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Spigel D.R.,Sarah Cannon Research Institute Tennessee Oncology PLLC | Patel J.D.,Northwestern University | Reynolds C.H.,Ocala Oncology | Reynolds C.H.,U.S. Oncology Research LLC | And 10 more authors.
Journal of Thoracic Oncology | Year: 2015

INTRODUCTION:: Treatment impact on quality of life (QoL) informs treatment management decisions in advanced nonsquamous non-small-cell lung cancer (NS NSCLC). QoL outcomes from the phase III PointBreak trial are reported. METHODS:: Chemonaive patients (n = 939) with stage IIIB/IV nonsquamous non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status 0 to 1 were randomized (1:1) to pemetrexed-carboplatin-bevacizumab (pemetrexed arm) or paclitaxel-carboplatin-bevacizumab (paclitaxel arm). Patients without progressive disease received maintenance pemetrexed-bevacizumab (pemetrexed arm) or bevacizumab (paclitaxel arm). QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-General (FACT-G), FACT-Lung (FACT-L), and FACT/Gynecologic Oncology Group-Neurotoxicity (FACT-Ntx) instruments. Subscale scores, total scores, and trial outcome indices were analyzed using linear mixed-effects models. Post hoc analyses examined the association between baseline FACT scores and overall survival (OS). RESULTS:: Mean score differences in change from baseline significantly favored the pemetrexed arm for the neurotoxicity subscale score, FACT-Ntx total scores, and FACT-Ntx trial outcome index. They occurred at cycle 2 (p < 0.001) and persisted through induction cycles 2 to 4 and six maintenance cycles. Investigator-assessed, qualitative, drug-related differences in grade 2 (1.6% versus 10.6%) and grade 3 (0.0% versus 4.1%) sensory neuropathy and grade 3/4 fatigue (10.9% versus 5.0%, p = 0.0012) were observed between the pemetrexed and paclitaxel arms. Baseline FACT-G, FACT-L, and FACT-Ntx scores were significant prognostic factors for OS (p < 0.001). CONCLUSIONS:: Randomized patients reported similar changes in QoL, except for less change from baseline in neurotoxicity on the pemetrexed arm; investigators reported greater neurotoxicity on the paclitaxel arm and greater fatigue on the pemetrexed arm. Higher baseline FACT scores were favorable prognostic factors for OS. © 2014 by the International Association for the Study of Lung Cancer. Source

Marsh R.D.W.,University of Florida | George T.J.,University of Florida | Siddiqui T.,University of Florida | Mendenhall W.M.,University of Florida | And 6 more authors.
American Journal of Clinical Oncology: Cancer Clinical Trials | Year: 2010

Objective: Preoperative treatment of rectal cancer with combined chemotherapy and radiation therapy has become a widely accepted strategy. The current challenge is to improve outcomes whereas minimizing morbidity and maximizing the potential for a sphincter sparing procedure. This study sought to evaluate the safety and efficacy of a combination of 2 novel approaches-accelerated, hyperfractionated radiation therapy and twice daily oral capecitabine. Methods: Consenting patients with locally advanced T3-T4, N0-1, M0 rectal adenocarcinoma, located no further than 15 cm from the anal verge, were treated with twice daily fractions of 1.2 Gy M-F to a total of 50.4 Gy for T3 lesions and 55.2 Gy for T4 lesions. Concomitantly, the patients received capecitabine 825 mg/m twice per day 7 days per week. Patients were operated on 4 to 6 weeks after completion of therapy. Results: Sixteen of 17 enrolled patients were eligible and all 16 completed the full course of treatment including definitive surgery. Eleven patients had a sphincter sparing procedure and 5 had an abdominoperineal resection. Tumor and/or nodal downstaging occurred in 81% of patients, 100% of resections were R0, and the sphincter preservation rate was 68%. There were 18% pathologic complete remissions and 68% of specimens were node negative with an additional 12% Nx owing to transanal excision. The therapy was well tolerated and there were no unexpected toxicities with only diarrhea reaching grade 3 in 4 patients. Conclusions: This novel approach to preoperative treatment of rectal adenocarcinoma was well tolerated and effective. Comparison with more established approaches appears justified. Copyright © 2010 by Lippincott Williams & Wilkins. Source

Patel J.D.,Northwestern University | Socinski M.A.,University of Pittsburgh | Garon E.B.,University of California at Los Angeles | Reynolds C.H.,Us Oncology Research | And 14 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose PointBreak (A Study of Pemetrexed, Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer) compared the efficacy and safety of pemetrexed (Pem) plus carboplatin (C) plus bevacizumab (Bev) followed by pemetrexed plus bevacizumab (PemCBev) with paclitaxel (Pac) plus carboplatin (C) plus bevacizumab (Bev) followed by bevacizumab (PacCBev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). Patients and Methods Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were randomly assigned to receive pemetrexed 500 mg/m2 or paclitaxel 200 mg/m2 combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles. Eligible patients received maintenance until disease progression: pemetrexed plus bevacizumab (for the PemCBev group) or bevacizumab (for the PacCBev group). The primary end point of this superiority study was overall survival (OS). Results Patients were randomly assigned to PemCBev (n = 472) or PacCBev (n = 467). For PemCBev versus PacCBev, OS hazard ratio (HR) was 1.00 (median OS, 12.6 v 13.4 months; P = .949); progression-free survival (PFS) HR was 0.83 (median PFS, 6.0 v 5.6 months; P = .012); overall response rate was 34.1% versus 33.0%; and disease control rate was 65.9% versus 69.8%. Significantly more study drug-related grade 3 or 4 anemia (14.5% v 2.7%), thrombocytopenia (23.3% v 5.6%), and fatigue (10.9% v 5.0%) occurred with PemCBev; significantly more grade 3 or 4 neutropenia (40.6% v 25.8%), febrile neutropenia (4.1% v 1.4%), sensory neuropathy (4.1% v 0%), and alopecia (grade 1 or 2; 36.8% v 6.6%) occurred with PacCBev. Conclusion OS did not improve with the PemCBev regimen compared with the PacCBev regimen, although PFS was significantly improved with PemCBev. Toxicity profiles differed; both regimens demonstrated tolerability. © 2013 by American Society of Clinical Oncology. Source

Hortobagyi G.N.,University of Texas M. D. Anderson Cancer Center | Young R.R.,Center for Cancer and Blood | Karwal M.,University of Iowa | Ibrahim N.K.,University of Texas M. D. Anderson Cancer Center | And 8 more authors.
Cancer | Year: 2010

BACKGROUND: UFT, a combination of uracil and ftorafur, was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin is combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provide higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. METHODS: Ninety-four patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m 2, which was given in 2 divided doses every 12 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (OR = complete response [CR] + partial response [PR]) and overall survival (OS). RESULTS: Of the 94 patients enrolled, 68 were evaluable for efficacy. Although no CRs were observed, 9 patients achieved PRs, for an OR of 13.2% in the evaluable population. The median TTP for the evaluable population was 10.3 weeks, and the proportion of patients free of disease progression at 6 months was 17%. The median OS was 61.6 weeks for all patients enrolled. The most common drug-related ≥ grade 3 adverse events (graded using the National Cancer Institute Common Toxicity Criteria version 2) were diarrhea, asthenia, nausea, and dehydration. CONCLUSIONS: The combination of UFT and leucovorin administered orally in a twice-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. © 2010 American Cancer Society. Source

Hermann R.C.,Northwest Georgia Oncology Centers | Makari-Judson G.,Hematology and Oncology mour Center for Cancer Care | Isaacs C.,Georgetown University | Beck J.T.,Highlands Oncology Group | And 16 more authors.
Clinical Cancer Research | Year: 2013

Purpose: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. Experimental Design: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m2 i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m2 orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). Results: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%). Conclusion: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions. © 2013 AACR. Source

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