Long-Term Toxicity of Radical Radiotherapy in Urinary Bladder Carcinoma: A Systematic Review of Genitourinary, Gastrointestinal, and Sexual Outcomes in the Era of Modern Radiotherapy Techniques

Abstract

Radical radiotherapy (RT) with or without concurrent chemotherapy is proven bladder-conserving treatment for muscle-invasive bladder cancer (MIBC). Although technological improvements, such as intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT) and online adaptive radiotherapy (oART), have been developed and implemented, long-term adverse effects still have a significant clinical impact that is only partially described in the survivorship literature. A systematic review and critical synthesis of the existing evidence on long-term toxicity after radical RT for MIBC, with a focus on genitourinary (GU), gastrointestinal (GI), sexual, and health-related quality-of-life (HRQoL) outcomes, broken down by radiotherapy technique, fractionation schedule, and era treated. The systematic review was performed using PRISMA 2020 guidelines and included the PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library databases (from January 1990 to March 2025). The included studies were all conducted in adults who had histologically confirmed MIBC and were undergoing radical RT ± chemotherapy, and reported toxicity data at 6+ months after treatment. The Newcastle-Ottawa Scale (NOS) was used to evaluate the risk of bias for observational studies while the Cochrane RoB2 was used for randomised trials. The GRADE framework was used to rate the evidence certainty. Grade ≥2 and grade ≥3 GU and GI toxicity was also summarised using meta-analysis of proportions (random-effects model DerSimonian-Laird). A total of 26 studies with a total of 8400 patients met the inclusion criteria. Pooled meta-analytic rates for grade ≥2 late GU toxicity were 22.4% (95% CI: 16.8–28.2%; I²=76%) and for grade ≥3 GU toxicity were 7.1% (95% CI: 4.9–9.8%). Pooled grade ≥2 late GI toxicity was 14.6% (95% CI: 10.1–19.3%; I²=68%) and grade ≥3 was 3.9% (95% CI: 2.4–5.6%). Two technique-dependent factors, namely RT technique (coefficient: −0.31 per era-step, p=0.003) and publication year (p=0.01) were identified by meta-regression as important moderators of GI toxicity. In 40–80% of patients evaluated for them, sexual dysfunction was reported, and in less than 50% of studies, they were formally assessed. Early data for oART show a potential reduction of 30-40% in dose to the rectum and bowel, and modern IMRT and oART show significantly reduced organ-at-risk exposure. Long-term toxicity after radical RT for MIBC is a complex clinical problem that involves both short-term and intermediate side effects and that is highly technique-dependent yet cannot be avoided in the era of modern radiosurgical techniques. Adopting a standardised prospective reporting system that incorporates patient-reported outcomes, sexual health and genomics toxicity reporting is a critical step in improving survivorship care. The most immediate route to personalised toxicity reduction is through the integration of normal tissue complication probability (NTCP) modelling and radiogenomics in clinical practice.