastatic sites following induction therapy. The median disease-free interval was 18 months, and nine patients remain disease-free with a follow-up of 22 to 72 months. Local failure as a manifestation of initial relapse occurred in only three patients (15%), each having synchronous distant failure. Eight patients failed initially with only distant metastases, usually within 1-2 years following a complete clinical response. Two patterns of granulocyte recovery following consolidative therapy (including TBI and ABMI) were recognized. The time to platelet recovery was different for the groups with early and late granulocyte recovery. Patients with late recovery did not tolerate maintenance chemotherapy. However, there was no difference in disease-free and overall survival, when comparing the groups with early and late granulocyte recovery. It is concluded that these high-risk Ewing's sarcoma patients remain a poor-prognosis group in spite of intensive combined modality therapy including low-dose TBI. The control of microscopic systemic disease remains the major challenge to improving the cure rate. A new combined modality protocol with high-dose 'therapeutic' TBI (800 rad/2 fractions) is being used and the protocol design is outlined.

  17. Evaluation of Radiation Dose Received by Premature Neonates Admitted to Neonatal Intensive Care Unit

    PubMed Central

    Aramesh, Mohmmadreza; Zanganeh, Kobra Aria; Dehdashtian, Masoud; Malekian, Arash; Fatahiasl, Jafar

    2017-01-01

    Background This study aimed to evaluate the radiation dose received by premature neonates using diagnostic radiographies. Methods This cross-sectional study was conducted on 116 premature neonates with gestational age from 25 to 37 weeks; with the diagnosis of neonatal respiratory distress syndrome (NRDS) and tachypnea, they were admitted to a neonatal intensive care unit (NICU) at Ahvaz Imam Khomeini Hospital in 2015. For assessing the dose received, the model GR-200 thermoluminescent dosimeter (TLD) was used. For each premature neonate under radiation, three TLDs separately (one for each) were placed on surfaces of Ch1, T1, and G1 (chest, thyroid, and gonad of first newborn, respectively). Moreover, for the adjacent neonate at a distance of 60 - 100 cm, two TLDs were laid in the surfaces of T2 and G2 (thyroid and gonad of second newborn, respectively). The dose received by TLDs for any baby and the adjacent neonate under the entrance surface dose (ESD) was estimated. Results The mean of neonates’ weight under study was 1,950.78 ± 484.9 g. During the hospitalization period, minimum one and maximum three radiographies were done for any premature neonate. The doses received in the premature neonates to Ch1, T1 and G1 were 0.08 ± 0.01, 0.06 ± 0.01, and 0.05 ± 0.01 mSv, respectively and for adjacent infants for T2 and G2 were 0.003 ± 0.001 and 0.002 ± 0.0009 mSv, respectively. Conclusions In the study, radiation dose received by organs at risk of premature neonates was lower than the international criteria and standards, therefore, also due to the lack of radiation damage threshold, to limit collimator, and the use of the proper filtration, kilovoltage and time during radiography of premature neonates are recommended. PMID:28090228

  18. Escalation: How Much is Enough?

    NASA Technical Reports Server (NTRS)

    Butts, Glenn

    2007-01-01

    Determining the escalation percentage to an estimate is often the subject of fierce debate. Cost increases are determined by dynamic relati onships between many factors, including acts of nature, interest rate s, oil prices, global commodity markets, wars, wage rates, and the ov erall health of the economy, as well as supply and demand for the required goods or services. How much escalation is enough? Are the recen t price increases temporary aberrations, or will they continue to pla gue us? This paper examines historical escalation rates, as well as i ndications of trends. Various analysis methods -- Monte Carlo simulations, neural networks, trend impact analysis, and the Delphi method -- are examined in an attempt to determine future trends.

  19. Dose-Volume Comparison of Proton Therapy and Intensity-Modulated Radiotherapy for Prostate Cancer

    SciTech Connect

    Vargas, Carlos Fryer, Amber; Mahajan, Chaitali; Indelicato, Daniel; Horne, David C.; Chellini, Angela; McKenzie, Craig C.; Lawlor, Paula C.; Henderson, Randal; Li Zuofeng; Lin Liyong; Olivier, Kenneth; Keole, Sameer

    2008-03-01

    Purpose: The contrast in dose distribution between proton radiotherapy (RT) and intensity-modulated RT (IMRT) is unclear, particularly in regard to critical structures such as the rectum and bladder. Methods and Materials: Between August and November 2006, the first 10 consecutive patients treated in our Phase II low-risk prostate proton protocol (University of Florida Proton Therapy Institute protocol 0001) were reviewed. The double-scatter proton beam plans used in treatment were analyzed for various dosimetric endpoints. For all plans, each beam dose distribution, angle, smearing, and aperture margin were optimized. IMRT plans were created for all patients and simultaneously analyzed. The IMRT plans were optimized through multiple volume objectives, beam weighting, and individual leaf movement. The patients were treated to 78 Gray-equivalents (GE) in 2-GE fractions with a biologically equivalent dose of 1.1. Results: All rectal and rectal wall volumes treated to 10-80 GE (percentage of volume receiving 10-80 GE [V{sub 10}-V{sub 80}]) were significantly lower with proton therapy (p < 0.05). The rectal V{sub 50} was reduced from 31.3% {+-} 4.1% with IMRT to 14.6% {+-} 3.0% with proton therapy for a relative improvement of 53.4% and an absolute benefit of 16.7% (p < 0.001). The mean rectal dose decreased 59% with proton therapy (p < 0.001). For the bladder and bladder wall, proton therapy produced significantly smaller volumes treated to doses of 10-35 GE (p < 0.05) with a nonsignificant advantage demonstrated for the volume receiving {<=}60 GE. The bladder V{sub 30} was reduced with proton therapy for a relative improvement of 35.3% and an absolute benefit of 15.1% (p = 0.02). The mean bladder dose decreased 35% with proton therapy (p = 0.002). Conclusion: Compared with IMRT, proton therapy reduced the dose to the dose-limiting normal structures while maintaining excellent planning target volume coverage.

  20. Low-intensity laser therapy to treat dentin hypersensitivity: comparative clinical study using different light doses

    NASA Astrophysics Data System (ADS)

    Lizarelli, Rosane F. Z.; Mazzetto, Marcello O.; Bagnato, Vanderlei S.

    2001-04-01

    Dentin hypersensitivity is the most common patient's complain related to pain. In fact, this is a challenge to treat specially if conventional techniques are used. The possibility to treat pain through a low intensity laser gives us an opportunity to solve this important clinical problem without promote a discomfort to patient. The main point here is not if this kind of treatment is anti- inflammatory to pulp and/or biostimulatory to production of irregular secondary dentin. The most important point here is to understand how much energy is necessary to reach conditions where to tooth become insensible to external stimulus. Our double-blinded study compared a group without laser (Placebo) with five other groups where different doses at 660 nm low intensity laser were employed. The final conclusion is that for 660 nm laser therapy, the doses from 0.13 to 2.0 J/cm2 were more efficiency than the others. The follow up care in this study was of 45 days.

  1. Dose to Larynx Predicts for Swallowing Complications After Intensity-Modulated Radiotherapy

    SciTech Connect

    Caglar, Hale B.; Tishler, Roy B.; Burke, Elaine; Li Yi; Goguen, Laura; Norris, Carl M.; Allen, Aaron M.

    2008-11-15

    Purpose: To evaluate early swallowing after intensity-modulated radiotherapy for head and neck squamous cell carcinoma and determine factors correlating with aspiration and/or stricture. Methods and Materials: Consecutive patients treated with intensity-modulated radiotherapy with or without chemotherapy between September 2004 and August 2006 at the Dana Farber Cancer Institute/Brigham and Women's Hospital were evaluated with institutional review board approval. Patients underwent swallowing evaluation after completion of therapy; including video swallow studies. The clinical- and treatment-related variables were examined for correlation with aspiration or strictures, as well as doses to the larynx, pharyngeal constrictor muscles, and cervical esophagus. The correlation was assessed with logistic regression analysis. Results: A total of 96 patients were evaluated. Their median age was 55 years, and 79 (82%) were men. The primary site of cancer was the oropharynx in 43, hypopharynx/larynx in 17, oral cavity in 13, nasopharynx in 11, maxillary sinus in 2, and unknown primary in 10. Of the 96 patients, 85% underwent definitive RT and 15% postoperative RT. Also, 28 patients underwent induction chemotherapy followed by concurrent chemotherapy, 59 received concurrent chemotherapy, and 9 patients underwent RT alone. The median follow-up was 10 months. Of the 96 patients, 31 (32%) had clinically significant aspiration and 36 (37%) developed a stricture. The radiation dose-volume metrics, including the volume of the larynx receiving {>=}50 Gy (p = 0.04 and p = 0.03, respectively) and volume of the inferior constrictor receiving {>=}50 Gy (p = 0.05 and p = 0.02, respectively) were significantly associated with both aspiration and stricture. The mean larynx dose correlated with aspiration (p = 0.003). Smoking history was the only clinical factor to correlate with stricture (p = 0.05) but not aspiration. Conclusion: Aspiration and stricture are common side effects after

  2. A spatially encoded dose difference maximal intensity projection map for patient dose evaluation: A new first line patient quality assurance tool

    SciTech Connect

    Hu Weigang; Graff, Pierre; Boettger, Thomas; Pouliot, Jean; and others

    2011-04-15

    Purpose: To develop a spatially encoded dose difference maximal intensity projection (DD-MIP) as an online patient dose evaluation tool for visualizing the dose differences between the planning dose and dose on the treatment day. Methods: Megavoltage cone-beam CT (MVCBCT) images acquired on the treatment day are used for generating the dose difference index. Each index is represented by different colors for underdose, acceptable, and overdose regions. A maximal intensity projection (MIP) algorithm is developed to compress all the information of an arbitrary 3D dose difference index into a 2D DD-MIP image. In such an algorithm, a distance transformation is generated based on the planning CT. Then, two new volumes representing the overdose and underdose regions of the dose difference index are encoded with the distance transformation map. The distance-encoded indices of each volume are normalized using the skin distance obtained on the planning CT. After that, two MIPs are generated based on the underdose and overdose volumes with green-to-blue and green-to-red lookup tables, respectively. Finally, the two MIPs are merged with an appropriate transparency level and rendered in planning CT images. Results: The spatially encoded DD-MIP was implemented in a dose-guided radiotherapy prototype and tested on 33 MVCBCT images from six patients. The user can easily establish the threshold for the overdose and underdose. A 3% difference between the treatment and planning dose was used as the threshold in the study; hence, the DD-MIP shows red or blue color for the dose difference >3% or {<=}3%, respectively. With such a method, the overdose and underdose regions can be visualized and distinguished without being overshadowed by superficial dose differences. Conclusions: A DD-MIP algorithm was developed that compresses information from 3D into a single or two orthogonal projections while hinting the user whether the dose difference is on the skin surface or deeper.

  3. Crisis and Escalation in Cyberspace

    DTIC Science & Technology

    2012-01-01

    alliance. NATO concludes that it lacks a comparably good nuclear target that would have a similar effect, so it escalates to find its own sweet spot...note. Economic theory says that the greater the price of something, the less people will want it: If potato prices rises, people will eat pasta. If

  4. In vitro study of cell survival following dynamic MLC intensity-modulated radiation therapy dose delivery

    SciTech Connect

    Moiseenko, Vitali; Duzenli, Cheryl; Durand, Ralph E.

    2007-04-15

    The possibility of reduced cell kill following intensity-modulated radiation therapy (IMRT) compared to conventional radiation therapy has been debated in the literature. This potential reduction in cell kill relates to prolonged treatment times typical of IMRT dose delivery and consequently increased repair of sublethal lesions. While there is some theoretical support to this reduction in cell kill published in the literature, direct experimental evidence specific to IMRT dose delivery patterns is lacking. In this study we present cell survival data for three cell lines: Chinese hamster V79 fibroblasts, human cervical carcinoma, SiHa and colon adenocarcinoma, WiDr. Cell survival was obtained for 2.1 Gy delivered as acute dose with parallel-opposed pair (POP), irradiation time 75 s, which served as a reference; regular seven-field IMRT, irradiation time 5 min; and IMRT with a break for multiple leaf collimator (MLC) re-initialization after three fields were delivered, irradiation time 10 min. An actual seven-field dynamic MLC IMRT plan for a head and neck patient was used. The IMRT plan was generated for a Varian EX or iX linear accelerator with 120 leaf Millenium MLC. Survival data were also collected for doses 1x, 2x, 3x, 4x, and 5x 2.1 Gy to establish parameters of the linear-quadratic equation describing survival following acute dose delivery. Cells were irradiated inside an acrylic cylindrical phantom specifically designed for this study. Doses from both IMRT and POP were validated using ion chamber measurements. A reproducible increase in cell survival was observed following IMRT dose delivery. This increase varied from small for V79, with a surviving fraction of 0.8326 following POP vs 0.8420 following uninterrupted IMRT, to very pronounced for SiHa, with a surviving fraction of 0.3903 following POP vs 0.5330 for uninterrupted IMRT. When compared to IMRT or IMRT with a break for MLC initialization, cell survival following acute dose delivery was

  5. Treatment of urban runoff at Lake Tahoe: low-intensity chemical dosing.

    PubMed

    Trejo-Gaytan, Julieta; Bachand, Philip; Darby, Jeannie

    2006-12-01

    A systematic investigation of the effect of coagulant type and dose and temperature, mixing, and water quality on subsequent charge neutralization and removal of phosphorus and fine particles from urban and/or stormwater runoff entering Lake Tahoe (Sierra Nevada mountains, western United States) was conducted. Dosing based on streaming current values resulted in turbidities of less than 10.9 +/- 0.35 NTU and filterable and total phosphorus concentrations of less than 9.83 +/- 0.54 and 25.6 +/- 5.71 microg/L, respectively. Inadequate slow mixing could be partially compensated for by increased settling time; however, such quiescent conditions are difficult to obtain in natural systems. For prehydrolyzed forms of aluminum, high intensity rapid mixing was counterproductive. Several classes of coagulants responded robustly to water quality and temperature changes. However, polyaluminum chlorides modified with silica or sulfate, with low to medium basicity, were consistently the best performers in these tests, in terms of simultaneously removing phosphorus and fine particles under a wide range of operating conditions with low doses.

  6. Overview of escalator applications in rail transit

    NASA Technical Reports Server (NTRS)

    Deshpande, G.; Rubenstein, L.

    1980-01-01

    The difference in operating environment and in construction between escalators in transit and nontransit use, the impact of recent escalator innovations, and areas which could benefit from urban mass transportation administration sponsored research and development are determined. Several factors causing a more severe transit escalator operating environment are identified. There are no significant design differences between transit and nontransit escalators. Recent innovations that have affected performance and cost include outdoor escalators, extra flat steps at both landings, and modular escalators. Data were collected by interviews at transit agencies. Long term, unscheduled, escalator maintenance records were available for analysis from one property. A description of escalator operating principles is provided. Transit represents less than 5% of the U.S. escalator market. Transit agencies have limited leverage on escalator industry practices. A substantial impact on transit escalator cost and performance can be achieved by research identifying when and how to apply and specify several of the more recent innovations. Purchase of escalators under long term (25 year) maintenance contracts is one method that has been used to promote escalators manufactured for minimum life cycle cost.

  7. Multivariate analysis of factors predicting prostate dose in intensity-modulated radiotherapy

    SciTech Connect

    Tomita, Tsuneyuki; Nakamura, Mitsuhiro; Hirose, Yoshinori; Kitsuda, Kenji; Notogawa, Takuya; Miki, Katsuhito; Nakamura, Kiyonao; Ishigaki, Takashi

    2014-01-01

    We conducted a multivariate analysis to determine relationships between prostate radiation dose and the state of surrounding organs, including organ volumes and the internal angle of the levator ani muscle (LAM), based on cone-beam computed tomography (CBCT) images after bone matching. We analyzed 270 CBCT data sets from 30 consecutive patients receiving intensity-modulated radiation therapy for prostate cancer. With patients in the supine position on a couch with the HipFix system, data for center of mass (COM) displacement of the prostate and the state of individual organs were acquired and compared between planning CT and CBCT scans. Dose distributions were then recalculated based on CBCT images. The relative effects of factors on the variance in COM, dose covering 95% of the prostate volume (D{sub 95%}), and percentage of prostate volume covered by the 100% isodose line (V{sub 100%}) were evaluated by a backward stepwise multiple regression analysis. COM displacement in the anterior-posterior direction (COM{sub AP}) correlated significantly with the rectum volume (δVr) and the internal LAM angle (δθ; R = 0.63). Weak correlations were seen for COM in the left-right (R = 0.18) and superior-inferior directions (R = 0.31). Strong correlations between COM{sub AP} and prostate D{sub 95%} and V{sub 100%} were observed (R ≥ 0.69). Additionally, the change ratios in δVr and δθ remained as predictors of prostate D{sub 95%} and V{sub 100%}. This study shows statistically that maintaining the same rectum volume and LAM state for both the planning CT simulation and treatment is important to ensure the correct prostate dose in the supine position with bone matching.

  8. SU-F-BRD-06: Robust Dose Calculation in Intensity Modulated Proton Therapy

    SciTech Connect

    Brosch, R; Liu, W

    2015-06-15

    Purpose: Commissioning data for intensity modulated proton therapy (IMPT) must be post-processed by fits to ad-hoc functions to derive the dose calculation kernel parameters in a treatment planning system (TPS). Whether from experimental measurement or Monte Carlo simulation, the limited and noisy nature of such data makes this task very challenging. We present a method to improve the modeling of the lateral dose distribution of clinical energy proton beams in water to commission an in-house IMPT dose calculation engine. Methods: A linear sum of three Gaussian distribution functions was fitted to the lateral dose data in logarithmic scale. Starting values of fitting solutions were determined from the Generalized Highland Approximation. We exhaustively optimized the combinations of data weights with upper bounds of the fitting solutions to minimize confidence intervals of the fitting solutions while maintaining the coefficient of determination (R{sup 2}). Results: Across all energies, average confidence bounds improved 72.88% [Max: 88.28%, Min: 55.05%] for small angle coulomb scattering, 114.25% [409.13%, 66.72%,] for nuclear scattering, and 68.66% [141.09%, 33.27%] for large angle coulomb scattering, while the coefficients of determination of the fits (R{sup 2}) remained comparable. On average R {sup 2} only changed 0.18% and were very close to 1 (approx. 0.999). Wilcoxon signed rank tests comparing unweighted/unbounded fits with weighted/bounded fits averaged 0.0146 (Max: 0.177, Min: 7.05×10−{sup 7}) for small angle Coulomb, 0.0903 (0.945, 7.05×10−{sup 7}) for nuclear, and 0.254 (0.871, 1.86×10−{sup 6}) for large angle Coulomb scattering. This allows rejection of the null hypothesis for small angle Coulomb scattering at the 0.015 level and nuclear interaction at the 0.1 level. Conclusion: Optimal weights assigned to IMPT lateral dose data minimized fitting to stochastic noise in the tail region. Optimizing the upper bounds of fitting parameters improved

  9. [Phenylephrine dosing error in Intensive Care Unit. Case of the trimester].

    PubMed

    2013-01-01

    A real clinical case reported to SENSAR is presented. A patient admitted to the surgical intensive care unit following a lung resection, suffered arterial hypotension. The nurse was asked to give the patient 1 mL of phenylephrine. A few seconds afterwards, the patient experienced a hypertensive crisis, which resolved spontaneously without damage. Thereafter, the nurse was interviewed and a dosing error was identified: she had mistakenly given the patient 1 mg of phenylephrine (1 mL) instead of 100 mcg (1 mL of the standard dilution, 1mg in 10 mL). The incident analysis revealed latent factors (event triggers) due to the lack of protocols and standard operating procedures, communication errors among team members (physician-nurse), suboptimal training, and underdeveloped safety culture. In order to preempt similar incidents in the future, the following actions were implemented in the surgical intensive care unit: a protocol for bolus and short lived infusions (<30 min) was developed and to close the communication gap through the adoption of communication techniques. The protocol was designed by physicians and nurses to standardize the administration of drugs with high potential for errors. To close the communication gap, repeated checks about saying and understanding was proposed ("closed loop"). Labeling syringes with the drug dilution was also recommended.

  10. Elective Lymph Node Irradiation With Intensity-Modulated Radiotherapy: Is Conventional Dose Fractionation Necessary?

    SciTech Connect

    Bedi, Meena; Firat, Selim; Semenenko, Vladimir A.; Schultz, Christopher; Tripp, Patrick; Byhardt, Roger; Wang, Dian

    2012-05-01

    Purpose: Intensity-modulated radiation therapy (IMRT) is the standard of care for head-and-neck cancer (HNC). We treated patients with HNC by delivering either a moderate hypofractionation (MHF) schedule (66 Gy at 2.2 Gy per fraction to the gross tumor [primary and nodal]) with standard dose fractionation (54-60 Gy at 1.8-2.0 Gy per fraction) to the elective neck lymphatics or a conventional dose and fractionation (CDF) schedule (70 Gy at 2.0 Gy per fraction) to the gross tumor (primary and nodal) with reduced dose to the elective neck lymphatics. We analyzed these two cohorts for treatment outcomes. Methods and Materials: Between November 2001 and February 2009, 89 patients with primary carcinomas of the oral cavity, larynx, oropharynx, hypopharynx, and nasopharynx received definitive IMRT with or without concurrent chemotherapy. Twenty patients were treated using the MHF schedule, while 69 patients were treated with the CDF schedule. Patient characteristics and dosimetry plans were reviewed. Patterns of failure including local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), overall survival (OS), and toxicities, including rate of feeding tube placement and percentage of weight loss, were reviewed and analyzed. Results: Median follow-up was 31.2 months. Thirty-five percent of patients in the MHF cohort and 77% of patients in the CDF cohort received chemotherapy. No RR was observed in either cohort. OS, DFS, LR, and DM rates for the entire group at 2 years were 89.3%, 81.4%, 7.1%, and 9.4%, respectively. Subgroup analysis showed no significant differences in OS (p = 0.595), DFS (p = 0.863), LR (p = 0.833), or DM (p = 0.917) between these two cohorts. Similarly, no significant differences were observed in rates of feeding tube placement and percentages of weight loss. Conclusions: Similar treatment outcomes were observed for MHF and CDF cohorts. A dose of 50 Gy at 1.43 Gy per fraction may be sufficient to electively

  11. Influence of robust optimization in intensity-modulated proton therapy with different dose delivery techniques

    SciTech Connect

    Liu Wei; Li Yupeng; Li Xiaoqiang; Cao Wenhua; Zhang Xiaodong

    2012-06-15

    Purpose: The distal edge tracking (DET) technique in intensity-modulated proton therapy (IMPT) allows for high energy efficiency, fast and simple delivery, and simple inverse treatment planning; however, it is highly sensitive to uncertainties. In this study, the authors explored the application of DET in IMPT (IMPT-DET) and conducted robust optimization of IMPT-DET to see if the planning technique's sensitivity to uncertainties was reduced. They also compared conventional and robust optimization of IMPT-DET with three-dimensional IMPT (IMPT-3D) to gain understanding about how plan robustness is achieved. Methods: They compared the robustness of IMPT-DET and IMPT-3D plans to uncertainties by analyzing plans created for a typical prostate cancer case and a base of skull (BOS) cancer case (using data for patients who had undergone proton therapy at our institution). Spots with the highest and second highest energy layers were chosen so that the Bragg peak would be at the distal edge of the targets in IMPT-DET using 36 equally spaced angle beams; in IMPT-3D, 3 beams with angles chosen by a beam angle optimization algorithm were planned. Dose contributions for a number of range and setup uncertainties were calculated, and a worst-case robust optimization was performed. A robust quantification technique was used to evaluate the plans' sensitivity to uncertainties. Results: With no uncertainties considered, the DET is less robust to uncertainties than is the 3D method but offers better normal tissue protection. With robust optimization to account for range and setup uncertainties, robust optimization can improve the robustness of IMPT plans to uncertainties; however, our findings show the extent of improvement varies. Conclusions: IMPT's sensitivity to uncertainties can be improved by using robust optimization. They found two possible mechanisms that made improvements possible: (1) a localized single-field uniform dose distribution (LSFUD) mechanism, in which the

  12. Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors1

    PubMed Central

    Ziegler, David S.; Cohn, Richard J.; McCowage, Geoffrey; Alvaro, Frank; Oswald, Cecilia; Mrongovius, Robert; White, Les

    2006-01-01

    The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children’s Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed

  13. Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors.

    PubMed

    Ziegler, David S; Cohn, Richard J; McCowage, Geoffrey; Alvaro, Frank; Oswald, Cecilia; Mrongovius, Robert; White, Les

    2006-01-01

    The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children's Cancer Study Group--VETOPEC I, Baby Brain 91, and VETOPEC II--have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed

  14. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

    PubMed

    Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

    2014-08-01

    Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

  15. Hypofractionated Dose-Painting Intensity Modulated Radiation Therapy With Chemotherapy for Nasopharyngeal Carcinoma: A Prospective Trial

    SciTech Connect

    Bakst, Richard L.; Lee, Nancy; Pfister, David G.; Zelefsky, Michael J.; Hunt, Margie A.; Kraus, Dennis H.; Wolden, Suzanne L.

    2011-05-01

    Purpose: To evaluate the feasibility of dose-painting intensity-modulated radiation therapy (DP-IMRT) with a hypofractionated regimen to treat nasopharyngeal carcinoma (NPC) with concomitant toxicity reduction. Methods and Materials: From October 2002 through April 2007, 25 newly diagnosed NPC patients were enrolled in a prospective trial. DP-IMRT was prescribed to deliver 70.2 Gy using 2.34-Gy fractions to the gross tumor volume for the primary and nodal sites while simultaneously delivering 54 Gy in 1.8-Gy fractions to regions at risk of microscopic disease. Patients received concurrent and adjuvant platin-based chemotherapy similar to the Intergroup 0099 trial. Results: Patient and disease characteristics are as follows: median age, 46; 44% Asian; 68% male; 76% World Health Organization III; 20% T1, 52% T2, 16% T3, 12% T4; 20% N0, 36% N1, 36% N2, 8% N3. With median follow-up of 33 months, 3-year local control was 91%, regional control was 91%, freedom from distant metastases was 91%, and overall survival was 89%. The average mean dose to each cochlea was 43 Gy. With median audiogram follow-up of 14 months, only one patient had clinically significant (Grade 3) hearing loss. Twelve percent of patients developed temporal lobe necrosis; one patient required surgical resection. Conclusions: Preliminary findings using a hypofractionated DP-IMRT regimen demonstrated that local control, freedom from distant metastases, and overall survival compared favorably with other series of IMRT and chemotherapy. The highly conformal boost to the tumor bed resulted low rates of severe ototoxicity (Grade 3-4). However, the incidence of in-field brain radiation necrosis indicates that 2.34 Gy per fraction is not safe in this setting.

  16. A comparison of intensity modulated x-ray therapy to intensity modulated proton therapy for the delivery of non-uniform dose distributions

    NASA Astrophysics Data System (ADS)

    Flynn, Ryan

    2007-12-01

    The distribution of biological characteristics such as clonogen density, proliferation, and hypoxia throughout tumors is generally non-uniform, therefore it follows that the optimal dose prescriptions should also be non-uniform and tumor-specific. Advances in intensity modulated x-ray therapy (IMXT) technology have made the delivery of custom-made non-uniform dose distributions possible in practice. Intensity modulated proton therapy (IMPT) has the potential to deliver non-uniform dose distributions as well, while significantly reducing normal tissue and organ at risk dose relative to IMXT. In this work, a specialized treatment planning system was developed for the purpose of optimizing and comparing biologically based IMXT and IMPT plans. The IMXT systems of step-and-shoot (IMXT-SAS) and helical tomotherapy (IMXT-HT) and the IMPT systems of intensity modulated spot scanning (IMPT-SS) and distal gradient tracking (IMPT-DGT), were simulated. A thorough phantom study was conducted in which several subvolumes, which were contained within a base tumor region, were boosted or avoided with IMXT and IMPT. Different boosting situations were simulated by varying the size, proximity, and the doses prescribed to the subvolumes, and the size of the phantom. IMXT and IMPT were also compared for a whole brain radiation therapy (WBRT) case, in which a brain metastasis was simultaneously boosted and the hippocampus was avoided. Finally, IMXT and IMPT dose distributions were compared for the case of non-uniform dose prescription in a head and neck cancer patient that was based on PET imaging with the Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone (Cu-ATSM) hypoxia marker. The non-uniform dose distributions within the tumor region were comparable for IMXT and IMPT. IMPT, however, was capable of delivering the same non-uniform dose distributions within a tumor using a 180° arc as for a full 360° rotation, which resulted in the reduction of normal tissue integral dose by a factor of

  17. Predictors of Local Control After Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases

    SciTech Connect

    Greco, Carlo; Zelefsky, Michael J.; Lovelock, Michael; Fuks, Zvi; Hunt, Margie; Rosenzweig, Kenneth; Zatcky, Joan; Kim, Balem; Yamada, Yoshiya

    2011-03-15

    Purpose: To report tumor local control after treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) to extracranial metastatic sites. Methods and Materials: A total of 126 metastases in 103 patients were treated with SD-IGRT to prescription doses of 18-24 Gy (median, 24 Gy) between 2004 and 2007. Results: The overall actuarial local relapse-free survival (LRFS) rate was 64% at a median follow-up of 18 months (range, 2-45 months). The median time to failure was 9.6 months (range, 1-23 months). On univariate analysis, LRFS was significantly correlated with prescription dose (p = 0.029). Stratification by dose into high (23 to 24 Gy), intermediate (21 to 22 Gy), and low (18 to 20 Gy) dose levels revealed highly significant differences in LRFS between high (82%) and low doses (25%) (p < 0.0001). Overall, histology had no significant effect on LRFS (p = 0.16). Renal cell histology displayed a profound dose-response effect, with 80% LRFS at the high dose level (23 to 24 Gy) vs. 37% with low doses ({<=}22 Gy) (p = 0.04). However, for patients who received the high dose level, histology was not a statistically significant predictor of LRFS (p = 0.90). Target organ (bone vs. lymph node vs. soft tissues) (p = 0.5) and planning target volume size (p = 0.55) were not found to be associated with long-term LRFS probability. Multivariate Cox regression analysis confirmed prescription dose to be a significant predictor of LRFS (p = 0.003). Conclusion: High-dose SD-IGRT is a noninvasive procedure resulting in high probability of local tumor control. Single-dose IGRT may be effectively used to locally control metastatic deposits regardless of histology and target organ, provided sufficiently high doses (> 22 Gy) of radiation are delivered.

  18. Practical considerations for the dosing and adjustment of continuous renal replacement therapy in the intensive care unit.

    PubMed

    Galvagno, Samuel M; Hong, Caron M; Lissauer, Matthew E; Baker, Andrew K; Murthi, Sarah B; Herr, Daniel L; Stein, Deborah M

    2013-12-01

    Familiarity with the initiation, dosing, adjustment, and termination of continuous renal replacement therapy (CRRT) is a core skill for contemporary intensivists. Guidelines for how to administer CRRT in the intensive care unit are not well documented. The purpose of this review is to discuss the modalities, terminology, and components of CRRT, with an emphasis on the practical aspects of dosing, adjustments, and termination. Management of electrolyte and acid-base derangements commonly encountered with acute renal failure is emphasized. Knowledge regarding the practical aspects of managing CRRT in the intensive care unit is a prerequisite for achieving desired physiological end points.

  19. Glutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice.

    PubMed

    Takahashi, Aki; Lee, Ray X; Iwasato, Takuji; Itohara, Shigeyoshi; Arima, Hiroshi; Bettler, Bernhard; Miczek, Klaus A; Koide, Tsuyoshi

    2015-04-22

    Although the dorsal raphe nucleus (DRN) has long been linked to neural control of aggression, little is known about the regulatory influences of the DRN when an animal engages in either adaptive species-typical aggressive behavior or escalated aggression. Therefore it is important to explore which neurotransmitter inputs into the DRN determine the escalation of aggression in male mice. Previously, we observed that microinjection of the GABAB receptor agonist baclofen into the DRN escalates aggressive behavior in male mice. Here, we used a serotonin (5-HT) neuron-specific GABAB receptor knock-out mouse to demonstrate that baclofen acts on nonserotonergic neurons to escalate aggression. Intra-DRN baclofen administration increased glutamate release, but did not alter GABA release, within the DRN. Microinjection of l-glutamate into the DRN escalated dose-dependently attack bites toward an intruder. In vivo microdialysis showed that glutamate release increased in the DRN during an aggressive encounter, and the level of glutamate was further increased when the animal was engaged in escalated aggressive behavior after social instigation. Finally, 5-HT release was increased within the DRN and also in the medial prefrontal cortex when animals were provoked by social instigation, and during escalated aggression after social instigation, but this increase in 5-HT release was not observed when animals were engaged in species-typical aggression. In summary, glutamate input into the DRN is enhanced during escalated aggression, which causes a phasic increase of 5-HT release from the DRN 5-HT neurons.

  20. Dose-Dependent Pulmonary Toxicity After Postoperative Intensity-Modulated Radiotherapy for Malignant Pleural Mesothelioma

    SciTech Connect

    Rice, David C. Smythe, W. Roy; Liao Zhongxing; Guerrero, Thomas; Chang, Joe Y.; McAleer, Mary F.; Jeter, Melenda D.; Correa, Arlene Ph.D.; Vaporciyan, Ara A.; Liu, H. Helen; Komaki, Ritsuko; Forster, Kenneth M.; Stevens, Craig W.

    2007-10-01

    Purpose: To determine the incidence of fatal pulmonary events after extrapleural pneumonectomy and hemithoracic intensity-modulated radiotherapy (IMRT) for malignant pleural mesothelioma. Methods and Materials: We retrospectively reviewed the records of 63 consecutive patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy and IMRT at University of Texas M. D. Anderson Cancer Center. The endpoints studied were pulmonary-related death (PRD) and non-cancer-related death within 6 months of IMRT. Results: Of the 63 patients, 23 (37%) had died within 6 months of IMRT (10 of recurrent cancer, 6 of pulmonary causes [pneumonia in 4 and pneumonitis in 2], and 7 of other noncancer causes [pulmonary embolus in 2, sepsis after bronchopleural fistula in 1, and cause unknown but without pulmonary symptoms or recurrent disease in 4]). On univariate analysis, the factors that predicted for PRD were a lower preoperative ejection fraction (p = 0.021), absolute volume of lung spared at 10 Gy (p = 0.025), percentage of lung volume receiving {>=}20 Gy (V{sub 20}; p 0.002), and mean lung dose (p = 0.013). On multivariate analysis, only V{sub 20} was predictive of PRD (p = 0.017; odds ratio, 1.50; 95% confidence interval, 1.08-2.08) or non-cancer-related death (p = 0.033; odds ratio, 1.21; 95% confidence interval, 1.02-1.45). Conclusion: The results of our study have shown that fatal pulmonary toxicities were associated with radiation to the contralateral lung. V{sub 20} was the only independent determinant for risk of PRD or non-cancer-related death. The mean V{sub 20} of the non-PRD patients was considerably lower than that accepted during standard thoracic radiotherapy, implying that the V{sub 20} should be kept as low as possible after extrapleural pneumonectomy.

  1. Optimal matching of 3D film-measured and planned doses for intensity-modulated radiation therapy quality assurance.

    PubMed

    Shin, Dongho; Yoon, Myonggeun; Park, Sung Yong; Park, Dong Hyun; Lee, Se Byeong; Kim, Dae Yong; Cho, Kwan Ho

    2007-01-01

    Intensity-modulated radiation therapy (IMRT) is one of the most complex applications of radiotherapy that requires patient-specific quality assurance (QA). Here, we describe a novel method of 3-dimensional (3D) dose-verification using 12 acrylic slabs in a 3D phantom (30 x 30 x 12 cm(3)) with extended dose rate (EDR2) films, which is both faster than conventionally used methods, and clinically useful. With custom-written software modules written in Microsoft Excel Visual Basic Application, the measured and planned dose distributions for the axial, coronal, and sagittal planes were superimposed by matching their origins, and the point doses were compared at all matched positions. Then, an optimization algorithm was used to correct the detected setup errors. The results show that this optimization method significantly reduces the average maximum dose difference by 7.73% and the number of points showing dose differences of more than 5% by 8.82% relative to the dose differences without an optimization. Our results indicate that the dose difference was significantly decreased with optimization and this optimization method is statistically reliable and effective. The results of 3D optimization are discussed in terms of various patient-specific QA data obtained from statistical analyses.

  2. The radiobiological effect of intra-fraction dose-rate modulation in intensity modulated radiation therapy (IMRT)

    NASA Astrophysics Data System (ADS)

    Bewes, J. M.; Suchowerska, N.; Jackson, M.; Zhang, M.; McKenzie, D. R.

    2008-07-01

    Intensity-modulated radiation therapy (IMRT) achieves optimal dose conformity to the tumor through the use of spatially and temporally modulated radiation fields. In particular, average dose rate and instantaneous dose rate (pulse amplitude) are highly variable within a single IMRT fraction. In this study we isolate these variables and determine their impact on cell survival. Survival was assessed using a clonogenic assay. Two cell lines of differing radiosensitivity were examined: melanoma (MM576) and non-small cell lung cancer (NCI-H460). The survival fraction was observed to be independent of instantaneous dose rate. A statistically significant trend to increased survival was observed as the average dose rate was decreased, for a constant total dose. The results are relevant to IMRT practice, where average treatment times can be significantly extended to allow for movement of the multi-leaf collimator (MLC). Our in vitro study adds to the pool of theoretical evidence for the consequences of protracted treatments. We find that extended delivery times can substantially increase the cell survival. This also suggests that regional variation in the dose-rate history across a tumor, which is inherent to IMRT, will affect radiation dose efficacy.

  3. Parotid Gland Dose in Intensity-Modulated Radiotherapy for Head and Neck Cancer: Is What You Plan What You Get?

    SciTech Connect

    O'Daniel, Jennifer C.; Garden, Adam S.; Schwartz, David L.; Wang He; Ang, Kian K.; Ahamad, Anesa; Rosenthal, David I.; Morrison, William H.; Asper, Joshua A.; Zhang Lifei; Tung Shihming; Mohan, Radhe; Dong Lei

    2007-11-15

    Purpose: To quantify the differences between planned and delivered parotid gland and target doses, and to assess the benefits of daily bone alignment for head and neck cancer patients treated with intensity-modulated radiotherapy (IMRT). Methods and Materials: Eleven head and neck cancer patients received two CT scans per week with an in-room CT scanner over the course of their radiotherapy. The clinical IMRT plans, designed with 3-mm to 4-mm planning margins, were recalculated on the repeat CT images. The plans were aligned using the actual treatment isocenter marked with radiopaque markers (BB) and bone alignment to the cervical vertebrae to simulate image-guided setup. In-house deformable image registration software was used to map daily dose distributions to the original treatment plan and to calculate a cumulative delivered dose distribution for each patient. Results: Using conventional BB alignment led to increases in the parotid gland mean dose above the planned dose by 5 to 7 Gy in 45% of the patients (median, 3.0 Gy ipsilateral, p = 0.026; median, 1.0 Gy contralateral, p = 0.016). Use of bone alignment led to reductions relative to BB alignment in 91% of patients (median, 2 Gy; range, 0.3-8.3 Gy; 15 of 22 parotids improved). However, the parotid dose from bone alignment was still greater than planned (median, 1.0 Gy, p = 0.007). Neither approach affected tumor dose coverage. Conclusions: With conventional BB alignment, the parotid gland mean dose was significantly increased above the planned mean dose. Using daily bone alignment reduced the parotid dose compared with BB alignment in almost all patients. A 3- to 4-mm planning margin was adequate for tumor dose coverage.

  4. Nuclear fuel pellet transfer escalator

    SciTech Connect

    Huggins, T.B. Sr.; Roberts, E.; Edmunds, M.O.

    1991-09-17

    This patent describes a nuclear fuel pellet escalator for loading nuclear fuel pellets into a sintering boat. It comprises a generally horizontally-disposed pellet transfer conveyor for moving pellets in single file fashion from a receiving end to a discharge end thereof, the conveyor being mounted about an axis at its receiving end for pivotal movement to generally vertically move its discharge end toward and away from a sintering boat when placed below the discharge end of the conveyor, the conveyor including an elongated arm swingable vertically about the axis and having an elongated channel recessed below an upper side of the arm and extending between the receiving and discharge ends of the conveyor; a pellet dispensing chute mounted to the arm of the conveyor at the discharge end thereof and extending therebelow such that the chute is carried at the discharge end of the conveyor for generally vertical movement therewith toward and away from the sintering boat.

  5. Dose distribution analysis of physical and dynamic wedges by using an intensity-modulated radiotherapy MatriXX

    NASA Astrophysics Data System (ADS)

    Lee, Hae-Kag; Cho, Jae-Hwan; Cho, Dae-chul

    2013-05-01

    This study investigated differences between the physical wedge and the dynamic wedge distributions of radiation by using an intensity-modulated radiotherapy (ImRT) MatriXX. The linear accelerator used X-rays with energy levels of 6 MV and 10 MV to adjust the collimator by motoring the independent jaws (X1, X2, Y1, Y2) for setting wedge angles of 15, 30, 45, and 60 degrees. The collimator field size was set as 10 × 10 cm2 or 20 × 20 cm2 at the maximum dose point. The dose distribution for each wedge had ±5% and ±11% errors for field sizes of 10 × 10 cm2 and 20 × 20 cm2, respectively. The error was greatest at a wedge angle of 45 degrees and was pronounced at the end of the dynamic wedge where Y1 and Y2 met. Consequently, concluded that the dose distributions were similar for both wedges for the field size of a small beam profile. The beam dose was greatly increased at the end of the dynamic wedge. A more precise estimate of the therapeutic dose of radiation for a dynamic wedge that nearly matches that of the physical wedge can be achieved by correcting of the increasing part of the beam dose. The findings imply that a heavy wedge filter should not be used when calculating the isodose distribution and the therapeutic dose.

  6. CN-18RELATIONSHIPS BETWEEN DOSE INTENSITY, TOXICITY, AND OUTCOME IN OLIGODENDROGLIAL TUMORS (OG) TREATED WITH PCV REGIMEN

    PubMed Central

    Tabouret, Emeline; Reyes-Botero, German; Dehais, Caroline; Daros, Marine; Barrie, Maryline; Matta, Mona; Petrirena, Gregorio; Autran, Didier; Duran, Alberto; Boucard, Celine; Delattre, Jean Yves; Chinot, Olivier

    2014-01-01

    BACKGROUND: In grade II and codeleted grade III gliomas, the procarbazine-CCNU-vincristine (PCV) combination increase survival when added to radiotherapy as first line treatment, despite the important toxicity of this treatment schedule. Our objective was to analyze the tolerance, feasibility and impact of dose intensity of the PCV regimen on outcome for patients with OG. METHODS: We retrospectively reviewed all grade III OG patients receiving PCV (CCNU:110mg/m2) who were referred to our two institutions. The total dose and dose adaptation, cycle delay, dose intensity, toxicity and premature discontinuation of CCNU were analyzed. Impact of these factors on patient outcome was evaluated. RESULTS: Between 2007 and 2011, 89 patients received PCV. Only 37% completed 6 cycles, whereas 13.4% prematurely discontinued PCV because of toxicity. Cycle delay and dose reduction were observed for 62% and 70% patients, respectively. Grade 3 and 4 toxicities were observed in 38% and 8% patients, respectively. Among patients who did not progress under PCV regimen, by multivariate analysis, premature discontinuation for toxicity was significantly correlated with poor PFS (p = 0.023, Hazard ratio (HR):2.354) and OS (p = 0.021, HR:5.093). By univariate analyses, absence of CCNU dose adaptation was correlated to poor PFS (p = 0.032). For OS, pejorative factors were high total CCNU dose (p = 0.029), absence of cycle delay (p = 0.009), absence of CCNU dose adaptation (p = 0.020) and grade 3/4 toxicities (p = 0.013). High CCNU dose-intensity tended to poorly impact PFS (p = 0.053) and OS (p = 0.112). By multivariate analysis, absence of CCNU dose adaptation remained significant for PFS (p = 0.001), while OS was negatively impacted by the absence of cycle delay (p = 0.049) and grade 3/4 toxicities (p = 0.045). CONCLUSION: Despite the efficacy of the PCV regimen, significant toxicity is associated with this schedule, which appears to impact its feasibility and efficacy. The optimal PCV

  7. High-Dose, Single-Fraction Image-Guided Intensity-Modulated Radiotherapy for Metastatic Spinal Lesions

    SciTech Connect

    Yamada, Yoshiya Bilsky, Mark H.; Lovelock, D. Michael; Venkatraman, Ennapadam S.; Toner, Sean; Johnson, Jared; Zatcky, Joan N.P.; Zelefsky, Michael J.; Fuks, Zvi

    2008-06-01

    Purpose: To report tumor control and toxicity for patients treated with image-guided intensity-modulated radiotherapy (RT) for spinal metastases with high-dose single-fraction RT. Methods and Materials: A total of 103 consecutive spinal metastases in 93 patients without high-grade epidural spinal cord compression were treated with image-guided intensity-modulated RT to doses of 18-24 Gy (median, 24 Gy) in a single fraction between 2003 and 2006. The spinal cord dose was limited to a 14-Gy maximal dose. The patients were prospectively examined every 3-4 months with clinical assessment and cross-sectional imaging. Results: The overall actuarial local control rate was 90% (local failure developed in 7 patients) at a median follow-up of 15 months (range, 2-45 months). The median time to local failure was 9 months (range, 2-15 months) from the time of treatment. Of the 93 patients, 37 died. The median overall survival was 15 months. In all cases, death was from progression of systemic disease and not local failure. The histologic type was not a statistically significant predictor of survival or local control. The radiation dose was a significant predictor of local control (p = 0.03). All patients without local failure also reported durable symptom palliation. Acute toxicity was mild (Grade 1-2). No case of radiculopathy or myelopathy has developed. Conclusion: High-dose, single-fraction image-guided intensity-modulated RT is a noninvasive intervention that appears to be safe and very effective palliation for patients with spinal metastases, with minimal negative effects on quality of life and a high probability of tumor control.

  8. [Intensity-modulated radiotherapy of head and neck cancers. Dose constraint for spinal cord and brachial plexus].

    PubMed

    Boisselier, P; Racadot, S; Thariat, J; Graff, P; Pointreau, Y

    2016-10-01

    Given the ballistic opportunities it offers, intensity-modulated radiotherapy has emerged as the gold standard treatment for head and neck cancers. Protection of organs at risk is one of the objectives of optimization during the planning process. The compliance of dose constraints to the nervous system must be prioritized over all others. To avoid complications, it is recommended to respect a maximum dose of 50Gy to the spinal cord, and 60Gy to the brachial plexus using conventional fractionation of 2Gy per fraction. These constraints can be adapted depending on the clinical situation; they will probably be refocused by the follow-up of the IMRT studies.

  9. Toxicity-dependent feasibility bounds for the escalation with overdose control approach in phase I cancer trials.

    PubMed

    Wheeler, Graham M; Sweeting, Michael J; Mander, Adrian P

    2017-03-15

    Phase I trials of anti-cancer therapies aim to identify a maximum tolerated dose (MTD), defined as the dose that causes unacceptable toxicity in a target proportion of patients. Both rule-based and model-based methods have been proposed for MTD recommendation. The escalation with overdose control (EWOC) approach is a model-based design where the dose assigned to the next patient is one that, given all available data, has a posterior probability of exceeding the MTD equal to a pre-specified value known as the feasibility bound. The aim is to conservatively dose-escalate and approach the MTD, avoiding severe overdosing early on in a trial. The EWOC approach has been applied in practice with the feasibility bound either fixed or varying throughout a trial, yet some of the methods may recommend incoherent dose-escalation, that is, an increase in dose after observing severe toxicity at the current dose. We present examples where varying feasibility bounds have been used in practice, and propose a toxicity-dependent feasibility bound approach that guarantees coherent dose-escalation and incorporates the desirable features of other EWOC approaches. We show via detailed simulation studies that the toxicity-dependent feasibility bound approach provides improved MTD recommendation properties to the original EWOC approach for both discrete and continuous doses across most dose-toxicity scenarios, with comparable performance to other approaches without recommending incoherent dose escalation. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  10. Impact of Dose to the Bladder Trigone on Long-Term Urinary Function After High-Dose Intensity Modulated Radiation Therapy for Localized Prostate Cancer

    SciTech Connect

    Ghadjar, Pirus; Zelefsky, Michael J.; Spratt, Daniel E.; Munck af Rosenschöld, Per; Oh, Jung Hun; Hunt, Margie; Kollmeier, Marisa; Happersett, Laura; Yorke, Ellen; Deasy, Joseph O.; Jackson, Andrew

    2014-02-01

    Purpose: To determine the potential association between genitourinary (GU) toxicity and planning dose–volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients. Methods and Materials: A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose–volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analyses were done by the Kaplan-Meier method and Cox proportional hazard models, respectively. Results: Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19). Conclusions: The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the

  11. De-escalation, adequacy of antibiotic therapy and culture positivity in septic patients: an observational study

    PubMed Central

    Moraes, Rafael Barberena; Guillén, Julián Alberto Viteri; Zabaleta, William Javier Castillo; Borges, Flavia Kessler

    2016-01-01

    Objective To evaluate the prevalence of antibiotic de-escalation in patients diagnosed with severe sepsis or septic shock at a public academic tertiary hospital and to evaluate antibiotic adequacy and culture positivity. Methods The prevalence of antibiotic de-escalation, the adequacy of antibiotic treatment and the rates of culture positivity were analyzed in patients with severe sepsis and septic shock between April and December 2013 at an intensive care unit in a tertiary university hospital. Results Among the 224 patients included in the study, de-escalation was appropriate in 66 patients (29.4%) but was implemented in 44 patients (19.6%). Among the patients who underwent de-escalation, half experienced narrowing of the antimicrobial spectrum. The mortality rate was 56.3%, with no differences between the patients with or without de-escalation (56.8% versus 56.1%; p = 0.999) nor in the length of hospital stay. Empirical antibiotic therapy was appropriate in 89% of cases. Microorganisms were isolated from total cultures in 30% of cases and from blood cultures in 26.3% of cases. Conclusion The adequacy rate of empirical antibiotic therapy was high, reflecting an active institutional policy of monitoring epidemiological profiles and institutional protocols on antimicrobial use. However, antibiotic de-escalation could have been implemented in a greater number of patients. De-escalation did not affect mortality rates. PMID:27626951

  12. A phase 1-2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function.

    PubMed

    Ghali, Jalal K; Smith, William B; Torre-Amione, Guillermo; Haynos, William; Rayburn, Barry K; Amato, Antonino; Zhang, Dan; Cowart, Doug; Valentini, Giovanni; Carminati, Paolo; Gheorghiade, Mihai

    2007-01-22

    Istaroxime (PST2744) is a luso-inotrope that stimulates the sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a without chronotropic effects. Additionally, it has beneficial effects on myocardial energetics. This phase 1-2 clinical trial in patients with chronic stable heart failure (HF) is the first evaluation of istaroxime in humans. Three cohorts of 6 patients each were exposed to 4 sequentially increasing 1-hour infusions with a random placebo. Doses were 0.005-5.0 micro/kg per min. Safety and hemodynamics were evaluated by impedance cardiography, digital Holter recorder, and electrocardiography. Pharmacokinetic data were obtained for 1 hour during treatment and for 6 hours after dosing. The mean age was 53+/-7 years, and the mean left ventricular ejection fraction was 0.27+/-0.08. Impedance cardiography demonstrated enhanced contractility as measured by the acceleration index, left cardiac work index, cardiac index, and pulse pressure at doses>or=1 micro/kg per min, with evidence of activity at doses of 0.5 micro/kg per min. Istaroxime shortened QTc. After infusion, the hemodynamic effect rapidly dissipated over 1-2 hours. Istaroxime was pharmacologically active and well tolerated at doses up to 3.33 micro/kg per min. Side effects were related to gastrointestinal symptoms and injection site pain at higher doses, which dissipated within minutes after the infusion ended. Ventricular ectopy was not altered. This study suggests that istaroxime is potentially useful in the treatment of HF and may offer a unique treatment for systolic and/or diastolic dysfunction. Additional studies are under way to further define its utility in acute HF.

  13. A simple optimization approach for improving target dose homogeneity in intensity-modulated radiotherapy for sinonasal cancer

    PubMed Central

    Lu, Jia-Yang; Zhang, Ji-Yong; Li, Mei; Cheung, Michael Lok-Man; Li, Yang-Kang; Zheng, Jing; Huang, Bao-Tian; Zhang, Wu-Zhe

    2015-01-01

    Homogeneous target dose distribution in intensity-modulated radiotherapy (IMRT) for sinonasal cancer (SNC) is challenging to achieve. To solve this problem, we established and evaluated a basal-dose-compensation (BDC) optimization approach, in which the treatment plan is further optimized based on the initial plans. Generally acceptable initial IMRT plans for thirteen patients were created and further optimized individually by (1) the BDC approach and (2) a local-dose-control (LDC) approach, in which the initial plan is further optimized by addressing hot and cold spots. We compared the plan qualities, total planning time and monitor units (MUs) among the initial, BDC, LDC IMRT plans and volumetric modulated arc therapy (VMAT) plans. The BDC approach provided significantly superior dose homogeneity/conformity by 23%–48%/6%–9% compared with both the initial and LDC IMRT plans, as well as reduced doses to the organs at risk (OARs) by up to 18%, with acceptable MU numbers. Compared with VMAT, BDC IMRT yielded superior homogeneity, inferior conformity and comparable overall OAR sparing. The planning of BDC, LDC IMRT and VMAT required 30, 59 and 58 minutes on average, respectively. Our results indicated that the BDC optimization approach can achieve significantly better dose distributions with shorter planning time in the IMRT for SNC. PMID:26497620

  14. A phase II study of dose-dense and dose-intense ABVD (ABVDDD-DI ) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma.

    PubMed

    Russo, Filippo; Corazzelli, Gaetano; Frigeri, Ferdinando; Capobianco, Gaetana; Aloj, Luigi; Volzone, Francesco; De Chiara, Annarosaria; Bonelli, Annamaria; Gatani, Tindaro; Marcacci, Gianpaolo; Donnarumma, Daniela; Becchimanzi, Cristina; de Lutio, Elisabetta; Ionna, Franco; De Filippi, Rosaria; Lastoria, Secondo; Pinto, Antonello

    2014-07-01

    We explored activity and safety of a dose-dense/dose-intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVDDD-DI ) in 82 patients with advanced Hodgkin Lymphoma. Patients entered a two-stage Bryant-Day Phase II study to receive six cycles of ABVDDD-DI without consolidation radiotherapy. Cycles were supported with granulocyte colony-stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m2; first four cycles only). Co-primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event-free (EFS) and disease-free survival (DFS). All patients received the four doxorubicin-intensified courses and 96% concluded all six cycles (82.3% within the intended 18 weeks). This translated into a 66.9% increase of received dose-intensity for doxorubicin and 31.8% for the other agents over standard ABVD. The CR rate was 95.1% (78/82) and 87.8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14.6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five-year EFS and DFS was 88.3% and 93.7%, respectively. ABVDDD-DI regimen was well-tolerated and ensured substantial CR and EFS rates without radiotherapy.

  15. Idarubicin appears equivalent to dose-intense daunorubicin for remission induction in patients with acute myeloid leukemia.

    PubMed

    Trifilio, Steven; Zhou, Zheng; Mehta, Jayesh; Czerniak, Colleen; Pi, Judy; Greenberg, Deborah; Koslosky, Molly; Pantiru, Mihaela; Altman, Jessica

    2013-08-01

    Daunorubicin has historically been considered the anthracycline of choice at many cancer centers for the treatment of acute myeloid leukemia (AML). Drug shortages have required the substitution of daunorubicin with idarubicin. Randomized studies have shown idarubicin (10-12mg/m(2)) to be comparable or superior to standard dose daunorubicin (45-60mg/m(2)) for achieving complete remission (CR). Whether these results can be extrapolated to dose-intense daunorubicin (90mg/m(2)), recently shown to improve CR rates when compared to standard daunorubicin doses remains uncertain. This observational study was conducted at Northwestern Memorial Hospital (NMH) to compare CR rates. The results suggest idarubicin is equivalent to daunorubicin, and for some subsets of patients, idarubicin may have superior CR rates.

  16. [Intensity-modulated radiotherapy of head and neck cancers: Dose effects on the ocular, orbital and eyelid structures].

    PubMed

    Thariat, J; Racadot, S; Pointreau, Y; Boisselier, P; Grange, J-D; Graff, P; Weber, D C

    2016-10-01

    Radiation-induced damage of ocular, orbital and eyelid structures are mainly reported for the optic nerve, retina, lens and lacrimal gland. Dose-volume relationships are, however, inaccurate due to the small volume of most of the organs at risk involved and limited ability of irradiation techniques to spare these structures in the pre-IMRT (intensity-modulated radiation therapy) era. The ability of newest radiation techniques including IMRT and proton therapy to generate steep dose gradients may yield more accurate models in the future. Some toxicities are severe and irreversible, leading to vision loss, as in the case of radiation-induced optic neuropathy for which curative treatments are suboptimal. Other toxicities can lead to reversible vision loss but can be surgically corrected, as is the case for radiation-induced cataract. In this paper, we will review the dose effects for the ocular; orbital and eyelid structures.

  17. Dose verification of intensity-modulated arc therapy using an ERGO++ treatment planning system and Elekta internal multileaf collimators for prostate cancer treatment.

    PubMed

    Yoda, K; Nakagawa, K; Shiraishi, K; Okano, Y; Ohtomo, K; Pellegrini, R G

    2009-04-01

    Dose verification of intensity-modulated arc therapy using an ERGO++ treatment planning system and Elekta internal multileaf collimators is described. Prostate intensity-modulated arc therapy was planned using the arc modulation optimization algorithm inverse planning module of ERGO++. After transferring the plan to Elekta Synergy's controller (Elekta Ltd, Crawley, UK), the isocentre dose was measured and compared with a calculated dose using a pinpoint chamber and a water phantom in a cylindrical acrylic enclosure. Subsequently, an EDR2 film was placed inside a multilayer plastic phantom, and total dose distributions were measured in three axial planes as well as in the coronal and sagittal planes to compare the actual dose with the calculated dose. The dose discrepancy at the isocentre was 1.7%. The calculated gamma indices were less than 1 over 90% of the three axial planes, as well as in the coronal and sagittal planes, having a dose greater than 50% of the maximum target dose.

  18. The Integrated Web Portal for Escalation with Overdose Control (EWOC).

    PubMed

    Wang, Haibin; Tighiouart, Mourad; Huang, Shao-Chi; Berel, Dror; Cook-Wiens, Galen; Bresee, Catherine; Li, Quanlin; Rogatko, André

    2013-01-01

    In this paper, we present the design and implementation of a novel web portal for the cancer phase I clinical trial design method Escalation with Overdose Control (EWOC). The web portal has two major components: a web-based dose finding calculator; and a standalone and downloadable dose finding software which can be installed on Windows operating systems. The web-based dose finding calculator uses industry standards and is a database-driven and distributed computing platform for designing and conducting dose finding in cancer phase I clinical trials utilizing EWOC methodology. The web portal is developed using open source software: PHP, JQuery, R and OpenBUGS. It supports any standard browsers with internet connection. The web portal can be accessed at: http://biostatistics.csmc.edu.

  19. Large Cohort Dose-Volume Response Analysis of Parotid Gland Function After Radiotherapy: Intensity-Modulated Versus Conventional Radiotherapy

    SciTech Connect

    Dijkema, Tim Terhaard, Chris H.J.; Roesink, Judith M.; Braam, Petra M.; Gils, Carla H. van; Moerland, Marinus A.; Raaijmakers, Cornelis P.J.

    2008-11-15

    Purpose: To compare parotid gland dose-volume response relationships in a large cohort of patients treated with intensity-modulated (IMRT) and conventional radiotherapy (CRT). Methods and materials: A total of 221 patients (64 treated with IMRT, 157 with CRT) with various head-and-neck malignancies were prospectively evaluated. The distribution of tumor subsites in both groups was unbalanced. Stimulated parotid flow rates were measured before and 6 weeks, 6 months, and 1 year after radiotherapy. Parotid gland dose-volume histograms were derived from computed tomography-based treatment planning. The normal tissue complication probability (NTCP) model proposed by Lyman was fit to the data. A complication was defined as stimulated parotid flow ratio <25% of the pretreatment flow rate. The relative risk of complications was determined for IMRT vs. CRT and adjusted for the mean parotid gland dose using Poisson regression modeling. Results: One year after radiotherapy, NTCP curves for IMRT and CRT were comparable with a TD{sub 50} (uniform dose leading to a 50% complication probability) of 38 and 40 Gy, respectively. Until 6 months after RT, corrected for mean dose, different complication probabilities existed for IMRT vs. CRT. The relative risk of a complication for IMRT vs. CRT after 6 weeks was 1.42 (95% CI 1.21-1.67), after 6 months 1.41 (95% CI; 1.12-1.77), and at 1 year 1.21 (95% CI 0.87-1.68), after correcting for mean dose. Conclusions: One year after radiotherapy, no difference existed in the mean dose-based NTCP curves for IMRT and CRT. Early after radiotherapy (up to 6 months) mean dose based (Lyman) models failed to fully describe the effects of radiotherapy on the parotid glands.

  20. Contribution of Occupation to High Doses of Light-Intensity Activity and Cardiovascular Risk Factors among Mexican American Adults

    PubMed Central

    Gay, Jennifer L.; Kohl, Harold W.; Salinas, Jennifer J.; McCormick, Joseph B.; Fisher-Hoch, Susan P.

    2015-01-01

    Background The association between light-intensity activity and cardiovascular disease risk is not well understood. The purpose of this study was to determine the association of light-intensity activity with census-based occupational activity classifications and cardiovascular risk factors among Mexican American adults. Methods 118 Mexican American adults (68.6% female) provided cross-sectional accelerometer and biological data. Self-reported occupations were classified by activity level (sedentary, low, moderate). Participants were classified as At-Risk for BMI, glucose, triglycerides, HDL, blood pressure, waist circumference, and percent body fat. Results Participants engaged in > 5 hours of light-intensity activity on average, and those in sedentary occupations engaged in fewer light-intensity activity minutes than low-active or moderately active workers (P < .001). Self-reported occupation explained 14% of the variation in light-intensity activity (P < .001). Participants in moderately active occupations were at increased risk for high %body fat than other workers (P = .01), but no other associations between occupation and cardiovascular risk were detected. Conclusion Early work in physical activity underscored the importance of occupational activity. This study presents evidence of a dose-response association for light-intensity activity by occupational category such that workers in sedentary occupations had less light-intensity activity than employees in more active occupations. Future research on how light-intensity activity derived from occupation may reduce the risk of chronic disease will contribute to improved interventions as light-intensity activity participation may be more feasible than meeting current physical activity guidelines. PMID:24368819

  1. Dose Volume Histogram (DVH) Analysis in Intensity Modulation Radiation Therapy (IMRT) Treatments for Prostate Cancers

    NASA Astrophysics Data System (ADS)

    Pyakuryal, Anil

    2009-05-01

    Studies have shown that as many as 8 out of 10 men had prostate cancer by age 80.Prostate cancer begins with small changes (prostatic intraepithelial neoplasia(PIN)) in size and shape of prostate gland cells,known as prostate adenocarcinoma.With advent in technology, prostate cancer has been the most widely used application of IMRT with the longest follow-up periods.Prostate cancer fits the ideal target criteria for IMRT of adjacent sensitive dose-limiting tissue (rectal, bladder).A retrospective study was performed on 10 prostate cancer patients treated with radiation to a limited pelvic field with a standard 4 field arrangements at dose 45 Gy, and an IMRT boost field to a total isocenter dose of 75 Gy.Plans were simulated for 4 field and the supplementary IMRT treatments with proposed dose delivery at 1.5 Gy/fraction in BID basis.An automated DVH analysis software, HART (S. Jang et al., 2008,Med Phys 35,p.2812)was used to perform DVH assessments in IMRT plans.A statistical analysis of dose coverage at targets in prostate gland and neighboring critical organs,and the plan indices(homogeneity, conformality etc) evaluations were also performed using HART extracted DVH statistics.Analyzed results showed a better correlation with the proposed outcomes (TCP, NTCP) of the treatments.

  2. Escalate shamefully, de-escalate angrily or gratefully: the influence of discrete emotions on escalation of commitment.

    PubMed

    Dang, Junhua; Xiao, Shanshan; Liljedahl, Sophie

    2014-08-01

    Decision makers often tend to escalate their commitment when faced with a dilemma of whether to continue a losing course of action. Researchers recently began to investigate the influence of discrete emotions on this decision tendency. However, this work has mainly focused on negative emotions and rarely considered positive emotions, to say nothing of comparing the effects of both of them simultaneously. The current study addresses this need by presenting the results of three experiments that examined the effects of four emotions of both positive and negative valences in escalation situations. Experiment 1 investigated the relationships of three trait emotions (hope, shame, and anger) and escalation of commitment. Experiments 2 and 3 examined the effects of three induced emotions (anger, shame, and gratitude) on escalation of commitment in a student sample and an employee sample, respectively. The results revealed that the effects of discrete emotions in escalation situations are mainly due to their associated differences on the appraisal dimension of responsibility that is related to escalation situations rather than their valence. The theoretical and practical implications are discussed.

  3. Escalation and De-escalation of Therapy in COPD: Myths, Realities and Perspectives.

    PubMed

    Cazzola, Mario; Rogliani, Paola; Matera, Maria Gabriella

    2015-09-01

    Chronic obstructive pulmonary disease (COPD) guidelines and strategies suggest escalating treatment, mainly depending on the severity of airflow obstruction. However, some de-escalation of therapy in COPD would be appropriate, although we still do not know when we should switch, step-up or step-down treatments in our patients. Unfortunately, trials comparing different strategies of step-up and step-down treatment (e.g. treatment initiation with one single agent and then further step-up if symptoms are not controlled versus initial use of double or triple therapy, possibly with lower doses of the individual components, or the role of N-acetylcysteine in combination therapy for a step-down approach) are still lacking. In general, there is a large and often inappropriate use of the inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination. However, the withdrawal of the ICS in COPD patients at low risk of exacerbation can be safe, provided that patients are under regular treatment with long-acting bronchodilators. Maximising the treatment in patients with a degree of clinical instability by including an ICS in the therapeutic regimen is useful to control the disease, but may not be needed during periods of clinical stability. In patients with severe but stable COPD, the withdrawal of the ICS from triple therapy [LABA + long-acting muscarinic antagonist (LAMA) + ICS] is possible, but not when the patient has been hospitalised for an acute exacerbation of COPD. We must still establish how long we should wait before withdrawing the ICS. It is still unclear whether the same is true when only the LABA or the LAMA is withdrawn while continuing treatment with the other bronchodilator and the ICS. In any case, we strongly believe that it is always better to avoid a therapeutic step-up progression when it is not needed rather than being forced subsequently into a step-down approach in which the outcome is always unpredictable.

  4. [Intensity modulated radiotherapy for head and neck cancer, dose constraint for normal tissue: Cochlea vestibular apparatus and brainstem].

    PubMed

    Guimas, V; Thariat, J; Graff-Cailleau, P; Boisselier, P; Pointreau, Y; Pommier, P; Montbarbon, X; Laude, C; Racadot, S

    2016-10-01

    Modern techniques such as intensity modulated radiation therapy (IMRT) have been proven to significantly decrease the dose delivered to the cochleovestibular apparatus, limiting consecutive toxicity especially for sensorineural hearing loss. However, recent data still report a 42% rate of radio-induced hypoacusia underscoring the need to protect the cochleovestibular apparatus. Due to the small size of the cochlea, a precise dose-volume analysis could not be performed, and recommendations only refer to the mean dose. Confusing factors such as age, concomitant chemotherapy, primary site and tumor stage should be taken into account at the time of treatment planning. (Non-coplanar) VMAT and tomotherapy have been proven better at sparing the cochlea in comparison with 3D CRT. Brainstem radio-induced injuries were poorly studied because of their infrequency and the difficulty of distinguishing between necrosis and tumor progression in the case of a primary tumor located at the base of skull. The following toxicities have been described: brainstem focal radionecrosis, cognitive disorders without dementia, cranial nerve injuries and sensori motor disability. Maximal dose to the brainstem should be kept to < 54Gy for conventional fractionation. This dose could be exceeded (no more than 10mL should receive more than 59Gy), provided this hot spot is located in the peripheral area of the organ.

  5. Comparison of linear and nonlinear programming approaches for "worst case dose" and "minmax" robust optimization of intensity-modulated proton therapy dose distributions.

    PubMed

    Zaghian, Maryam; Cao, Wenhua; Liu, Wei; Kardar, Laleh; Randeniya, Sharmalee; Mohan, Radhe; Lim, Gino

    2017-03-01

    Robust optimization of intensity-modulated proton therapy (IMPT) takes uncertainties into account during spot weight optimization and leads to dose distributions that are resilient to uncertainties. Previous studies demonstrated benefits of linear programming (LP) for IMPT in terms of delivery efficiency by considerably reducing the number of spots required for the same quality of plans. However, a reduction in the number of spots may lead to loss of robustness. The purpose of this study was to evaluate and compare the performance in terms of plan quality and robustness of two robust optimization approaches using LP and nonlinear programming (NLP) models. The so-called "worst case dose" and "minmax" robust optimization approaches and conventional planning target volume (PTV)-based optimization approach were applied to designing IMPT plans for five patients: two with prostate cancer, one with skull-based cancer, and two with head and neck cancer. For each approach, both LP and NLP models were used. Thus, for each case, six sets of IMPT plans were generated and assessed: LP-PTV-based, NLP-PTV-based, LP-worst case dose, NLP-worst case dose, LP-minmax, and NLP-minmax. The four robust optimization methods behaved differently from patient to patient, and no method emerged as superior to the others in terms of nominal plan quality and robustness against uncertainties. The plans generated using LP-based robust optimization were more robust regarding patient setup and range uncertainties than were those generated using NLP-based robust optimization for the prostate cancer patients. However, the robustness of plans generated using NLP-based methods was superior for the skull-based and head and neck cancer patients. Overall, LP-based methods were suitable for the less challenging cancer cases in which all uncertainty scenarios were able to satisfy tight dose constraints, while NLP performed better in more difficult cases in which most uncertainty scenarios were hard to meet

  6. Strategies for Online Organ Motion Correction for Intensity-Modulated Radiotherapy of Prostate Cancer: Prostate, Rectum, and Bladder Dose Effects

    SciTech Connect

    Rijkhorst, Erik-Jan; Lakeman, Annemarie; Nijkamp, Jasper; Bois, Josien de; Herk, Marcel van; Lebesque, Joos V.; Sonke, Jan-Jakob

    2009-11-15

    Purpose: To quantify and evaluate the accumulated prostate, rectum, and bladder dose for several strategies including rotational organ motion correction for intensity-modulated radiotherapy (IMRT) of prostate cancer using realistic organ motion data. Methods and Materials: Repeat computed tomography (CT) scans of 19 prostate patients were used. Per patient, two IMRT plans with different uniform margins were created. To quantify prostate and seminal vesicle motion, repeat CT clinical target volumes (CTVs) were matched onto the planning CTV using deformable registration. Four different strategies, from online setup to full motion correction, were simulated. Rotations were corrected for using gantry and collimator angle adjustments. Prostate, rectum, and bladder doses were accumulated for each patient, plan, and strategy. Minimum CTV dose (D{sub min}), rectum equivalent uniform dose (EUD, n = 0.13), and bladder surface receiving >=78 Gy (S78), were calculated. Results: With online CTV translation correction, a 7-mm margin was sufficient (i.e., D{sub min} >= 95% of the prescribed dose for all patients). A 4-mm margin required additional rotational correction. Margin reduction lowered the rectum EUD(n = 0.13) by approx2.6 Gy, and the bladder S78 by approx1.9%. Conclusions: With online correction of both translations and rotations, a 4-mm margin was sufficient for 15 of 19 patients, whereas the remaining four patients had an underdosed CTV volume <1%. Margin reduction combined with online corrections resulted in a similar or lower dose to the rectum and bladder. The more advanced the correction strategy, the better the planned and accumulated dose agreed.

  7. Decreasing Temporal Lobe Dose With Five-Field Intensity-Modulated Radiotherapy for Treatment of Pituitary Macroadenomas

    SciTech Connect

    Parhar, Preeti K.; Duckworth, Tamara; Shah, Parinda; DeWyngaert, J. Keith; Narayana, Ashwatha; Formenti, Silvia C.; Shah, Jinesh N.

    2010-10-01

    Purpose: To compare temporal lobe dose delivered by three pituitary macroadenoma irradiation techniques: three-field three-dimensional conformal radiotherapy (3D-CRT), three-field intensity-modulated radiotherapy (3F IMRT), and a proposed novel alternative of five-field IMRT (5F IMRT). Methods and Materials: Computed tomography-based external beam radiotherapy planning was performed for 15 pituitary macroadenoma patients treated at New York University between 2002 and 2007 using: 3D-CRT (two lateral, one midline superior anterior oblique [SAO] beams), 3F IMRT (same beam angles), and 5F IMRT (same beam angles with additional right SAO and left SAO beams). Prescription dose was 45 Gy. Target volumes were: gross tumor volume (GTV) = macroadenoma, clinical target volume (CTV) = GTV, and planning target volume = CTV + 0.5 cm. Structure contouring was performed by two radiation oncologists guided by an expert neuroradiologist. Results: Five-field IMRT yielded significantly decreased temporal lobe dose delivery compared with 3D-CRT and 3F IMRT. Temporal lobe sparing with 5F IMRT was most pronounced at intermediate doses: mean V25Gy (% of total temporal lobe volume receiving {>=}25 Gy) of 13% vs. 28% vs. 29% for right temporal lobe and 14% vs. 29% vs. 30% for left temporal lobe for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10{sup -7} for 5F IMRT vs. 3D-CRT and 5F IMRT vs. 3F IMRT). Five-field IMRT plans did not compromise target coverage, exceed normal tissue dose constraints, or increase estimated brain integral dose. Conclusions: Five-field IMRT irradiation technique results in a statistically significant decrease in the dose to the temporal lobes and may thus help prevent neurocognitive sequelae in irradiated pituitary macroadenoma patients.

  8. Tumor Control Outcomes After Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases From Renal Cell Carcinoma

    SciTech Connect

    Zelefsky, Michael J.; Greco, Carlo; Motzer, Robert; Magsanoc, Juan Martin; Pei Xin; Lovelock, Michael; Mechalakos, Jim; Zatcky, Joan; Fuks, Zvi; Yamada, Yoshiya

    2012-04-01

    Purpose: To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Patients and Methods: Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48). Results: The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a high single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). Conclusion: High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking.

  9. Flu, risks, and videotape: escalating fear and avoidance.

    PubMed

    Rosoff, Heather; John, Richard S; Prager, Fynnwin

    2012-04-01

    While extensive risk perception research has focused on emotions, cognitions, and behavior at static points in time, less attention has been paid to how these variables might change over time. This study assesses how negative affect, threat beliefs, perceived risk, and intended avoidance behavior change over the course of an escalating biological disaster. A scenario simulation methodology was used that presents respondents with a video simulation of a 15-day series of local news reports to immerse respondents in the developing details of the disaster. Systemic manipulation of the virus's causal origin (terrorist attack, medical lab accident, unknown) and the respondent's proximity to the virus (local vs. opposite coast) allowed us to investigate the dynamics of public response. The unfolding scenario was presented in discrete episodes, allowing responses to be tracked over the episodes. The sample includes 600 respondents equally split by sex and by location, with half in the Washington, DC area, and half in the Los Angeles area. The results showed respondents' reactions to the flu epidemic increased as the disaster escalated. More importantly, there was considerable consistency across respondents' emotional, cognitive, and behavioral responses to the epidemic over the episodes. In addition, the reactions of respondents proximally closer to the epidemic increased more rapidly and with greater intensity than their distant counterparts. Finally, as the flu epidemic escalated, both terrorist and accidental flu releases were perceived as being less risky and were less likely to lead to avoidance behavior compared to the unknown flu release.

  10. Intensity-modulated radiation therapy for pancreatic and prostate cancer using pulsed low–dose rate delivery techniques

    SciTech Connect

    Li, Jie; Lang, Jinyi; Wang, Pei; Kang, Shengwei; Lin, Mu-han; Chen, Xiaoming; Chen, Fu; Guo, Ming; Chen, Lili; Ma, Chang-Ming Charlie

    2014-01-01

    Reirradiation of patients who were previously treated with radiotherapy is vastly challenging. Pulsed low–dose rate (PLDR) external beam radiotherapy has the potential to reduce normal tissue toxicities while providing significant tumor control for recurrent cancers. This work investigates treatment planning techniques for intensity-modulated radiation therapy (IMRT)-based PLDR treatment of various sites, including cases with pancreatic and prostate cancer. A total of 20 patients with clinical recurrence were selected for this study, including 10 cases with pancreatic cancer and 10 with prostate cancer. Large variations in the target volume were included to test the ability of IMRT using the existing treatment planning system and optimization algorithm to deliver uniform doses in individual gantry angles/fields for PLDR treatments. Treatment plans were generated with 10 gantry angles using the step-and-shoot IMRT delivery technique, which can be delivered in 3-minute intervals to achieve an effective low dose rate of 6.7 cGy/min. Instead of dose constraints on critical structures, ring structures were mainly used in PLDR-IMRT optimization. In this study, the PLDR-IMRT plans were compared with the PLDR-3-dimensional conformal radiation therapy (3DCRT) plans and the PLDR-RapidArc plans. For the 10 cases with pancreatic cancer that were investigated, the mean planning target volume (PTV) dose for each gantry angle in the PLDR-IMRT plans ranged from 17.6 to 22.4 cGy. The maximum doses ranged between 22.9 and 34.8 cGy. The minimum doses ranged from 8.2 to 17.5 cGy. For the 10 cases with prostate cancer that were investigated, the mean PTV doses for individual gantry angles ranged from 18.8 to 22.6 cGy. The maximum doses per gantry angle were between 24.0 and 34.7 cGy. The minimum doses per gantry angle ranged from 4.4 to 17.4 cGy. A significant reduction in the organ at risk (OAR) dose was observed with the PLDR-IMRT plan when compared with that using the PLDR-3DCRT

  11. Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness

    NASA Technical Reports Server (NTRS)

    Cajochen, C.; Zeitzer, J. M.; Czeisler, C. A.; Dijk, D. J.

    2000-01-01

    Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to <3 lux for several hours. Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

  12. Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness.

    PubMed

    Cajochen, C; Zeitzer, J M; Czeisler, C A; Dijk, D J

    2000-10-01

    Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to <3 lux for several hours. Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

  13. First dose-map measured with a polycrystalline diamond 2D dosimeter under an intensity modulated radiotherapy beam

    NASA Astrophysics Data System (ADS)

    Scaringella, M.; Zani, M.; Baldi, A.; Bucciolini, M.; Pace, E.; de Sio, A.; Talamonti, C.; Bruzzi, M.

    2015-10-01

    A prototype of bidimensional dosimeter made on a 2.5×2.5 cm2 active area polycrystalline Chemical Vapour Deposited (pCVD) diamond film, equipped with a matrix of 12×12 contacts connected to the read-out electronics, has been used to evaluate a map of dose under Intensity Modulated Radiation Therapy (IMRT) fields for a possible application in pre-treatment verifications of cancer treatments. Tests have been performed under a 6-10 MVRX beams with IMRT fields for prostate and breast cancer. Measurements have been taken by measuring the 144 pixels in different positions, obtained by shifting the device along the x/y axes to span a total map of 14.4×10 cm2. Results show that absorbed doses measured by our pCVD diamond device are consistent with those calculated by the Treatment Planning System (TPS).

  14. Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34+ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation.

    PubMed

    Martin, Paul S; Li, Shuli; Nikiforow, Sarah; Alyea, Edwin P; Antin, Joseph H; Armand, Philippe; Cutler, Corey S; Ho, Vincent T; Kekre, Natasha; Koreth, John; Luckey, C John; Ritz, Jerome; Soiffer, Robert J

    2016-04-01

    Mobilized peripheral blood is the most common graft source for allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning. In assessing the effect of donor cell dose and graft composition on major transplant outcomes in the reduced-intensity setting, prior studies focused primarily on CD34(+)cell dose and reported conflicting results, especially in relation to survival end-points. While the impact of total nucleated cell dose has been less frequently evaluated, available studies suggest higher total nucleated cell dose is associated with improved survival outcomes in the reduced-intensity setting. In order to further explore the relationship between CD34(+)cell dose and total nucleated cell dose on reduced-intensity transplant outcomes, we analyzed the effect of donor graft dose and composition on outcomes of 705 patients with hematologic malignancies who underwent reduced-intensity peripheral blood stem cell transplantation at the Dana Farber Cancer Institute from 2000 to 2010. By multivariable analysis we found that higher total nucleated cell dose (top quartile; ≥10.8 × 10(10)cells) was associated with improved overall survival [HR 0.69 (0.54-0.88),P=0.0028] and progression-free survival [HR 0.68 (0.54-0.85),P=0.0006]. Higher total nucleated cell dose was independently associated with decreased relapse [HR 0.66 (0.51-0.85),P=0.0012] and increased incidence of chronic graft-versus-host disease [HR 1.4 (1.12-1.77),P=0.0032]. In contrast, higher doses of CD34(+)cells (top quartile; ≥10.9 × 10(6)/kg) had no significant effect on graft-versus-host disease or survival outcomes. These data suggest total nucleated cell dose is a more relevant prognostic variable for reduced-intensity transplant outcomes than the more commonly studied CD34(+)cell dose.

  15. Feasibility of a fast inverse dose optimization algorithm for IMRT via matrix inversion without negative beamlet intensities

    SciTech Connect

    Goldman, S.P.; Chen, J.Z.; Battista, J.J.

    2005-09-15

    A fast optimization algorithm is very important for inverse planning of intensity modulated radiation therapy (IMRT), and for adaptive radiotherapy of the future. Conventional numerical search algorithms such as the conjugate gradient search, with positive beam weight constraints, generally require numerous iterations and may produce suboptimal dose results due to trapping in local minima. A direct solution of the inverse problem using conventional quadratic objective functions without positive beam constraints is more efficient but will result in unrealistic negative beam weights. We present here a direct solution of the inverse problem that does not yield unphysical negative beam weights. The objective function for the optimization of a large number of beamlets is reformulated such that the optimization problem is reduced to a linear set of equations. The optimal set of intensities is found through a matrix inversion, and negative beamlet intensities are avoided without the need for externally imposed ad-hoc constraints. The method has been demonstrated with a test phantom and a few clinical radiotherapy cases, using primary dose calculations. We achieve highly conformal primary dose distributions with very rapid optimization times. Typical optimization times for a single anatomical slice (two dimensional) (head and neck) using a LAPACK matrix inversion routine in a single processor desktop computer, are: 0.03 s for 500 beamlets; 0.28 s for 1000 beamlets; 3.1 s for 2000 beamlets; and 12 s for 3000 beamlets. Clinical implementation will require the additional time of a one-time precomputation of scattered radiation for all beamlets, but will not impact the optimization speed. In conclusion, the new method provides a fast and robust technique to find a global minimum that yields excellent results for the inverse planning of IMRT.

  16. Feasibility of a fast inverse dose optimization algorithm for IMRT via matrix inversion without negative beamlet intensities.

    PubMed

    Goldman, S P; Chen, J Z; Battista, J J

    2005-09-01

    A fast optimization algorithm is very important for inverse planning of intensity modulated radiation therapy (IMRT), and for adaptive radiotherapy of the future. Conventional numerical search algorithms such as the conjugate gradient search, with positive beam weight constraints, generally require numerous iterations and may produce suboptimal dose results due to trapping in local minima. A direct solution of the inverse problem using conventional quadratic objective functions without positive beam constraints is more efficient but will result in unrealistic negative beam weights. We present here a direct solution of the inverse problem that does not yield unphysical negative beam weights. The objective function for the optimization of a large number of beamlets is reformulated such that the optimization problem is reduced to a linear set of equations. The optimal set of intensities is found through a matrix inversion, and negative beamlet intensities are avoided without the need for externally imposed ad-hoc constraints. The method has been demonstrated with a test phantom and a few clinical radiotherapy cases, using primary dose calculations. We achieve highly conformal primary dose distributions with very rapid optimization times. Typical optimization times for a single anatomical slice (two dimensional) (head and neck) using a LAPACK matrix inversion routine in a single processor desktop computer, are: 0.03 s for 500 beamlets; 0.28 s for 1000 beamlets; 3.1 s for 2000 beamlets; and 12 s for 3000 beamlets. Clinical implementation will require the additional time of a one-time precomputation of scattered radiation for all beamlets, but will not impact the optimization speed. In conclusion, the new method provides a fast and robust technique to find a global minimum that yields excellent results for the inverse planning of IMRT.

  17. Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma

    PubMed Central

    Jethava, Y; Mitchell, A; Zangari, M; Waheed, S; Schinke, C; Thanendrarajan, S; Sawyer, J; Alapat, D; Tian, E; Stein, C; Khan, R; Heuck, C J; Petty, N; Avery, D; Steward, D; Smith, R; Bailey, C; Epstein, J; Yaccoby, S; Hoering, A; Crowley, J; Morgan, G; Barlogie, B; van Rhee, F

    2016-01-01

    Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance. PMID:27471869

  18. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study

    PubMed Central

    O'Sullivan, Amy; Kennedy, Ryan C.; Abbas, Mohammad; Dai, Lijun; Pregja, Silvana Lalo; Burt, Steve; Boyiadzis, Michael; Roodman, G. David; Mapara, Markus Y.; Agha, Mounzer; Waas, John; Shuai, Yongli; Normolle, Daniel; Zonder, Jeffrey A.

    2012-01-01

    This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m2 (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704. PMID:22451423

  19. Comparison of dose accuracy between film and two-dimensional detectors in intensity-modulated radiation therapy

    NASA Astrophysics Data System (ADS)

    Onishi, Yuichi; Nakayama, Shinichi; Watanabe, Shinsaku; Kaneshige, Souichirou; Monzen, Hajime; Matsumoto, Kenji; Shintani, Naoya; Kamomae, Takeshi

    2015-07-01

    We constructed seven intensity-modulated radiation therapy (IMRT) treatment plans for prostate cancer (49 irradiation fields which contained seven randomly-sampled patients and seven fields) and evaluated the dose distributions by using a radiochromic film (EBT3 film) and a 2D detector. We superposed the calculated dose distribution of the IMRT treatment plan on EBT3 film and the 2D detector results and then compared those with the γ-analysis pass rate. The relative positions of the beam and the detector were varied; the results of the analysis of the superior-inferior (SI) direction potentially differed, depending on the detector position, under an irradiation beam with the same fluence map. The detector was moved over a range of' 8 mm in the SI direction in 1-mm step increments, measurement were made at each position, and the results were analyzed. The γ-analysis compared the dose distributions from EBT3 film and the radiation treatment planning system (RTPS) for each patient and field; the pass rate with the γ-analysis from 98 to 100% was 2.04%. When we compared the dose distributions of the 2D detector and the RTPS, the pass rate from 98 to 100% was 63.2%. The mean values for the ?-analysis pass rates for EBT3 film and the 2D detector were 94.2 and 97.6%, respectively. Volume averaging of the data indicated a mean pass rate and standard deviation of 98.6 and 0.91%, respectively, and a pass rate of more than 96% for all positions. A 2D detector can, therefore, be used as an alternative apparatus for IMRT dose verification.

  20. Intensity Modulated Radiation Therapy with Dose-painting: A Brain-sparing Technique for Intracranial Germ Cell Tumors

    PubMed Central

    Yang, Joanna C.; Terezakis, Stephanie A.; Dunkel, Ira J.; Gilheeney, Stephen W.; Wolden, Suzanne L.

    2016-01-01

    Purpose To assess patterns of failure in pediatric patients with intracranial germ cell tumors (GCT) treated with intensity-modulated radiation therapy with dose-painting (DP-IMRT). Methods Between July 2007 and October 2013, 11 patients with localized GCT, 5 germinomas and 6 non-germinoma germ cell tumors (NGGCT), received definitive treatment with DP-IMRT. Three representative patients were selected for re-planning with (1) whole ventricular irradiation (WVI) with opposed-lateral beams plus IMRT to the primary tumor and (2) sequential-IMRT. These plans were compared to the patients' original DP-IMRT plans for dosimetric analyses. Results Four patients with germinoma received RT alone: 45 Gy in 1.8 Gy fractions to the primary tumor and 25 Gy in 1.0 Gy fractions to whole ventricles using a dose-painting plan. One patient with germinoma received a reduced dose of 30.6 Gy to the primary tumor after neoadjuvant chemotherapy. Patients with NGGCT (n=6) underwent multimodality treatment including chemotherapy (n=6) and surgery (n=3). These patients received 54 Gy to the primary tumor and 32.4-36 Gy to the whole ventricles. Dosimetric analyses showed DP-IMRT delivered decreased mean dose to whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With median follow-up of 4 years, 3-year failure free survival was 100% for patients with germinoma and 67% for patients with NGGCT. One patient with a pineal NGGCT experienced a local recurrence within the high-dose volume while another experienced an isolated biochemical failure. Conclusions DP-IMRT is dosimetrically superior to standard IMRT techniques for sparing of normal tissues. Disease control in this small series appears at least comparable to published results. PMID:26703370

  1. Intensity-modulated radiotherapy for nasopharyngeal carcinoma: Clinical correlation of dose to the pharyngo-esophageal axis and dysphagia

    SciTech Connect

    Fua, Tsien F. . E-mail: tsien-fei.fua@petermac.org; Corry, June; Milner, Alvin D.; Cramb, Jim; Walsham, Sue F.; Peters, Lester J.

    2007-03-15

    Purpose: The aim of this study was to quantify the dose delivered to the pharyngo-esophageal axis using different intensity-modulated radiation therapy (IMRT) techniques for treatment of nasopharyngeal carcinoma and to correlate this with acute swallowing toxicity. Methods and Materials: The study population consisted of 28 patients treated with IMRT between February 2002 and August 2005: 20 with whole field IMRT (WF-IMRT) and 8 with IMRT fields junctioned with an anterior neck field with central shielding (j-IMRT). Dose to the pharyngo-esophageal axis was measured using dose-volume histograms. Acute swallowing toxicity was assessed by review of dysphagia grade during treatment and enteral feeding requirements. Results: The mean pharyngo-esophageal dose was 55.2 Gy in the WF-IMRT group and 27.2 Gy in the j-IMRT group, p < 0.001. Ninety-five percent (19/20) of the WF-IMRT group developed Grade 3 dysphagia compared with 62.5% (5/8) of the j-IMRT group, p = 0.06. Feeding tube duration was a median of 38 days for the WF-IMRT group compared with 6 days for the j-IMRT group, p = 0.04. Conclusions: Clinical vigilance must be maintained when introducing new technology to ensure that unanticipated adverse effects do not result. Although newer planning systems can reduce the dose to the pharyngo-esophageal axis with WF-IMRT, the j-IMRT technique is preferred at least in patients with no gross disease in the lower neck.

  2. Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA

    PubMed Central

    Richie, Thomas L.; Charoenvit, Yupin; Wang, Ruobing; Epstein, Judith E.; Hedstrom, Richard C.; Kumar, Sanjai; Luke, Thomas C.; Freilich, Daniel A.; Aguiar, Joao C.; Sacci, Jr., John B.; Sedegah, Martha; Nosek, Jr., Ronald A.; De La Vega, Patricia; Berzins, Mara P.; Majam, Victoria F.; Abot, Esteban N.; Ganeshan, Harini; Richie, Nancy O.; Banania, Jo Glenna; Baraceros, Maria Fe B.; Geter, Tanya G.; Mere, Robin; Bebris, Lolita; Limbach, Keith; Hickey, Bradley W.; Lanar, David E.; Ng, Jennifer; Shi, Meng; Hobart, Peter M.; Norman, Jon A.; Soisson, Lorraine A.; Hollingdale, Michael R.; Rogers, William O.; Doolan, Denise L.; Hoffman, Stephen L.

    2012-01-01

    When introduced in the 1990s, immunization with DNA plasmids was considered potentially revolutionary for vaccine development, particularly for vaccines intended to induce protective CD8 T cell responses against multiple antigens. We conducted, in 1997−1998, the first clinical trial in healthy humans of a DNA vaccine, a single plasmid encoding Plasmodium falciparum circumsporozoite protein (PfCSP), as an initial step toward developing a multi-antigen malaria vaccine targeting the liver stages of the parasite. As the next step, we conducted in 2000–2001 a clinical trial of a five-plasmid mixture called MuStDO5 encoding pre-erythrocytic antigens PfCSP, PfSSP2/TRAP, PfEXP1, PfLSA1 and PfLSA3. Thirty-two, malaria-naïve, adult volunteers were enrolled sequentially into four cohorts receiving a mixture of 500 μg of each plasmid plus escalating doses (0, 20, 100 or 500 μg) of a sixth plasmid encoding human granulocyte macrophage-colony stimulating factor (hGM-CSF). Three doses of each formulation were administered intramuscularly by needle-less jet injection at 0, 4 and 8 weeks, and each cohort had controlled human malaria infection administered by five mosquito bites 18 d later. The vaccine was safe and well-tolerated, inducing moderate antigen-specific, MHC-restricted T cell interferon-γ responses but no antibodies. Although no volunteers were protected, T cell responses were boosted post malaria challenge. This trial demonstrated the MuStDO5 DNA and hGM-CSF plasmids to be safe and modestly immunogenic for T cell responses. It also laid the foundation for priming with DNA plasmids and boosting with recombinant viruses, an approach known for nearly 15 y to enhance the immunogenicity and protective efficacy of DNA vaccines. PMID:23151451

  3. Intensity Modulated Radiation Therapy Dose Painting for Localized Prostate Cancer Using {sup 11}C-choline Positron Emission Tomography Scans

    SciTech Connect

    Chang, Joe H.; Lim Joon, Daryl; Lee, Sze Ting; Gong, Sylvia J.; Anderson, Nigel J.; Scott, Andrew M.; Davis, Ian D.; Clouston, David; Bolton, Damien; Hamilton, Christopher S.; Khoo, Vincent

    2012-08-01

    Purpose: To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using {sup 11}C-choline positron emission tomography PET scans in patients with localized prostate cancer. Methods and Materials: This was an RT planning study of 8 patients with prostate cancer who had {sup 11}C-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV{sub 60%} and SUV{sub 70%}). Three IMRT plans were generated for each patient: PLAN{sub 78}, which consisted of whole-prostate radiation therapy to 78 Gy; PLAN{sub 78-90}, which consisted of whole-prostate RT to 78 Gy, a boost to the SUV{sub 60%} to 84 Gy, and a further boost to the SUV{sub 70%} to 90 Gy; and PLAN{sub 72-90}, which consisted of whole-prostate RT to 72 Gy, a boost to the SUV{sub 60%} to 84 Gy, and a further boost to the SUV{sub 70%} to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCP{sub PET}) and on prostatectomy-defined volumes (TCP{sub path}), and rectal normal tissue complication probabilities (NTCP) were compared between the plans. Results: All plans for all patients reached prescription doses while adhering to dose constraints. TCP{sub PET} values for PLAN{sub 78}, PLAN{sub 78-90}, and PLAN{sub 72-90} were 65%, 97%, and 96%, respectively. TCP{sub path} values were 71%, 97%, and 89%, respectively. Both PLAN{sub 78-90} and PLAN{sub 72-90} had significantly higher TCP{sub PET} (P=.002 and .001) and TCP{sub path} (P<.001 and .014) values than PLAN{sub 78}. PLAN{sub 78-90} and PLAN{sub 72-90} were not significantly different in terms of TCP{sub PET} or TCP{sub path}. There were no significant differences in rectal NTCPs between the 3 plans. Conclusions: IMRT dose painting for

  4. Effects of tumor type, degree of obesity, and chemotherapy regimen on chemotherapy dose intensity in obese cancer patients.

    PubMed

    Miyahara, T; Mochinaga, S; Kimura, S; Aragane, N; Yakabe, T; Morita, S; Okudaira, K; Fujito, H

    2013-01-01

    The American Society of Clinical Oncology recently published a Clinical Practice Guideline entitled "Appropriate Chemotherapy Dosing for Obesity Adult Patients with Cancer." The panel recommended that full weight (actual weight)-based cytotoxic chemotherapy doses are used to treat obese patients with cancer, particularly when the goal of treatment is cure. However, no study has examined dosage calculation methods used for obese cancer patients in Japan. Here, we retrospectively studied the relationships between chemotherapy dose intensity, the occurrence of adverse events, and treatment outcomes in obese patients undergoing chemotherapy. Patients were divided into two groups: the actual BW group (BWg) was composed of patients receiving dosage amounts calculated using their actual BW (n = 64), and the ideal BWg was composed of patients receiving dosage amounts calculated using their ideal BW (n = 41). There were significant differences in the incidence of Grade 3/4 hematological toxicity in the actual and ideal BWg in solid tumor patients, but not in patients with hematological malignancies. In solid tumor patients with ≥30 body mass index (BMI), the incidence of Grade 3/4 hematological toxicity was significantly lower in the ideal BWg than in the actual BWg. Particularly, in patients with complications, incidence of Grade 4 hematological toxicity was significantly higher in the actual BWg than in the ideal BWg. These results suggest that the tumor type, degree of obesity, complications, and choice of chemotherapy regimen should be considered when determining chemotherapy dosage for obese patients.

  5. Safety and immunogenicity of novel respiratory syncytial virus (RSV) vaccines based on the RSV viral proteins F, N and M2-1 encoded by simian adenovirus (PanAd3-RSV) and MVA (MVA-RSV); protocol for an open-label, dose-escalation, single-centre, phase 1 clinical trial in healthy adults

    PubMed Central

    Green, C A; Scarselli, E; Voysey, M; Capone, S; Vitelli, A; Nicosia, A; Cortese, R; Thompson, A J; Sande, C S; de Lara, Catherine; Klenerman, P; Pollard, A J

    2015-01-01

    Introduction Respiratory syncytial virus (RSV) infection causes respiratory disease throughout life, with infants and the elderly at risk of severe disease and death. RSV001 is a phase 1 (first-in-man), open-label, dose-escalation, clinical trial of novel genetic viral-vectored vaccine candidates PanAd3-RSV and modified vaccinia virus Ankara (MVA)-RSV. The objective of RSV001 is to characterise the (primary objective) safety and (secondary objective) immunogenicity of these vaccines in healthy younger and older adults. Methods and analysis Heterologous and homologous ‘prime’/boost combinations of PanAd3-RSV and single-dose MVA-RSV are evaluated in healthy adults. 40 healthy adults aged 18–50 years test one of four combinations of intramuscular (IM) or intranasal (IN) PanAd3-RSV prime and IM PanAd3 or IM MVA-RSV boost vaccination, starting at a low dose for safety. The following year an additional 30 healthy adults aged 60–75 years test either a single dose of IM MVA-RSV, one of three combinations of IN or IM PanAd3-RSV prime and PanAd3-RSV or MVA-RSV boost vaccination used in younger volunteers, and a non-vaccinated control group. Study participants are self-selected volunteers who satisfy the eligibility criteria and are assigned to study groups by sequential allocation. Safety assessment includes the daily recording of solicited and unsolicited adverse events for 1 week after vaccination, as well as visit (nursing) observations and safety bloods obtained at all scheduled attendances. Laboratory measures of RSV-specific humoral and cellular immune responses after vaccination will address the secondary end points. All study procedures are performed at the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Oxford, UK. Ethics and dissemination RSV001 has clinical trial authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics approval from NRES Berkshire (reference 13/SC/0023). All study procedures adhere

  6. An elective radiation dose of 46 Gy is feasible in nasopharyngeal carcinoma treated by intensity-modulated radiotherapy

    PubMed Central

    Hung, Tsung-Min; Fan, Kang-Hsing; Chen, Eric Yen-Chao; Lin, Chien-Yu; Kang, Chung-Jan; Huang, Shiang-Fu; Liao, Chun-Ta; Ng, Shu-Hang; Wang, Hung-Ming; Chang, Joseph Tung-Chieh

    2017-01-01

    Abstract The purpose of this study is to compare the treatment outcome of different radiation doses of elective neck irradiation (ENI) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). In total, 504 patients with nondisseminated NPC who underwent magnetic resonance imaging before radical IMRT between 2000 and 2008 were retrospectively reviewed. The patients were classified into 2 groups based on the ENI dose: low ENI when the ENI dose was 46 Gy (n = 446) and high ENI when the ENI doses were 50 to 60 Gy (n = 58). All the patients in both the groups received a median dose of 72 Gy to the gross tumor and involved nodes. The fraction size was 2 Gy per fraction. Matching was performed between low ENI and high ENI in a 2:1 ratio, and the matching criteria were N-stage, T-stage, treatment modality, pathology classification, sex, and age. The median follow-up for all patients was 63.5 months. In all patients, the 5-year progression-free survival (PFS), local control (LC), regional control (RC), distant metastasis-free survival (DMFS), overall survival (OS), and cancer-specific survival (CSS) for low ENI and high ENI patients were 69.0% and 63.2% (P = 0.331), 89.0% and 83.9% (P = 0.235), 90.1% and 85.2% (P = 0.246), 86.8% and 76.6% (P = 0.056), 77.5% and 80.8% (P = 0.926), and 84.4% and 82.5% (P = 0.237), respectively. In the matched-pair analysis, the 5-year PFS, LC, RC, DMFS, OS, and CSS for matched low ENI and high ENI patients were 74.1% and 63.2% (P = 0.134), 92.0% and 83.9% (P = 0.152), 90.1% and 85.2% (P = 0.356), 86.2% and 76.6% (P = 0.125), 87.0% and 80.8% (P = 0.102), and 88.6% and 82.5% (P = 0.080), respectively. In the multivariable analysis for all patients, the ENI group was not a significant factor for PFS, LC, RC, DMFS, OS, and CSS. A low ENI dose of 46 Gy in 23 fractions is feasible in NPC patients treated with IMRT, and this concept should be validated in

  7. The benefit of using bladder sub-volume equivalent uniform dose constraints in prostate intensity-modulated radiotherapy planning

    PubMed Central

    Zhu, Jian; Simon, Antoine; Haigron, Pascal; Lafond, Caroline; Acosta, Oscar; Shu, Huazhong; Castelli, Joel; Li, Baosheng; De Crevoisier, Renaud

    2016-01-01

    Background To assess the benefits of bladder wall sub-volume equivalent uniform dose (EUD) constraints in prostate cancer intensity-modulated radiotherapy (IMRT) planning. Methods Two IMRT plans, with and without EUD constraints on the bladder wall, were generated using beams that deliver 80 Gy to the prostate and 46 Gy to the seminal vesicles and were compared in 53 prostate cancer patients. The bladder wall was defined as the volume between the external manually delineated wall and a contraction of 7 mm apart from it. The bladder wall was then separated into two parts: the internal-bladder wall (bla-in) represented by the portion of the bladder wall that intersected with the planning target volume (PTV) plus 5 mm extension; the external-bladder wall (bla-ex) represented by the remaining part of the bladder wall. In the IMRT plan with EUD constraints, the values of “a” parameter for the EUD models were 10.0 for bla-in and 2.3 for bla-ex. The plans with and without EUD constraints were compared in terms of dose–volume histograms, 5-year bladder and rectum normal tissue complication probability values, as well as tumor control probability (TCP) values. Results The use of bladder sub-volume EUD constraints decreased both the doses to the bladder wall (V70: 22.76% vs 19.65%, Dmean: 39.82 Gy vs 35.45 Gy) and the 5-year bladder complication probabilities (≥LENT/SOMA Grade 2: 20.35% vs 17.96%; bladder bleeding: 10.63% vs 8.64%). The doses to the rectum wall and the rectum complication probabilities were also slightly decreased by the EUD constraints compared to physical constraints only. The minimal dose and the V76Gy of PTVprostate were, however, slightly decreased by EUD optimization, nevertheless without significant difference in TCP values between the two plans, and the PTV parameters finally respected the Groupe d’Etude des Tumeurs Uro-Génitales recommendations. Conclusion Separating the bladder wall into two parts with appropriate EUD optimization may

  8. High dose chemoradiation for unresectable hilar cholangiocarcinomas using intensity modulated external beam radiotherapy: a single tertiary care centre experience

    PubMed Central

    Mehta, Shaesta; Kalyani, Nikhil; Chaudhari, Suresh; Dharia, Tejas; Shetty, Nitin; Chopra, Supriya; Goel, Mahesh; Kulkarni, Suyash; Shrivastava, Shyam Kishore

    2017-01-01

    Background We present results of patients diagnosed with unresectable hilar cholangiocarcinomas treated with high dose radiotherapy and concurrent chemotherapy. Methods From Aug 2005 to Dec 2012, 68 consecutive patients were treated. Fifty patients (group 1) presenting to us with obstructive jaundice were planned for endobiliary brachytherapy (EBBT 14 Gy) followed external beam radiotherapy (EBRT 45 Gy). Twenty-two patients (group 2) who had previously undergone biliary drainage underwent EBRT (57 Gy). All patients received injection Gemcitabine 300 mg/m2/weekly along with EBRT. Results Twenty-nine patients in group 1 and 22 patients in group 2 completed the treatment. Twenty-six (55%) patients achieved complete radiological response, 16 (64%) belonging to group 1 and 8 (44%) of group 2 (P=0.05). The median overall survival (MOS) was 17.5 and 16 months for group 1 and 2 respectively (P=0.07). The 1- and 2-year survival was 63%, and 18% for group I and 61% and 22% for group II respectively. The MOS was 5 months and 1 year survival was 14% for patients receiving EBBT only. MOS was significantly better after complete response (P=0.001). Conclusions Intensity modulated radiotherapy (IMRT) modulated high dose radiotherapy used either alone or with brachytherapy demonstrates potential to prolonged overall survival in unresectable hilar cholangiocarcinomas. PMID:28280622

  9. A system for intensity modulated dose plan verification based on an experimental pencil beam kernel obtained by deconvolution.

    PubMed

    Azcona, Juan Diego; Burguete, Javier

    2008-01-01

    The number of intensity modulated radiation therapy (IMRT) procedures is continuously growing worldwide and it is necessary to develop tools for patient specific quality assurance (QA) that avoid using machine time that could be employed in treating additional patients. One way of achieving this goal is to perform a multileaf collimator quality assurance periodically in the linear accelerator and check the treatment planning system (TPS) calculation by employing an independent calculation system. Within the work frame of the pencil beam kernel approach, a new system was developed for obtaining an experimental kernel. This new technique is based on a deconvolution procedure using the Hankel transform. The resulting kernel is obtained in a way completely independent of those employed in commercial treatment planning systems, usually calculated by Monte Carlo simulations. Also provided are comparisons between calculated and measured doses with radiographic film, linear array of diodes, and ionization chamber. Measurements taken in polystyrene and water for clinical IMRT plans demonstrate that this method can calculate IMRT dose distributions, as well as treatment times, with great accuracy. Apart from other applications, it can be used as a double-check algorithm for IMRT QA.

  10. Reduced dose of foscarnet as preemptive therapy for cytomegalovirus infection following reduced-intensity cord blood transplantation.

    PubMed

    Narimatsu, H; Kami, M; Kato, D; Matsumura, T; Murashige, N; Kusumi, E; Yuji, K; Hori, A; Shibata, T; Masuoka, K; Wake, A; Miyakoshi, S; Morinaga, S; Taniguchi, S

    2007-03-01

    Although foscarnet is a promising alternative for the treatment of cytomegalovirus (CMV) infection, its toxicity can be significant in patients with advanced age. We retrospectively reviewed medical records of 123 patients (median age of 55; range, 17-79) who received reduced-intensity cord blood transplantation (RI-CBT). Patients preemptively received reduced-dose foscarnet 30 mg/kg twice daily when CMV antigenemia exceeded 10/50,000. Sixty-three patients developed CMV antigenemia on a median of day 34, and 29 received foscarnet preemptively. The median level of CMV antigenemia at the initiation of foscarnet was 30. Median duration of foscarnet administration was 24 days. Adverse effects included electrolyte abnormalities (n=19), renal impairment (n=13), and skin eruption requiring discontinuation of foscarnet (n=1). Preemptive therapy of foscarnet was completed in 18 patients. Seven patients died during foscarnet use without developing CMV disease. The remaining 3 developed CMV enterocolitis 5, 14, and 17 days after initiation of foscarnet. All of them were successfully treated with ganciclovir or foscarnet. Reduced dose of foscarnet is beneficial to control CMV reactivation following RI-CBT; however, it has considerable toxicities in RI-CBT recipients with advanced age. Further studies are warranted to minimize toxicities and identify optimal dosages.

  11. Tumor Control Outcomes Following Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases from Renal Cell Carcinoma

    PubMed Central

    Zelefsky, Michael J; Greco, Carlo; Motzer, Robert; Magsanoc, Juan Martin; Pei, Xin; Lovelock, Michael; Mechalakos, Jim; Zatcky, Joan; Fuks, Zvi; Yamada, Yoshiya

    2014-01-01

    Purpose To report tumor local progression-free outcomes following treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Methods and Materials Between 2004 and 2010, a total of 105 lesions from renal cell carcinomas were treated with either SD-IGRT to prescription doses of 18–24 Gy (median, 24 Gy) or hypofractionation (3 or 5 fractions) with prescription doses ranging between 20 and 30 Gy. The median follow-up was 12 months (range, 1–48 months). Results The overall 3-year actuarial local progression-free survival (LPFS) for all lesions was 44%. The 3-year LPFS for those who received high single-dose (24 Gy; n = 45), low single-dose (< 24 Gy; n = 14), and hypofractionation regimens (n = 46) were 88%, 21%, and 17%, respectively (high single dose versus low single dose, p = 0.001; high single dose versus hypofractionation, p < 0.001). Multivariate analysis revealed the following variables as significant predictors of improved LPFS: dose of 24 Gy compared with lower dose (p = 0.009), and single dose versus hypofractionation (p = 0.008). Conclusion High-dose SD-IGRT is a non-invasive procedure resulting in high probability of local tumor control for metastatic renal cell cancers, generally considered radioresistant according to classical radiobiological ranking. PMID:21596489

  12. Prostate Dose Escalation by Innovative Inverse Planning-Driven IMRT

    DTIC Science & Technology

    2006-11-01

    utility with data from phantom and clinical prostate cases. The inverse planring for ART is particularly relevant considering that the emergence of on...and demonstrate their utility with data from phantom and clinical cases 14. Closed-loop control algorithms are a general tool for dealing with time...therapy (ART) and demonstrate their utility with data from phantom and clinical cases. To meet the needs of different clinical applications, we study two

  13. Prostate Dose Escalation by Innovative Inverse Planning-Driven IMRT

    DTIC Science & Technology

    2007-11-01

    cases. In Fig. 3 we show the results of a digital phantom experiment, in which an image (1a) is intentionally deformed into two dramatically different...CBCT scanning (Appendix 13). To assure the functionality of the system we have also developed an image phantom and software tool for the onboard...Mao W, Xing L, Design of Multi-Purpose Phantom and Automated Software Analysis Tool for Quality Assurance of Onboard kV/MV Imaging System, Medical

  14. Prolonged high-dose intravenous magnesium therapy for severe tetanus in the intensive care unit: a case series

    PubMed Central

    2010-01-01

    Introduction Tetanus rarely occurs in developed countries, but it can result in fatal complications including respiratory failure due to generalized muscle spasms. Magnesium infusion has been used to treat spasticity in tetanus, and its effectiveness is supported by several case reports and a recent randomized controlled trial. Case presentations Three Caucasian Greek men aged 30, 50 and 77 years old were diagnosed with tetanus and admitted to a general 12-bed intensive care unit in 2006 and 2007 for respiratory failure due to generalized spasticity. Intensive care unit treatment included antibiotics, hydration, enteral nutrition, early tracheostomy and mechanical ventilation. Intravenous magnesium therapy controlled spasticity without the need for additional muscle relaxants. Their medications were continued for up to 26 days, and adjusted as needed to control spasticity. Plasma magnesium levels, which were measured twice a day, remained in the 3 to 4.5 mmol/L range. We did not observe hemodynamic instability, arrhythmias or other complications related to magnesium therapy in these patients. All patients improved, came off mechanical ventilation, and were discharged from the intensive care unit in a stable condition. Conclusion In comparison with previous reports, our case series contributes the following meaningful additional information: intravenous magnesium therapy was used on patients already requiring mechanical ventilation and remained effective for up to 26 days (significantly longer than in previous reports) without significant toxicity in two patients. The overall outcome was good in all our patients. However, the optimal dose, optimal duration and maximum safe duration of intravenous magnesium therapy are unknown. Therefore, until more data on the safety and efficacy of magnesium therapy are available, its use should be limited to carefully selected tetanus cases. PMID:20356376

  15. Intensive Care, Intense Conflict: A Balanced Approach.

    PubMed

    Paquette, Erin Talati; Kolaitis, Irini N

    2015-01-01

    Caring for a child in a pediatric intensive care unit is emotionally and physically challenging and often leads to conflict. Skilled mediators may not always be available to aid in conflict resolution. Careproviders at all levels of training are responsible for managing difficult conversations with families and can often prevent escalation of conflict. Bioethics mediators have acknowledged the important contribution of mediation training in improving clinicians' skills in conflict management. Familiarizing careproviders with basic mediation techniques is an important step towards preventing escalation of conflict. While training in effective communication is crucial, a sense of fairness and justice that may only come with the introduction of a skilled, neutral third party is equally important. For intense conflict, we advocate for early recognition, comfort, and preparedness through training of clinicians in de-escalation and optimal communication, along with the use of more formally trained third-party mediators, as required.

  16. Intensive dose ifosfamide, carboplatin, and etoposide followed by autologous stem cell rescue: results of a phase I/II study in breast cancer patients.

    PubMed

    Fields, K K; Perkins, J P; Hiemenz, J W; Zorsky, P E; Janssen, W E; Kronish, L E; Machak, M C; Elfenbein, G J

    1993-01-01

    We have recently treated 66 women with breast cancer with escalating doses of ifosfamide, carboplatin, and etoposide (ICE) followed by autologous stem cell rescue (ASCR). Patients received ifosfamide (6000-24,000 mg m-2), carboplatin (1200-2100 mg m-2), and etoposide (1800-3000 mg m-2) divided over 6 days with ASCR 48 h after completion of chemotherapy. Our patient population consisted of seven patients with stage II disease with eight or more positive nodes being treated in the adjuvant setting, 16 patients with a history of stage III or inflammatory breast cancer, and 43 patients with stage IV disease. Six patients were not evaluable for response due to early death from infection (three patients) and incomplete restaging (three patients). The overall response rate in patients with measurable metastatic disease was 50%. Of those patients with stage II disease, 85% remain alive and progression-free with a median follow-up of greater than one year. The two most frequent toxicities encountered were reversible elevations of liver function tests and mucositis/enteritis. The dose-limiting toxicities were central nervous system toxicity and nephrotoxicity.

  17. Benefits and unintended consequences of antimicrobial de-escalation: Implications for stewardship programs

    PubMed Central

    Hurford, Amy; Lan, Kunquan; Coburn, Bryan; Morris, Andrew; Wu, Jianhong

    2017-01-01

    Sequential antimicrobial de-escalation aims to minimize resistance to high-value broad-spectrum empiric antimicrobials by switching to alternative drugs when testing confirms susceptibility. Though widely practiced, the effects de-escalation are not well understood. Definitions of interventions and outcomes differ among studies. We use mathematical models of the transmission and evolution of Pseudomonas aeruginosa in an intensive care unit to assess the effect of de-escalation on a broad range of outcomes, and clarify expectations. In these models, de-escalation reduces the use of high-value drugs and preserves the effectiveness of empiric therapy, while also selecting for multidrug-resistant strains and leaving patients vulnerable to colonization and superinfection. The net effect of de-escalation in our models is to increase infection prevalence while also increasing the probability of effective treatment. Changes in mortality are small, and can be either positive or negative. The clinical significance of small changes in outcomes such as infection prevalence and death may exceed more easily detectable changes in drug use and resistance. Integrating harms and benefits into ranked outcomes for each patient may provide a way forward in the analysis of these tradeoffs. Our models provide a conceptual framework for the collection and interpretation of evidence needed to inform antimicrobial stewardship. PMID:28182774

  18. Preliminary Toxicity Analysis of 3-Dimensional Conformal Radiation Therapy Versus Intensity Modulated Radiation Therapy on the High-Dose Arm of the Radiation Therapy Oncology Group 0126 Prostate Cancer Trial

    SciTech Connect

    Michalski, Jeff M.; Yan, Yan; Watkins-Bruner, Deborah; Bosch, Walter R.; Winter, Kathryn; Galvin, James M.; Bahary, Jean-Paul; Morton, Gerard C.; Parliament, Matthew B.; Sandler, Howard M.

    2013-12-01

    Purpose: To give a preliminary report of clinical and treatment factors associated with toxicity in men receiving high-dose radiation therapy (RT) on a phase 3 dose-escalation trial. Methods and Materials: The trial was initiated with 3-dimensional conformal RT (3D-CRT) and amended after 1 year to allow intensity modulated RT (IMRT). Patients treated with 3D-CRT received 55.8 Gy to a planning target volume that included the prostate and seminal vesicles, then 23.4 Gy to prostate only. The IMRT patients were treated to the prostate and proximal seminal vesicles to 79.2 Gy. Common Toxicity Criteria, version 2.0, and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late morbidity scores were used for acute and late effects. Results: Of 763 patients randomized to the 79.2-Gy arm of Radiation Therapy Oncology Group 0126 protocol, 748 were eligible and evaluable: 491 and 257 were treated with 3D-CRT and IMRT, respectively. For both bladder and rectum, the volumes receiving 65, 70, and 75 Gy were significantly lower with IMRT (all P<.0001). For grade (G) 2+ acute gastrointestinal/genitourinary (GI/GU) toxicity, both univariate and multivariate analyses showed a statistically significant decrease in G2+ acute collective GI/GU toxicity for IMRT. There were no significant differences with 3D-CRT or IMRT for acute or late G2+ or 3+ GU toxicities. Univariate analysis showed a statistically significant decrease in late G2+ GI toxicity for IMRT (P=.039). On multivariate analysis, IMRT showed a 26% reduction in G2+ late GI toxicity (P=.099). Acute G2+ toxicity was associated with late G3+ toxicity (P=.005). With dose–volume histogram data in the multivariate analysis, RT modality was not significant, whereas white race (P=.001) and rectal V70 ≥15% were associated with G2+ rectal toxicity (P=.034). Conclusions: Intensity modulated RT is associated with a significant reduction in acute G2+ GI/GU toxicity. There is a trend for a

  19. SU-E-T-632: Preliminary Study On Treating Nose Skin Using Energy and Intensity Modulated Electron Beams with Monte Carlo Based Dose Calculations

    SciTech Connect

    Jin, L; Eldib, A; Li, J; Price, R; Ma, C

    2015-06-15

    Purpose: Uneven nose surfaces and air cavities underneath and the use of bolus present complexity and dose uncertainty when using a single electron energy beam to plan treatments of nose skin with a pencil beam-based planning system. This work demonstrates more accurate dose calculation and more optimal planning using energy and intensity modulated electron radiotherapy (MERT) delivered with a pMLC. Methods: An in-house developed Monte Carlo (MC)-based dose calculation/optimization planning system was employed for treatment planning. Phase space data (6, 9, 12 and 15 MeV) were used as an input source for MC dose calculations for the linac. To reduce the scatter-caused penumbra, a short SSD (61 cm) was used. Our previous work demonstrates good agreement in percentage depth dose and off-axis dose between calculations and film measurement for various field sizes. A MERT plan was generated for treating the nose skin using a patient geometry and a dose volume histogram (DVH) was obtained. The work also shows the comparison of 2D dose distributions between a clinically used conventional single electron energy plan and the MERT plan. Results: The MERT plan resulted in improved target dose coverage as compared to the conventional plan, which demonstrated a target dose deficit at the field edge. The conventional plan showed higher dose normal tissue irradiation underneath the nose skin while the MERT plan resulted in improved conformity and thus reduces normal tissue dose. Conclusion: This preliminary work illustrates that MC-based MERT planning is a promising technique in treating nose skin, not only providing more accurate dose calculation, but also offering an improved target dose coverage and conformity. In addition, this technique may eliminate the necessity of bolus, which often produces dose delivery uncertainty due to the air gaps that may exist between the bolus and skin.

  20. SU-E-T-288: Dose Volume Population Histogram (DVPH): A New Method to Evaluate Intensity Modulated Proton Therapy Plans With Geometrical Uncertainties

    SciTech Connect

    Nguyen, T; Mai, N; Nguyen, B

    2015-06-15

    Purpose: In Proton therapy, especially intensity modulated proton therapy(IMPT), the dose distribution shape is very sensitive to errors due to sharp dose gradients at the Bragg peaks. The concept of the conventional margin is based on the assumption that dose distribution is shifted rather than deformed due to geometrical uncertainties. The goal of this study is to access the validity of the margin concept as well as propose a new approach using Dose Volume Population Histogram (DVPH) in evaluating IMPT plans. Methods: For a prostate case, an intensity modulated proton therapy is optimized based on the conventional PTV based objective function. The plan is evaluated based on the PTV DVH and CTV DVPH (dose volume population histogram) which explicitly taking into account geometric uncertainties. The DVPH is calculated based on 2197 dose distributions at different CTV possible positions for both random and systematic errors. The DVPH with a 90% confidence level is used for the comparison. Results: The minimum dose of the CTV DVPH with a 90% confidence level is only about 18% of the prescribed dose, while the minimum dose of the PTV is 95%. For bladder DVHs, the D50 and D35 is 26% and 30%, compared to 65% and 70% of the prescribed dose from the bladder DVPH with 90% confidence level. Conclusion: The results showed that the PTV concept for ensuring the prescribed dose actually delivered to the CTV is invalid in proton therapy. The good PTV DVH might Result in an underdose to the target and should not be used for IMPT optimization. For OARs, the conventional evaluation approach underestimates dose volume end points. The new concept DVPH has been proved to provide a more accurate DVH evaluation in proton therapy.

  1. Treatment Planning Study to Determine Potential Benefit of Intensity-Modulated Radiotherapy Versus Conformal Radiotherapy for Unresectable Hepatic Malignancies

    SciTech Connect

    Eccles, Cynthia L.; Bissonnette, Jean-Pierre; Craig, Tim; Taremi, Mojgan; Wu Xia; Dawson, Laura A.

    2008-10-01

    Purpose: To compare intensity-modulated radiotherapy (IMRT) with conformal RT (CRT) for hypofractionated isotoxicity liver RT and explore dose escalation using IMRT for the same/improved nominal risk of liver toxicity in a treatment planning study. Methods and Materials: A total of 26 CRT plans were evaluated. Prescription doses (24-54 Gy within six fractions) were individualized on the basis of the effective liver volume irradiated maintaining {<=}5% risk of radiation-induced liver disease. The dose constraints included bowel (0.5 cm{sup 3}) and stomach (0.5 cm{sup 3}) to {<=}30 Gy, spinal cord to {<=}25 Gy, and planning target volume (PTV) to {<=}140% of the prescribed dose. Two groups were evaluated: (1) PTV overlapping or directly adjacent to serial functioning normal tissues (n = 14), and (2) the liver as the dose-limiting normal tissue (n = 12). IMRT plans using direct machine parameter optimization maintained the CRT plan beam arrangements, an estimated radiation-induced liver disease risk of 5%, and underwent dose escalation, if all normal tissue constraints were maintained. Results: IMRT improved PTV coverage in 19 of 26 plans (73%). Dose escalation was feasible in 9 cases by an average of 3.8 Gy (range, 0.6-13.2) in six fractions. Three of seven plans without improved PTV coverage had small gross tumor volumes ({<=}105 cm{sup 3}) already receiving 54 Gy, the maximal prescription dose allowed. In the remaining cases, the PTV range was 9.6-689 cm{sup 3}; two had overlapped organs at risk; and one had four targets. IMRT did not improve these plans owing to poor target coverage (n = 2) and nonliver (n = 2) dose limits. Conclusion: Direct machine parameter optimization IMRT improved PTV coverage while maintaining normal tissue tolerances in most CRT liver plans. Dose escalation was possible in a minority of patients.

  2. Dose esclation in radioimmunotherapy based on projected whole body dose

    SciTech Connect

    Wahl, R.L.; Kaminski, M.S.; Regan, D.

    1994-05-01

    A variety of approaches have been utilized in conducting phase I radioimmunotherapy dose-escalation trials. Escalation of dose has been based on graded increases in administered mCi; mCi/kg; or mCi/m2. It is also possible to escalate dose based on tracer-projected marrow, blood or whole body radiation dose. We describe our results in performing a dose-escalation trial in patients with non-Hodgkin lymphoma based on escalating administered whole-body radiation dose. The mCi dose administered was based on a patient-individualized tracer projected whole-body dose. 25 patients were entered on the study. RIT with 131 I anti-B-1 was administered to 19 patients. The administered dose was prescribed based on the projected whole body dose, determined from patient-individualized tracer studies performed prior to RIT. Whole body dose estimates were based on the assumption that the patient was an ellipsoid, with 131 antibody kinetics determined using a whole-body probe device acquiring daily conjugate views of 1 minute duration/view. Dose escalation levels proceeded with 10 cGy increments from 25 cGy whole-body and continues, now at 75 cGy. The correlation among potential methods of dose escalation and toxicity was assessed. Whole body radiation dose by probe was strongly correlated with the blood radiation dose determined from sequential blood sampling during tracer studies (r=.87). Blood radiation dose was very weakly correlated with mCi dose (r=.4) and mCi/kg (r=.45). Whole body radiation dose appeared less well-correlated with injected dose in mCi (r=.6), or mCi/kg (r=.64). Toxicity has been infrequent in these patients, but appears related to increasing whole body dose. Non-invasive determination of whole-body radiation dose by gamma probe represents a non-invasive method of estimating blood radiation dose, and thus of estimating bone marrow radiation dose.

  3. Escalation of polymerization in a thermal gradient.

    PubMed

    Mast, Christof B; Schink, Severin; Gerland, Ulrich; Braun, Dieter

    2013-05-14

    For the emergence of early life, the formation of biopolymers such as RNA is essential. However, the addition of nucleotide monomers to existing oligonucleotides requires millimolar concentrations. Even in such optimistic settings, no polymerization of RNA longer than about 20 bases could be demonstrated. How then could self-replicating ribozymes appear, for which recent experiments suggest a minimal length of 200 nt? Here, we demonstrate a mechanism to bridge this gap: the escalated polymerization of nucleotides by a spatially confined thermal gradient. The gradient accumulates monomers by thermophoresis and convection while retaining longer polymers exponentially better. Polymerization and accumulation become mutually self-enhancing and result in a hyperexponential escalation of polymer length. We describe this escalation theoretically under the conservative assumption of reversible polymerization. Taking into account the separately measured thermophoretic properties of RNA, we extrapolate the results for primordial RNA polymerization inside a temperature gradient in pores or fissures of rocks. With a dilute, nanomolar concentration of monomers the model predicts that a pore length of 5 cm and a temperature difference of 10 K suffice to polymerize 200-mers of RNA in micromolar concentrations. The probability to generate these long RNAs is raised by a factor of >10(600) compared with polymerization in a physical equilibrium. We experimentally validate the theory with the reversible polymerization of DNA blocks in a laser-driven thermal trap. The results confirm that a thermal gradient can significantly enlarge the available sequence space for the emergence of catalytically active polymers.

  4. Escalation of polymerization in a thermal gradient

    PubMed Central

    Mast, Christof B.; Schink, Severin; Gerland, Ulrich; Braun, Dieter

    2013-01-01

    For the emergence of early life, the formation of biopolymers such as RNA is essential. However, the addition of nucleotide monomers to existing oligonucleotides requires millimolar concentrations. Even in such optimistic settings, no polymerization of RNA longer than about 20 bases could be demonstrated. How then could self-replicating ribozymes appear, for which recent experiments suggest a minimal length of 200 nt? Here, we demonstrate a mechanism to bridge this gap: the escalated polymerization of nucleotides by a spatially confined thermal gradient. The gradient accumulates monomers by thermophoresis and convection while retaining longer polymers exponentially better. Polymerization and accumulation become mutually self-enhancing and result in a hyperexponential escalation of polymer length. We describe this escalation theoretically under the conservative assumption of reversible polymerization. Taking into account the separately measured thermophoretic properties of RNA, we extrapolate the results for primordial RNA polymerization inside a temperature gradient in pores or fissures of rocks. With a dilute, nanomolar concentration of monomers the model predicts that a pore length of 5 cm and a temperature difference of 10 K suffice to polymerize 200-mers of RNA in micromolar concentrations. The probability to generate these long RNAs is raised by a factor of >10600 compared with polymerization in a physical equilibrium. We experimentally validate the theory with the reversible polymerization of DNA blocks in a laser-driven thermal trap. The results confirm that a thermal gradient can significantly enlarge the available sequence space for the emergence of catalytically active polymers. PMID:23630280

  5. Comparison of testicular dose delivered by intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) in patients with prostate cancer

    SciTech Connect

    Martin, Jeffrey M.; Handorf, Elizabeth A.; Price, Robert A.; Cherian, George; Buyyounouski, Mark K.; Chen, David Y.; Kutikov, Alexander; Johnson, Matthew E.; Ma, Chung-Ming Charlie; Horwitz, Eric M.

    2015-10-01

    A small decrease in testosterone level has been documented after prostate irradiation, possibly owing to the incidental dose to the testes. Testicular doses from prostate external beam radiation plans with either intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) were calculated to investigate any difference. Testicles were contoured for 16 patients being treated for localized prostate cancer. For each patient, 2 plans were created: 1 with IMRT and 1 with VMAT. No specific attempt was made to reduce testicular dose. Minimum, maximum, and mean doses to the testicles were recorded for each plan. Of the 16 patients, 4 received a total dose of 7800 cGy to the prostate alone, 7 received 8000 cGy to the prostate alone, and 5 received 8000 cGy to the prostate and pelvic lymph nodes. The mean (range) of testicular dose with an IMRT plan was 54.7 cGy (21.1 to 91.9) and 59.0 cGy (25.1 to 93.4) with a VMAT plan. In 12 cases, the mean VMAT dose was higher than the mean IMRT dose, with a mean difference of 4.3 cGy (p = 0.019). There was a small but statistically significant increase in mean testicular dose delivered by VMAT compared with IMRT. Despite this, it unlikely that there is a clinically meaningful difference in testicular doses from either modality.

  6. Mixing intensity modulated electron and photon beams: combining a steep dose fall-off at depth with sharp and depth-independent penumbras and flat beam profiles.

    PubMed

    Korevaar, E W; Heijmen, B J; Woudstra, E; Huizenga, H; Brahme, A

    1999-09-01

    For application in radiotherapy, intensity modulated high-energy electron and photon beams were mixed to create dose distributions that feature: (a) a steep dose fall-off at larger depths, similar to pure electron beams, (b) flat beam profiles and sharp and depth-independent beam penumbras, as in photon beams, and (c) a selectable skin dose that is lower than for pure electron beams. To determine the required electron and photon beam fluence profiles, an inverse treatment planning algorithm was used. Mixed beams were realized at a MM50 racetrack microtron (Scanditronix Medical AB, Sweden), and evaluated by the dose distributions measured in a water phantom. The multileaf collimator of the MM50 was used in a static mode to shape overlapping electron beam segments, and the dynamic multileaf collimation mode was used to realize the intensity modulated photon beam profiles. Examples of mixed beams were generated at electron energies of up to 40 MeV. The intensity modulated electron beam component consists of two overlapping concentric fields with optimized field sizes, yielding broad, fairly depth-independent overall beam penumbras. The matched intensity modulated photon beam component has high fluence peaks at the field edges to sharpen this penumbra. The combination of the electron and the photon beams yields dose distributions with the characteristics (a)-(c) mentioned above.

  7. Evaluation of Uncertainty-Based Stopping Criteria for Monte Carlo Calculations of Intensity-Modulated Radiotherapy and Arc Therapy Patient Dose Distributions

    SciTech Connect

    Vanderstraeten, Barbara Olteanu, Ana Maria Luiza; Reynaert, Nick; Leal, Antonio; Neve, Wilfried de; Thierens, Hubert

    2007-10-01

    Purpose: To formulate uncertainty-based stopping criteria for Monte Carlo (MC) calculations of intensity-modulated radiotherapy and intensity-modulated arc therapy patient dose distributions and evaluate their influence on MC simulation times and dose characteristics. Methods and Materials: For each structure of interest, stopping criteria were formulated as follows: {sigma}{sub rel} {<=}{sigma}{sub rel,tol} or D{sigma}{sub rel} {<=}D{sub lim}{sigma}{sub rel,tol} within {>=}95% of the voxels, where {sigma}{sub rel} represents the relative statistical uncertainty on the estimated dose, D. The tolerated uncertainty ({sigma}{sub rel,tol}) was 2%. The dose limit (D{sub lim}) equaled the planning target volume (PTV) prescription dose or a dose value related to the organ at risk (OAR) planning constraints. An intensity-modulated radiotherapy-lung, intensity-modulated radiotherapy-ethmoid sinus, and intensity-modulated arc therapy-rectum patient case were studied. The PTV-stopping criteria-based calculations were compared with the PTV+OAR-stopping criteria-based calculations. Results: The MC dose distributions complied with the PTV-stopping criteria after 14% (lung), 21% (ethmoid), and 12% (rectum) of the simulation times of a 100 million histories reference calculation, and increased to 29%, 44%, and 51%, respectively, by the addition of the OAR-stopping criteria. Dose-volume histograms corresponding to the PTV-stopping criteria, PTV+OAR-stopping criteria, and reference dose calculations were indiscernible. The median local dose differences between the PTV-stopping criteria and the reference calculations amounted to 1.4% (lung), 2.1% (ethmoid), and 2.5% (rectum). Conclusions: For the patient cases studied, the MC calculations using PTV-stopping criteria only allowed accurate treatment plan evaluation. The proposed stopping criteria provided a flexible tool to assist MC patient dose calculations. The structures of interest and appropriate values of {sigma}{sub rel

  8. Dose Gradient Near Target-Normal Structure Interface for Nonisocentric CyberKnife and Isocentric Intensity-Modulated Body Radiotherapy for Prostate Cancer

    SciTech Connect

    Hossain, Sabbir; Xia Ping; Huang, Kim; Descovich, Martina; Chuang, Cynthia; Gottschalk, Alexander R.; Roach, Mack; Ma Lijun

    2010-09-01

    Purpose: The treatment planning quality between nonisocentric CyberKnife (CK) and isocentric intensity modulation treatment was studied for hypofractionated prostate body radiotherapy. In particular, the dose gradient across the target and the critical structures such as the rectum and bladder was characterized. Methods and Materials: In the present study, patients treated with CK underwent repeat planning for nine fixed-field intensity-modulated radiotherapy (IMRT) using identical contour sets and dose-volume constraints. To calculate the dose falloff, the clinical target volume contours were expanded 30 mm anteriorly and posteriorly and 50 mm uniformly in other directions for all patients in the CK and IMRT plans. Results: We found that all the plans satisfied the dose-volume constraints, with the CK plans showing significantly better conformity than the IMRT plans at a relative greater dose inhomogeneity. The rectal and bladder volumes receiving a low dose were also lower for CK than for IMRT. The average conformity index, the ratio of the prescription isodose volume and clinical target volume, was 1.18 {+-} 0.08 for the CK plans vs. 1.44 {+-} 0.11 for the IMRT plans. The average homogeneity index, the ratio of the maximal dose and the prescribed dose to the clinical target volume, was 1.45 {+-} 0.12 for the CK plans vs. 1.28 {+-} 0.06 for the IMRT plans. The average percentage of dose falloff was 2.9% {+-} 0.8%/mm for CK and 3.1% {+-} 1.0%/mm for IMRT in the anterior direction, 3.8% {+-} 1.6%/mm for CK and 3.2% {+-} 1.9%/mm for IMRT in the posterior direction, and 3.6% {+-} 0.4% for CK and 3.6% {+-} 0.4% for IMRT in all directions. Conclusion: Nonisocentric CK was as capable of producing equivalent fast dose falloff as high-number fixed-field IMRT delivery.

  9. Dose verification of a clinical intensity-modulated radiation therapy eye case by the magnetic resonance imaging of N-isopropylacrylamide gel dosimeters

    NASA Astrophysics Data System (ADS)

    Chen, Yen-Li; Hsieh, Bor-Tsung; Chiang, Chih-Ming; Shih, Cheng-Ting; Cheng, Kai-Yuan; Hsieh, Ling-Ling

    2014-11-01

    In this study, N-isopropylacrylamide (NIPAM) polymer gel, together with magnetic resonance imaging (MRI), was used to measure the relative three-dimensional (3D) dose distribution of an intensity-modulated radiation therapy (IMRT) eye case. The gels were enclosed in cylindrical acrylic vessels with 10 cm outer diameter and 10 cm length. The gels were subsequently irradiated by delivering 5 Gy of a prescribed dose with a 6 MV linear accelerator using five fields. The 3D maps of the proton relaxation rate R2 were obtained using a 1.5 T MRI system correlated with the dose. The treatment planning system (TPS) data and NIPAM gel dosimeter data were compared with the experimental results in the form of relative dose distributions, including isodose curves, dose profiles, and gamma index maps. Results indicated that the linear relationship of the R2-dose for NIPAM gel dosimeters reached 0.999 within the dose range of 0 Gy to 12 Gy. Comparison of planar dose distributions among the gel dosimeters and TPS showed that the isodose lines corresponded to selected planes in the axial plane. For the 50% to 110% dose analysis, the maximum dose differences varied from 4.04% to 13.53%. Gamma evaluation of the planar dose profile resulted in pass rates of 96.84%, 83.16%, and 53.42% when the acceptance criteria of 3%/3 mm, 2%/2 mm, and 1%/1 mm, respectively, were used in the axial plane. Overall, the results showed that NIPAM polymer gel dosimeters can serve as a high-resolution, accurate, 3D tool for IMRT dose distribution verification.

  10. Experimental Evaluation of the Impact of Different Head-and-Neck Intensity-Modulated Radiation Therapy Planning Techniques on Doses to the Skin and Shallow Targets

    SciTech Connect

    Court, Laurence E. Tishler, Roy B.

    2007-10-01

    Purpose: To investigate experimentally the impact of different head-and-neck intensity-modulated radiation therapy (IMRT) planning techniques on doses to the skin and shallow targets. Methods and Materials: A semicylindrical phantom was constructed with micro-MOSFET dosimeters (Thomson-Nielson, Ottawa, Ontario, Canada) at 0-, 3-, 6-, 9-, and 12-mm depths. The planning target volume (PTV) was pulled back 0, 3, or 5 mm from the body contour. The IMRT plans were created to maximize PTV coverage, with one of the following strategies: (a) aim for a maximum 110% hotspot, with 115% allowed; (b) aims for a maximum 105% hotspot; (c) aims for a maximum 105% hotspot and 50% of skin to get a maximum 70% of the prescribed dose; and (d) aim for 99% of the PTV volume to receive 90-93% of prescribed dose, with a maximum 105% hotspot, and with the dose to the skin structure minimized. Doses delivered using a linear accelerator were measured. Setup uncertainty was simulated by intentionally shifting the phantom in a range of {+-}8 mm, and calculating the delivered dose for a range of systematic and random uncertainties. Results: From lowest to highest skin dose, the planning strategies were in the order of c, d, b, and a, but c showed a tendency to underdose tissues at depth. Delivered doses varied by 10-20%, depending on planning strategy. For typical setup uncertainties, cumulative dose reduction to a point 6 mm deep was <4%. Conclusions: It is useful to use skin as a sensitive structure, but a minimum dose constraint must be used for the PTV if unwanted reductions in dose to nodes near the body surface are to be avoided. Setup uncertainties are unlikely to give excessive reductions in cumulative dose.

  11. Data-Driven Approach to Generating Achievable Dose-Volume Histogram Objectives in Intensity-Modulated Radiotherapy Planning

    SciTech Connect

    Wu Binbin; Ricchetti, Francesco; Sanguineti, Giuseppe; Kazhdan, Michael; Simari, Patricio; Jacques, Robert; Taylor, Russell; McNutt, Todd

    2011-03-15

    Purpose: To propose a method of intensity-modulated radiotherapy (IMRT) planning that generates achievable dose-volume histogram (DVH) objectives using a database containing geometric and dosimetric information of previous patients. Methods and Materials: The overlap volume histogram (OVH) is used to compare the spatial relationships between the organs at risk and targets of a new patient with those of previous patients in a database. From the OVH analysis, the DVH objectives of the new patient were generated from the database and used as the initial planning goals. In a retrospective OVH-assisted planning demonstration, 15 patients were randomly selected from a database containing clinical plans (CPs) of 91 previous head-and-neck patients treated by a three-level IMRT-simultaneous integrated boost technique. OVH-assisted plans (OPs) were planned in a leave-one-out manner by a planner who had no knowledge of CPs. Thus, DVH objectives of an OP were generated from a subdatabase containing the information of the other 90 patients. Those DVH objectives were then used as the initial planning goals in IMRT optimization. Planning efficiency was evaluated by the number of clicks of the 'Start Optimization' button in the course of planning. Although the Pinnacle{sup 3} treatment planning system allows planners to interactively adjust the DVH parameters during optimization, planners in our institution have never used this function in planning. Results: The average clicks required for completing the CP and OP was 27.6 and 1.9, respectively (p <.00001); three OPs were finished within a single click. Ten more patient's cord + 4 mm reached the sparing goal D{sub 0.1cc} <44 Gy (p <.0001), where D{sub 0.1cc} represents the dose corresponding to 0.1 cc. For planning target volume uniformity, conformity, and other organ at risk sparing, the OPs were at least comparable with the CPs. Additionally, the averages of D{sub 0.1cc} to the cord + 4 mm decreased by 6.9 Gy (p <.0001

  12. Photosensitized damage inflicted on plasma membranes of live cells by an extracellular generator of singlet oxygen--a linear dependence of a lethal dose on light intensity.

    PubMed

    Zarębski, Mirosław; Kordon, Magdalena; Dobrucki, Jurek W

    2014-01-01

    We describe a study of the influence of a dose rate, i.e. light intensity or photon flux, on the efficiency of induction of a loss of integrity of plasma membranes of live cells in culture. The influence of a photon flux on the size of the light dose, which was capable of causing lethal effects, was measured in an experimental system where singlet oxygen was generated exclusively outside of live cells by ruthenium(II) phenantroline complex. Instantaneous, sensitive detection of a loss of integrity of a plasma membrane was achieved by fluorescence confocal imaging of the entry of this complex into a cell interior. We demonstrate that the size of the lethal dose of light is directly proportional to the intensity of the exciting light. Thus, the probability of a photon of the exciting light inflicting photosensitized damage on plasma membranes diminishes with increasing density of the incident photons.

  13. Factors influencing the implementation of antibiotic de-escalation and impact of this strategy in critically ill patients

    PubMed Central

    2013-01-01

    Introduction A rational use of antibiotics is of paramount importance in order to prevent the emergence of multidrug resistant bacteria that can lead to therapeutic impasse, especially in intensive care units (ICUs). A de-escalation strategy is therefore naturally advocated as part of better antibiotics usage. However, the clinical impact of such a strategy has not been widely studied. We aimed to assess the feasibility and the clinical impact of a de-escalation strategy in a medical ICU and to identify factors associated when de-escalation was possible. Methods We performed a retrospective study of patients hospitalized in a medical ICU over a period of six months. Independent factors associated with de-escalation and its clinical impact were assessed. Results Two hundred and twenty-nine patients were included in the study. Antibiotics were de-escalated in 117 patients (51%). The appropriateness of initial antibiotic therapy was the only independent factor associated with the performance of de-escalation (OR = 2.9, 95% CI, 1.5-5.7; P = 0.002). By contrast, inadequacy of initial antibiotic therapy (OR = 0.1, 0.0 to 0.1, P <0.001) and the presence of multidrug resistant bacteria (OR = 0.2, 0.1 to 0.7, P = 0.006) prevented from de-escalation. There were no differences in terms of short (ICU) or long-term (at 1 year) mortality rates or any secondary criteria such as ICU length of stay, duration of antibiotic therapy, mechanical ventilation, incidence of ICU-acquired infection, or multi-drug resistant bacteria emergence. Conclusions De-escalation appears feasible in most cases without any obvious negative clinical impact in a medical ICU. PMID:23849321

  14. Tobacco and the Escalating Global Cancer Burden

    PubMed Central

    Oppeltz, Richard F.; Jatoi, Ismail

    2011-01-01

    The global burden of cancer is escalating as a result of dramatic increases in the use of tobacco in the developing world. The use of tobacco is linked to the development of a broad variety of cancers, mainly lung cancer, the single most common cancer in the world. Tobacco smoking-attributable deaths extends beyond cancer and include stroke, heart attack and COPD. Widening disparities in cancer-related mortality have shifted towards a more dramatic burden in the developing world. Appropriate interventions must be implemented to reduce tobacco use and prevent global mortality that has escalated to epidemic levels. Tobacco control policies, including public health advertisement campaigns, warning labels, adoption of smoke-free laws, comprehensive bans and tax policies are highly effective measures to control tobacco use. Clinicians and academic institutions have to be actively committed to support tobacco control initiatives. The reduction in cancer related morbidity and mortality should be viewed as a global crisis and definitive results will depend on a multilevel effort to effectively reduce the burden of cancer, particularly in underprivileged regions of the world. PMID:21869888

  15. [Head and neck intensity-modulated radiation therapy: Normal tissues dose constraints. Pharyngeal constrictor muscles and larynx].

    PubMed

    Graff, P; Woisard, V; Racadot, S; Thariat, J; Pointreau, Y

    2016-10-01

    Radio-induced pharyngolaryngeal chronic disorders may challenge the quality of life of head and neck cancer long survivors. Many anatomic structures have been identified as potentially impaired by irradiation and responsible for laryngeal edema, dysphonia and dysphagia. Some dose constraints might be plausible such as keeping the mean dose to the pharyngeal constrictor muscles under 50 to 55Gy, the mean dose to the supra-glottic larynx under 40 to 45Gy and, if feasible, the mean dose to the glottic larynx under 20Gy. A reduction of the dose delivered to the muscles of the floor of the mouth and the cervical esophagus would be beneficial as well. Nevertheless, the publications available do not provide an extensive enough level of proof. One should consider limiting as low as possible the dose delivered to these structures without compromising the quality of irradiation of the target tumor volumes.

  16. Intensity-Modulated Radiotherapy of Head and Neck Cancer Aiming to Reduce Dysphagia: Early Dose-Effect Relationships for the Swallowing Structures

    SciTech Connect

    Feng, Felix Y.; Kim, Hyungjin M.; Lyden, Teresa H.; Haxer, Marc J.; Feng, Mary; Worden, Frank P.; Eisbruch, Avraham . E-mail: eisbruch@umich.edu

    2007-08-01

    Purpose: To present initial results of a clinical trial of intensity-modulated radiotherapy (IMRT) aiming to spare the swallowing structures whose dysfunction after chemoradiation is a likely cause of dysphagia and aspiration, without compromising target doses. Methods and Materials: This was a prospective, longitudinal study of 36 patients with Stage III-IV oropharyngeal (31) or nasopharyngeal (5) cancer. Definitive chemo-IMRT spared salivary glands and swallowing structures: pharyngeal constrictors (PC), glottic and supraglottic larynx (GSL), and esophagus. Lateral but not medial retropharyngeal nodes were considered at risk. Dysphagia endpoints included objective swallowing dysfunction (videofluoroscopy), and both patient-reported and observer-rated scores. Correlations between doses and changes in these endpoints from pre-therapy to 3 months after therapy were assessed. Results: Significant correlations were observed between videofluoroscopy-based aspirations and the mean doses to the PC and GSL, as well as the partial volumes of these structures receiving 50-65 Gy; the highest correlations were associated with doses to the superior PC (p = 0.005). All patients with aspirations received mean PC doses >60 Gy or PC V{sub 65} >50%, and GSL V{sub 50} >50%. Reduced laryngeal elevation and epiglottic inversion were correlated with mean PC and GSL doses (p < 0.01). All 3 patients with strictures had PC V{sub 70} >50%. Worsening patient-reported liquid swallowing was correlated with mean PC (p = 0.05) and esophageal (p 0.02) doses. Only mean PC doses were correlated with worsening patient-reported solid swallowing (p = 0.04) and observer-rated swallowing scores (p = 0.04). Conclusions: These dose-volume-effect relationships provide initial IMRT optimization goals and motivate further efforts to reduce swallowing structures doses to reduce dysphagia and aspiration.

  17. Correlating planned radiation dose to the cochlea with primary site and tumor stage in patients with head and neck cancer treated with intensity-modulated radiation therapy

    SciTech Connect

    Zhang, Jeanette; Qureshi, Muhammad M.; Kovalchuk, Nataliya; Truong, Minh Tam

    2014-04-01

    The aim of the study was to determine tumor characteristics that predict higher planned radiation (RT) dose to the cochlea in patients with head and neck cancer (HNC) treated with intensity-modulated radiotherapy (IMRT). From 2004 to 2012, 99 patients with HNC underwent definitive IMRT to a median dose of 69.96 Gy in 33 fractions, with the right and left cochlea-vestibular apparatus contoured for IMRT optimization as avoidance structures. If disease involvement was adjacent to the cochlea, preference was given to tumor coverage by prescription dose. Descriptive statistics were calculated for dose-volume histogram planning data, and mean planning dose to the cochlea (from left or right cochlea, receiving the greater amount of RT dose) was correlated to primary site and tumor stage. Mean (standard deviation) cochlear volume was 1.0 (0.60) cm{sup 3} with maximum and mean planned doses of 31.9 (17.5) Gy and 22.1 (13.7) Gy, respectively. Mean planned dose (Gy) to cochlea by tumor site was as follows: oral cavity (18.6, 14.4), oropharynx (21.7, 9.1), nasopharynx (36.3, 10.4), hypopharynx (14.9, 7.1), larynx (2.1, 0.62), others including the parotid gland, temporal bone, and paranasal sinus (33.6, 24.0), and unknown primary (25.6, 6.7). Average mean planned dose (Gy) to the cochlea in T0-T2 and T3-T4 disease was 22.0 and 29.2 Gy, respectively (p = 0.019). By site, a significant difference was noted for nasopharynx and others (31.6 and 50.7, p = 0.012) but not for oropharynx, oral cavity, and hypopharynx. Advanced T category predicted for higher mean cochlear dose, particularly for nasopharyngeal, parotid gland, temporal bone, and paranasal sinus HNC sites.

  18. [Radiotherapy of a glioma in a pregnant woman: evaluation of the foetal dose in conformational 3D or intensity-modulated].

    PubMed

    Lefebvre, L; Doyeux, K; Linca, S; Challand, T; Hanzen, C

    2014-12-01

    The purpose was to assess three treatments planning techniques including one in intensity-modulated radiation therapy (IMRT) for cerebral irradiation of pregnant woman, in order to limit the dose delivered to the foetus. The treatment provided was 60 Gy to the planning target volume. Estimated foetal dose was measured using an anthropomorphic phantom, on the upper and middle part of the uterus. The first plan consisted in four beams in conformational technique delivered from a Varian accelerator with a 120 leaves collimator, the second one used non-coplanar fields and the third one assessed IMRT. With the conformational technique, the dose at the upper part of the uterus was 8.3 mGy and 6.3 mGy at the middle part. The dose delivered to the foetus was higher with the non-coplanar fields. In IMRT, the dose at the upper part of the uterus was 23.8 mGy and 14.3 mGy at the middle part. The three plans used 6 MV X-rays. Because of the use of leaves and non-coplanar fields, IMRT does not seem to be the optimal technique for the treatment of pregnant woman. However, the dose delivered to the foetus remains low and below the dose of 100 mGy recommended by the International Commission of Radiological Protection. It seems possible to consider the use of this technique for a better sparing of organs at risk for the mother.

  19. The role of Cobalt-60 source in Intensity Modulated Radiation Therapy: From modeling finite sources to treatment planning and conformal dose delivery

    NASA Astrophysics Data System (ADS)

    Dhanesar, Sandeep Kaur

    Cobalt-60 (Co-60) units played an integral role in radiation therapy from the mid-1950s to the 1970s. Although they continue to be used to treat cancer in some parts of the world, their role has been significantly reduced due to the invention of medical linear accelerators. A number of groups have indicated a strong potential for Co-60 units in modern radiation therapy. The Medical Physics group at the Cancer Center of the Southeastern Ontario and Queen's University has shown the feasibility of Intensity Modulated Radiation Therapy (IMRT) via simple conformal treatment planning and dose delivery using a Co-60 unit. In this thesis, initial Co-60 tomotherapy planning investigations on simple uniform phantoms are extended to actual clinical cases based on patient CT data. The planning is based on radiation dose data from a clinical Co-60 unit fitted with a multileaf collimator (MLC) and modeled in the EGSnrc Monte Carlo system. An in house treatment planning program is used to calculate IMRT dose distributions. Conformal delivery in a single slice on a uniform phantom based on sequentially delivered pencil beams is verified by Gafchromic film. Volumetric dose distributions for Co-60 serial tomotherapy are then generated for typical clinical sites that had been treated at our clinic by conventional 6MV IMRT using Varian Eclipse treatment plans. The Co-60 treatment plans are compared with the clinical IMRT plans using conventional matrices such as dose volume histograms (DVH). Dose delivery based on simultaneously opened MLC leaves is also explored and a novel MLC segmentation method is proposed. In order to increase efficiency of dose calculations, a novel convolution based fluence model for treatment planning is also proposed. The ion chamber measurements showed that the Monte Carlo modeling of the beam data under the MIMiC MLC is accurate. The film measurements from the uniform phantom irradiations confirm that IMRT plans from our in-house treatment planning system

  20. Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients.

    PubMed

    Kishi, Y; Murashige, N; Kami, M; Miyakoshi, S; Shibagaki, Y; Hamaki, T; Takaue, Y; Taniguchi, S

    2005-06-01

    Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n=25), renal dysfunction (n=3), hepatic dysfunction (n=2), and hypertension (n=2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n=4), hyperbilirubinemia (n=2), and hypertension (n=2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

  1. Investigation of conformal and intensity-modulated radiation therapy techniques to determine the absorbed fetal dose in pregnant patients with breast cancer

    SciTech Connect

    Öğretici, Akın Akbaş, Uğur; Köksal, Canan; Bilge, Hatice

    2016-07-01

    The aim of this research was to investigate the fetal doses of pregnant patients undergoing conformal radiotherapy or intensity-modulated radiation therapy (IMRT) for breast cancers. An Alderson Rando phantom was chosen to simulate a pregnant patient with breast cancer who is receiving radiation therapy. This phantom was irradiated using the Varian Clinac DBX 600 system (Varian Medical System, Palo Alto, CA) linear accelerator, according to the standard treatment plans of both three-dimensional conformal radiation therapy (3-D CRT) and IMRT techniques. Thermoluminescent dosimeters were used to measure the irradiated phantom's virtually designated uterus area. Thermoluminescent dosimeter measurements (in the phantom) revealed that the mean cumulative fetal dose for 3-D CRT is 1.39 cGy and for IMRT it is 8.48 cGy, for a pregnant breast cancer woman who received radiation treatment of 50 Gy. The fetal dose was confirmed to increase by 70% for 3-D CRT and 40% for IMRT, if it is closer to the irradiated field by 5 cm. The mean fetal dose from 3-D CRT is 1.39 cGy and IMRT is 8.48 cGy, consistent with theoretic calculations. The IMRT technique causes the fetal dose to be 5 times more than that of 3-D CRT. Theoretic knowledge concerning the increase in the peripheral doses as the measurements approached the beam was also practically proven.

  2. Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer.

    PubMed

    Bernhard, J; Zahrieh, D; Zhang, J J; Martinelli, G; Basser, R; Hürny, C; Forbes, J F; Aebi, S; Yeo, W; Thürlimann, B; Green, M D; Colleoni, M; Gelber, R D; Castiglione-Gertsch, M; Price, K N; Goldhirsch, A; Coates, A S

    2008-01-15

    Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P<0.01), but a faster recovery 3 months following chemotherapy than patients receiving SD-CT, for example, less coping effort (P<0.01). Average Q-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, -2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy.

  3. Radiation dose to the brachial plexus in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: An increased risk of an excessive dose to the brachial plexus adjacent to gross nodal disease

    PubMed Central

    FENG, GUOSHENG; LU, HEMING; LIANG, YUAN; CHEN, HUASHENG; SHU, LIUYANG; LU, SHUI; ZHU, JIANFANG; GAO, WEIWEI

    2012-01-01

    This retrospective study aimed to evaluate the dose to the brachial plexus in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). Twenty-eight patients were selected and the brachial plexus was delineated retrospectively. Brachial plexus adjacent/not adjacent to nodes were defined and abbreviated as BPAN and BPNAN, respectively. Dose distribution was recalculated and a dose-volume histogram was generated based on the original treatment plan. The maximum dose to the left brachial plexus was 59.12–78.47 Gy, and the percentage of patients receiving the maximum dose exceeding 60, 66 and 70 Gy was 96.4, 57.1 and 25.0%, respectively; the maximum dose to the right brachial plexus was 59.74–80.31 Gy, and the percentage of patients exposed to a maximum dose exceeding 60, 66 and 70 Gy was 96.4, 64.3 and 39.3%, respectively. For the left brachial plexus, the maximum doses to the BPANs and the BPNANs were 72.84±3.91 and 64.81±3.47 Gy, respectively (p<0.001). For the right brachial plexus, the maximum doses to the BPANs and the BPNANs were 72.91±4.74 and 64.91±3.52 Gy, respectively (p<0.001). The difference between the left BPANs and the left BPNANs was statistically significant not only for V60 (3.60 vs. 1.01 cm3, p=0.028) but also for V66 (1.26 vs. 0.11 cm3, p=0.046). There were significant differences in V60 (3.68 vs. 1.16 cm3, p<0.001) and V66 (1.83 vs. 1.23 cm3, p=0.012) between the right BPANs and the right BPNANs. In conclusion, a large proportion of patients were exposed to the maximum dose to the brachial plexus exceeding the Radiation Therapy Oncology Group-recommended restraints when the brachial plexus was not outlined. The BPANs are at a significantly higher risk of receiving an excessive radiation dose when compared to the BPNANs. A further study is underway to test whether brachial plexus contouring assists in the dose reduction to the brachial plexus for IMRT optimization. PMID:22970028

  4. Correlates Associated with Escalation of Delinquent Behavior in Incarcerated Youths.

    ERIC Educational Resources Information Center

    van Dorn, Richard A.; Williams, James Herbert

    2003-01-01

    Investigates the extent to which attitudes, family, and environmental correlates are associated with the escalation from nonviolent to violent offending among incarcerated youths. Beliefs that power equates safety and a violent home environment were salient in understanding escalation in offending behavior, and prior criminal victimization was…

  5. Twelve Practical Strategies To Prevent Behavioral Escalation in Classroom Settings.

    ERIC Educational Resources Information Center

    Shukla-Mehta, Smita; Albin, Richard W.

    2003-01-01

    Twelve practical strategies that can be used by classroom teachers to prevent behavioral escalation are discussed, including reinforce calm, know the triggers, pay attention to anything unusual, do not escalate, intervene early, know the function of problem behavior, use extinction wisely, teach prosocial behavior, and teach academic survival…

  6. Twelve Practical Strategies to Prevent Behavioral Escalation in Classroom Settings

    ERIC Educational Resources Information Center

    Shukla-Mehta, Smita; Albin, Richard W.

    2003-01-01

    In this article, the authors describe 12 practical strategies identified as empirically effective in preventing behavioral escalation in students: (1) Reinforce calm and on-task behaviors; (2) Know the triggers; (3) Pay attention to anything unusual about the student's behavior; (4) Do not escalate along with the student; (5) Offer students…

  7. Comparison of Heart and Coronary Artery Doses Associated With Intensity-Modulated Radiotherapy Versus Three-Dimensional Conformal Radiotherapy for Distal Esophageal Cancer

    SciTech Connect

    Kole, Thomas P.; Aghayere, Osarhieme; Kwah, Jason; Yorke, Ellen D.; Goodman, Karyn A.

    2012-08-01

    Purpose: To compare heart and coronary artery radiation exposure using intensity-modulated radiotherapy (IMRT) vs. four-field three-dimensional conformal radiotherapy (3D-CRT) treatment plans for patients with distal esophageal cancer undergoing chemoradiation. Methods and Materials: Nineteen patients with distal esophageal cancers treated with IMRT from March 2007 to May 2008 were identified. All patients were treated to 50.4 Gy with five-field IMRT plans. Theoretical 3D-CRT plans with four-field beam arrangements were generated. Dose-volume histograms of the planning target volume, heart, right coronary artery, left coronary artery, and other critical normal tissues were compared between the IMRT and 3D-CRT plans, and selected parameters were statistically evaluated using the Wilcoxon rank-sum test. Results: Intensity-modulated radiotherapy treatment planning showed significant reduction (p < 0.05) in heart dose over 3D-CRT as assessed by average mean dose (22.9 vs. 28.2 Gy) and V30 (24.8% vs. 61.0%). There was also significant sparing of the right coronary artery (average mean dose, 23.8 Gy vs. 35.5 Gy), whereas the left coronary artery showed no significant improvement (mean dose, 11.2 Gy vs. 9.2 Gy), p = 0.11. There was no significant difference in percentage of total lung volume receiving at least 10, 15, or 20 Gy or in the mean lung dose between the planning methods. There were also no significant differences observed for the kidneys, liver, stomach, or spinal cord. Intensity-modulated radiotherapy achieved a significant improvement in target conformity as measured by the conformality index (ratio of total volume receiving 95% of prescription dose to planning target volume receiving 95% of prescription dose), with the mean conformality index reduced from 1.56 to 1.30 using IMRT. Conclusions: Treatment of patients with distal esophageal cancer using IMRT significantly decreases the exposure of the heart and right coronary artery when compared with 3D

  8. Comparison of the dose distribution obtained from dosimetric systems with intensity modulated radiotherapy planning system in the treatment of prostate cancer

    NASA Astrophysics Data System (ADS)

    Gökçe, M.; Uslu, D. Koçyiǧit; Ertunç, C.; Karalı, T.

    2016-03-01

    The aim of this study is to compare Intensity Modulated Radiation Therapy (IMRT) plan of prostate cancer patients with different dose verification systems in dosimetric aspects and to compare these systems with each other in terms of reliability, applicability and application time. Dosimetric control processes of IMRT plan of three prostate cancer patients were carried out using thermoluminescent dosimeter (TLD), ion chamber (IC) and 2D Array detector systems. The difference between the dose values obtained from the dosimetric systems and treatment planning system (TPS) were found to be about % 5. For the measured (TLD) and calculated (TPS) doses %3 percentage differences were obtained for the points close to center while percentage differences increased at the field edges. It was found that TLD and IC measurements will increase the precision and reliability of the results of 2D Array.

  9. Dose Sparing of Brainstem and Spinal Cord for Re-Irradiating Recurrent Head and Neck Cancer with Intensity-Modulated Radiotherapy

    SciTech Connect

    Chen, Chin-Cheng; Lee, Chen-Chiao; Mah, Dennis; Sharma, Rajiv; Landau, Evan; Garg, Madhur; Wu, Andrew

    2011-04-01

    Because of the dose limit for critical structures such as brainstem and spinal cord, administering a dose of 60 Gy to patients with recurrent head and neck cancer is challenging for those who received a previous dose of 60-70 Gy. Specifically, previously irradiated head and neck patients may have received doses close to the tolerance limit to their brainstem and spinal cord. In this study, a reproducible intensity-modulated radiation therapy (IMRT) treatment design is presented to spare the doses to brainstem and spinal cord, with no compromise of prescribed dose delivery. Between July and November 2008, 7 patients with previously irradiated, recurrent head and neck cancers were treated with IMRT. The jaws of each field were set fixed with the goal of shielding the brainstem and spinal cord at the sacrifice of partial coverage of the planning target volume (PTV) from any particular beam orientation. Beam geometry was arranged to have sufficient coverage of the PTV and ensure that the constraints of spinal cord <10 Gy and brainstem <15 Gy were met. The mean maximum dose to the brainstem was 12.1 Gy (range 6.1-17.3 Gy), and the corresponding mean maximum dose to spinal cord was 10.4 Gy (range 8.2-14.1 Gy). For most cases, 97% of the PTV volume was fully covered by the 95% isodose volume. We found empirically that if the angle of cervical spine curvature (Cobb's angle) was less than {approx}30{sup o}, patients could be treated by 18 fields. Six patients met these criteria and were treated in 25 minutes per fraction. One patient exceeded a 30{sup o} Cobb's angle and was treated by 31 fields in 45 minutes per fraction. We have demonstrated a new technique for retreatment of head and neck cancers. The angle of cervical spine curvature plays an important role in the efficiency and effectiveness of our approach.

  10. Half-Fan-Based Intensity-Weighted Region-of-Interest Imaging for Low-Dose Cone-Beam CT in Image-Guided Radiation Therapy

    PubMed Central

    Yoo, Boyeol; Son, Kihong; Pua, Rizza; Kim, Jinsung; Solodov, Alexander

    2016-01-01

    Objectives With the increased use of computed tomography (CT) in clinics, dose reduction is the most important feature people seek when considering new CT techniques or applications. We developed an intensity-weighted region-of-interest (IWROI) imaging method in an exact half-fan geometry to reduce the imaging radiation dose to patients in cone-beam CT (CBCT) for image-guided radiation therapy (IGRT). While dose reduction is highly desirable, preserving the high-quality images of the ROI is also important for target localization in IGRT. Methods An intensity-weighting (IW) filter made of copper was mounted in place of a bowtie filter on the X-ray tube unit of an on-board imager (OBI) system such that the filter can substantially reduce radiation exposure to the outer ROI. In addition to mounting the IW filter, the lead-blade collimation of the OBI was adjusted to produce an exact half-fan scanning geometry for a further reduction of the radiation dose. The chord-based rebinned backprojection-filtration (BPF) algorithm in circular CBCT was implemented for image reconstruction, and a humanoid pelvis phantom was used for the IWROI imaging experiment. Results The IWROI image of the phantom was successfully reconstructed after beam-quality correction, and it was registered to the reference image within an acceptable level of tolerance. Dosimetric measurements revealed that the dose is reduced by approximately 61% in the inner ROI and by 73% in the outer ROI compared to the conventional bowtie filter-based half-fan scan. Conclusions The IWROI method substantially reduces the imaging radiation dose and provides reconstructed images with an acceptable level of quality for patient setup and target localization. The proposed half-fan-based IWROI imaging technique can add a valuable option to CBCT in IGRT applications. PMID:27895964

  11. Low CD34 dose is associated with poor survival after reduced-intensity conditioning allogeneic transplantation for acute myeloid leukemia and myelodysplastic syndrome.

    PubMed

    Törlén, Johan; Ringdén, Olle; Le Rademacher, Jennifer; Batiwalla, Minoo; Chen, Junfang; Erkers, Tom; Ho, Vincent; Kebriaei, Partow; Keever-Taylor, Carolyn; Kindwall-Keller, Tamila; Lazarus, Hillard M; Laughlin, Mary J; Lill, Michael; O'Brien, Tracey; Perales, Miguel-Angel; Rocha, Vanderson; Savani, Bipin N; Szwajcer, David; Valcarcel, David; Eapen, Mary

    2014-09-01

    Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34(+) dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34(+) dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 × 10(6) CD34(+)/kg was associated with higher nonrelapse mortality (hazard ratio [HR], 2.03; P = .001), overall mortality (HR, 1.48; P = .008), and lower neutrophil (odds ratio [OR], .76; P = .03) and platelet (OR, .76; P = .03) recovery. PBPC from unrelated donors with CD34(+) dose < 6 × 10(6) CD34(+)/kg was also associated with higher nonrelapse (HR, 1.38; P = .02) and overall mortality (HR, 1.20; P = .05). In contrast to reports after myeloablative HCT, CD34(+) dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34(+) doses >4 × 10(6) CD34(+)/kg and >6 × 10(6) CD34(+)/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively.

  12. Dose-volume relationships for moderate or severe neck muscle atrophy after intensity-modulated radiotherapy in patients with nasopharyngeal carcinoma.

    PubMed

    Zhang, Lu-Lu; Wang, Xiao-Ju; Zhou, Guan-Qun; Tang, Ling-Long; Lin, Ai-Hua; Ma, Jun; Sun, Ying

    2015-12-18

    This study aimed to identify the dosimetric parameters and radiation dose tolerances associated with moderate or severe sternocleidomastoid muscle (SCM) atrophy after intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC). We retrospectively analysed 138 patients treated with IMRT between 2011 and 2012 for whom IMRT treatment plans and pretreatment and 3-year post-IMRT MRI scans were available. The association between mean dose (Dmean), maximum dose (Dmax), VX (% SCM volume that received more than X Gy), DX (dose to X% of the SCM volume) at X values of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 and SCM atrophy at 3 years after IMRT were analyzed. All dosimetric parameters, except V40, V50 and V80, were significantly associated with moderate or severe SCM atrophy. Multivariate analysis showed that V65 was an independent predictor of moderate or severe SCM atrophy (P < 0.001). Receiver operating characteristic (ROC) curve indicated a V65 of 21.47% (area under ROC curves, 0.732; P < 0.001) was the tolerated dose for moderate or severe SCM atrophy. We suggest a limit of 21.47% for V65 to optimize NPC treatment planning, whilst minimizing the risk of moderate or severe SCM atrophy.

  13. Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives.

    PubMed

    Mirghani, H; Amen, F; Blanchard, P; Moreau, F; Guigay, J; Hartl, D M; Lacau St Guily, J

    2015-04-01

    Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High-risk human papillomavirus (HR-HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de-escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de-escalation in HPV-positive OPSCC.

  14. Evaluation of the potential impact of a carbapenem de-escalation program in an academic healthcare system.

    PubMed

    Ahmad, Farah; Pogue, Jason M; Marchaim, Dror; Chopra, Teena; Bheemreddy, Suchita; Lee, Jiha; Mudegowdra, Niveditha S; Chaudhry, Aaisha; Kaye, Keith S

    2014-02-01

    The primary objective of this analysis was to evaluate group 2 carbapenem usage and to model the impact that a formalized de-escalation protocol to ertapenem could potentially have on group 2 carbapenem usage in the hope of alleviating the selective pressure on Acinetobacter and Pseudomonas. This analysis was conducted in three hospitals within the Detroit Medical Center in 2009. Patients were considered candidates for de-escalation of carbapenem therapy when a group 2 carbapenem was utilized to treat Enterobacteriaceae, such as extended spectrum β-lactamase (ESBL)-producing organisms, or if cultures were negative in non-intensive care unit (ICU) patients. In total, 179 patients (28%) and 1074 patient-days (29%) were deemed eligible for de-escalation according to our pre-defined criteria. We concluded that preferential utilization of ertapenem in appropriate patients warranting carbapenem therapy has the potential to significantly decrease group 2 carbapenem usage at our institution.

  15. High-Dose and Extended-Field Intensity Modulated Radiation Therapy for Early-Stage NK/T-Cell Lymphoma of Waldeyer's Ring: Dosimetric Analysis and Clinical Outcome

    SciTech Connect

    Bi, Xi-Wen; Li, Ye-Xiong Fang, Hui; Jin, Jing; Wang, Wei-Hu; Wang, Shu-Lian; Liu, Yue-Ping; Song, Yong-Wen; Ren, Hua; Dai, Jian-Rong

    2013-12-01

    Purpose: To assess the dosimetric benefit, treatment outcome, and toxicity of high-dose and extended-field intensity modulated radiation therapy (IMRT) in patients with early-stage NK/T-cell lymphoma of Waldeyer's ring (WR-NKTCL). Methods and Materials: Thirty patients with early-stage WR-NKTCL who received extended-field IMRT were retrospectively reviewed. The prescribed dose was 50 Gy to the primary involved regions and positive cervical lymph nodes (planning target volume requiring radical irradiation [PTV{sub 50}]) and 40 Gy to the negative cervical nodes (PTV{sub 40}). Dosimetric parameters for the target volume and critical normal structures were evaluated. Locoregional control (LRC), overall survival (OS), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Results: The median mean doses to the PTV{sub 50} and PTV{sub 40} were 53.2 Gy and 43.0 Gy, respectively. Only 1.4% of the PTV{sub 50} and 0.9% of the PTV{sub 40} received less than 95% of the prescribed dose, indicating excellent target coverage. The average mean doses to the left and right parotid glands were 27.7 and 28.4 Gy, respectively. The 2-year OS, PFS, and LRC rates were 71.2%, 57.4%, and 87.8%. Most acute toxicities were grade 1 to 2, except for grade ≥3 dysphagia and mucositis. The most common late toxicity was grade 1-2 xerostomia, and no patient developed any ≥grade 3 late toxicities. A correlation between the mean dose to the parotid glands and the degree of late xerostomia was observed. Conclusions: IMRT achieves excellent target coverage and dose conformity, as well as favorable survival and locoregional control rates with acceptable toxicities in patients with WR-NKTCL.

  16. Dependences of mucosal dose on photon beams in head-and-neck intensity-modulated radiation therapy: a Monte Carlo study

    SciTech Connect

    Chow, James C.L.; Owrangi, Amir M.

    2012-07-01

    Dependences of mucosal dose in the oral or nasal cavity on the beam energy, beam angle, multibeam configuration, and mucosal thickness were studied for small photon fields using Monte Carlo simulations (EGSnrc-based code), which were validated by measurements. Cylindrical mucosa phantoms (mucosal thickness = 1, 2, and 3 mm) with and without the bone and air inhomogeneities were irradiated by the 6- and 18-MV photon beams (field size = 1 Multiplication-Sign 1 cm{sup 2}) with gantry angles equal to 0 Degree-Sign , 90 Degree-Sign , and 180 Degree-Sign , and multibeam configurations using 2, 4, and 8 photon beams in different orientations around the phantom. Doses along the central beam axis in the mucosal tissue were calculated. The mucosal surface doses were found to decrease slightly (1% for the 6-MV photon beam and 3% for the 18-MV beam) with an increase of mucosal thickness from 1-3 mm, when the beam angle is 0 Degree-Sign . The variation of mucosal surface dose with its thickness became insignificant when the beam angle was changed to 180 Degree-Sign , but the dose at the bone-mucosa interface was found to increase (28% for the 6-MV photon beam and 20% for the 18-MV beam) with the mucosal thickness. For different multibeam configurations, the dependence of mucosal dose on its thickness became insignificant when the number of photon beams around the mucosal tissue was increased. The mucosal dose with bone was varied with the beam energy, beam angle, multibeam configuration and mucosal thickness for a small segmental photon field. These dosimetric variations are important to consider improving the treatment strategy, so the mucosal complications in head-and-neck intensity-modulated radiation therapy can be minimized.

  17. Impact of dose rate on accuracy of intensity modulated radiation therapy plan delivery using the pretreatment portal dosimetry quality assurance and setting up the workflow at hospital levels

    PubMed Central

    Kaviarasu, Karunakaran; Raj, N. Arunai Nambi; Murthy, K. Krishna; Babu, A. Ananda Giri; Prasad, Bhaskar Laxman Durga

    2015-01-01

    The aim of this study was to examine the impact of dose rate on accuracy of intensity modulated radiation therapy (IMRT) plan delivery by comparing the gamma agreement between the calculated and measured portal doses by pretreatment quality assurance (QA) using electronic portal imaging device dosimetry and creating a workflow for the pretreatment IMRT QA at hospital levels. As the improvement in gamma agreement leads to increase in the quality of IMRT treatment delivery, gamma evaluation was carried out for the calculated and the measured portal images for the criteria of 3% dose difference and 3 mm distance-to-agreement (DTA). Three gamma parameters: Maximum gamma, average gamma, and percentage of the field area with a gamma value>1.0 were analyzed. Three gamma index parameters were evaluated for 40 IMRT plans (315 IMRT fields) which were calculated for 400 monitor units (MU)/min dose rate and maximum multileaf collimator (MLC) speed of 2.5 cm/s. Gamma parameters for all 315 fields are within acceptable limits set at our center. Further, to improve the gamma results, we set an action level for this study using the mean and standard deviation (SD) values from the 315 fields studied. Forty out of 315 IMRT fields showed low gamma agreement (gamma parameters>2 SD as per action level of the study). The parameters were recalculated and reanalyzed for the dose rates of 300, 400 and 500 MU/min. Lowering the dose rate helped in getting an enhanced gamma agreement between the calculated and measured portal doses of complicated fields. This may be attributed to the less complex motion of MLC over time and the MU of the field/segment. An IMRT QA work flow was prepared which will help in improving the quality of IMRT delivery. PMID:26865759

  18. SU-E-T-166: Evaluation of Integral Dose in Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy for Head and Neck Cancer Patient

    SciTech Connect

    Al-Basheer, A; Hunag, J; Kaminski, J; Dasher, B; Howington, J; Stewart, J; Martin, D; Kong, F; Jin, J

    2014-06-01

    Purpose: Volumetric Modulated Arc Therapy (VMAT) usually achieves higher conformity of radiation doses to targets and less delivery time than Intensity Modulated Radiation Therapy (IMRT). We hypothesized that VMAT will increase integral dose (ID) to patients which will decrease the count of white blood count (WBC) lymphocytes, and consequently has a subsequent impact on the immune system. The purpose of this study is to evaluate the ID to patients undergoing IMRT and VMAT for Head and Neck cancers and its impact on the immune system. Methods: As a pilot study, 30 head and neck patients who received 9-fields IMRT or 3-arcs Radip-Arcbased VMAT were included in this study. Ten of these patients who received the VMAT plans were re-planned using IMRT with the same objectives. ID was calculated for all cases. All patients also had a baseline WBC obtained prior to treatment, and 3 sets of labs drawn during the course of radiation treatment. Results: For the 10 re-planned patients, the mean ID was 13.3 Gy/voxel (range 10.2–17.5 Gy/voxel) for the 9-fields IMRT plans, and was 15.9 Gy/voxel (range 12.4-20.9 Gy/voxel) for the 3-Arc VMAT plan (p=0.01). The integral dose was significant correlated with reducing WBC count during RT even when controlling for concurrent chemotherapy (R square =0.56, p=0.008). Conclusion: Although VMAT can deliver higher radiation dose conformality to targets, this benefit is achieved generally at the cost of greater integral doses to normal tissue outside the planning target volume (PTV). Lower WBC counts during RT were associated with higher Integral doses even when controlling for concurrent chemotherapy. This study is ongoing in our Institution to exam the impact of integral doses and WBC on overall survival.

  19. Targeted Manipulation of Serotonergic Neurotransmission Affects the Escalation of Aggression in Adult Male Drosophila melanogaster

    PubMed Central

    Alekseyenko, Olga V.; Lee, Carol; Kravitz, Edward A.

    2010-01-01

    Dopamine (DA) and serotonin (5HT) are reported to serve important roles in aggression in a wide variety of animals. Previous investigations of 5HT function in adult Drosophila behavior have relied on pharmacological manipulations, or on combinations of genetic tools that simultaneously target both DA and 5HT neurons. Here, we generated a transgenic line that allows selective, direct manipulation of serotonergic neurons and asked whether DA and 5HT have separable effects on aggression. Quantitative morphological examination demonstrated that our newly generated tryptophan hydroxylase (TRH)-Gal4 driver line was highly selective for 5HT-containing neurons. This line was used in conjunction with already available Gal4 driver lines that target DA or both DA and 5HT neurons to acutely alter the function of aminergic systems. First, we showed that acute impairment of DA and 5HT neurotransmission using expression of a temperature sensitive form of dynamin completely abolished mid- and high-level aggression. These flies did not escalate fights beyond brief low-intensity interactions and therefore did not yield dominance relationships. We showed next that manipulation of either 5HT or DA neurotransmission failed to duplicate this phenotype. Selective disruption of 5HT neurotransmission yielded flies that fought, but with reduced ability to escalate fights, leading to fewer dominance relationships. Acute activation of 5HT neurons using temperature sensitive dTrpA1 channel expression, in contrast, resulted in flies that escalated fights faster and that fought at higher intensities. Finally, acute disruption of DA neurotransmission produced hyperactive flies that moved faster than controls, and rarely engaged in any social interactions. By separately manipulating 5HT- and DA- neuron systems, we collected evidence demonstrating a direct role for 5HT in the escalation of aggression in Drosophila. PMID:20520823

  20. Retrospective analysis of the effect of CAPOX and mFOLFOX6 dose intensity on survival in colorectal patients in the adjuvant setting

    PubMed Central

    Mamo, A.; Easaw, J.; Ibnshamsah, F.; Baig, A.; Rho, Y.S.; Kavan, T.; Batist, G.; Kavan, P.

    2016-01-01

    Background Despite lack of a true comparative study, the folfox (5-fluorouracil–leucovorin–oxaliplatin) and capox (capecitabine–oxaliplatin) regimens are believed to be similar in their efficacy and tolerability in the treatment of stage iii colorectal cancer. However, that belief has been disputed, because real-life data suggest that the capox regimen is more toxic, leading to more frequent reductions in the delivered dose intensity—thus raising questions about the effect of dose intensity on clinical outcomes. Methods A retrospective data review for two Canadian institutions, the Segal Cancer Centre and the Tom Baker Cancer Centre, considered patients diagnosed with stage iii colorectal cancer during 2006–2013. Primary endpoints were dose intensity and toxicity, with a secondary endpoint of disease-free survival. Results The study enrolled 180 eligible patients (80 at the Segal Cancer Centre, 100 at the Tom Baker Cancer Centre). Of those 180 patients, 75 received capox, and 105 received mfolfox6. In the capox group, a significant dose reduction was identified for capecitabine compared with 5-fluorouracil in mfolfox6 group (p = 0.0014). Similarly, a significant dose reduction was observed for oxaliplatin in mfolfox6 compared with oxaliplatin in capox (p = 0.0001). Compared with the patients receiving capox, those receiving mfolfox6 were twice as likely to experience a treatment delay of more than 1 cycle-length (p = 0.03855). Toxicity was more frequent in patients receiving mfolfox6 (nausea: 30% vs. 18%; diarrhea: 47% vs. 24%; peripheral sensory neuropathy: 32% vs. 3%). At a median follow-up of 40 months, preliminary data showed no difference in disease-free survival (p = 0.598). Pooled data from both institutions were also separately analyzed, and no significant differences were found. Conclusions Our results support the use of capox despite a lack of head-to-head randomized trial data. PMID:27330345

  1. Radiation Dose to the Brachial Plexus in Head-and-Neck Intensity-Modulated Radiation Therapy and Its Relationship to Tumor and Nodal Stage

    SciTech Connect

    Truong, Minh Tam; Romesser, Paul B.; Qureshi, Muhammad M.; Kovalchuk, Nataliya; Orlina, Lawrence; Willins, John

    2012-09-01

    Purpose: The purpose of this retrospective study was to determine tumor factors contributing to brachial plexus (BP) dose in head-and-neck cancer (HNC) patients treated with intensity-modulated radiotherapy (IMRT) when the BP is routinely contoured as an organ at risk (OAR) for IMRT optimization. Methods and Materials: From 2004 to 2011, a total of 114 HNC patients underwent IMRT to a total dose of 69.96 Gy in 33 fractions, with the right and left BP prospectively contoured as separate OARs in 111 patients and the ipsilateral BP contoured in 3 patients (total, 225 BP). Staging category T4 and N2/3 disease were present in 34 (29.8%) and 74 (64.9%) patients, respectively. During IMRT optimization, the intent was to keep the maximum BP dose to {<=}60 Gy, but prioritizing tumor coverage over achieving the BP constraints. BP dose parameters were compared with tumor and nodal stage. Results: With a median follow-up of 16.2 months, 43 (37.7%) patients had {>=}24 months of follow-up with no brachial plexopathy reported. Mean BP volume was 8.2 {+-} 4.5 cm{sup 3}. Mean BP maximum dose was 58.1 {+-} 12.2 Gy, and BP mean dose was 42.2 {+-} 11.3 Gy. The BP maximum dose was {<=}60, {<=}66, and {<=}70 Gy in 122 (54.2%), 185 (82.2%), and 203 (90.2%) BP, respectively. For oropharynx, hypopharynx, and larynx sites, the mean BP maximum dose was 58.4 Gy and 63.4 Gy in T0-3 and T4 disease, respectively (p = 0.002). Mean BP maximum dose with N0/1 and N2/3 disease was 52.8 Gy and 60.9 Gy, respectively (p < 0.0001). Conclusions: In head-and-neck IMRT, dose constraints for the BP are difficult to achieve to {<=}60 to 66 Gy with T4 disease of the larynx, hypopharynx, and oropharynx or N2/3 disease. The risk of brachial plexopathy is likely very small in HNC patients undergoing IMRT, although longer follow-up is required.

  2. Intensity modulated radiation therapy (IMRT): differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma

    PubMed Central

    2011-01-01

    Background A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer. Methods Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. Results IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005), bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005), and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment volumes were typically larger than that covered by classic

  3. Supply of a nondrug substitute reduces escalated heroin consumption.

    PubMed

    Lenoir, Magalie; Ahmed, Serge H

    2008-08-01

    Escalation of drug consumption-a hallmark of addiction-has been hypothesized to be associated with a relative devaluation of alternative nondrug rewards and thus with a decrease in their ability to compete with or to substitute for the drug. In a behavioral economic framework, decreased substitutability of nondrug rewards for drug would explain why drug consumption is behaviorally dominant and relatively resistant to change (eg price-inelastic) in drug-addicted individuals. The goal of the present study was to test this hypothesis using a validated rat model of heroin intake escalation. Escalation was precipitated by long (6 h, long access (LgA)), but not short (1 h, short access (ShA)), daily access to i.v. heroin self-administration. After escalation, the effects of price (ie fixed-ratio value) on heroin consumption were assessed under two alternative reward conditions: in the presence or absence of a nondrug substitute for heroin (ie four freely available chow pellets). As expected, escalated heroin consumption by LgA rats was less sensitive to price than heroin consumption by ShA rats, showing that heroin had acquired greater reinforcing strength during escalation. However, supplying a substitute during access to heroin was sufficient to reverse this post-escalation increase in the reinforcing effectiveness of heroin. Thus, escalated heroin consumption is not associated with a decreased sensitivity to competing nondrug rewards. Escalated drug use may therefore persist, not so much because of a relative devaluation of nondrug substitutes, but because of a loss or reduction of their availability.

  4. Agricultural intensification escalates future conservation costs.

    PubMed

    Phelps, Jacob; Carrasco, Luis Roman; Webb, Edward L; Koh, Lian Pin; Pascual, Unai

    2013-05-07

    The supposition that agricultural intensification results in land sparing for conservation has become central to policy formulations across the tropics. However, underlying assumptions remain uncertain and have been little explored in the context of conservation incentive schemes such as policies for Reducing Emissions from Deforestation and forest Degradation, conservation, sustainable management, and enhancement of carbon stocks (REDD+). Incipient REDD+ forest carbon policies in a number of countries propose agricultural intensification measures to replace extensive "slash-and-burn" farming systems. These may result in conservation in some contexts, but will also increase future agricultural land rents as productivity increases, creating new incentives for agricultural expansion and deforestation. While robust governance can help to ensure land sparing, we propose that conservation incentives will also have to increase over time, tracking future agricultural land rents, which might lead to runaway conservation costs. We present a conceptual framework that depicts these relationships, supported by an illustrative model of the intensification of key crops in the Democratic Republic of Congo, a leading REDD+ country. A von Thünen land rent model is combined with geographic information systems mapping to demonstrate how agricultural intensification could influence future conservation costs. Once postintensification agricultural land rents are considered, the cost of reducing forest sector emissions could significantly exceed current and projected carbon credit prices. Our analysis highlights the importance of considering escalating conservation costs from agricultural intensification when designing conservation initiatives.

  5. Agricultural intensification escalates future conservation costs

    PubMed Central

    Phelps, Jacob; Carrasco, Luis Roman; Webb, Edward L.; Koh, Lian Pin; Pascual, Unai

    2013-01-01

    The supposition that agricultural intensification results in land sparing for conservation has become central to policy formulations across the tropics. However, underlying assumptions remain uncertain and have been little explored in the context of conservation incentive schemes such as policies for Reducing Emissions from Deforestation and forest Degradation, conservation, sustainable management, and enhancement of carbon stocks (REDD+). Incipient REDD+ forest carbon policies in a number of countries propose agricultural intensification measures to replace extensive “slash-and-burn” farming systems. These may result in conservation in some contexts, but will also increase future agricultural land rents as productivity increases, creating new incentives for agricultural expansion and deforestation. While robust governance can help to ensure land sparing, we propose that conservation incentives will also have to increase over time, tracking future agricultural land rents, which might lead to runaway conservation costs. We present a conceptual framework that depicts these relationships, supported by an illustrative model of the intensification of key crops in the Democratic Republic of Congo, a leading REDD+ country. A von Thünen land rent model is combined with geographic information systems mapping to demonstrate how agricultural intensification could influence future conservation costs. Once postintensification agricultural land rents are considered, the cost of reducing forest sector emissions could significantly exceed current and projected carbon credit prices. Our analysis highlights the importance of considering escalating conservation costs from agricultural intensification when designing conservation initiatives. PMID:23589860

  6. Pediatric multiple sclerosis: Escalation and emerging treatments.

    PubMed

    Chitnis, Tanuja; Ghezzi, Angelo; Bajer-Kornek, Barbara; Boyko, Alexey; Giovannoni, Gavin; Pohl, Daniela

    2016-08-30

    Over the last 20 years, there have been significant advances in multiple sclerosis (MS) therapeutics, with regulatory approval for 13 therapies in adults by the European Medicines Agency (EMA) and Food and Drug Administration. However, there is only limited approval for interferon-β and glatiramer acetate use in children 12 years and older by the EMA. Availability of disease-modifying therapies to children and adolescents with MS is variable by region, and is extremely limited in some regions of the world. Up to 30% of children experience breakthrough disease requiring therapies beyond traditional first-line agents. Recent legislation in both the United States and Europe has mandated clinical studies for all new therapeutics applicable to children. Several clinical trials in children are underway that will provide important information regarding the efficacy and safety of newer drugs. This review summarizes the current knowledge of breakthrough disease, escalation, and induction treatment approaches in children with MS, especially pertaining to disease course and disability outcomes in this group of patients. In addition, ongoing clinical trials and approaches and challenges in conducting clinical trials in the pediatric population are discussed.

  7. Lack of Osteoradionecrosis of the Mandible After Intensity-Modulated Radiotherapy for Head and Neck Cancer: Likely Contributions of Both Dental Care and Improved Dose Distributions

    SciTech Connect

    Ben-David, Merav A.; Diamante, Maximiliano; Vineberg, Karen A.; Stroup, Cynthia; Murdoch-Kinch, Carol-Anne . E-mail: eisbruch@med.umich.edu

    2007-06-01

    Purpose: To assess the prevalence and dosimetric and clinical predictors of mandibular osteoradionecrosis (ORN) in patients with head and neck cancer who underwent a pretherapy dental evaluation and prophylactic treatment according to a uniform policy and were treated with intensity-modulated radiotherapy (IMRT). Methods and Materials: Between 1996 and 2005, all patients with head-and-neck cancer treated with parotid gland-sparing IMRT in prospective studies underwent a dental examination and prophylactic treatment according to a uniform policy that included extractions of high-risk, periodontally involved, and nonrestorable teeth in parts of the mandible expected to receive high radiation doses, fluoride supplements, and the placement of guards aiming to reduce electron backscatter off metal teeth restorations. The IMRT plans included dose constraints for the maximal mandibular doses and reduced mean parotid gland and noninvolved oral cavity doses. A retrospective analysis of Grade 2 or worse (clinical) ORN was performed. Results: A total of 176 patients had a minimal follow-up of 6 months. Of these, 31 (17%) had undergone teeth extractions before RT and 13 (7%) after RT. Of the 176 patients, 75% and 50% had received {>=}65 Gy and {>=}70 Gy to {>=}1% of the mandibular volume, respectively. Falloff across the mandible characterized the dose distributions: the average gradient (in the axial plane containing the maximal mandibular dose) was 11 Gy (range, 1-27 Gy; median, 8 Gy). At a median follow-up of 34 months, no cases of ORN had developed (95% confidence interval, 0-2%). Conclusion: The use of a strict prophylactic dental care policy and IMRT resulted in no case of clinical ORN. In addition to the dosimetric advantages offered by IMRT, meticulous dental prophylactic care is likely an essential factor in reducing ORN risk.

  8. SU-E-T-340: Use of Intensity Modulated Proton Therapy (IMPT) for Reducing the Dose to Cochlea in Craniospinal Irradiation (CSI) of Pediatric Patients

    SciTech Connect

    Dormer, J; Kassaee, A; Lin, H; Ding, X; Lustig, R

    2014-06-01

    Purpose: To evaluate use of intensity modulated proton therapy (IMPT) and number of beams for sparing cochlea in treatment of whole brain for pediatric medulloblastoma patients. Methods: In our institution, craniospinal irradiation patients are treated in supine position on our proton gantries using pencil beam scanning with each beam uniformly covering the target volume (SFUD). Each treatment plan consists of two opposed lateral whole brain fields and one or two spinal fields. For sparing the cochlea for the whole brain treatment, we created three different plans using IMPT for five pediatric patients. The first plan consisted of two lateral fields, the second two lateral fields and a superior-inferior field, and the third two lateral fields and two superior oblique fields. Optimization was performed with heavy weights applied to the eye, lens and cochlea while maintaining a dose prescription of 36 Gy to the whole brain. Results: IMPT plans reduce the dose to the cochlea. Increasing the number of treatment fields was found to lower the average dose to the cochlea: 15.0, 14.5 and 12.5 Gy for the two-field, three-field, and four-field plans respectively. The D95 for the two-field plan was 98.2%, compared to 100.0% for both the three-field and four-field plan. Coverage in the mid-brain was noticeably better in the three- and four-field plans, with more dose conformality surrounding the cochlea. Conclusion: IMPT plans for CSI and the whole brain irradiations are capable of sparing cochlea and reduce the dose considerably without compromising treating brain tissues. The reduction in average dose increases with three and four field plans as compared to traditional two lateral beam plans.

  9. The effects of two different doses of calcium lactate on blood pH, bicarbonate, and repeated high-intensity exercise performance.

    PubMed

    Painelli, Vitor de Salles; da Silva, Rafael Pires; de Oliveira, Odilon Marques; de Oliveira, Luana Farias; Benatti, Fabiana Braga; Rabelo, Tobias; Guilherme, João Paulo Limongi França; Lancha, Antonio Herbert; Artioli, Guilherme Giannini

    2014-06-01

    We investigated the effects of low- and high-dose calcium lactate supplementation on blood pH and bicarbonate (Study A) and on repeated high-intensity performance (Study B). In Study A, 10 young, physically active men (age: 24 ± 2.5 years; weight: 79.2 ± 9.45 kg; height: 1.79 ± 0.06 m) were assigned to acutely receive three different treatments, in a crossover fashion: high-dose calcium lactate (HD: 300 mg · kg(-1) body mass), low-dose calcium lactate (LD: 150 mg · kg(-1) body mass) and placebo (PL). During each visit, participants received one of these treatments and were assessed for blood pH and bicarbonate 0, 60, 90, 120, 150, 180, and 240 min following ingestion. In Study B, 12 young male participants (age: 26 ± 4.5 years; weight: 82.0 ± 11.0 kg; height: 1.81 ± 0.07 m) received the same treatments of Study A. Ninety minutes after ingestion, participants underwent 3 bouts of the upper-body Wingate test and were assessed for blood pH and bicarbonate 0 and 90 min following ingestion and immediately after exercise. In Study A, both HD and LD promoted slight but significant increases in blood bicarbonate (31.47 ± 1.57 and 31.69 ± 1.04 mmol · L(-1, respectively) and pH levels (7.36 ± 0.02 and 7.36 ± 0.01, respectively), with no effect of PL. In Study B, total work done, peak power, mean power output were not affected by treatments. In conclusion, low- and high-dose calcium lactate supplementation induced similar, yet very discrete, increases in blood pH and bicarbonate, which were not sufficiently large to improve repeated high-intensity performance.

  10. Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen

    PubMed Central

    Giacchetti, S; Porcher, R; Lehmann-Che, J; Hamy, A-S; de Roquancourt, A; Cuvier, C; Cottu, P-H; Bertheau, P; Albiter, M; Bouhidel, F; Coussy, F; Extra, J-M; Marty, M; de Thé, H; Espié, M

    2014-01-01

    Background: Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers. Methods: We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide–anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features. Results: Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07–0.86), P=0.028). Conclusions: AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours. PMID:24569467

  11. 20. BANKING ROOM, LOOKING SOUTH FROM NORTHWEST CORNER, SHOWING ESCALATOR ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    20. BANKING ROOM, LOOKING SOUTH FROM NORTHWEST CORNER, SHOWING ESCALATOR ENTRANCE FROM STREET ON RIGHT AND BALCONY EDGES OF TWO MEZZANINES BEYOND - Philadelphia Saving Fund Society, Twelfth & Market Streets, Philadelphia, Philadelphia County, PA

  12. Image-guided intensity-modulated radiotherapy for prostate cancer: Dose constraints for the anterior rectal wall to minimize rectal toxicity

    SciTech Connect

    Peterson, Jennifer L.; Buskirk, Steven J.; Heckman, Michael G.; Diehl, Nancy N.; Bernard, Johnny R.; Tzou, Katherine S.; Casale, Henry E.; Bellefontaine, Louis P.; Serago, Christopher; Kim, Siyong; Vallow, Laura A.; Daugherty, Larry C.; Ko, Stephen J.

    2014-04-01

    Rectal adverse events (AEs) are a major concern with definitive radiotherapy (RT) treatment for prostate cancer. The anterior rectal wall is at the greatest risk of injury as it lies closest to the target volume and receives the highest dose of RT. This study evaluated the absolute volume of anterior rectal wall receiving a high dose to identify potential ideal dose constraints that can minimize rectal AEs. A total of 111 consecutive patients with Stage T1c to T3a N0 M0 prostate cancer who underwent image-guided intensity-modulated RT at our institution were included. AEs were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The volume of anterior rectal wall receiving 5 to 80 Gy in 2.5-Gy increments was determined. Multivariable Cox regression models were used to identify cut points in these volumes that led to an increased risk of early and late rectal AEs. Early AEs occurred in most patients (88%); however, relatively few of them (13%) were grade ≥2. At 5 years, the cumulative incidence of late rectal AEs was 37%, with only 5% being grade ≥2. For almost all RT doses, we identified a threshold of irradiated absolute volume of anterior rectal wall above which there was at least a trend toward a significantly higher rate of AEs. Most strikingly, patients with more than 1.29, 0.73, or 0.45 cm{sup 3} of anterior rectal wall exposed to radiation doses of 67.5, 70, or 72.5 Gy, respectively, had a significantly increased risk of late AEs (relative risks [RR]: 2.18 to 2.72; p ≤ 0.041) and of grade ≥ 2 early AEs (RR: 6.36 to 6.48; p = 0.004). Our study provides evidence that definitive image-guided intensity-modulated radiotherapy (IG-IMRT) for prostate cancer is well tolerated and also identifies dose thresholds for the absolute volume of anterior rectal wall above which patients are at greater risk of early and late complications.

  13. Intensity-Modulated Radiotherapy Might Increase Pneumonitis Risk Relative to Three-Dimensional Conformal Radiotherapy in Patients Receiving Combined Chemotherapy and Radiotherapy: A Modeling Study of Dose Dumping

    SciTech Connect

    Vogelius, Ivan S.; Westerly, David C.; Cannon, George M.; Mackie, Thomas R.; Mehta, Minesh P.; Sugie, Chikao; Bentzen, Soren M.

    2011-07-01

    Purpose: To model the possible interaction between cytotoxic chemotherapy and the radiation dose distribution with respect to the risk of radiation pneumonitis. Methods and Materials: A total of 18 non-small-cell lung cancer patients previously treated with helical tomotherapy at the University of Wisconsin were selected for the present modeling study. Three treatment plans were considered: the delivered tomotherapy plans; a three-dimensional conformal radiotherapy (3D-CRT) plan; and a fixed-field intensity-modulated radiotherapy (IMRT) plan. The IMRT and 3D-CRT plans were generated specifically for the present study. The plans were optimized without adjusting for the chemotherapy effect. The effect of chemotherapy was modeled as an independent cell killing process by considering a uniform chemotherapy equivalent radiation dose added to all voxels of the organ at risk. The risk of radiation pneumonitis was estimated for all plans using the Lyman and the critical volume models. Results: For radiotherapy alone, the critical volume model predicts that the two IMRT plans are associated with a lower risk of radiation pneumonitis than the 3D-CRT plan. However, when the chemotherapy equivalent radiation dose exceeds a certain threshold, the radiation pneumonitis risk after IMRT is greater than after 3D-CRT. This threshold dose is in the range estimated from clinical chemoradiotherapy data sets. Conclusions: Cytotoxic chemotherapy might affect the relative merit of competing radiotherapy plans. More work is needed to improve our understanding of the interaction between chemotherapy and the radiation dose distribution in clinical settings.

  14. Evaluation of Dose Uncertainty to the Target Associated With Real-Time Tracking Intensity-Modulated Radiation Therapy Using the CyberKnife Synchrony System.

    PubMed

    Iwata, Hiromitsu; Inoue, Mitsuhiro; Shiomi, Hiroya; Murai, Taro; Tatewaki, Koshi; Ohta, Seiji; Okawa, Kohei; Yokota, Naoki; Shibamoto, Yuta

    2016-02-01

    We investigated the dose uncertainty caused by errors in real-time tracking intensity-modulated radiation therapy (IMRT) using the CyberKnife Synchrony Respiratory Tracking System (SRTS). Twenty lung tumors that had been treated with non-IMRT real-time tracking using CyberKnife SRTS were used for this study. After validating the tracking error in each case, we did 40 IMRT planning using 8 different collimator sizes for the 20 patients. The collimator size was determined for each planning target volume (PTV); smaller ones were one-half, and larger ones three-quarters, of the PTV diameter. The planned dose was 45 Gy in 4 fractions prescribed at 95% volume border of the PTV. Thereafter, the tracking error in each case was substituted into calculation software developed in house and randomly added in the setting of each beam. The IMRT planning incorporating tracking errors was simulated 1000 times, and various dose data on the clinical target volume (CTV) were compared with the original data. The same simulation was carried out by changing the fraction number from 1 to 6 in each IMRT plan. Finally, a total of 240 000 plans were analyzed. With 4 fractions, the change in the CTV maximum and minimum doses was within 3.0% (median) for each collimator. The change in D99 and D95 was within 2.0%. With decreases in the fraction number, the CTV coverage rate and the minimum dose decreased and varied greatly. The accuracy of real-time tracking IMRT delivered in 4 fractions using CyberKnife SRTS was considered to be clinically acceptable.

  15. Optimal patterns for sequentially multiple focusing in high intensity focused ultrasound and their application to thermal dose

    NASA Astrophysics Data System (ADS)

    Shim, Mun-Bo; Lee, Hyoungki; Lee, Hotaik; Park, Junho; Ahn, Minsu

    2012-11-01

    The purpose of this study is to propose a new method for multiple-focus generation to shorten overall treatment time as well as to avoid the formation of high intensity regions outside the target volume. A numerical simulation of the acoustic fields produced by a 1017-element spherical-section ultrasound phased array transducer operating at a frequency of 1.0MHz with 16 cm radius of curvature is performed for the proposed multiple-focus generation. The total foci are partitioned into the several patterns because multiple focusing generally gives rise to the grating lobes outside of the three dimensional region of interest even if applying the optimization of intensity gain in determining the phases and amplitudes of the excitation source vector. The optimization problem is repeatedly formulated in term of the focal points until the multiple-focus patterns cover all the focal points. Genetic algorithm is used for selecting the patterns without the grating lobes. The obtained set of multiple-focus patterns can sequentially be used to necrose a given volume in the short time as well as in the safe treatment. The proposed method might prove useful to improve the speed and safety of focused ultrasound thermal ablation. This strategy will also be effective for any transducers as well as for other cases of multiple-focus generation.

  16. Non-intensive treatment with low-dose 5-aza-2'-deoxycytidine (DAC) prior to allogeneic blood SCT of older MDS/AML patients.

    PubMed

    Lübbert, M; Bertz, H; Rüter, B; Marks, R; Claus, R; Wäsch, R; Finke, J

    2009-11-01

    Novel, non-intensive treatment options in older MDS/AML patients planned for allografting, with the goal of down-staging the underlying disease and bridging time to transplantation, are presently being developed. 5-azacytidine and decitabine (DAC) are of particular interest, as they can be given repetitively, with very limited non-hematologic toxicity and result in responses both in MDS and AML even at low doses. We describe 15 consecutive patients (median age 69 years, range 60-75 years) with MDS (n=10) or AML (n=5) who all received first-line treatment with DAC and subsequent allografting (from sibling donor in four patients, unrelated donor in 11) after reduced-intensity conditioning with the FBM regimen. Successful engraftment was attained in 14/15 patients, all of whom achieved a CR, with a median duration of 5 months (range 1+ to 51+). Six of these 14 patients are alive (4 with complete donor chimerism), 8 have died either from relapse (n=4) or treatment-related complications while in CR (n=4). We conclude that allografting after low-dose DAC and subsequent conditioning with FBM is feasible, with no unexpected toxicities and appears as a valid alternative to standard chemotherapy ('InDACtion instead of induction') in elderly patients with MDS/AML.

  17. Ecologically relevant UV-B dose combined with high PAR intensity distinctly affect plant growth and accumulation of secondary metabolites in leaves of Centella asiatica L. Urban.

    PubMed

    Müller, Viola; Albert, Andreas; Barbro Winkler, J; Lankes, Christa; Noga, Georg; Hunsche, Mauricio

    2013-10-05

    We investigated the effects of environmentally relevant dose of ultraviolet (UV)-B and photosynthetic active radiation (PAR) on saponin accumulation in leaves on the example of Centella asiatica L. Urban. For this purpose, plants were exposed to one of four light regimes i.e., two PAR intensities with or without UV-B radiation. The experiment was conducted in technically complex sun simulators under almost natural irradiance and climatic conditions. As observed, UV-B radiation increased herb and leaf production as well as the content of epidermal flavonols, which was monitored by non-destructive fluorescence measurements. Specific fluorescence indices also indicate an increase in the content of anthocyanins under high PAR; this increase was likewise observed for the saponin concentrations. In contrast, UV-B radiation had no distinct effects on saponin and sapogenin concentrations. Our findings suggest that besides flavonoids, also saponins were accumulated under high PAR protecting the plant from oxidative damage. Furthermore, glycosylation of sapogenins seems to be important either for the protective function and/or for compartmentalization of the compounds. Moreover, our study revealed that younger leaves contain higher amounts of saponins, while in older leaves the sapogenins were the most abundant constituents. Concluding, our results proof that ambient dose of UV-B and high PAR intensity distinctly affect the accumulation of flavonoids and saponins, enabling the plant tissue to adapt to the light conditions.

  18. [{sup 18}F]fluoromisonidazole and a New PET System With Semiconductor Detectors and a Depth of Interaction System for Intensity Modulated Radiation Therapy for Nasopharyngeal Cancer

    SciTech Connect

    Yasuda, Koichi; Onimaru, Rikiya; Okamoto, Shozo; Shiga, Tohru; Katoh, Norio; Tsuchiya, Kazuhiko; Suzuki, Ryusuke; Takeuchi, Wataru; Kuge, Yuji; Tamaki, Nagara; Shirato, Hiroki

    2013-01-01

    Purpose: The impact of a new type of positron emission tomography (New PET) with semiconductor detectors using {sup 18}F-labeled fluoromisonidazole (FMISO)-guided intensity modulated radiation therapy (IMRT) was compared with a state-of-the-art PET/computed tomography (PET/CT) system in nasopharyngeal cancer (NPC) patients. Methods and Materials: Twenty-four patients with non-NPC malignant tumors (control group) and 16 patients with NPC were subjected to FMISO-PET. The threshold of the tumor-to-muscle (T/M) ratio in each PET scan was calculated. The hypoxic volume within the gross tumor volume (GTVh) was determined using each PET ({sub NewPET}GTVh and {sub PET/CT}GTVh, respectively). Dose escalation IMRT plans prescribing 84 Gy to each GTVh were carried out. Results: The threshold of the T/M ratio was 1.35 for New PET and 1.23 for PET/CT. The mean volume of {sub NewPET}GTVh was significantly smaller than that of {sub PET/CT}GTVh (1.5 {+-} 1.6 cc vs 4.7 {+-} 4.6 cc, respectively; P=.0020). The dose escalation IMRT plans using New PET were superior in dose distribution to those using PET/CT. Dose escalation was possible in all 10 New PET-guided plans but not in 1 PET/CT-guided plan, because the threshold dose to the brainstem was exceeded. Conclusions: New PET was found to be useful for accurate dose escalation in FMISO-guided IMRT for patients with NPC.

  19. Phase 2 Trial of Hypofractionated High-Dose Intensity Modulated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Newly Diagnosed Glioblastoma

    SciTech Connect

    Iuchi, Toshihiko; Hatano, Kazuo; Kodama, Takashi; Sakaida, Tsukasa; Yokoi, Sana; Kawasaki, Koichiro; Hasegawa, Yuzo; Hara, Ryusuke

    2014-03-15

    Purpose/Objectives: To assess the effect and toxicity of hypofractionated high-dose intensity modulated radiation therapy (IMRT) with concurrent and adjuvant temozolomide (TMZ) in 46 patients with newly diagnosed glioblastoma multiforme (GBM). Methods and Materials: All patients underwent postsurgical hypofractionated high-dose IMRT. Three layered planning target volumes (PTVs) were contoured. PTV1 was the surgical cavity and residual tumor on T1-weighted magnetic resonance images with 5-mm margins, PTV2 was the area with 15-mm margins surrounding the PTV1, and PTV3 was the high-intensity area on fluid-attenuated inversion recovery images. Irradiation was performed in 8 fractions at total doses of 68, 40, and 32 Gy for PTV1, PTV2, and PTV3, respectively. Concurrent TMZ was given at 75 mg/m{sup 2}/day for 42 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m{sup 2}/day for 5 days every 28 days. Overall and progression-free survivals were evaluated. Results: No acute IMRT-related toxicity was observed. The dominant posttreatment failure pattern was dissemination. During a median follow-up time of 16.3 months (range, 4.3-80.8 months) for all patients and 23.7 months (range, 12.4-80.8 months) for living patients, the median overall survival was 20.0 months after treatment. Radiation necrosis was diagnosed in 20 patients and was observed not only in the high-dose field but also in the subventricular zone (SVZ). Necrosis in the SVZ was significantly correlated with prolonged survival (hazard ratio, 4.08; P=.007) but caused deterioration in the performance status of long-term survivors. Conclusions: Hypofractionated high-dose IMRT with concurrent and adjuvant TMZ altered the dominant failure pattern from localized to disseminated and prolonged the survival of patients with GBM. Necrosis in the SVZ was associated with better patient survival, but the benefit of radiation to this area remains controversial.

  20. Cervical Gross Tumor Volume Dose Predicts Local Control Using Magnetic Resonance Imaging/Diffusion-Weighted Imaging—Guided High-Dose-Rate and Positron Emission Tomography/Computed Tomography—Guided Intensity Modulated Radiation Therapy

    SciTech Connect

    Dyk, Pawel; Jiang, Naomi; Sun, Baozhou; DeWees, Todd A.; Fowler, Kathryn J.; Narra, Vamsi; Garcia-Ramirez, Jose L.; Schwarz, Julie K.; Grigsby, Perry W.

    2014-11-15

    Purpose: Magnetic resonance imaging/diffusion weighted-imaging (MRI/DWI)-guided high-dose-rate (HDR) brachytherapy and {sup 18}F-fluorodeoxyglucose (FDG) — positron emission tomography/computed tomography (PET/CT)-guided intensity modulated radiation therapy (IMRT) for the definitive treatment of cervical cancer is a novel treatment technique. The purpose of this study was to report our analysis of dose-volume parameters predicting gross tumor volume (GTV) control. Methods and Materials: We analyzed the records of 134 patients with International Federation of Gynecology and Obstetrics stages IB1-IVB cervical cancer treated with combined MRI-guided HDR and IMRT from July 2009 to July 2011. IMRT was targeted to the metabolic tumor volume and lymph nodes by use of FDG-PET/CT simulation. The GTV for each HDR fraction was delineated by use of T2-weighted or apparent diffusion coefficient maps from diffusion-weighted sequences. The D100, D90, and Dmean delivered to the GTV from HDR and IMRT were summed to EQD2. Results: One hundred twenty-five patients received all irradiation treatment as planned, and 9 did not complete treatment. All 134 patients are included in this analysis. Treatment failure in the cervix occurred in 24 patients (18.0%). Patients with cervix failures had a lower D100, D90, and Dmean than those who did not experience failure in the cervix. The respective doses to the GTV were 41, 58, and 136 Gy for failures compared with 67, 99, and 236 Gy for those who did not experience failure (P<.001). Probit analysis estimated the minimum D100, D90, and Dmean doses required for ≥90% local control to be 69, 98, and 260 Gy (P<.001). Conclusions: Total dose delivered to the GTV from combined MRI-guided HDR and PET/CT-guided IMRT is highly correlated with local tumor control. The findings can be directly applied in the clinic for dose adaptation to maximize local control.

  1. Weekly Dose-Volume Parameters of Mucosa and Constrictor Muscles Predict the Use of Percutaneous Endoscopic Gastrostomy During Exclusive Intensity-Modulated Radiotherapy for Oropharyngeal Cancer

    SciTech Connect

    Sanguineti, Giuseppe; Gunn, G. Brandon; Parker, Brent C.; Endres, Eugene J.; Zeng Jing; Fiorino, Claudio

    2011-01-01

    Purpose: To define predictors of percutaneous endoscopic gastrostomy (PEG) use during intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer. Methods and Materials: Data for 59 consecutive patients treated with exclusive IMRT at a single institution were recovered. Of 59 patients, 25 were treated with hyperfractionation (78 Gy, 1.3 Gy per fraction, twice daily; 'HYPER'); and 34 of 59 were treated with a once-daily fractionation schedule (66 Gy, 2.2 Gy per fraction, or 70 Gy, 2 Gy per fraction; 'no-HYPER'). On the basis of symptoms during treatment, a PEG tube could have been placed as appropriate. A number of clinical/dosimetric factors, including the weekly dose-volume histogram of oral mucosa (OM DVHw) and weekly mean dose to constrictors and larynx, were considered. The OM DVHw of patients with and without PEG were compared to assess the most predictive dose-volume combinations. Results: Of 59 patients, 22 needed a PEG tube during treatment (for 15 of 22, {>=}3 months). The best cutoff values for OM DVHw were V9.5 Gy/week <64 cm{sup 3} and V10 Gy/week <54 cm{sup 3}. At univariate analysis, fractionation, mean weekly dose to OM and superior and middle constrictors, and OM DVHw were strongly correlated with the risk of PEG use. In a stepwise multivariate logistic analysis, OM V9.5 Gy/week ({>=}64 vs. <64 cm{sup 3}) was the most predictive parameter (odds ratio 30.8, 95% confidence interval 3.7-254.2, p = 0.0015), confirmed even in the no-HYPER subgroup (odds ratio 21, 95% CI 2.1 confidence interval 210.1, p = 0.01). Conclusions: The risk of PEG use is drastically reduced when OM V9.5-V10 Gy/week is <50-60 cm{sup 3}. These data warrant prospective validation.

  2. Reduced-intensity conditioning regimen using low-dose total body irradiation before allogeneic transplant for hematologic malignancies: Experience from the European Group for Blood and Marrow Transplantation

    SciTech Connect

    Belkacemi, Yazid . E-mail: y-belkacemi@o-lambret.fr; Labopin, Myriam; Hennequin, Christophe; Hoffstetter, Sylvette; Mungai, Raffaello; Wygoda, Marc; Lundell, Marie; Finke, Jurgen; Aktinson, Chris; Lorchel, Frederic; Durdux, Catherine; Basara, Nadezda

    2007-02-01

    Purpose: The high rate of toxicity is the limitation of myelobalative regimens before allogeneic transplantation. A reduced intensity regimen can allow engraftment of stem cells and subsequent transfer of immune cells for the induction of a graft-vs.-tumor reaction. Methods and Materials: The data from 130 patients (80 males and 50 females) treated between 1998 and 2003 for various hematologic malignancies were analyzed. The median patient age was 50 years (range, 3-72 years). Allogeneic transplantation using peripheral blood or bone marrow, or both, was performed in 104 (82%), 22 (17%), and 4 (3%) patients, respectively, from HLA identical sibling donors (n = 93, 72%), matched unrelated donors (n = 23, 18%), mismatched related donors (4%), or mismatched unrelated donors (6%). Total body irradiation (TBI) at a dose of 2 Gy delivered in one fraction was given to 101 patients (78%), and a total dose of 4-6 Gy was given in 29 (22%) patients. The median dose rate was 14.3 cGy/min (range, 6-16.4). Results: After a median follow-up period of 20 months (range, 1-62 months), engraftment was obtained in 122 patients (94%). Acute graft-vs.-host disease of Grade 2 or worse was observed in 37% of patients. Multivariate analysis showed three favorable independent factors for event-free survival: HLA identical sibling donor (p < 0.0001; relative risk [RR], 0.15), complete remission (p < 0.0001; RR, 3.08), and female donor to male patient (p = 0.006; RR 2.43). For relapse, the two favorable prognostic factors were complete remission (p < 0.0001, RR 0.11) and HLA identical sibling donor (p = 0.0007; RR 3.59). Conclusions: In this multicenter study, we confirmed high rates of engraftment and chimerism after the reduced intensity regimen. Our results are comparable to those previously reported. Radiation parameters seem to have no impact on outcome. However, the lack of a statistically significant difference in terms of dose rate may have been due, in part, to the small population

  3. Cases of organophosphate poisoning treated with high-dose of atropine in an intensive care unit and the novel treatment approaches.

    PubMed

    Karakus, Ali; Celik, Muhammet Murat; Karcioglu, Murat; Tuzcu, Kasim; Erden, Ersin Sukru; Zeren, Cem

    2014-06-01

    Organophosphate poisoning is a life-threatening condition, which is being responsible for the symptoms due to cholinergic effects. Clinical status and blood levels of cholinesterase are used its diagnosis. While atropine and pralidoxime (PAM) appear as essential medications, hemofiltration treatments and lipid solutions have been widely studied in recent years. In this study, the importance of high-dose atropine therapy and early intervention and novel treatment approaches are discussed. Records of a total of 25 patients treated for organophosphate poisoning in the intensive care unit (ICU) between April 2007 and December 2011 were evaluated retrospectively. Of the 25 patients, 14 (56%) were male and 11 (44%) were female with a mean age of 34.8 ± 17.66 years (range: 14-77 years). The patients were most frequently admitted in June (n = 4) and July (n = 4) (16%). Of the 25 patients, 22 patients (88%) were poisoned by oral intake, two (8%) by inhalation, and one (4%) by dermal route. Of them, 20 patients (80%) took organophosphates intentionally for suicidal purposes, while five (20%) cases poisoned due to accidental exposure. The scores of Glasgow Coma Scale of nine patients (36%) were below 8 point upon admission to hospital. The highest dose of atropine given was 100 mg intravenously on admission and 100 mg/h/day during follow-up. The total dose given was 11.6 g/12 days. A total of 11 patients (44%) were on mechanical ventilation for a mean duration of 5.73 ± 4.83 days. The mean duration of ICU stay was 6.52 ± 4.80 days. Of all, 23 patients (92%) were discharged in good clinical condition and one patient (4%) was referred to another hospital. This study suggests that atropine can be administered until secretions disappear and intensive care should be exerted in follow-up of these patients. In addition, in case of necessity for high doses, sufficient amounts of atropine and PAM should be available in hospitals.

  4. Lowering Whole-Body Radiation Doses in Pediatric Intensity-Modulated Radiotherapy Through the Use of Unflattened Photon Beams;Flattening filter; Pediatric; Intensity-modulated radiotherapy; Second cancers; Radiation-induced malignancies

    SciTech Connect

    Cashmore, Jason; Ramtohul, Mark; Ford, Dan

    2011-07-15

    Purpose: Intensity modulated radiotherapy (IMRT) has been linked with an increased risk of secondary cancer induction due to the extra leakage radiation associated with delivery of these techniques. Removal of the flattening filter offers a simple way of reducing head leakage, and it may be possible to generate equivalent IMRT plans and to deliver these on a standard linear accelerator operating in unflattened mode. Methods and Materials: An Elekta Precise linear accelerator has been commissioned to operate in both conventional and unflattened modes (energy matched at 6 MV) and a direct comparison made between the treatment planning and delivery of pediatric intracranial treatments using both approaches. These plans have been evaluated and delivered to an anthropomorphic phantom. Results: Plans generated in unflattened mode are clinically identical to those for conventional IMRT but can be delivered with greatly reduced leakage radiation. Measurements in an anthropomorphic phantom at clinically relevant positions including the thyroid, lung, ovaries, and testes show an average reduction in peripheral doses of 23.7%, 29.9%, 64.9%, and 70.0%, respectively, for identical plan delivery compared to conventional IMRT. Conclusions: IMRT delivery in unflattened mode removes an unwanted and unnecessary source of scatter from the treatment head and lowers leakage doses by up to 70%, thereby reducing the risk of radiation-induced second cancers. Removal of the flattening filter is recommended for IMRT treatments.

  5. Effect of energy drink dose on exercise capacity, heart rate recovery and heart rate variability after high-intensity exercise

    PubMed Central

    An, Sang Min; Park, Jong Suk; Kim, Sang Ho

    2014-01-01

    [Purpose] The purpose of this research was to investigate the effects of exercise capacity, heart rate recovery and heart rate variability after high-intensity exercise on caffeine concentration of energy drink. [Methods] The volunteers for this study were 15 male university student. 15 subjects were taken basic physical examinations such as height, weight and BMI before the experiment. Primary tests were examined of VO2max per weight of each subjects by graded exercise test using Bruce protocol. Each of five subject was divided 3 groups (CON, ECGⅠ, ECGⅡ) by matched method based on weight and VO2max per weight what gained of primary test for minimize the differences of exercise capacity and ingestion of each groups. For the secondary tests, the groups of subjects were taken their materials before and after exercise as a blind test. After the ingestion, subjects were experimented on exercise test of VO2max 80% by treadmill until the all-out. Heart rate was measured by 1minute interval, and respiratory variables were analyzed VO2, VE, VT, RR and so on by automatic respiratory analyzer. And exercise exhaustion time was determined by stopwatch. Moreover, HRV was measured after exercise and recovery 3 min. [Results] Among the intake groups, ECGⅡ was showed the longest of exercise exhaustion time more than CON group (p = .05). Result of heart rate during exercise according to intake groups, there was significant differences of each time (p < .001), however, not significant differences of each groups and group verse time (p > .05). Result of RPE during exercise according to intake groups, there was significant differences of each time (p < .001), however, not significant differences of each groups and group verse time (p > .05). [Conclusion] In conclusion, EDGⅡ showed the significant increase of exercise exhaustion time more than CON group (p=.05) and not significant differences in HR, RPE, RER, HRV, HRR, blood pressure (p > .05). Therefore, 2.5 mg/kg-1 ingestion

  6. Fractionated gemtuzumab ozogamicin combined with intermediate-dose cytarabine and daunorubicin as salvage therapy in very high-risk AML patients: a bridge to reduced intensity conditioning transplant?

    PubMed

    Paubelle, Etienne; Ducastelle-Leprêtre, Sophie; Labussière-Wallet, Hélène; Nicolini, Franck Emmanuel; Barraco, Fiorenza; Plesa, Adriana; Salles, Gilles; Wattel, Eric; Thomas, Xavier

    2017-03-01

    Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index. Complete remission was achieved in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Thirteen patients could be referred for transplant. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a 1-year overall survival of 50.7 versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a longer survival as compared to those undergoing myeloablative conditioning regimen mainly because of decreased toxicity.Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant.

  7. Prophylactic ciprofloxacin treatment prevented high mortality, and modified systemic and intestinal immune function in tumour-bearing rats receiving dose-intensive CPT-11 chemotherapy.

    PubMed

    Xue, H; Field, C J; Sawyer, M B; Dieleman, L A; Baracos, V E

    2009-05-19

    Infectious complications are a major cause of morbidity and mortality from dose-intensive cancer chemotherapy. In spite of the importance of intestinal bacteria translocation in these infections, information about the effect of high-dose chemotherapy on gut mucosal immunity is minimal. We studied prophylactic ciprofloxacin (Cipro) treatment on irinotecan (CPT-11) toxicity and host immunity in rats bearing Ward colon tumour. Cipro abolished chemotherapy-related mortality, which was 45% in animals that were not treated with Cipro. Although Cipro reduced body weight loss and muscle wasting, it was unable to prevent severe late-onset diarrhoea. Seven days after CPT-11, splenocytes were unable to proliferate (stimulation index=0.10+/-0.02) and produce proliferative and inflammatory cytokines (i.e., Interleukin (IL)-2, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) IL-1beta, IL-6) on mitogen stimulation in vitro (P<0.05 vs controls), whereas mesenteric lymph node (MLN) cells showed a hyper-proliferative response and a hyper-production of pro-inflammatory cytokines on mitogen stimulation. This suggests compartmentalised effects by CPT-11 chemotherapy on systemic and intestinal immunity. Cipro normalised the hyper-responsiveness of MLN cells, and in the spleen, it partially restored the proliferative response and normalised depressed production of IL-1beta and IL-6. Taken together, Cipro prevented infectious challenges associated with immune hypo-responsiveness in systemic immune compartments, and it may also alleviate excessive pro-inflammatory responses mediating local gut injury.

  8. Determination of dosimetric leaf gap using amorphous silicon electronic portal imaging device and its influence on intensity modulated radiotherapy dose delivery

    PubMed Central

    Balasingh, S. Timothy Peace; Singh, I. Rabi Raja; Rafic, K. Mohamathu; Babu, S. Ebenezer Suman; Ravindran, B. Paul

    2015-01-01

    As complex treatment techniques such as intensity modulated radiotherapy (IMRT) entail the modeling of rounded leaf-end transmission in the treatment planning system, it is important to accurately determine the dosimetric leaf gap (DLG) value for a precise calculation of dose. The advancements in the application of the electronic portal imaging device (EPID) in quality assurance (QA) and dosimetry have facilitated the determination of DLG in this study. The DLG measurements were performed using both the ionization chamber (DLGion) and EPID (DLGEPID) for sweeping gap fields of different widths. The DLGion values were found to be 1.133 mm and 1.120 mm for perpendicular and parallel orientations of the 0.125 cm3 ionization chamber, while the corresponding DLGEPID values were 0.843 mm and 0.819 mm, respectively. It was found that the DLG was independent of volume and orientation of the ionization chamber, depth, source to surface distance (SSD), and the rate of dose delivery. Since the patient-specific QA tests showed comparable results between the IMRT plans based on the DLGEPID and DLGion, it is concluded that the EPID can be a suitable alternative in the determination of DLG. PMID:26500398

  9. The effect of uterine motion and uterine margins on target and normal tissue doses in intensity modulated radiation therapy of cervical cancer

    NASA Astrophysics Data System (ADS)

    Gordon, J. J.; Weiss, E.; Abayomi, O. K.; Siebers, J. V.; Dogan, N.

    2011-05-01

    In intensity modulated radiation therapy (IMRT) of cervical cancer, uterine motion can be larger than cervix motion, requiring a larger clinical target volume to planning target volume (CTV-to-PTV) margin around the uterine fundus. This work simulates different motion models and margins to estimate the dosimetric consequences. A virtual study used image sets from ten patients. Plans were created with uniform margins of 1 cm (PTVA) and 2.4 cm (PTVC), and a margin tapering from 2.4 cm at the fundus to 1 cm at the cervix (PTVB). Three inter-fraction motion models (MM) were simulated. In MM1, all structures moved with normally distributed rigid body translations. In MM2, CTV motion was progressively magnified as one moved superiorly from the cervix to the fundus. In MM3, both CTV and normal tissue motion were magnified as in MM2, modeling the scenario where normal tissues move into the void left by the mobile uterus. Plans were evaluated using static and percentile DVHs. For a conventional margin (PTVA), quasi-realistic uterine motion (MM3) reduces fundus dose by about 5 Gy and increases normal tissue volumes receiving 30-50 Gy by ~5%. A tapered CTV-to-PTV margin can restore fundus and CTV doses, but will increase normal tissue volumes receiving 30-50 Gy by a further ~5%.

  10. The use of intensity-modulated radiation therapy photon beams for improving the dose uniformity of electron beams shaped with MLC

    SciTech Connect

    Mosalaei, Homeira; Karnas, Scott; Shah, Sheel; Van Doodewaard, Sharon; Foster, Tim; Chen, Jeff

    2012-04-01

    Electrons are ideal for treating shallow tumors and sparing adjacent normal tissue. Conventionally, electron beams are collimated by cut-outs that are time-consuming to make and difficult to adapt to tumor shape throughout the course of treatment. We propose that electron cut-outs can be replaced using photon multileaf collimator (MLC). Two major problems of this approach are that the scattering of electrons causes penumbra widening because of a large air gap, and available commercial treatment planning systems (TPSs) do not support MLC-collimated electron beams. In this study, these difficulties were overcome by (1) modeling electron beams collimated by photon MLC for a commercial TPS, and (2) developing a technique to reduce electron beam penumbra by adding low-energy intensity-modulated radiation therapy (IMRT) photons (4 MV). We used blocks to simulate MLC shielding in the TPS. Inverse planning was used to optimize boost photon beams. This technique was applied to a parotid and a central nervous system (CNS) clinical case. Combined photon and electron plans were compared with conventional plans and verified using ion chamber, film, and a 2D diode array. Our studies showed that the beam penumbra for mixed beams with 90 cm source to surface distance (SSD) is comparable with electron applicators and cut-outs at 100 cm SSD. Our mixed-beam technique yielded more uniform dose to the planning target volume and lower doses to various organs at risk for both parotid and CNS clinical cases. The plans were verified with measurements, with more than 95% points passing the gamma criteria of 5% in dose difference and 5 mm for distance to agreement. In conclusion, the study has demonstrated the feasibility and potential advantage of using photon MLC to collimate electron beams with boost photon IMRT fields.

  11. Three-dimensional conformal versus intensity-modulated radiotherapy dose planning in stereotactic radiotherapy: Application of standard quality parameters for plan evaluation

    SciTech Connect

    Grzadziel, Aleksandra; Grosu, Anca-Ligia . E-mail: anca-ligia.grosu@lrz.tum.de; Kneschaurek, Peter

    2006-11-15

    Purpose: The implementation of intensity-modulated radiotherapy (IMRT) technique into clinical practice is becoming routine, but still lacks a generally accepted method for plan evaluation. We present a comparison of the dose distribution of conformal three-dimensional radiotherapy plans with IMRT plans for cranial lesions in stereotactic radiotherapy. The primary aim of this study was to judge the quality of the treatment plans. The next purpose was to assess the usefulness of several quality factors for plan evaluation. Methods and Materials: Five patients, who were treated in our department, were analyzed. Four had meningioma and one had pituitary adenoma. For each case, 10 different plans were created and analyzed: 2 conventional conformal three-dimensional plans and 8 IMRT plans, using the 'step and shoot' delivery method. The first conventional plan was an individually designed beam arrangement and was used for patient treatment. The second plan was a standard plan with the same beam arrangement for all patients. Beam arrangements from the conformal plans were the base for the inversely planned IMRT. To evaluate the plans, the following factors were investigated: minimal and maximal dose to the planning target volume, homogeneity index, coverage index, conformity index, and tumor control probabilities and normal tissue complication probabilities. These quantities were incorporated into scoring factors and assigned to each plan. Results: The greatest homogeneity was reached in the conformal plans and IMRT plans with high planning target volume priority in the optimization process. This consequently led to a better probability of tumor control. Better protection of organs at risk and thereby lower normal tissue complication probabilities were achieved in the IMRT plans with increased weighting of the organs at risk. Conclusion: These results show the efficiency, as well as some limitations, of the IMRT techniques. The use of different quality factors allowed us

  12. Targeting MRS-Defined Dominant Intraprostatic Lesions with Inverse-Planned High Dose Rate Brachytherapy

    DTIC Science & Technology

    2011-06-01

    requirements depending on rectal and bladder doses. The class solution in inverse planned HDR prostate brachythe - rapy for dose escalation of a DIL...High-dose-rate brachyther- apy without external beam irradiation for locally advanced prostate cancer. Radiother Oncol 2006; 80: 62-68. 7. Galalae RM... prostate brachytherapy for dose escalation of DIL defined by combined MRI/MRSI. Radiother Oncol 2008; 88: 148-155. 16. Pouliot J, Kim Y, Lessard E et al

  13. After the First Shots: Managing Escalation in Northeast Asia

    DTIC Science & Technology

    2015-01-01

    JFQ 77, 2nd Quarter 2015 Manzo 91 After the First Shots Managing Escalation in Northeast Asia By Vincent A. Manzo T he United States has never fought...escalation will be an essential part of U.S. efforts to extend deterrence and assure its allies in Northeast Asia . Thomas Schelling’s writing on... Asia 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7

  14. Dose-intensive chemotherapy including rituximab is highly effective but toxic in human immunodeficiency virus-infected patients with Burkitt lymphoma/leukemia: parallel study of 81 patients.

    PubMed

    Xicoy, Blanca; Ribera, Josep-Maria; Müller, Markus; García, Olga; Hoffmann, Christian; Oriol, Albert; Hentrich, Marcus; Grande, Carlos; Wasmuth, Jan-Christian; Esteve, Jordi; van Lunzen, Jan; Del Potro, Eloy; Knechten, Heribert; Brunet, Salut; Mayr, Christoph; Escoda, Lourdes; Schommers, Philipp; Alonso, Natalia; Vall-Llovera, Ferran; Pérez, Montserrat; Morgades, Mireia; González, José; Fernández, Angeles; Thoden, Jan; Gökbuget, Nicola; Hoelzer, Dieter; Fätkenheuer, Gerd; Wyen, Christoph

    2014-10-01

    The results of intensive immunochemotherapy were analyzed in human immunodeficiency virus (HIV)-related Burkitt lymphoma/leukemia (BLL) in two cohorts (Spain and Germany). Alternating cycles of chemotherapy were administered, with dose reductions for patients over 55 years. Eighty percent of patients achieved remission, 11% died during induction, 9% failed and 7% died in remission. Four-year overall survival (OS) and progression-free survival (PFS) probabilities were 72% (95% confidence interval [CI]: 62-82%) and 71% (95% CI: 61-81%). CD4 T-cell count < 200/μL and bone marrow involvement were associated with poor OS (hazard ratio [HR] 3.2 [1.2-8.3] and HR 2.7 [1.1-6.6]) and PFS (HR 3.5 [1.3-9.1] and HR 2.4 [1-5.7]), bone marrow involvement with poor disease-free survival (DFS) (HR 14.4 [1.7-119.7] and Eastern Cooperative Oncology Group (ECOG) score > 2 (odds ratio [OR] 11.9 [1.4-99.9]) with induction death. In HIV-related BLL, intensive immunochemotherapy was feasible and effective, but toxic. Prognostic factors were performance status, CD4 T-cell count and bone marrow involvement.

  15. Prospective Trial of High-Dose Reirradiation Using Daily Image Guidance With Intensity-Modulated Radiotherapy for Recurrent and Second Primary Head-and-Neck Cancer

    SciTech Connect

    Chen, Allen M.; Farwell, D. Gregory; Luu, Quang; Cheng, Suzan; Donald, Paul J.; Purdy, James A.

    2011-07-01

    Purpose: To report a single-institutional experience using intensity-modulated radiotherapy with daily image-guided radiotherapy for the reirradiation of recurrent and second cancers of the head and neck. Methods and Materials: Twenty-one consecutive patients were prospectively treated with intensity-modulated radiotherapy from February 2006 to March 2009 to a median dose of 66 Gy (range, 60-70 Gy). None of these patients received concurrent chemotherapy. Daily helical megavoltage CT scans were obtained before each fraction as part of an image-guided radiotherapy registration protocol for patient alignment. Results: The 1- and 2-year estimates of in-field control were 72% and 65%, respectively. A total of 651 daily megavoltage CT scans were obtained. The mean systematic shift to account for interfraction motion was 1.38 {+-} 1.25 mm, 1.79 {+-} 1.45 mm, and 1.98 {+-} 1.75 mm for the medial-lateral, superior-inferior, and anterior-posterior directions, respectively. Pretreatment shifts of >3 mm occurred in 19% of setups in the medial-lateral, 27% in the superior-inferior, and 33% in the anterior-posterior directions, respectively. There were no treatment-related fatalities or hospitalizations. Complications included skin desquamation, odynophagia, otitis externa, keratitis, naso-lacrimal duct stenosis, and brachial plexopathy. Conclusions: Intensity-modulated radiotherapy with daily image guidance results in effective disease control with relatively low morbidity and should be considered for selected patients with recurrent and second primary cancers of the head and neck.

  16. Methylphenidate as a reinforcer for rats: contingent delivery and intake escalation.

    PubMed

    Marusich, Julie A; Beckmann, Joshua S; Gipson, Cassandra D; Bardo, Michael T

    2010-06-01

    Methylphenidate (MPH) is one of the most widely prescribed drugs for treating attention-deficit hyperactivity disorder. Previous research suggested that MPH is a reinforcer for rats, but not all of the manipulations to show that lever pressing is controlled by the contingency to obtain MPH have been examined. In Experiment 1, responding for MPH on a progressive ratio (PR) schedule was assessed. Rats self-administered varying doses of MPH (0.056-1.0 mg/kg/infusion) on a PR schedule of reinforcement, and self-administered more MPH than saline, with maximal responding occurring at a unit dose of 0.56 mg/kg/infusion. Experiment 2 examined if there were differences in responding between contingent and noncontingent MPH (0.56 mg/kg/infusion) on a fixed ratio schedule of reinforcement. Results showed that rats responded for contingent MPH, and that responding was not maintained when MPH was delivered noncontingently. Experiment 3 examined self-administration of MPH (0.1 or 0.3 mg/kg/infusion) during long access (6 hr) compared to short access sessions (1 hr). Results showed that rats given long access to MPH showed an escalation of intake across sessions, with this escalation being more pronounced at the lower unit dose (0.1 mg/kg/infusion); in contrast, rats given short access to MPH did not show an increase in MPH self-administration across sessions at either MPH dose tested. Taken together, these results indicate that MPH is an effective intravenous reinforcer for rats and that, similar to other stimulants such as cocaine, amphetamine and methamphetamine, MPH is subject to abuse as reflected by dysregulated intake across repeated long access sessions.

  17. Adaptive Dose Painting by Numbers for Head-and-Neck Cancer

    SciTech Connect

    Duprez, Frederic; De Neve, Wilfried; De Gersem, Werner; Coghe, Marc; Madani, Indira

    2011-07-15

    Purpose: To investigate the feasibility of adaptive intensity-modulated radiation therapy (IMRT) using dose painting by numbers (DPBN) for head-and-neck cancer. Methods and Materials: Each patient's treatment used three separate treatment plans: fractions 1-10 used a DPBN ([{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography [{sup 18}F-FDG-PET]) voxel intensity-based IMRT plan based on a pretreatment {sup 18}F-FDG-PET/computed tomography (CT) scan; fractions 11-20 used a DPBN plan based on a {sup 18}F-FDG-PET/CT scan acquired after the eighth fraction; and fractions 21-32 used a conventional (uniform dose) IMRT plan. In a Phase I trial, two dose prescription levels were tested: a median dose of 80.9 Gy to the high-dose clinical target volume (CTV{sub highdose}) (dose level I) and a median dose of 85.9 Gy to the gross tumor volume (GTV) (dose level II). Between February 2007 and August 2009, 7 patients at dose level I and 14 patients at dose level II were enrolled. Results: All patients finished treatment without a break, and no Grade 4 acute toxicity was observed. Treatment adaptation (i.e., plans based on the second {sup 18}F-FDG-PET/CT scan) reduced the volumes for the GTV (41%, p = 0.01), CTV{sub highdose} (18%, p = 0.01), high-dose planning target volume (14%, p = 0.02), and parotids (9-12%, p < 0.05). Because the GTV was much smaller than the CTV{sub highdose} and target adaptation, further dose escalation at dose level II resulted in less severe toxicity than that observed at dose level I. Conclusion: To our knowledge, this represents the first clinical study that combines adaptive treatments with dose painting by numbers. Treatment as described above is feasible.

  18. Implementation of Constant Dose Rate and Constant Angular Spacing Intensity-modulated Arc Therapy for Cervical Cancer by Using a Conventional Linear Accelerator

    PubMed Central

    Zhang, Ruo-Hui; Fan, Xiao-Mei; Bai, Wen-Wen; Cao, Yan-Kun

    2016-01-01

    Background: Volumetric-modulated arc therapy (VMAT) can only be implemented on the new generation linacs such as the Varian Trilogy® and Elekta Synergy®. This prevents most existing linacs from delivering VMAT. The purpose of this study was to investigate the feasibility of using a conventional linear accelerator delivering constant dose rate and constant angular spacing intensity-modulated arc therapy (CDR-CAS-IMAT) for treating cervical cancer. Methods: Twenty patients with cervical cancer previously treated with intensity-modulated radiation therapy (IMRT) using Varian Clinical 23EX were retreated using CDR-CAS-IMAT. The planning target volume (PTV) was set as 50.4 Gy in 28 fractions. Plans were evaluated based on the ability to meet the dose volume histogram. The homogeneity index (HI), target volume conformity index (CI), the dose to organs at risk, radiation delivery time, and monitor units (MUs) were also compared. The paired t-test was used to analyze the two data sets. All statistical analyses were performed using SPSS 19.0 software. Results: Compared to the IMRT group, the CDR-CAS-IMAT group showed better PTV CI (0.85 ± 0.03 vs. 0.81 ± 0.03, P = 0.001), clinical target volume CI (0.46 ± 0.05 vs. 0.43 ± 0.05, P = 0.001), HI (0.09±0.02 vs. 0.11 ± 0.02, P = 0.005) and D95 (5196.33 ± 28.24 cGy vs. 5162.63 ± 31.12 cGy, P = 0.000), and cord D2 (3743.8 ± 118.7 cGy vs. 3806.2 ± 98.7 cGy, P = 0.017) and rectum V40 (41.9 ± 6.1% vs. 44.2 ± 4.8%, P = 0.026). Treatment time (422.7 ± 46.7 s vs. 84.6 ± 7.8 s, P = 0.000) and the total plan Mus (927.4 ± 79.1 vs. 787.5 ± 78.5, P = 0.000) decreased by a factor of 0.8 and 0.15, respectively. The IMRT group plans were superior to the CDR-CAS-IMAT group plans considering decreasing bladder V50 (17.4 ± 4.5% vs. 16.6 ± 4.2%, P = 0.049), bowel V30 (39.6 ± 6.5% vs. 36.6 ± 7.5%, P = 0.008), and low-dose irradiation volume; there were no significant differences in other statistical indexes. Conclusions

  19. Late Toxicity After Intensity-Modulated Radiation Therapy for Localized Prostate Cancer: An Exploration of Dose-Volume Histogram Parameters to Limit Genitourinary and Gastrointestinal Toxicity

    SciTech Connect

    Pederson, Aaron W.; Fricano, Janine; Correa, David; Pelizzari, Charles A.; Liauw, Stanley L.

    2012-01-01

    Purpose: To characterize the late genitourinary (GU) and gastrointestinal (GI) toxicity for prostate cancer patients treated with intensity-modulated radiation therapy (IMRT) and propose dose-volume histogram (DVH) guidelines to limit late treatment-related toxicity. Methods and Materials: In this study 296 consecutive men were treated with IMRT for adenocarcinoma of the prostate. Most patients received treatment to the prostate with or without proximal seminal vesicles (90%), to a median dose of 76 Gy. Concurrent androgen deprivation therapy was given to 150 men (51%) for a median of 4 months. Late toxicity was defined by Common Toxicity Criteria version 3.0 as greater than 3 months after radiation therapy completion. Four groupings of DVH parameters were defined, based on the percentage of rectal or bladder tissue receiving 70 Gy (V{sub 70}), 65 Gy (V{sub 65}), and 40 Gy (V{sub 40}). These DVH groupings, as well as clinical and treatment characteristics, were correlated to maximal Grade 2+ GU and GI toxicity. Results: With a median follow-up of 41 months, the 4-year freedom from maximal Grade 2+ late toxicity was 81% and 91% for GU and GI systems, respectively, and by last follow-up, the rates of Grade 2+ GU and GI toxicity were 9% and 5%, respectively. On multivariate analysis, whole-pelvic IMRT was associated with Grade 2+ GU toxicity and age was associated with Grade 2+ GI toxicity. Freedom from Grade 2+ GI toxicity at 4 years was 100% for men with rectal V{sub 70} {<=}10%, V{sub 65} {<=}20%, and V{sub 40} {<=}40%; 92% for men with rectal V{sub 70} {<=}20%, V{sub 65} {<=}40%, and V{sub 40} {<=}80%; and 85% for men exceeding these criteria (p = 0.13). These criteria were more highly associated with GI toxicity in men aged {>=}70 years (p = 0.07). No bladder dose-volume relationships were associated with the risk of GU toxicity. Conclusions: IMRT is associated with low rates of severe GU or GI toxicity after treatment for prostate cancer. Rectal dose constraints

  20. SU-E-T-417: The Impact of Normal Tissue Constraints On PTV Dose Homogeneity for Intensity Modulated Radiotherapy (IMRT), Volume Modulated Arc Therapy (VMAT) and Tomotherapy<