Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials

Abstract

Background: Two radiotherapy fractionation schedules are used to treat locally advanced bladder cancer: 64 Gy in 32 fractions over 6·5 weeks and a hypofractionated schedule of 55 Gy in 20 fractions over 4 weeks. Long-term outcomes of these schedules in several cohort studies and case series suggest that response, survival, and toxicity are similar, but no direct comparison has been published. The present study aimed to assess the non-inferiority of 55 Gy in 20 fractions to 64 Gy in 32 fractions in terms of invasive locoregional control and late toxicity in patients with locally advanced bladder cancer.

Methods: We did a meta-analysis of individual patient data from patients (age ≥18 years) with locally advanced bladder cancer (T1G3 [high-grade non-muscle invasive] or T2-T4, N0M0) enrolled in two multicentre, randomised, controlled, phase 3 trials done in the UK: BC2001 (NCT00024349; assessing addition of chemotherapy to radiotherapy) and BCON (NCT00033436; assessing hypoxia-modifying therapy combined with radiotherapy). In each trial, the fractionation schedule was chosen according to local standard practice. Co-primary endpoints were invasive locoregional control (non-inferiority margin hazard ratio [HR]=1·25); and late bladder or rectum toxicity, assessed with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (non-inferiority margin for absolute risk difference [RD]=10%). If non-inferiority was met for invasive locoregional control, superiority could be considered if the 95% CI for the treatment effect excluded the null effect (HR=1). One-stage individual patient data meta-analysis models for the time-to-event and binary outcomes were used, accounting for trial differences, within-centre correlation, randomised treatment received, baseline variable imbalances, and potential confounding from relevant prognostic factors.

Findings: 782 patients with known fractionation schedules (456 from the BC2001 trial and 326 from the BCON trial; 376 (48%) received 64 Gy in 32 fractions and 406 (52%) received 55 Gy in 20 fractions) were included in our meta-analysis. Median follow-up was 120 months (IQR 99-159). Patients who received 55 Gy in 20 fractions had a lower risk of invasive locoregional recurrence than those who received 64 Gy in 32 fractions (adjusted HR 0·71 [95% CI 0·52-0·96]). Both schedules had similar toxicity profiles (adjusted RD -3·37% [95% CI -11·85 to 5·10]).

Interpretation: A hypofractionated schedule of 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity, and is superior with regard to invasive locoregional control. 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer.

Funding: Cancer Research UK.

Figure 1

Trial profiles and final dataset MMC=mytomicin C. FU=fluorouracil. *98 excluded from chemotherapy randomisation (radiotherapy plus chemotherapy vs radiotherapy alone): 53 ineligible for chemotherapy; 34 withdrew or were withdrawn by physician; four had other reasons; and seven had unknown reasons. †239 excluded from radiotherapy randomisation (standard radiotherapy vs reduced high-dose volume radiotherapy): 84 entered the trial after radiotherapy randomisation closed; 54 at centres not participating in radiotherapy randomisation; 47 with multiple tumours; 44 withdrew or were withdrawn by physician; and ten with administrative or unknown reasons.

Figure 2

Kaplan-Meier estimates of observed invasive locoregional control (A) and observed overall survival (B) by trial and fractionation group

Figure 3

Forest plots of the fractionation effect of 64 Gy in 32 fractions versus 55 Gy in 20 fractions for invasive locoregional control and overall survival (A) and toxicity (B) Invasive locoregional control combined HR estimates adjusted for age, sex, randomised treatment, extent of resection, tumour stage, haemoglobin, and neoadjuvant chemotherapy. Overall survival combined HR estimates adjusted for age, sex, randomised treatment, extent of resection, tumour stage, and haemoglobin. Invasive locoregional control and overall survival were modelled on random effects for treatment site and stratified by trial. Late rectum or bladder toxicity combined absolute RD estimates adjusted for age, sex, randomised treatment, and trial, with a random-effects model for treatment site. Models were adjusted on the subset of patients with available values for variables in the model. Red dotted line represents the non-inferiority margin. HR=hazard ratio. RD=risk difference.