Ananya Choudhury, PhD
In an individual patient-level meta-analysis of two phase III trials reported in The Lancet Oncology, Choudhury et al found that a hypofractionated radiotherapy regimen was associated with improved invasive locoregional control and similar toxicity vs a standard fractionation regimen in patients with locally advanced bladder cancer.
The meta-analysis involved data from patients with locally advanced T1G3 (high-grade non–muscle-invasive) or T2–T4, N0M0 bladder cancer enrolled in the BC2001 trial assessing the addition of chemotherapy to radiotherapy and the BCON trial assessing hypoxia-modifying therapy combined with radiotherapy. A total of 782 patients with known fractionation schedules (456 from BC2001 and 326 from BCON) were included in the analysis; of these, 376 (48%) received standard fractionation with 64 Gy in 32 fractions and 406 (52%) received a hypofractionated regimen of 55 Gy in 20 fractions.
“A hypofractionated schedule of 55 Gy in 20 fractions is noninferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity and is superior with regard to invasive locoregional control. Fifty-five Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer.”— Choudhury et al
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The co-primary endpoints were invasive locoregional control (noninferiority margin hazard ratio [HR] = 1.25) and late bladder or rectum toxicity as assessed by the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (noninferiority margin for absolute risk difference [RD] = 10%). If noninferiority was met for invasive locoregional control, superiority could be considered if the 95% confidence interval for treatment effect excluded the null effect (HR = 1).
Median follow-up for analysis of invasive locoregional control was 60 months (interquartile range [IQR] = 21–60 months). Invasive locoregional recurrence was observed in 28% of patients in the hypofractionation group and 28% of patients in the standard fractionation group within 5 years. In analysis adjusted for age, sex, trial intervention, extent of resection, tumor stage, hemoglobin, and use of neoadjuvant chemotherapy, the hypofractionation regimen was associated with a reduced risk of invasive locoregional recurrence vs the 32-fraction regimen; the adjusted hazard ratio was 0.71, with a 95% confidence interval of 0.52 to 0.96, thus meeting criteria for noninferiority and superiority.
Overall median follow-up was 120 months (IQR = 99–159 months). Death occurred in 73% of patients in each group during follow-up. In analysis of overall survival accounting for age, sex, trial intervention, extent of resection, tumor stage, and hemoglobin, the hypofractionation regimen was associated with a nonsignificant survival benefit (adjusted HR = 0.87, 95% CI = 0.72–1.06).
Rates of grade 3 or 4 late rectum, bladder, and rectum or bladder toxicity in the hypofractionation vs standard fractionation group were 6% vs 3%, 25% vs 24%, and 28% vs 25% at 2 years and 7% vs 3%, 30% vs 31%, and 33% vs 32% at 5 years. In analysis adjusted for age, sex, and trial intervention, the adjusted risk difference was –3.37% (95% CI = –11.85 to 5.10), meeting the noninferiority criterion for toxicity risk.
The investigators concluded, “A hypofractionated schedule of 55 Gy in 20 fractions is noninferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity and is superior with regard to invasive locoregional control. Fifty-five Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer.”
Ananya Choudhury, PhD, of The Christie NHS Foundation Trust, Manchester, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Cancer Research UK. For full disclosures of the study authors, visit thelancet.com.