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 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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram describing cohort, p53 analysis, randomization, and treatment. MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin.

Fig 2.

Effect of p53 immunohistochemistry on recurrence and survival. (A) Estimated cumulative incidence curves for time to recurrence and (B) Kaplan-Meier curves for overall survival, based on p53 nuclear immunoreactivity (negative is wild type and positive is altered). (C) Estimated cumulative incidence curves for time to recurrence and (D) Kaplan-Meier curves for overall survival among patients with p53-altered tumors in patients randomly assigned to observation versus chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC; intent-to-treat analysis). Two-sided P values are based on the log-rank test for (A) and (B) and on the stratified log-rank test (stratified by age (< 65 v ≥ 65 years), stage (pT1 v pT2), grade (1 to 2 v 3 to 4), and p21 status for (C) and (D).

Fig 3.

Post hoc analysis and forest plots of time to recurrence and overall survival hazard ratios with 95% CIs to assess the impact of noncompliance with assigned therapy in the arm treated with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). Compliant excludes patients who refused assigned treatment; as treated includes all patients and analyzes them according to treatment received; 4-month and 6-month landmark analyses assessed only those patients in each arm as assigned who survived without recurrence to a 4- or 6-month landmark, respectively; and ITT represents protocol-specified intent-to-treat analysis.