Development of chemopreventive agents for bladder cancer

Abstract

The term cancer chemoprevention refers to the prevention or prolongation of carcinogenesis by intervention with drugs prior to the malignant (i.e., invasive) stage. The development of chemopreventive drugs is the major objective of the Chemoprevention Branch of the National Cancer Institute. Neoplastic lesions of the urinary bladder present a unique opportunity for evaluating chemopreventive agents because of (1) the accessibility of the lesions to observation and biopsy, and (2) those patients who have been successfully treated for a primary lesion represent a population at unusually high risk for recurrence and/or progression. Although 70-80% of bladder cancers initially present as superficial, papillary transitional cell neoplasms with limited potential for invasion, the incidence of recurrence is high after resection (60-75%). Recurrent tumors are highly unpredictable, and may be of higher grade or stage (progression). Although recurrence is responsible for high treatment-related morbidity, progression represents the greatest potential for mortality. Thus, potential chemopreventive agents considered here would modulate bladder carcinogenesis from initiation of normal-appearing tissue through progression of superficial tumors. Clinical trials of chemopreventive drugs involve healthy target populations, and the endpoints are reduced cancer incidence or mortality, reduced/eliminated precancerous lesions or increased latency, with none to minimal toxicity. Since cancers may not appear for 20-30 years, two of the most difficult aspects of testing these drugs in intervention trials are the long observation periods and large study populations required to measure cancer incidence reduction. However, observing the regression or recurrence of superficial bladder lesions (TIS, T1, Ta) requires relatively short time periods. Thus, these lesions lend themselves to the investigation of intermediate biomarkers, defined as morphologic and/or molecular alterations in tissue between initiation and tumor invasion. It is hypothesized that modulation of one or more biomarkers would interrupt carcinogenesis and result in a decrease in cancer incidence. Thus, evaluation of biomarkers as surrogate endpoints would allow bladder trials to be of even shorter duration, use fewer subjects and be lower in cost. In addition, intermediate biomarkers could predict which superficial lesions (or normal-appearing tissue) have the greatest potential for neoplastic progression. Development of strategies for the design of intervention trials for bladder cancer and review of the current status of intermediate biomarkers in the bladder, and methods for their validation, are major objectives of this workshop.