Acute and chronic GU/GI toxicity after conventional versus hypofractionated radiotherapy (HFRT) with concurrent chemotherapy for muscle-invasive bladder cancer: A multi-institutional analysis by CURE-BC - Consortium for Urothelial Radiation Excellence – Bladder Cancer.

718 Background: HFRT is increasingly used as a bladder-preserving regimen for muscle-invasive bladder cancer (MIBC), although comparative data on acute and late genitourinary (GU) and gastrointestinal (GI) toxicity versus conventional fractionation (CFRT), particularly with pelvic nodal fields or concurrent cisplatin or gemcitabine, remain limited. Methods: We conducted a multi-institutional retrospective analysis of patients with MIBC treated with definitive radiotherapy between January 2010 to March 2024. Patients were categorized based on fractionation schedule (CFRT 1.8-2 Gy/fraction, mean dose 6300 cGy vs. HFRT 2.25-2.75 Gy/fraction, mean dose 5500 cGy), nodal treatment (pelvic RT vs bladder-only), receipt of neoadjuvant chemotherapy (NAC), and concurrent chemotherapy. Acute (≤6 months of RT) and chronic physician documented GU and GI toxicities were graded per CTCAE v5.0. Statistical comparisons were done using chi-square. Results: A total of 174 patients from 3 institutions were included: 59 received HFRT, (6 received NAC, 7 had pelvic RT); 115 received CFRT, (22 received NAC, 56 had pelvic RT). Overall, 160 patients received concurrent chemotherapy—39 cisplatin, 77 gemcitabine, and 32 5FU/MMC. The incidence of acute ≥Grade 2 GU toxicity was 52.5% vs 52.2% (p = 0.9634), chronic ≥Grade 2 GU 16.9% vs 28.7% (p = 0.089), acute ≥Grade 2 GI 30.5% vs 18.3% (p = 0.0667), and chronic ≥Grade 2 GI 3.4% vs 6.9% (p = 0.3386), in HFRT vs CFRT groups respectively. Subset analysis showed HFRT vs CFRT patients had no difference in toxicity within those treated with any of the three chemotherapy agents, or with pelvic RT or with neoadjuvant chemotherapy. Paradoxically, there were fewer acute GU/GI and chronic GU toxicities in those treated with pelvic RT vs. bladder only and fewer acute GU and chronic GU/GI toxicities in those treated with NAC, likely reflecting selection bias. In the HFRT subgroup, gemcitabine (17/41) was associated with worse acute ≥Grade 2 GI toxicity, 41.5% vs. 0% with cisplatin (0/8), (p = 0.0242) while acute ≥Grade 2 GU and chronic ≥Grade 2 GU/GI toxicities were not statistically different. Conclusions: In this large multi-institutional cohort, hypofractionated radiotherapy demonstrated comparable acute and chronic toxicity outcomes relative to conventional fractionation in MIBC. Trends toward increased chronic ≥Grade 2 GU toxicity in those treated with CFRT and acute GI toxicity with HFRT, especially when given with gemcitabine warrant further study.