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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 25 Pg. 3443-9 (Sep 01 2011) ISSN: 1527-7755 [Electronic] United States
• PMID: 21810677 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• TP53 protein, human
• Tumor Suppressor Protein p53
• Vinblastine
• Doxorubicin
• Cisplatin
• Methotrexate

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma in Situ (drug therapy, genetics)
• Carcinoma, Transitional Cell (drug therapy, metabolism)
• Cisplatin (administration & dosage)
• Doxorubicin (administration & dosage)
• Female
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Male
• Methotrexate (administration & dosage)
• Molecular Targeted Therapy
• Prospective Studies
• Survival Rate
• Treatment Outcome
• Tumor Suppressor Protein p53 (metabolism)
• Urinary Bladder Neoplasms (drug therapy, metabolism)
• Vinblastine (administration & dosage)