With the recent paradigm-shifting developments in the management of advanced renal cell carcinoma, advanced bladder (urothelial) cancer is now officially the most depressing genitourinary neoplasm. The heady days of the mid‒1980s saw impressive and, in some cases, natural history-altering responses to cisplatin-based combination chemotherapy.1 Unfortunately, the management of advanced bladder cancer has evolved over the past 20 years into a small cell lung cancer paradigm, in which a host of cytotoxic agents provide relatively high objective response rates, with only a small subset of patients cured and limited utility of “salvage” therapy. In this issue of Cancer, Gallagher et al provide a perspective on the initial systemic management options for patients with metastatic bladder cancer and an overview of the status of second-line therapy.2
Urologic and medical oncologists have long expressed the opinion that bladder cancer presents an intriguing and perhaps unique neoplasm in which to conduct clinical research. In 2008, it is estimated that there will be nearly 69,000 patients diagnosed with bladder cancer (superficial plus advanced disease), with more than 14,000 deaths (essentially all from advanced disease).3 In patients with superficial and locally advanced disease, multiple assessments (cystoscopy) with acquisition of tumor (for both pathologic assessment and translational science) are possible, and are in fact the standard of care in the management of superficial disease. In the current era of “targeted” therapies, bladder cancer is known to be influenced by a variety of molecular pathways that are amenable to treatment with current agents, including overexpression of epidermal growth factor receptor and vascular endothelial growth factor.4 In contrast to prostate cancer patients, standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria remain useful (at least in trials of cytotoxic agents) in the majority of patients with advanced urothelial cancer. To contrast the former with the stark reality of current therapeutics, the last 2 agents to gain US Food and Drug Administration (FDA) approval for use in superficial bladder cancer (bacillus Calmette–Guerin and valrubicin) were introduced a decade ago. The situation for patients with advanced disease is even more distressing; cisplatin as a single agent was approved by the FDA in 1993.
Gallagher et al touch briefly on the challenges of conducting clinical research in patients with advanced urothelial cancer.2 In the first decade after the introduction of cisplatin-based combination chemotherapy, the cooperative groups and other US academic centers successfully developed and completed phase 3 trials in patients with advanced urothelial cancer. Studies comparing the methotrextate, vinblastine, doxorubicin, and cisplatin (M-VAC) regimen with cisplatin and M-VAC versus cisplatin, cyclophosphamide, and doxorubicin combinations culminated in establishing M-VAC as the standard of care.5, 6 The Southwest Oncology Group completed a phase 3 trial of neoadjuvant M-VAC followed by cystectomy versus cystectomy alone and demonstrated the survival benefit of chemotherapy in this clinical setting.7
The second decade of the cisplatin era in urothelial cancer saw a rather dramatic shift in the phase 3 environment, with successful studies driven by European investigators and major accrual challenges for US cooperative groups trials. Von der Maase et al compared the M-VAC regimen with the combination of gemcitabine and cisplatin (GC), leading to broad acceptance of the GC regimen as a standard of care.8 Investigators from the Hellenic Cooperative Group compared the combination of docetaxel and cisplatin with M-VAC; 2 additional phase 3 trials have been completed by the European Organization for Research and Treatment of Cancer, 1 of which compared high-dose M-VAC with conventional‒dose M-VAC and, most recently, a study comparing the combination of paclitaxel, cisplatin, and gemcitabine with GC.9-11 In contrast to the European experience, in the US, 2 Eastern Cooperative Oncology Group (ECOG) phase 3 trials compared M-VAC versus the combination of carboplatin and paclitaxel (1 in the metastatic setting and 1 in the adjuvant setting), and a Cancer and Leukemia Group B adjuvant phase 3 chemotherapy trial was closed prematurely because of a lack of accrual.12
Approximately 2% of adult cancer patients in the US are enrolled in clinical trials on an annual basis, and although there are few data to evaluate, there is no reason a priori to believe that patients with urothelial cancer have intrinsic differences (eg, lack of interest in research, distance from trial centers, unwillingness to be randomized if a phase 3 trial is offered) from other patients with a variety of neoplasms that would preclude trial participation. A common theme that cuts across many solid tumors is the dissemination of clinical experience into the medical community. An example is the management of the “unfit” patient with advanced urothelial cancer. Conventional chemotherapy regimens such as GC or M-VAC have long been administered by community medical oncologists; however, given the average age and comorbidities of many patients with advanced urothelial cancer, there was a widely appreciated need to develop noncisplatin-based therapies. In the mid‒1990s, ECOG investigators conducted a phase 2 trial of paclitaxel and carboplatin in patients with advanced urothelial cancer and renal dysfunction. This trial enrolled 42 patients over a 3-year period and demonstrated the modest clinical activity and relative safety of this doublet in this patient group.13 However, a follow-up ECOG phase 2 trial in the same patient population evaluating the combination of carboplatin and gemcitabine was closed (in 2003) secondary to poor accrual.
However, there are some unique issues facing patients and physicians in the context of clinical trials and the clinical management of advanced urothelial cancer. Although not a rare disease, advanced urothelial cancer represents a relatively small component of most community medical oncology practice. Given the rapidly expanding knowledge base and therapeutic advances in the more common epithelial cancers (eg, those of the breast, colon, and lung), and the associated clinical trials available either in community clinical oncology programs or via the National Cancer Institute–funded Clinical Trials Support Unit, it would not be a stretch to suggest that the ongoing trials in advanced urothelial cancer might not be on the top of the list. Attempts to study more novel approaches are tempered by the concern that altering the current therapy paradigm (ie, cisplatin-based combination therapy) might negatively impact on potentially curative therapy for a small subset of patients. In addition, given the pressure that all centers face, irrespective of size, regarding the costs associated with opening and maintaining clinical trials, disease sites less likely to accrue patients are increasingly less likely to be opened. It is the latter point that most likely represents the greatest challenge to clinical trial accrual in the current environment.
Gallagher et al provide a snapshot of the current status of systemic management options in the second-line setting.2 Unfortunately, this entire area can be summarized as follows: 1) there are many single agents (cytotoxics) with objective response rates demonstrated in phase 2 trials with overlapping confidence intervals; and 2) to my knowledge there is no evidence that combination chemotherapy is either “better” than single agents, or that any therapy improves survival and/or quality of life.
However, there is hope. Urologic oncologists need only remind themselves of the therapy paradigm for advanced renal cell carcinoma that existed just a few years ago to believe that progress is possible. The review by Gallagher et al covers the current status of moving “targeted” agents into the urothelial phase 2 setting. Although the evaluation of novel agents in combination with chemotherapy in the initial management of patients with advanced urothelial cancer will still need overall survival endpoints, lessons learned from the renal cell cancer experience suggest that study endpoints for noncytotoxic agents in the second-line setting will need to move from objective response to progression-free survival (PFS) to lessen the chance of missing clinical activity.14 Novel trial designs, such as the University of Michigan–led randomized phase 2 trial discussed by the authors, are just 1 example of new approaches that will be required to facilitate drug development in patients with urothelial cancer. The second-line setting remains a viable setting in which to study novel agents, although as noted earlier, some of these agents (or combinations) will require PFS endpoints, the potential to have a “renal cancer-like sunitinib moment” ie, the recognition of striking antitumor activity in a salvage setting) could also lead to the rapid movement of new agents into early‒stage clinical trials.
For more than the last 20 years, we have essentially squeezed out the maximum benefit from conventional cytotoxics in the management of advanced urothelial cancer. Going forward, the urologic oncology community will need to be more creative regarding the design of clinical trials, and we need to rededicate ourselves to improving clinical trial accrual. It is past time to move on.