Conditional Risk and Predictive Factors Associated with Late Toxicity for Prostate Cancer Patients Treated with External Beam Radiotherapy Alone on Randomized Trial RTOG 0126

Abstract

Patients with localized prostate cancer (PCA) treated with RT alone have excellent outcomes, making quality of life and minimization of toxicities of great concern. The risk of developing toxicity may evolve with time from treatment which is of interest to patients seen in follow up. The primary objective of this study is to determine the conditional risk of grade 2+ GI or GU toxicity for patients treated with RT. A secondary objective is to determine risk factors associated with the development of late toxicities. We performed a post-hoc analysis of RTOG 0126, which enrolled patients with intermediate risk PCa who were randomized to receive standard dose RT of 70.2 Gy in 39 fractions vs dose escalated dose RT (DE-RT) of 79.2 Gy in 44 fractions. Cumulative incidence was used to calculate risk of grade 2+ GU and grade 2+ GI toxicity at initial time points, as well as for patients who survived 2 years and 5 years without respective grade 2+ toxicity. Risk factors of age, race, urinary incontinence, baseline urinary frequency, acute GU toxicity, treatment arm, RT method (3DCRT vs IMRT), and OAR contouring protocol violation were analyzed using univariate and multivariate Cox proportional hazards modeling for late GU toxicity. Risk factors of age, race, RT method, acute GI toxicity, DE-RT, RT method, and OAR contouring protocol violation were analyzed for late GI toxicity. One thousand four hundred ninety-nine patients with a median follow up of 8.4 years (range 0.02-13 years) were included for analysis. The conditional cumulative 5-year risk of late grade 2+ GI toxicity at enrollment, 2-, and 5-years of grade 2+GI toxicity free survivorship was 14.7%, 6.2%, and 1.8% respectively. The cumulative 5-year risk of late grade 2+ GU toxicity at enrollment, 2-, and 5-years of late grade 2+ GU toxicity free survivorship was 7.9%, 4.7%, and 2.7% respectively. Initially DE-RT (HR 1.401, 95% CI 1.099-1.787; p = 0.0066), acute GI toxicity (HR 1.962, 95% CI 1.271-2.616; P<0.0001), and black race (HR 0.630, 95% CI 0.4-0.993; p<0.0463) were predictive of late GI toxicity. After two years of 2+ GI toxicity free survivorship, only acute GI toxicity (HR 2.015, 95% CI 1.238-3.279, p<0.0048) remained predictive of late GI toxicity on MVA. DE-RT (HR 1.616, 95% CI 1.187-2.2, p<0.0023), IMRT (HR 0.559, 95% CI 0.389-0.804, p = 0.0017), and urinary frequency at baseline (HR 1.377, 95% CI 1-1.895 p<0.0498) were predictive of late GU toxicity at enrollment. This data suggests that as patients proceed further from completion of EBRT, the conditional risk of late toxicity decreases. The majority of grade 2+ GI and GU toxicities occur in the first two years of treatment and patients who have not had a grade 2+ GU or GI toxicity within the first five years are likely to remain toxicity free. Factors such as presence of baseline urinary dysfunction, presence of acute toxicities, DE-RT, and radiation modality predict for late toxicity. These findings are of relevance for clinicians and patients in the post treatment setting.