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

PurposeTo 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 MaterialsIn 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).ResultsOverall 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.ConclusionsIn 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.

Whole Versus Partial Bladder Radiation

“…Randomized trials have attempted to harness the dosimetric advantages of PB hypofractionation for dose escalation and have shown no excess toxicity; further exploration of the possibilities would be worthwhile. [15][16][17] Our patients had higher bladder-intact survival rates compared with induction BPCR patients than might be expected. Perhaps (as in head and neck and cervical cancers) treatment duration is relevant.…”

“…28 Similar to recent reports on reduced bladder volume receiving high-dose radiation, our data showed that hypofractionated true PB only radiation trended toward improved local control and survival. 16,17 One shortcoming is that with a small number of patients, our study was underpowered to validate this finding, but the results are intriguing nonetheless. Hypofractionation should translate into an LC advantage as the accelerated repopulation and short doubling times of tumor cells would favor shorter overall treatment regimens, and image-guidance facilitates dose escalation.…”

“…16 In addition, it did not compromise local control or survival and trended toward improved outcomes. 17 In that study, tumors received 100% of the prescription dose and the WB still received 80% of the prescription dose.…”

“…16 In addition, it did not compromise local control or survival and trended toward improved outcomes. 17 In that study, tumors received 100% of the prescription dose and the WB still received 80% of the prescription dose.Since these earlier studies, radiation and imaging techniques have evolved such that targeting deformable structures such as the bladder and subsequently limiting dose to adjacent normal structures such as the small bowel can be accomplished with advances in planning and image-guidance during treatments. Intensity-modulated radiation therapy (IMRT) reduces genitourinary and gastrointestinal toxicity, while improving target conformity and homogeneity.…”

Chimioradiothérapie concomitante des tumeurs infiltrantes de la vessie : acquis, controverses et perspectives

“…La non-infériorité n'a pu être prouvée dans l'essai de Huddard et al due à une faible puissance statistique, le bras de cet essai ayant été clôturé prématurément. Il n'en reste pas moins que ces deux essais ont donné des résultats équivalents : des taux de contrôle local et de survie comparables entre les deux bras sans différence significative de toxicité [62,63].…”