The management of invasive bladder cancer represents a challenge for medical and urologic oncologists. The unique bladder anatomy and the biologic characteristics of bladder cancer have permitted investigators to develop postoperative adjuvant therapy as well as preoperative neoadjuvant therapy. Additionally, bladder cancer poses a significant economic burden to the US health-care system in view of the frequent surveillance procedures required and the often long natural history of superficial bladder tumors. In view of these issues, the article by Sonpavde and Lerner is timely, discussing in detail the rationale and evidence for use of various types of therapy in patients with bladder cancer.
Chemotherapy for Bladder Cancer
In the 1980s it became clear that advanced urothelial cancers were sensitive to a variety of chemotherapeutic agents, and that cisplatin combinations such as MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) were associated with the best outcomes. A series of randomized trials were then conducted to determine which single agent or regimen was superior. Sonpavde et al clearly discuss the regimens investigated, and those now considered as standards of care: MVAC, dose-dense-MVAC, and GC (gemcitabine [Gemzar]/cisplatin). The use of these approaches in patients with earlier-stage disease but at significant risk for recurrence was the next logical step.
Table 1 lists the varied options considered as adjunctive therapy in this patient population. These approaches involve multimodality care utilizing both local and systemic therapy. The rationale behind the use of neoadjuvant therapy prior to either surgery or radiation is to target micrometastatic disease that may be present at the time of diagnosis. Neoadjuvant chemotherapy is intended for patients with operable clinical stage T2–T4a muscle-invasive disease. As has been adequately described in the review, neoadjuvant therapy holds several benefits. It allows assessment of tumor response, and complete pathologic response may be used as a surrogate marker for overall survival.
Chemotherapy is better tolerated prior to cystectomy or radiation therapy, and delay due to postoperative morbidity is avoided. The dose of cisplatin—one of the most active agents in bladder cancer—may be affected if the cystectomy results in urinary diversion and compromised renal function. Additionally, drug delivery may be theoretically enhanced as a result of an intact vascular bed. Downstaging with neoadjuvant therapy may allow for better surgical resection and, in some cases, bladder preservation.
Administration of neoadjuvant therapy doesn't seem to increase perioperative morbidity, but there is a risk of overtreating patients. The frequency of clinical staging errors was found to be as high as 38% in a pilot study comparing clinical and pathologic staging. Also, it is important to realize that chemotherapy may delay a potentially curative cystectomy for patients whose tumors were biologically destined to fail chemotherapy.
The review describes the various neoadjuvant trials. The latest is the Southwest Oncology Group (SWOG) Intergroup trial, which showed a trend toward improved survival in the MVAC-treated arm. The meta-analysis reported in 2003 demonstrated a 5% reduction in death rate at 5 years, with 5-year survival improving from 45% to 50% with platinum-based therapy. This analysis included patients mostly from the European Organisation for Research and Treatment of Canacer (EORTC)/Medical Research Council (MRC) trial, and hence, the results were comparable to that trial.
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