Late Genitourinary Toxicity Following External Beam Radiotherapy for Prostate Cancer

Author: Rowan David

David, Rowan, 2023 Late Genitourinary Toxicity Following External Beam Radiotherapy for Prostate Cancer, Flinders University, College of Medicine and Public Health

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Background. Prostate cancer is common and often treated with radiation therapy. Some patients present to urology centres with treatment-related genitourinary (GU) toxicity following external beam radiotherapy (EBRT). However, the incidence and predictors of late GU toxicity occurring more than five years after EBRT remains under-reported.

Purpose. This thesis aims to examine GU toxicity following EBRT for localised prostate cancer. Firstly, we describe the incidence of GU toxicity reported in randomised controlled trials. Secondly, we determine the treatment burden associated with GU toxicity at a single institution. Thirdly, we determine the 10-year cumulative incidence of treatment-related GU toxicity at a population level. Finally, we develop, assess, and validate a novel model to predict GU toxicity for pre-treatment counselling.

Methods. Firstly, articles published from January 2008 - December 2021 describing prospective studies were systematically searched in MEDLINE and EMBASE. Meta-analysis was performed on the 60-month incidence of late genitourinary toxicity. Next, a prospective study was performed of all patients who presented to a tertiary urology department over 12 months with GU toxicity after pelvic radiotherapy. Subgroup analysis was performed on patients with prostate cancer. Thirdly, a prospective population-based cohort, including hospital admission and cancer registry data, for men with localised prostate cancer who underwent primary EBRT without nodal irradiation between 1998 and 2019 in South Australia was analysed to determine the cumulative incidence of treatment-related GU Toxicity. Finally,


a multivariable Cox proportional hazards model was developed to predict GU toxicity following EBRT. Model discrimination, calibration, internal validation, and utility were assessed using C-statistics, calibration plots, bootstrapping, and decision curve analysis.

Results. The systematic review included six studies (n=4,634), and meta-analysis revealed pooled 60-month cumulative incidence of (Radiation Therapy Oncology Group) RTOG and (Common Terminology Criteria for Adverse Event) CTCAE Grade ≥2 genitourinary toxicities of 17% (95% CI: 5-28%, n=678) and 33% (95% CI: 27-38%, n=153), respectively. Next, the prospective single-institution study (n=46, 117 admissions) determined that GU toxicity accounted for 3% of 1,524 urological admissions over 12 months. Patients with prostate cancer were associated with higher median RTOG scores (p=0.037), emergency admissions (p=0.048) and clot urinary retention (p<0.001). Following this, the population cohort study (n= 3,350) revealed a 10-year cumulative incidence of hospital admission and urological operative procedure of 28.4% (95% CI 26.3 – 30.6) and 18% (95% CI 16.1 – 19.9), respectively. Furthermore, diabetes (HR 1.28, 95% CI 1.08-1.53, p = 0.004), smoking (HR 1.67, 95% CI 1.40 – 2.00, p < 0.001), and bladder outlet obstruction without transurethral resection of prostate (HR 5.87, 95% CI 4.80 – 7.17, p < 0.001) were strong predictors of hospitalisation in multivariable analysis and the model performed well (censor-adjusted c-statistic = 0.80, AUC 0.75).

Conclusion. GU toxicity after EBRT for prostate cancer is common. Based on the meta-analysis and population-level data, the conservative estimated rates of GU toxicity are high. This is the first study to develop a predictive model for GU toxicity requiring hospitalisation amongst men with prostate cancer treated with EBRT.

Keywords: prostate cancer, radiotherapy, toxicity, hospitalisation, genitourinary, prediction, recurrent events,

Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2023
School: College of Medicine and Public Health
Supervisor: Dr Michael E O'Callaghan