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Valicenti R.K.,University of California at Davis | Bae K.,Radiation Therapy Oncology Group | Michalski J.,Washington University in St. Louis | Sandler H.,University of Michigan | And 3 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

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. © 2011 Elsevier Inc.


Chinnaiyan P.,H. Lee Moffitt Cancer Center and Research Institute | Won M.,Radiation Therapy Oncology Group | Wen P.Y.,Center for Neuro Oncology | Rojiani A.M.,Georgia Regents University | And 4 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m2 per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m2 on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response. © 2013 Elsevier Inc.


Farrell J.J.,University of California at Los Angeles | Bae K.,Radiation Therapy Oncology Group | Wong J.,University of California at Los Angeles | Dicker A.P.,Thomas Jefferson University | Elsaleh H.,Australian National University
Pharmacogenomics Journal | Year: 2012

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys 27 Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys27 Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys27Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys27 Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival. © 2012 Macmillan Publishers Limited. All rights reserved.


News Article | December 16, 2016
Site: www.eurekalert.org

Philadelphia, PA -- NRG Oncology clinical trial NRG-LU001 successfully reached its accrual goal of 168 patients. NRG-LU001: Randomized Phase II Trial of Concurrent Chemoradiotherapy with or without Metformin Hydrochloride (HCL) in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) is the first clinical trial that seeks to determine whether metformin added to standard, concurrent chemoradiotherapy can improve progression-free survival (PFS) for patients with locally advanced NSCLC. NRG-LU001 initially opened for patient enrollment on August 25, 2014 and over the past 15 months enrolled patients from 80 institutions in the United States, Canada, and Israel. Metformin is commonly used in the treatment of diabetic patients; however, pre-clinical and retrospective clinical studies have suggested that it may be able to improve the response of epithelial tumors to chemoradiotherapy. "Metformin modifies carbohydrate and lipid metabolism and mediates in cells a state of mild energy stress. This is shown to lead to inhibition of oncogenes and activation of molecular tumor suppressors," stated Theodoros Tsakiridis, MD, PhD, FRCPC, a radiation oncologist at the Juravinski Cancer Center in Ontario, Canada and co-principal investigator for NRG-LU001. "We hope that the results of this prospective randomized study will confirm the pre-clinical and retrospective trial results and help us design future trials with metformin." NRG-LU001 aims to examine if the connection between metformin and the modification of metabolism can improve chemoradiotherapy responses for patients with stage IIIA or IIIB NSCLC. "If the addition of a commonly used agent like metformin can improve outcomes following a diagnosis of locally advanced NSCLC, this could potentially open the gates to re-purposing drugs currently used for other diseases," said Heath Skinner, MD, PhD, assistant professor of radiation oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas and co-principal investigator for NRG-LU001. "Additionally, based on pre-clinical data, metformin sensitizes other tumor types to radiation and chemotherapy as well, thus a positive clinical trial in lung cancer could lead to trials in other types of cancer." "Thank you and congratulations to the research sites in the United States, Israel, and Canada that enrolled patients on the NRG-LU001 trial. We eagerly await the results of this NRG Oncology trial and the impact it could have for NSCLC patients," says Walter J. Curran, Jr, M.D., the report's senior author, NRG Oncology Group Co-Chair, and Executive Director of the Winship Cancer Institute of Emory University in Atlanta. For more information on this trial, please visit NRG-LU001. NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group. The research organization seeks to carry out clinical trials with emphases on gender-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology's extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI's National Clinical Trials Network.


Jha N.,University of Alberta | Harris J.,Radiation Therapy Oncology Group | Seikaly H.,University of Alberta | Jacobs J.R.,Wayne State University | And 5 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: We report the results of a phase II study to determine the reproducibility of a submandibular salivary gland transfer (SGT) surgical technique for prevention of radiation (XRT)-induced xerostomia in a multi-institutional setting and to assess severity of xerostomia. Methods and Materials: Eligible patients had surgery for primary, neck dissection, and SGT, followed by XRT, during which the transferred salivary gland was shielded. Intensity modulated radiation therapy, amifostine, and pilocarpine were not allowed, but postoperative chemotherapy was allowed. Each operation was reviewed by 2 reviewers and radiation by 1 reviewer. If 13 or more (of 43) were "not per protocol," then the technique would be considered not reproducible as per study design. The secondary endpoint was the rate of acute xerostomia, grade 2 or higher, and a rate of ≤51% was acceptable. Results: Forty-four of the total 49 patients were analyzable: male (81.8%), oropharynx (63.6%), stage IV (61.4%), median age 56.5 years. SGT was "per protocol" or within acceptable variation in 34 patients (77.3%) and XRT in 79.5%. Nine patients (20.9%) developed grade 2 acute xerostomia; 2 had grade 0-1 xerostomia (4.7%) but started on amifostine/pilocarpine. Treatment for these 11 patients (25.6%) was considered a failure for the xerostomia endpoint. Thirteen patients died; median follow-up for 31 surviving patients was 2.9 years. Two-year overall and disease-free survival rates were 76.4% and 71.7%, respectively. Conclusions: The technique of submandibular SGT is reproducible in a multicenter setting. Seventy-four percent of patients were prevented from XRT-induced acute xerostomia. © 2012 Elsevier Inc.


Wolfson A.H.,University of Miami | Bae K.,Radiation Therapy Oncology Group | Komaki R.,University of Texas M. D. Anderson Cancer Center | Meyers C.,University of Texas M. D. Anderson Cancer Center | And 6 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: To determine the effect of dose and fractionation schedule of prophylactic cranial irradiation (PCI) on the incidence of chronic neurotoxicity (CNt) and changes in quality of life for selected patients with limited-disease small-cell lung cancer (LD SCLC). Methods and Materials: Patients with LD SCLC who achieved a complete response after chemotherapy and thoracic irradiation were eligible for randomization to undergo PCI to a total dose of 25 Gy in 10 daily fractions (Arm 1) vs. the experimental cohort of 36 Gy. Those receiving 36 Gy underwent a secondary randomization between daily 18 fractions (Arm 2) and twice-daily 24 fractions (Arm 3). Enrolled patients participated in baseline and follow-up neuropsychological test batteries along with quality-of-life assessments. Results: A total of 265 patients were accrued, with 131 in Arm 1, 67 in Arm 2, and 66 in Arm 3 being eligible. There are 112 patients (42.2%) alive with 25.3 months of median follow-up. There were no significant baseline differences among groups regarding quality-of-life measures and one of the neuropsychological tests, namely the Hopkins Verbal Learning Test. However, at 12 months after PCI there was a significant increase in the occurrence of CNt in the 36-Gy cohort (p = 0.02). Logistic regression analysis revealed increasing age to be the most significant predictor of CNt (p = 0.005). Conclusions: Because of the increased risk of developing CNt in study patients with 36 Gy, a total PCI dose of 25 Gy remains the standard of care for patients with LD SCLC attaining a complete response to initial chemoradiation. Copyright © 2011 Elsevier Inc.


Suntharalingam M.,University of Maryland Baltimore County | Paulus R.,Radiation Therapy Oncology Group | Edelman M.J.,University of Maryland Baltimore County | Krasna M.,Cancer Center At St Joseph Medical Center | And 4 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To evaluate mediastinal nodal clearance (MNC) rates after induction chemotherapy and concurrent, full-dose radiation therapy (RT) in a phase II trimodality trial (Radiation Therapy Oncology Group protocol 0229). Patients and Methods: Patients (n=57) with stage III non-small cell lung cancer (pathologically proven N2 or N3) were eligible. Induction chemotherapy consisted of weekly carboplatin (AUC = 2.0) and paclitaxel 50 mg/m 2. Concurrent RT was prescribed, with 50.4 Gy to the mediastinum and primary tumor and a boost of 10.8 Gy to all gross disease. The mediastinum was pathologically reassessed after completion of chemoradiation. The primary endpoint of the study was MNC, with secondary endpoints of 2-year overall survival and postoperative morbidity/mortality. Results: The grade 3/4 toxicities included hematologic 35%, gastrointestinal 14%, and pulmonary 23%. Forty-three patients (75%) were evaluable for the primary endpoint. Twenty-seven patients achieved the primary endpoint of MNC (63%). Thirty-seven patients underwent resection. There was a 14% incidence of grade 3 postoperative pulmonary complications and 1 30-day, postoperative grade 5 toxicity (3%). With a median follow-up of 24 months for all patients, the 2-year overall survival rate was 54%, and the 2-year progression-free survival rate was 33%. The 2-year overall survival rate was 75% for those who achieved nodal clearance, 52% for those with residual nodal disease, and 23% for those who were not evaluable for the primary endpoint (P=.0002). Conclusions: This multi-institutional trial confirms the ability of neoadjuvant concurrent chemoradiation with full-dose RT to sterilize known mediastinal nodal disease. © 2012 Elsevier Inc.


Timmerman R.,University of Texas Southwestern Medical Center | Paulus R.,Radiation Therapy Oncology Group | Galvin J.,Thomas Jefferson University | Michalski J.,Washington University in St. Louis | And 9 more authors.
JAMA - Journal of the American Medical Association | Year: 2010

Context: Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management. Objective: To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer. Design, Setting, and Patients: Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non-small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 11/2 and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009. Main Outcome Measures: The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival. Results: A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for diseasefree survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported. Conclusion Patients with inoperable non-small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity. ©2010 American Medical Association. All rights reserved.


Werner-Wasik M.,Thomas Jefferson University | Paulus R.,Radiation Therapy Oncology Group | Curran Jr. W.,Emory University | Byhardt R.,Medical College of Wisconsin
Clinical Lung Cancer | Year: 2011

Background: We analyzed time course and factors associated with acute esophagitis (ES) and late lung toxicity (PN), as well as any association between ES and PN in patients (pts) with non-small-cell lung cancer (NSCLC) treated with concurrent chemoradiation (chemo-RT) on the Radiation Therapy Oncology Group (RTOG) trials. Materials and Methods: Multivariable analysis was used to investigate factors associated with ES or PN. Results: Patients (n = 528) received standard fractionated (SFX; 63 Gy) or hyperfractionated (HFX; 69.6 Gy) radiation therapy (RT) with cisplatinbased chemotherapy. Grade > 2 ES developed in 75% of pts; Grade > 3 ES, in 34%. Nineteen percent of pts developed ES by the first, 32% by the second, and 33% by the third month (and for Grade > 3 PN, 9% by 6 months, 15% by year 1, and 18% by year 2). Any PN developed in 59% of pts; Grade > 2, in 39%; Grade > 3, in 18%; and lethal PN, in 2%. Grade > 2 PN was associated with increasing RT dose and Grade > 3 PN, with HFX RT. No association was seen with ES. Grade > 3 ES was less likely to occur in non-whites and more likely, in pts treated with HFX RT. Conclusion: Most (95%) pts developed ES, and 33% had severe ES, peaking within the first or second month of RT. PN developed in 57% of pts, with 18% experiencing Grade > 3 PN, with most diagnosed by 1 year from RT. No relationship was observed between 1 toxicity (ES or PN) as predictor of the other. HFX RT was associated with more severe PN or ES. © 2011 Elsevier Inc. All rights reserved.


Pisansky T.M.,Mayo Medical School | Pugh S.L.,Radiation Therapy Oncology Group | Greenberg R.E.,Fox Chase Cancer Center | Pervez N.,Cross Cancer Institute | And 7 more authors.
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive agent is undefined. OBJECTIVES: To determine primarily whether tadalafil preserved erectile function in men treated with radiotherapy for prostate cancer, and secondarily to determine whether participant- or partner-reported overall sexual function and sexual and marital satisfaction were affected. DESIGN, SETTING, AND PARTICIPANTS: Stratified, placebo-controlled, double-blind, parallel-group study with 1:1 randomization at 76 community-based and tertiary medical sites in the United States and Canada. Two hundred forty-two participants with intact erectile function scheduled to receive radiotherapy for prostate cancer were recruited between November 2009 and February 2012 with follow-up through March 2013. INTERVENTIONS: One hundred twenty-one participants were assigned 5 mg of tadalafil daily and 121 were assigned placebo for 24 weeks starting with external radiotherapy (63%) or brachytherapy (37%). Participant-reported International Index of Erectile Function response before radiotherapy and at weeks 2 and 4, between weeks 20 and 24, between weeks 28 and 30, and 1 year thereafter. Participants and partners could respond also to the Sexual Adjustment Questionnaire and to the Locke Marital Adjustment Test before radiotherapy, between weeks 20 and 24 and weeks 28 and 30, and at 1 year. MAIN OUTCOMES AND MEASURES: Primary outcome was off-drug spontaneous erectile function 28 to 30 weeks after radiotherapy started. Secondary end points were spontaneous erection at 1 year; overall sexual function and satisfaction; marital adjustment; and partner-reported satisfaction and marital adjustment at 28 to 30 weeks and 1 year, predictors of tadalafil response; and adverse events. RESULTS: Among 221 evaluable participants, 80 (79%; 95% CI, 70%-88%) assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 (74%; 95% CI, 63%-85%) assigned to receive placebo (P = .49); an absolute difference of 5% (95% CI, -9% to 19%). A significant difference was also not observed at 1 year (72%; 95% CI, 60%-84% vs 71%; 95% CI, 59%-84%; P = .93). Tadalafil was not associated with significantly improved overall sexual function or satisfaction; a significant difference was not observed in any domain subscale. Partners of men assigned tadalafil noted no significant effect on sexual satisfaction, and marital adjustment was not significantly improved in participants or partners. CONCLUSIONS AND RELEVANCE: Among men undergoing radiotherapy for prostate cancer, daily use of tadalafil compared with placebo did not result in improved erectile function. These findings do not support daily use of tadalafil to prevent erectile dysfunction in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00931528. Copyright 2014 American Medical Association. All rights reserved.

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