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Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status.

ABSTRACT: INTRODUCTION:Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) adjuvant chemotherapy. PATIENTS AND METHODS:Patients with pT1/T2N0M0 disease whose tumors demonstrated ? 10% nuclear reactivity on centrally performed immunohistochemistry for p53 were offered random assignment to three cycles of adjuvant MVAC versus observation; p53-negative patients were observed. By using a log-rank test with one-sided ? = .05 and ? = .10, 190 p53-positive patients were planned to be randomly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30. RESULTS:A total of 521 patients were registered, 499 underwent p53 assessment, 272 (55%) were positive, and 114 (42%) were randomly assigned. Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis. Overall 5-year probability of recurring was 0.20 (95% CI, 0.16 to 0.24) with no difference on the basis of p53 status. Only 67% of patients randomly assigned to MVAC received all three cycles with 12 patients receiving no treatment. There was no difference in recurrence in the randomly assigned patients (hazard ratio, 0.78; 95% CI, 0.29 to 2.08; P = .62). CONCLUSION:Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed, but the high patient refusal rate, lower than expected event rate, and failures to receive assigned therapy severely compromised study power.

SUBMITTER: Stadler WM

PROVIDER: S-EPMC3164246 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status.

Stadler Walter M WM Lerner Seth P SP Groshen Susan S Stein John P JP Shi Shan-Rong SR Raghavan Derek D Esrig David D Steinberg Gary G Wood David D Klotz Laurence L Hall Craig C Skinner Donald G DG Cote Richard J RJ

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20110801 25

<h4>Introduction</h4>Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) adjuvant chemotherapy.<h4>Patients and methods</h4>Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10% nuclear reactivity on centrally performed immunohistochemistry for p53 were offered random assignment to three cycles of adjuvant MVAC v ...[more]

PMID: 21810677

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Project description:BackgroundThe standard of care for locally advanced bladder cancer (LABC) is neoadjuvant chemotherapy followed by cystectomy. However, the role of adjuvant therapy for locally advanced bladder cancer is unclear.ObjectiveThe purpose of this study was to evaluate the outcomes of adjuvant radiation therapy (RT) for patients with LABC, and to determine which risk factors best predict for patients who may best benefit from adjuvant RT.MethodsThe National Cancer Data Base (NCDB) was queried (2004- 2013) for patients with newly-diagnosed pT3-4N0-3M0 urothelial carcinoma of the bladder that received neoadjuvant chemotherapy and cystectomy. Patients were divided into two groups based on the adjuvant therapy they received: RT or observation. Statistics included multivariable logistic regression to determine factors predictive of receiving adjuvant RT, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS.ResultsAltogether, 1,646 patients met inclusion criteria; 59 (3.6%) patients received adjuvant RT, while 1,587 (96.4%) were observed. Patients treated with adjuvant RT were more likely to be female, have positive surgical margins, and receive treatment at a non-academic facility. There was no difference in median overall survival (OS) between patients treated with RT when compared to patients observed (17.7 months vs. 23.5 months; p = 0.085). However, an improvement in median OS with the use of adjuvant RT was observed among patients with positive surgical margins (20.3 months vs. 13.1 months; p = 0.032). On multivariate analysis, advancing age, pT4 stage, positive N stage, positive margins, and lower socioeconomic status were associated with worse OS.ConclusionsIn the largest study to date evaluating efficacy of adjuvant radiotherapy in patients with locally advanced bladder cancer, use of RT was not associated with OS in all patients, while RT was associated with improvemed OS among patients with positive surgical margins. Prospective studies are recommended to confirm these findings.

Project description:Importance:Locoregional failure for patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity and mortality. Adjuvant radiotherapy (RT) can decrease locoregional failure but has not been studied in the chemotherapy era. Objective:To investigate if adjuvant sequential RT plus chemotherapy can improve locoregional recurrence-free survival (LRFS) compared with adjuvant chemotherapy alone. Design, Setting, and Participants:A randomized phase 3 trial was opened to compare adjuvant RT vs sequential chemotherapy plus RT after RC for LABC, but a third arm was added later as a randomized phase 2 trial to compare chemotherapy plus RT vs adjuvant chemotherapy alone, an emerging standard. The intent-to-treat phase 2 trial reported herein enrolled patients from December 2002 to July 2008. Data were analyzed from August 3, 2015, to January 6, 2016. Routine follow-up and surveillance pelvic computed tomographic (CT) scans every 6 months during the first 2 years were performed. The setting was an academic center. Patients with bladder cancer 70 years or younger having 1 or more risk factors (≥pT3b, grade 3, or positive nodes) with negative margins after radical cystectomy plus pelvic lymph node dissection were eligible. Patients had Eastern Cooperative Oncology Group performance status of 0 to 2, no evidence of distant metastases on CT scan of the abdomen and pelvis or on chest imaging, and adequate renal, hepatic, and hematologic function. Ninety-one percent (109 of 120) had ≥ pT3 disease. Interventions:Chemotherapy plus RT included 2 cycles of gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15) and cisplatin (70 mg/m2 intravenously on day 2) before and after RT to 4500 cGy in 150 cGy twice-daily fractions over 3 weeks using 3-dimensional conformal techniques. Chemotherapy alone included 4 cycles of gemcitabine and cisplatin. Main Outcome and Measure:Locoregional recurrence-free survival. Results:The chemotherapy plus RT arm accrued 75 patients, and the chemotherapy-alone arm accrued 45 patients, with a weighted randomization to speed accrual. Fifty-three percent (64 of 120) had urothelial carcinoma, and 46.7% (56 of 120) had squamous cell carcinoma or other. The arms were balanced except for age (median, 52 vs 55 years; P = .04) and tumor size (mean, 4.9 vs 5.8 cm; P < .01), both favoring chemotherapy plus RT. Two-year outcomes and overall adjusted hazard ratios (HRs) for chemotherapy plus RT vs chemotherapy alone were 96% vs 69% (HR, 0.08; 95% CI, 0.02-0.39; P < .01) for LRFS, 68% vs 56% (HR, 0.53; 95% CI, 0.27-1.06; P = .07) for disease-free survival, and 71% vs 60% (HR, 0.61; 95% CI, 0.33-1.11; P = .11) for overall survival (OS). Five patients (7%) had RT-associated late grade 3 gastrointestinal tract adverse effects in the chemotherapy plus RT arm. Conclusions and Relevance:Adjuvant chemotherapy plus RT was reasonably well tolerated and was associated with significant improvements in LRFS and marginal improvements in disease-free survival vs chemotherapy alone in LABC. The addition of adjuvant RT should be considered for LABC. This regimen warrants further study in phase 3 trials. Trial Registration:clinicaltrials.gov Identifier: NCT01734798.

Dataset Information

Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status.

Publications

Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status.

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