European Urology

International Collaboration of Trialists on behalf of Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), the European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, the Australian Bladder Cancer Study Group, the National Cancer Institute of Canada Clinical Trials Group, Finnbladder, Norwegian Bladder Cancer Study Group, and Club Urologico Espanol de Tratamiento Oncologico Group
J Clin Oncol 2011; 29:2171–7
Expert's summary:
In this article, the authors present the final results of a large, multicenter, randomized, phase 3 trial comparing three cycles of cisplatin, methotrexate, and vinblastine (CMV) prior to local treatment versus local treatment alone in patients with muscle-invasive bladder cancer (MIBC). With a median follow-up period of 8 yr, the study demonstrates a 6% improvement in overall survival, with a reduction in risk of death of 16% (p = 0.037) in favor of the neoadjuvant chemotherapy arm. These results, reaching the highest level of scientific evidence (level 1a), are in agreement with previously published data on neoadjuvant chemotherapy [1] and [2]. This approach is already regarded by many colleagues in the field of uro-oncology as a new gold standard in the therapeutic management of patients with MIBC.
Expert's comments:
The scientific evidence given by one randomized study or more should always be evaluated taking clinical relevance into account before any novel therapeutic strategy can be considered a standard of practice. In this respect, the analysis of this article raises few important issues that deserve further scrutiny.

First, is neoadjuvant chemotherapy cost-effective when compared to local therapy alone? The present study proposes an absolute difference in overall survival of 10% at 2 yr as clinically relevant; however, the study only observed a 6% difference at 8 yr, with a survival advantage of 7 mo, translating into a number needed to treat (NNT) of 17 to achieve 1 survivor more with neoadjuvant chemotherapy. These results are more modest than those initially considered clinically relevant. Chemotherapy undoubtedly adds morbidity, with reported rates of severe toxicity (grades 3 and 4) and mortality of 26% and 1%, respectively. Furthermore, neoadjuvant chemotherapy results in a delay of local treatment for a minimum of 3 mo, with the long-term impact of such delays still unknown. These issues should be taken into account and should form the basis of a constructive debate about the questionable clinical relevance of routinely implementing a neoadjuvant policy in patients with MIBC.

Second, the study includes patients with three different approaches to local treatment: radical cystectomy alone, preoperative radiotherapy, and radiotherapy alone. Because these approaches have different morbidity and mortality rates, they should be evaluated separately, using cancer-specific mortality as a more realistic and clinically relevant end point. With these criteria, radical cystectomy achieves an absolute difference in overall survival of 10% in favor of the CMV neoadjuvant arm, with a 26% reduction in the risk of death (p = 0.002). The real difference in terms of cancer-specific survival is reduced to 3%, or to 1.4% when the cohort of neoadjuvant radiotherapy is added. These differences are unlikely to be statistically significant (data not mentioned in the article) and translate to an NNT ranging from 33 to 71. They raise concerns about the real benefit and the clinical relevance of neoadjuvant chemotherapy prior to radical cystectomy.

Third, in the case of radiotherapy, the absolute difference in terms of overall survival is reported as 6.4% in favor of the neoadjuvant cohort, representing a 20% reduction in the risk of death (p = 0.07). However, subset analysis of this cohort demonstrates a 7.1% difference in terms of cancer-specific mortality, which is likely to be statistically significant (although not mentioned in the article) and represents an NNT of 14. These findings suggest a potential clinical benefit of neoadjuvant chemotherapy prior to radiotherapy and, perhaps, a new standard of practice for patients opting for radiotherapy as local definitive therapy.

Fourth, would neoadjuvant chemotherapy be beneficial for all patients? The published analysis of the different subgroups would suggest that CMV is equally effective in all subgroups of patients in terms of overall survival, but a detailed description of the subgroups is not provided for further analysis. In contrast, the Southwest Oncology Group trial [2] reported a real benefit only in those patients reaching pT0 at the time of cystectomy—with transurethral resection of bladder tumor or with a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)—representing a net survival benefit for only 23% of patients receiving neoadjuvant chemotherapy. In other words, 77% of patients receiving neoadjuvant chemotherapy potentially would be exposed to delays, toxicity, and mortality from chemotherapy without any added clinical benefit. These figures raise further concerns about the routine use of adjuvant chemotherapy. Moreover, we do not know which patients are chemoresponders. Future biomolecular markers may improve our knowledge and help us to select those who respond to chemotherapy, optimizing indications, to achieve satisfactory clinical relevance.

Finally, we should not forget that although the combination of cisplatin plus gemcitabine has less toxicity than CMV or MVAC, its efficacy remains to be proven in the neoadjuvant setting [3].

In summary, although the survival benefit observed in patients with MIBC treated with neoadjuvant chemotherapy is good news and is welcomed by the uro-oncology community, the clinical relevance of this improvement still remains controversial for standard of care.

Conflicts of interest

The author has nothing to disclose.