Effect of Reducing Radiotherapy Volume on Bladder Toxicity: First Report of the BC2001 Trial; A Multicenter Phase III Randomized Trial of Standard versus Reduced Volume Radiotherapy Trial Iscrtn No. 68324339, Eudract No. 2004-000164-26

Abstract

Radiotherapy has been used as an alternative to radical cystectomy for the management of muscle-invasive bladder cancer. Limitations to its use are (1) the probability of attaining and maintaining local tumor control and (2) the risk of late bladder toxicity. The BC2001 trial addresses whether the use of concomitant chemotherapy improves locoregional control and whether radiotherapy volume modification reduces late toxicity without detriment to tumor control. This is the first report of this trial focusing on the radiotherapy volume randomization. The BC2001 was a randomized Phase III trial using a 2 x 2 design. Patients were randomized to one or both of two randomizations. The first randomization was to radiotherapy alone or radiotherapy with 5Fluoruracil (500 mg/m2 daily for 5 days as continuous infusion Weeks 1 and 4) and mitomycin C Day 1 of radiotherapy only. The second randomization was to radiotherapy to the tumor and whole bladder (sRT) with 1.5 cm margin vs. a reduced volume treatment (rvRT). In rvRT, the tumor +1.5 cm margin was treated to 100 +/− 5% target dose whilst the remaining bladder received 80% of the target dose delivered either by a 2 phase approach or a concomitant boost technique. Patients were CT planned on an empty bladder using 3 or 4 fields. Conformal fields were allowed but not mandated. Patients received either 55 Gy in 20f or 64 Gy in 32f. The primary endpoint for radiotherapy was late toxicity at 1 year as assessed by RTOG scores. The trial was designed to recruit 480 patients to have 86% power to detect a 15% reduction in RTOG Grade 3-4 toxicity from 40% to 25%. The trial was closed before full accrual due to slow recruitment in September 2006. Then, 212 patients had been recruited giving an estimated power of 73% a 2-sided alpha of 5% to detect an improvement in RTOG grade toxicity from 40% to 20%. Analysis will be by ITT. A total of 220 patients had been recruited into the stRT vs. rvRT comparison, 109 patients to sRT, and 111 to rvRT with 64 patients randomized to receive chemo-RT. The median age was 73 years, 80% were male, WHO performance status (0) 57%, (1) 37%, and (2) 6%. Preliminary analysis show that in the rvRT arm around 72% patients received two-phase treatment, 26% by concomitant boost, and 2% patients receiving sRT (protocol deviation). The median follow-up is currently over 2 years. The CTC Grade 3/4 acute toxicity was reported in 20% of stRT patients (n = 105) and 25% of rvRT patients (n = 106). The RTOG Grade 3/4 late GU toxicity was reported in 26/89 patients (with evaluable data) (13 stRT, 13 rvRt) and late GI toxicity in 8/53 patients (5 stRT, 3 rvRT). Full analysis of the randomized results will be undertaken in May 2008 and presented at the ASTRO meeting.