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

Walter M. Stadler, Seth P. Lerner, Susan Groshen, John P. Stein, Shan Rong Shi, Derek Raghavan, David Esrig, Gary Steinberg, David Wood, Laurence Klotz, Craig Hall, Donald G. Skinner, Richard J Cote

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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 α = .05 and β = .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.

Original languageEnglish
Pages (from-to)3443-3449
Number of pages7
JournalJournal of Clinical Oncology
Volume29
Issue number25
DOIs
StatePublished - Sep 1 2011

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Urinary Bladder Neoplasms
Vinblastine
Methotrexate
Doxorubicin
Cisplatin
Therapeutics
Clinical Trials Data Monitoring Committees
Medical Futility
Recurrence
Adjuvant Chemotherapy
Neoplasms
Retrospective Studies
Immunohistochemistry
Observation
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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.; Lerner, Seth P.; Groshen, Susan; Stein, John P.; Shi, Shan Rong; Raghavan, Derek; Esrig, David; Steinberg, Gary; Wood, David; Klotz, Laurence; Hall, Craig; Skinner, Donald G.; Cote, Richard J.

In: Journal of Clinical Oncology, Vol. 29, No. 25, 01.09.2011, p. 3443-3449.

Research output: Contribution to journalArticle

Stadler, WM, Lerner, SP, Groshen, S, Stein, JP, Shi, SR, Raghavan, D, Esrig, D, Steinberg, G, Wood, D, Klotz, L, Hall, C, Skinner, DG & Cote, RJ 2011, 'Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status', Journal of Clinical Oncology, vol. 29, no. 25, pp. 3443-3449. https://doi.org/10.1200/JCO.2010.34.4028
Stadler, Walter M. ; Lerner, Seth P. ; Groshen, Susan ; Stein, John P. ; Shi, Shan Rong ; Raghavan, Derek ; Esrig, David ; Steinberg, Gary ; Wood, David ; Klotz, Laurence ; Hall, Craig ; Skinner, Donald G. ; Cote, Richard J. / Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 25. pp. 3443-3449.
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T1 - Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status

AU - Stadler, Walter M.

AU - Lerner, Seth P.

AU - Groshen, Susan

AU - Stein, John P.

AU - Shi, Shan Rong

AU - Raghavan, Derek

AU - Esrig, David

AU - Steinberg, Gary

AU - Wood, David

AU - Klotz, Laurence

AU - Hall, Craig

AU - Skinner, Donald G.

AU - Cote, Richard J

PY - 2011/9/1

Y1 - 2011/9/1

N2 - 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 α = .05 and β = .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.

AB - 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 α = .05 and β = .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.

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