Second-Line Chemotherapy for Advanced Urothelial Cancer: Because We Should or Because We Can?

We are more than two decades removed from the heady days of the mid-1980s when hope that the unprecedented activity seen in advanced testes cancer by the cisplatin, vinblastine, and bleomycin regimen would be mirrored in advanced urothelial cancer by the novel cisplatin-based regimens, including both the methotrexate, vinblastine, doxorubicin, and cisplatin regimen and the cisplatin, methotrexate, and vinblastine regimen. The initial reports of these regimens in patients with advanced urothelial cancers provided evidence of impressive objective response rates, and many clinicians noted that therapy seemed to alter the natural history of the disease; occasional patients were now living long enough to develop brain metastases, a striking finding in a disease that typically led to rapid patient demise. Ultimately, phase III trials defined the utility of these combination regimens, which can be summarized as demonstrating relatively high objective response rates with little impact on overall survival, although a small subset of patients could be cured. The next 20 years saw evaluation of one novel cytotoxic regimen after another, ultimately highlighting a clinical picture that increasingly resembled the smallcell lung cancer paradigm. Because level I evidence demonstrated the utility of cisplatin-based chemotherapy in the metastatic setting, the subsequent evaluation of newer generations of cytotoxics was conducted in the salvage setting. Unfortunately, we can characterize the results of 20 years worth of phase II studies of cytotoxics (single agents or combinations) in the salvage setting as demonstrating objective response rates with overlapping CIs with no evidence that combination chemotherapy is better than single agents or that any therapy improves survival or quality of life. In this issue of Journal of Clinical Oncology, Bellmunt et al present the first randomized study of chemotherapy administered in the second-line setting for patients with metastatic urothelial cancer with progressive disease after first-line platinum-based chemotherapy (patients receiving prior perioperative therapy were excluded). Threehundred seventy patients were randomly assigned 2:1 to receive either vinflunine plus best supportive care (BSC) or BSC alone. Interestingly, random assignment was stratified by study site and refractoriness to previous platinum treatment but not by performance status, a factor of significant importance in the untreated metastatic setting. The authors report a statistically nonsignificant (P .287) median 2-month survival advantage favoring the vinflunine BSC arm versus the BSC alone arm (6.9 v 4.6 months, respectively), with a 12% reduction in the risk of death (hazard ratio 0.88; 95% CI, 0.69 to 1.12). Secondary end points, which included objective response rate, disease control rate, and progression-free survival, were significantly improved in the vinflunine BSC arm. Therapy was relatively well tolerated, and although grade 3 to 4 neutropenia was seen in approximately half of the vinflunine-treated patients, febrile neutropenia was seen in only 6%. Quality-of-life assessments were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, and treatment with vinflunine did not lead to a decrease in health-related quality of life when compared with BSC alone. The authors, other investigators, and, most of all, the patients who participated need to be congratulated and commended for completing the first and relatively large (by urothelial cancer standards) randomized trial in the second-line setting. Completion of phase III trials in urothelial cancer (especially in the United States) have become increasingly difficult, and for a variety of reasons, this multicenter study was conducted primarily in Europe. A similar trial design in the United States would have had great difficulty in accrual given the routine use of chemotherapy in this setting. Although this was a randomized trial comparing chemotherapy to BSC, it is interesting to note that 34% of the patients in the BSC alone arm ultimately received chemotherapy, with 29% of patients in the chemotherapy arm receiving third-line therapy. Several overarching questions arise from the results of this phase III trial. Do the results of this phase III trial establish the role of second-line therapy? If so, is the use of vinflunine now a standard of care in this setting? Finally, if second-line therapy is now a standard of care, is the next natural step additional phase III trials comparing other agents/combinations to vinflunine? I believe the answer to all three questions is no. In the intent-to-treat analysis, the 2-month improvement in median survival time did not reach the prespecified criteria for significance. The authors conducted a subsequent analysis including only eligible patients that did meet statistical significance for survival; the authors argue that this group represents an appropriate comparison group because the reasons for exclusion were not overtly related to treatment. This may, in fact, be reasonable; however, this assumes that eligibility was reviewed and acted on with equal rigor in both treatment arms and without knowledge of the patient outcomes. In addition, the investigators conducted a multivariable analysis that (although lacking in some detail) was based on the intent-to-treat population and demonstrated a superiority for the vinflunine arm. From the perspective of the practicing clinician, it is reasonable to ask whether the results of this clinical trial will alter our current management paradigm. Despite the lack of demonstrable progress in JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 27 SEPTEMBER 2