The Fraction Size Sensitivity of Late Genitourinary Toxicity: Analysis of Alpha/Beta (α/β) Ratios in the CHHiP Trial

Purpose: Moderately hypofractionated external beam intensity modulated radiation therapy (RT) for prostate cancer is now standard-of-care. Normal tissue toxicity responses to fraction size alteration are nonlinear: the linear-quadratic model is a widely used framework accounting for this, through the a/0 ratio. Few a/0 ratio estimates exist for human late genitourinary endpoints; here we provide estimates derived from a hypofractionation trial.Methods and Materials: The CHHiP trial randomized 3216 men with localized prostate cancer 1:1:1 between conventionally fractionated intensity modulated RT (74 Gy/37 fractions (Fr)) and 2 moderately hypofractionated regimens (60 Gy/20 Fr and 57 Gy/19 Fr). RT plan and suitable follow-up assessment was available for 2206 men. Three prospectively assessed clinician reported toxicity scales were amalgamated for common genitourinary endpoints: dysuria, hematuria, incontinence, reduced flow/stricture, and urine frequency. Per endpoint, only patients with baseline zero toxicity were included. Three models for endpoint grade & GE;1 (G1+) and G2+ toxicity were fitted: Lyman Kutcher-Burman (LKB) without equivalent dose in 2 Gy/Fr (EQD2) correction [LKB-NoEQD2]; LKB with EQD2-correction [LKB-EQD2]; LKB-EQD2 with dose-modifying-factor (DMF) inclusion [LKB-EQD2-DMF]. DMFs were age, diabetes, hypertension, pelvic surgery, prior transurethral resection of prostate (TURP), overall treatment time and acute genitourinary toxicity (G2+). Bootstrapping generated 95% confidence intervals and unbiased performance estimates. Models were compared by likelihood ratio test.Results: The LKB-EQD2 model significantly improved performance over LKB-NoEQD2 for just 3 endpoints: dysuria G1+ (a/0 = 2.0 Gy; 95% confidence interval [CI], 1.2-3.2 Gy), hematuria G1+ (a/0 = 0.9 Gy; 95% CI, 0.1-2.2 Gy) and hematuria G2 + (a/0 = 0.6 Gy; 95% CI, 0.1-1.7 Gy). For these 3 endpoints, further incorporation of 2 DMFs improved on LKB-EQD2: acute genitourinary toxicity and prior TURP (hematuria G1+ only), but a/0 ratio estimates remained stable.Conclusions: Inclusion of EQD2-correction significantly improved model fitting for dysuria and hematuria endpoints, where fitted a/0 ratio estimates were low: 0.6 to 2 Gy. This suggests therapeutic gain for clinician-reported GU toxicity, through hypofractionation, might be lower than expected by typical late a/0 ratio assumptions of 3 to 5 Gy.& COPY; 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Automated summary

This study provides estimates of the a/0 ratio for human genitourinary toxicity endpoints derived from a hypofractionation trial. The results showed that the symptoms of dysuria and hematuria were less severe when EQD2 correction was considered, and the a/0 ratio was lower, indicating that the therapeutic gain of hypofractionation may be lower than expected.