Neoadjuvant versus adjuvant chemotherapy in invasive bladder cancer

In a disease where the majority of deaths occur from metastases, improvement in survival requires the integration of systemic therapies. Research efforts must continue to focus on improving case selection criteria, improving complete response proportions, and overcoming drug resistance. Recommending a single treatment plan such as radical surgery, chemotherapy, or radiation therapy for all patients with an invasive bladder cancer is rapidly becoming outdated. Case selection is being refined by focusing on both clinical and pathologic features of the tumor. The latter include evaluation of NM23 RNA levels, or DNA ploidy and T138 surface antigen expression, which have been shown to correlate with metastatic potential. The use of hematopoietic growth factors has the potential to improve both the tolerance of chemotherapy and complete response proportions, a prerequisite for cure. However, the dose response curves for most of the known active agents are not well defined, and ultimately, new agents and strategies will be required. Drug resistance is a major barrier, but as the mechanisms are unravelled, more selective therapies can be designed. For example, resistance to adriamycin and vinblastine, two of the agents in the M-VAC regimen are mediated in part by the mdr1 gene. Ongoing studies are attempting to identify prospectively those tumors with high levels of expression which may be more amenable to treatment with drugs that do not act through this mechanism. The main advantages of the neoadjuvant approach are the ability to perform an in vivo response evaluation and the potential for bladder preservation. In most cases additional therapy for the primary tumor is required as clinical understaging is a significant problem. For some patients, initial surgery with the definition of the prognosis on firm pathologic grounds may represent a better strategy. When this is the case, the recommendation for adjuvant treatment potentially limits therapy to a more restricted population of patients for whom therapy is essential, including, for example, patients with positive lymph nodes at the time of surgery. Ideally, these patients should be entered on clinical trials designed to assess the impact of these strategies survival. Only large scale randomized trials have the potential to minimize the heterogeneity of this patient population.