Invasive bladder cancer is a common and dangerous disease that is becoming only more prevalent as the population ages. Radical surgical therapy with curative intent has been and continues to be a mainstay in the management of this condition; however, approximately half of clinically localized cases go on to develop distant metastases postoperatively.1 Platinum-based combination chemotherapy (methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC]) emerged more than 20 years ago in studies pioneered by Dr. Alan Yagoda and associates at Memorial Sloan-Kettering as the first effective systemic therapy for metastatic urothelial carcinoma.2 Despite this major advance, as well as concomitant improvements in surgical and perioperative care, bladder cancer mortality rates have not seen a dramatic improvement in recent years. A review of survival outcomes of contemporary versus historical cystectomy series (before and after 1985) stratified by pathologic stage revealed only modest improvements in survival in the modern era, with 5-year survival rates of 60% versus 67% for pT2, 33% versus 35% for pT3, and 21% versus 27% for pT4.3 The casual observer could be forgiven for a less than sanguine view of the state of the art in this setting; in 2008, there is clear room for improvement in the outcomes of patients with high-risk, muscle-invasive bladder cancer.
The observation of responses in the primary tumor among patients with metastatic disease led to the evaluation of MVAC given before cystectomy for muscle-invasive bladder cancer. A body of literature has emerged over the past 2 decades supporting neoadjuvant platinum-based chemotherapy followed by radical cystectomy as a particularly promising strategy to improve patient outcomes. A recent meta-analysis of over 3000 patients, representing 98% of all patients in relevant randomized controlled trials, demonstrated a significant benefit associated with neoadjuvant cisplatin-based chemotherapy, equivalent to a 5% improvement in overall survival, a 14% decrease in disease-specific mortality, and a 9% improvement in disease-specific survival at 5 years.4 The argument for neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer stands out in the field of urologic oncology as 1 of the few supported by level 1 evidence.
A neoadjuvant approach has several theoretical advantages that have been borne out by the experience of clinical trials, recently summarized in the cogent review by Herr et al.5 These include higher rates of effective dose delivery earlier in the natural history of disease than are achieved with the adjuvant approach. Another important observation with neoadjuvant chemotherapy in this setting has been an appreciation of the importance of pathological downstaging of disease, which has utility not only in the sense that it facilitates more effective extirpative therapy but also as an independent prognostic factor. Downstaging (both to pT0 and to <pT2) clearly defines the subgroup of patients whose subsequent outcomes in turn define the benefit associated with this strategy.
The extant literature evaluating neoadjuvant chemotherapy in bladder cancer relies on the outcomes of patients receiving MVAC, an effective albeit toxic regimen. In the setting of metastatic disease, the cisplatin and gemcitabine doublet (GC) has been shown to have comparable efficacy to MVAC in terms of response and long-term survival, but with substantially less toxicity.6, 7 The study by Dash and colleagues8 in this issue of Cancer, the latest in a long series of important contributions from the genitourinary oncology group at Memorial Sloan-Kettering, represents the first comprehensive report of outcomes after neoadjuvant chemotherapy with GC in this setting. Notwithstanding the duly acknowledged inherent limitations of the comparison to historical controls from the same institution receiving neoadjuvant MVAC, the authors report complete (pT0) and partial (<pT2) response rates with GC that are quite encouraging and associated with disease-free survival in responding patients comparable to those seen with MVAC. The neoadjuvant GC regimen was generally well tolerated, supporting the conjecture that the balance of toxicity and efficacy favoring GC over MVAC in the setting of metastatic disease might be translated to the neoadjuvant setting. In addition, the authors report excellent dose intensity with a 21-day schedule for GC as compared with the original 28-day GC schedule as well as previously reported doses for MVAC, providing important practical food for thought for practitioners. Until such time as there are data from prospective randomized trials directly comparing neoadjuvant GC to neoadjuvant MVAC, the data presented in this study provide strong support for the consideration of neoadjuvant GC as an effective and well-tolerated component in the armamentarium against high-risk bladder cancer.
Despite the body of evidence supporting a multimodal approach to high-risk, invasive bladder cancer with neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymphadenectomy, patterns of care suggest that substantial barriers exist within the urologic oncology community to the widespread adoption of this strategy. Data from over 11,000 patients from 1998 to 2003 with stage III bladder cancer in the National Cancer Database showed that only 0.7% received neoadjuvant chemotherapy.9 We can only speculate at the reasons underlying the impressively low penetration of multimodal therapy in practice, but it would seem that the ascertainment of approaches and strategies to address and reduce these obstacles might provide major opportunities for improvement in patient outcomes. Concerns over delay in the delivery of surgical therapy and/or the relative toxicity of MVAC, the neoadjuvant regimen supported by level 1 evidence, are commonly cited as arguments against widespread utilization of this strategy. Hopefully the results presented in this study may support the perception of GC as a reasonable and effective alternative deliverable on an efficient dose schedule, and thereby embolden more urologists and oncologists to consider this option for their patients.
Another potential barrier to the broader adoption of neoadjuvant chemotherapy in a multimodal approach to high-risk bladder cancer can be conceptualized as a concern over the burden of overtreatment. Stated simply, the modest—albeit statistically significant and consistent—benefit associated with neoadjuvant chemotherapy may be perceived by urologists to be of insufficient magnitude to justify subjecting all eligible patients with muscle-invasive bladder cancer to systemic chemotherapy. One could argue for surgical pathological staging as a means of more precisely selecting the patients at highest risk of occult micrometastatic disease and thereby guiding postoperative adjuvant chemotherapy. As Herr et al summarize, however, the complicated nature of this patient population coupled with the often somewhat rocky recovery from cystectomy appear to be associated with suboptimal dose delivery in this setting, as compared with that achievable with neoadjuvant schedules.5
Tools to individualize treatment to drug targets, transporters, and metabolizing enzymes—beyond the simple taxonomy of organ site—might represent another powerful means of improving the acceptance of systemic therapy and by extension, the outcomes of our patients. A body of experience accumulating from multiple disease sites suggests that molecular profiling may provide the means to more precisely identify the subgroup of patients likely to have a therapeutically meaningful response to a given chemotherapy regimen.10 In a study of patients with advanced and metastatic urothelial carcinoma, Bellmunt et al found an inverse association between mRNA levels of excision repair cross complementing 1 (ERCC1) and survival after treatment with GC,11 analogous to observed associations with survival and response to GC in the setting of nonsmall cell lung cancer.12–14 Further prospective study is needed to ascertain the extent to which ERCC1 or other markers might be practical and useful as tools to individualize the risk-adjusted delivery of systemic therapy to the subpopulation of patients with urothelial carcinoma most likely to benefit.
Finally, despite the promising and consistent improvements associated with the addition of neoadjuvant platinum-based chemotherapy to radical cystectomy, a glance at the survival curves in any of these studies reminds us that there remains a substantial cohort of patients whose disease is not controllable with the tools readily at hand in 2008. In a predominantly elderly patient population with a high prevalence of renal dysfunction and poor performance status frequently precluding cisplatin-based combination chemotherapy, the survival curves from these studies likely underestimate the true burden of mortality from muscle-invasive bladder cancer. A recent excellent review by Sonpavde and colleagues catalogues the variety of novel agents and combinations in development in this area of need.15 The proliferation in recent years of small molecule tyrosine kinase inhibitors and monoclonal antibodies targeting specific nodes in cancer signaling pathways has shown promise of significant advances in other solid tumor sites. The neoadjuvant paradigm may represent the ideal setting for accelerated development of new treatment strategies in urothelial carcinoma, given the rich opportunities for correlative science to evaluate surrogate endpoints of efficacy inherent to this approach. An open multidisciplinary dialogue between the urologists and medical oncologists caring for these patients, exemplified by the contributions of the authors of the current study, will hopefully pave the way for continued advances in the armamentarium of treatment options for patients with this common and too often deadly disease.