) Bladder cancer will account for about 5 4 , 5 0 0 new cancer cases and 11,700 deaths in the U.S. in 1997. C h emoprevention to counter the field defect, genetic instability and p r e rnalignant molecular and cellular changes associated with bladder carcinogenesis offers may be effective in reducing the substantial risk of morbidity and mortality from this disease. We propose a phase III clinical trial of fenretinide (4-HPR), to be of intermediate duration (15 months) and size (160 evaluable patients), in preventing superficial bladder tumors (after complete resection) and five correlative laboratory studies. This proposed study may validate between one and five currently promising surrogate endpoint biomarkers (SEBS) for chemoprevention of bladder cancer. Patient eligibility includes superficial (Ta) primary or recurrent (>1 year after primary) bladder tumors not requiring intraves'cal therapy. The five correlative studies are designed to validate the following potential SEBs: apoptosis; retinoid acid receptors; DNA ploidy; numerical abnormalities of chromosomes 4 and 9; and autocrine motility factor receptor. All five markers have been proven to be modulatable in vitro and/or in vivo. A sixth laboratory study will evaluate whether eight other retinamides induce apoptois more effectively than 4-HPR in vitro in bladder cancer cell lines. Hypotheses regarding 4-HPR's effects on these markers will be tested through statistical modeling of marker expression, modulation and clinical outcome. Bladder carcinogenesis is an excellent model for chemopreventive study. Eligible patients will have tumors that require no local or systemic treatment post-resection; are easily monitored and are associated with a very high rate of second primary tumors (SPTs) post-resection. Multifocal carcinogenesis within the bladder mucosa results in development of primary and second primary bladder tumors. 4 - HPR, the most promising chemopreventive retinoid, has an excellent activity:toxicity ratio and strong apoptosis-induction activity in the bladder. The latter can eliminate premalignant clones and so shorten chemoprevention characteristic of other active retinoids. The high incidence of bladder SPTs in these patients provides the opportunity to validate p o t e ntial SEBs against potential cancer-incidence reduction in this intermediate-size and -duration trial. SEB validation is crucial to reduce the size, duration and cost presently required for phase III definitive chemoprevention trials.
