Advances in the treatment of urothelial tract tumors.

Recently developed combination chemotherapy programs have now produced durable complete remissions in a significant percentage of patients with advanced urothelial tract malignancies. For advanced disease, efforts must still be directed at developing new agents but must also focus on understanding drug resistance. Some tumors appear to be resistant de novo; others respond for a period of time before a resistant population emerges. Clearly multiple factors come into play. In some cases, pharmacologic factors such as bioavailability metabolism, or toxicities predominate. In other cases, specific genes expressing surface proteins such as the p-glycoprotein identified in resistant ovarian tumors have been implicated. In the 1980s, it is no longer adequate to define tumors simply by pathologic inspection. As demonstrated by Russell and co-workers xenografts of phenotypically similar transitional cell tumors in nude mice demonstrated marked heterogeneity with respect to flow cytometric DNA analysis and immunocytochemistry. With the recent adoption of flow cytometric techniques, both from bladder washings and paraffin sections, insight into the biologic behavior of individual tumors may soon be possible. Blood group antigen expression and monoclonal antibodies to tumor-associated antigens may also help in this regard. For primary tumors, attention is now being focused on protocols aimed at bladder preservation. In some cases, radiation therapy alone can produce long-term survival, despite muscle infiltrating disease. Complete remissions have also been described with chemotherapy alone. The interaction of chemotherapy and radiation therapy has only recently begun to be investigated. In these trials, complete local control must still be the primary goal. Standard criteria for staging and response evaluation, including pathologic documentation of remission status, are crucial. To demonstrate a beneficial effect of therapy, long-term randomized trials will be required. The goal of individualized therapies may soon be possible, which will ideally translate into increased clinical benefit for patients with urothelial tract tumors.