Correlation of Biochemical Recurrence with Adverse Late Toxic Events Following Prostate Radiotherapy (COBALT Study): An Individual Patient Data Meta-Analysis of 7 Randomized Trials.

Abstract

BackgroundThe association between late toxicity and biochemical recurrence (BCR) following prostate radiotherapy is unclear. We set out to characterize the relationship between late gastrointestinal (GI) and genitourinary (GU) toxicity and BCR among patients receiving conventionally fractionated (CF) or moderately hypofractionated (MHF) prostate radiotherapy.Methods and materialsThis was an individual patient data (IPD) meta-analysis that identified randomized phase III trials of CF or MHF prostate radiotherapy in the MARCAP consortium that had individual-level late toxicity and BCR data available. Data were provided to MARCAP by study investigators. The associations between BCR and late (>3 months after radiotherapy) grade ≥2 GI and GU toxicities were assessed using Fine-Gray subdistribution hazard models with an 18-month landmark to address immortal time bias.ResultsSeven of 26 available trials met all eligibility criteria. 6,761 patients were included (CF: n=4,333; MHF: n=2,428). Median follow-up was 72 months (interquartile range, 61-94 months). BCR occurred in 17.0% of patients (1,142/6,732). The rate of late grade ≥2 GI toxicity was 14.3% (965/6,761), while the rate of grade ≥2 GU toxicity was 15.5% (1,045/6,761). BCR was inversely associated with late grade ≥2 GI toxicity (sHR 0.64, 95% confidence interval [CI]: 0.43-0.96, p=0.03). BCR was not significantly associated with late grade ≥2 GU toxicity (sHR 1.06, 95% CI: 0.70-1.60, p=0.78).ConclusionsLate grade ≥2 GI toxicity was significantly associated with lower rates of BCR. We hypothesize that this may be related to the impact of prostatic motion during treatment, specifically anterosuperior motion of the prostate that would increase the dose to the rectum and to posterior dominant intraprostatic lesions. Late grade ≥2 GU toxicity did not appear to be associated with BCR.