This is a renewal application to our on-going """"""""p53/MVAC"""""""" study. Tumor progression in transitional cell carcinoma (TCC) of the urinary bladder is believed to occur through a multistep accumulation of genetic alterations. p53 alterations are involved in the transformation of normal urothelium to carcinoma-in-situ of the bladder and in the progression to invasive disease. We have shown that (1) adjuvant chemotherapy prolongs the recurrence free interval in a group of patients with invasive TCC at high risk for recurrence and that (2) detection of p53 alterations in a bladder tumor is significantly associated with an increased chance of progression in patients with organ-confined TCC managed by radical cystectomy. Our hypothesis is that p53 alterations organ-confined TCC of the bladder significantly increase the risk of recurrence and death, and that adjuvant chemotherapy will improve survival in these high risk patients. To test this we have designed a study that will enroll patients who have already undergone a radical cystectomy with a pathologic stage of P1, P2a/b N0 M0. Patients with TCC demonstrating p53 alterations (p53+) who are willing to be randomized will be assigned either to no further treatment, i.e. observation which is the standard of care for patients with organ-confined disease, or to 3 cycles of MVAC chemotherapy. Those who are p53+ and decline randomization, and those who are p53- (no alteration in p53), will be observed.
The specific aims of this prospective study are to (I) compare the recurrence free interval and overall survival of p53+ patients who are treated with MVAC to p53+ patients who are observed, (II) compare the recurrence free and overall survival of p53+ patients who are observed to p53- patients who are also observed, (III) study the expression of other genes involved in cell cycle regulation that may be involved in the response to chemotherapy, (IV) examine the association of p53 mutational gene status with p53 protein expression, outcome, and response to chemotherapy. This is a new aim to this renewal application. To date over 30 academic institutions in the United States, Canada and Europe participate in this prospective study. The study was activated at the Southwest Oncology Group (SWOG) in 2001 and we are making a substantial effort to attract other Canadian and European institutions to this study. As of May 2002, 281 patients have been registered to the study and 58 p53+ patients have been randomized to MVAC or observation, making this one of the largest adjuvant trials in bladder cancer. The infrastructure to support this study is firmly established including 1) Full compatibility of data management with SWOG. (2) Completion of the interim audit by July 2002. (3) Fourth Annual meeting of the Data Safety Monitoring Committee planned for August 2002. (4) Institution of the patient advocacy program, the first for bladder cancer. (5) The 5th annual investigator's meeting took place May 2002. With the participation of new institutions and with patient accrual and randomization increasing, we expect to complete accrual by 2006 (approximately 33-35 patients randomized per year). This is the first study in bladder cancer in which therapeutic decisions are made based on the status of a molecular alteration. The results of this studio could fundamentally change the management of bladder cancer. ? ?
Showing the most recent 10 out of 18 publications
