The interplay between acute and late toxicity among patients receiving prostate radiotherapy: an individual patient data meta-analysis of six randomised trials.

Background: The association between acute and late toxicity following prostate radiotherapy has not been well studied using data from multiple randomised clinical trials and fractionation schedules. We aimed to characterise the relationship between acute and late genitourinary and gastrointestinal toxicity among patients receiving conventionally fractionated or moderately hypofractionated prostate radiotherapy.
Methods: This was an individual patient data meta-analysis that identified randomised phase 3 trials of conventionally fractionated or moderately hypofractionated prostate radiotherapy in the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium that had individual-level acute and late toxicity data available and were available before Dec 1, 2023. Trials without individual patient data were excluded. Data were provided to MARCAP by study investigators. The associations between acute (≤3 months after radiotherapy) and late (>3 months after radiotherapy) grade 2 or greater genitourinary and gastrointestinal toxicities were assessed using adjusted generalised linear mixed models (adjusted for age, androgen deprivation therapy status, type of radiotherapy, radiation dose, and radiation schedule). In the subset of trials that collected Expanded Prostate Cancer Index Composite quality of life (QOL) evaluations, the association between acute genitourinary and gastrointestinal toxicity and decrements at least twice the minimal clinically important difference (MCID) for urinary and bowel QOL were also evaluated.
Findings: Six of 26 available trials met all the eligibility criteria. 6593 patients were included (conventionally fractionated: n=4248; moderately hypofractionated: n=2345). Median follow-up was 72 months (IQR 61-94). Acute grade 2 or greater genitourinary toxicity was associated with both late grade 2 or greater genitourinary toxicity (odds ratio 2·20 [95% CI 1·88-2·57], p<0·0001) and decrement at least twice the MCID in urinary QOL (1·41 [1·17-1·68], p=0·0002). Acute grade 2 or greater gastrointestinal toxicity was associated with both late grade 2 or greater gastrointestinal toxicity (2·53 [2·07-3·08], p<0·0001) and decrement at least twice the MCID in bowel QOL (1·52 [1·26-1·83], p<0·0001).
Interpretation: Acute toxicity following prostate radiotherapy was statistically significantly associated with late toxicity and with decrement in patient-reported QOL metrics. These data support efforts to evaluate whether interventions that reduce acute toxicity ultimately reduce the risk of late toxicity.
Funding: National Institutes of Health and US Department of Defense.
Competing Interests: Declaration of interests AUK reports receiving grants from Janssen, Point Biopharma, ArteraAI, and Lantheus, consulting fees from Varian, honoraria from Varian and Accuray, and participating on an advisory board for Novartis, Lantheus, Janssen, and Boston Scientific outside the submitted work. ACT declares research funding from Elekta, Varian, and Accuray and honoraria or travel assistance from Elekta, Accuray, Astellas, and Janssen outside the submitted work. ACT also reports serving as Chair of the MR linac consortium, lead of the National Prostate Cancer Audit, and lead genitourinary editor for International Journal of Radiation Oncology, Biology, Physics. SR reports receiving support from the Young Investigator award from The Prostate Cancer Foundation, a research grant from Swim Across America Foundation, and speaker honoraria from Varian outside the submitted work. HS reports salary support from American College of Radiology-NRG Oncology and serving as Chair of the Board of American Society for Radiation Oncology (ASTRO). SR received honoraria from Varian Medical Systems and owns stock in Merck Pharmaceuticals. LFV reports consulting fees from the Dedham Group and Health Advances. DS reports receiving consulting fees from Boston Scientific and participating on an advisory board for Astellas, AstraZeneca, Bayer, GSK, Janssen, Novartis, and Pfizer outside the submitted work. DS also reports serving on the NCCN Prostate Cancer Guidelines. JMM reports serving on the ASTRO Board of Directors. EH reports receiving research grants from Varian Medical Systems, Accuray, AstraZeneca, Janssen-Cilag, Bayer, Roche Products, and Merck Sharp & Dohm. All other authors declare no competing interests.
(Copyright © 2025 Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)