Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: results of the BC2001 trial (CRUK/01/004)

Abstract

Purpose: To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer.

Methods and materials: In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years).

Results: Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT - sRT) was 6.4% (95% confidence interval -7.3%, 16.8%) under an intention to treat analysis and 2.6% (-12.8%, 14.6%) in the "per-protocol" population.

Conclusions: In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.

Fig. 1

Patient flow through the trial. RHDVRT = reduced high-dose volume radiation therapy; sRT = standard whole-bladder radiation therapy.

Fig. 2

Kaplan-Meier plot of time to first grade 3/4 toxicity using (a) Radiation Therapy Oncology Group and (b) Late Effects of Normal Tissue (Subjective, Objective, Management) toxicity gradings.

Fig. 3

Percentage of patients reporting late toxicity, by month and grade. GI = gastrointestinal; GU = genitourinary; LENT/SOM = Late Effects of Normal Tissue (Subjective, Objective, Management); RHDVRT = reduced high-dose volume radiation therapy; RTOG = Radiation Therapy Oncology Group; stRT = standard whole-bladder radiation therapy.

Fig. 4

(a) 2Kaplan-Meier plot of time to locoregional recurrence. Cox model estimated absolute difference in locoregional recurrence-free rate (95% confidence interval) at 2 years: 6.4% (−7.3%, 16.8%). First locoregional recurrence (standard whole-bladder radiation therapy [sRT] vs reduced high-dose volume radiation therapy [RHDVRT]) was noninvasive for 21 (19.4%) vs 18 (16.2%), invasive for 15 (13.9%) vs 11 (9.9%), in the pelvic nodes for 5 (4.6%) vs 5 (4.5%), and unknown for one RHDVRT patient. (b) Kaplan-Meier plot of overall survival by randomized group. Cox model estimated absolute difference (95% confidence interval) at 2 years: 4.7% (−6.0%, 13.4%).