Estimates of Alpha/Beta (α/β) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP trial.

Abstract Purpose Changes in fraction size of external beam radiotherapy (EBRT) exert non-linear impacts on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. Here we study individual α/β ratios for different late rectal side effects after prostate EBRT. Methods and Materials The XXXXXXX trial (XX-REGISTRATION-NUMBER-XX) randomised men with non-metastatic prostate cancer 1:1:1 to 74Gy/37 fractions (Fr), 60Gy/20Fr or 57Gy/19Fr. Patients included had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhoea, pain, proctitis, sphincter control and stricture. Lyman-Kutcher-Burman models +/- equivalent dose in 2 Gy/fraction correction were log-likelihood fitted by endpoint, estimating α/β ratios. α/β ratio estimate sensitivity was assessed by sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and haemorrhoids. 95% confidence intervals (95% CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared models. Results Late rectal α/β ratio estimates (without DMF) ranged from: bleeding G1+ α/β = 1.6 Gy (95% CI 0.9–2.5 Gy), up to sphincter control G1+ α/β = 3.1 Gy (1.4–9.1 Gy). Bowel pain modelled poorly (α/β 3.6 Gy, 95% CI 0.0 – 840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (p=0.00041) & proctitis G1+ (p=0.00046). However, the α/β ratios were similar in these no-DMF vs DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1+ α/β ratio=2.4 Gy; G2+ α/β ratio=2.3 Gy. Conclusions We estimated α/β ratios for several common late rectal radiotherapy side effects. When comparing dose-fractionation schedules we suggest using late rectal α/β ratio ≤ 3 Gy.