European Urology

Stadler WM, Lerner SP, Groshen S, et al
J Clin Oncol 2011;29:3443–9
Experts’ summary:
Conventional prognostic indicators for bladder cancer, such as tumor grade, stage, size, variant histopathology, and multifocality, incompletely predict clinical outcome. This trial represents the largest randomized study of adjuvant chemotherapy for bladder cancer and the first study to use methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) based on p53 genetic alteration. This study analyzed 499 patients with T1-T2N0 bladder cancer who had undergone radical cystectomy and pelvic lymph node dissection for p53 expression by immunohistochemistry. Subjects with altered p53 expression were then randomly assigned to three cycles of MVAC versus observation. The primary objective of this trial was to compare recurrence in patients with p53-positive tumors randomly assigned to MVAC versus observation. The secondary objective of the trial was to compare recurrence in the p53-positive and negative arms. Accrual was halted on the basis of an interim futility analysis. Overall 5-yr probability of recurring was 0.20 (95% confidence interval [CI], 0.16–0.24) with no difference on the basis of p53 status. Only 67% of patients randomly assigned to MVAC received all three cycles. The authors observed no prognostic value in p53 as a biomarker and no benefit of treatment with MVAC in p53-positive patients.
Experts’ comments:
Recurrence rates of ≤50% are still observed in patients undergoing radical cystectomy [1]. Although cisplatin-based combination neoadjuvant chemotherapy improves survival, administration of neoadjuvant chemotherapy for all patients undergoing radical cystectomy has not been widely adopted. This may be due to concerns over unnecessarily treating many patients and/or the belief that adjuvant chemotherapy may be as effective as neoadjuvant chemotherapy if administered selectively based on adverse pathologic characteristics [2]. This trial sought to use a strategy of selected adjuvant chemotherapy based on p53 status of the tumor at cystectomy. P53 is a cell-cycle regulatory gene that is mutated in many cancers, including bladder cancer [3]. This molecular marker was chosen because of compelling observations of the association of p53 with poor outcome in bladder cancer and because p53 inactivation was thought to predict tumor susceptibility to DNA-damaging chemotherapy. This study was halted after a scheduled interim data analysis determined that no significant benefit was observed for patients randomized to the p53-positive treatment arm with MVAC.

This important study highlights the challenges of using data based on observational studies to design prospective trials. Unlike statistical power and level of significance, which are generally chosen by convention, the underlying event rate and the expectant treatment effect must be established by other means, including observational studies. The p53 trial suffered from a low event rate and a 21% noncompliance rate, which ultimately compromised the ability to interpret the prognostic and predictive value of p53 tumor expression. This trial estimated a 20% absolute reduction in the probability of recurrence at 3 yr with an underlying event rate of 50%. In fact, the overall probability of recurring at 5 yr was only 20%. Despite convincing evidence for the poor prognostic value of p53, these patients were low-risk patients by conventional pathologic assessment (pT1–pT2). Although a survival advantage of adjuvant chemotherapy has not been definitely proven, the current data would indicate that if a survival advantage were to be gained, we would expect to see this in high-risk populations, such as patients with advanced pathologic stage and node positivity [4].

The authors should be commended for this pivotal trial in bladder cancer. At the current rate, the next decade will result in an overabundance of molecular markers and novel therapies whose investigation will require novel paradigms to scientifically prioritize their development. Concurrently, a similar emphasis should be placed on incorporating novel approaches to clinical trial design and patient selection [5].

Conflicts of interest

Robert S. Svatek has received financial compensation for participation in a scientific study/trial with Adolor Corp. and Alere Corp.