Brand Douglas H, Brüningk Sarah C, Wilkins Anna, Naismith Olivia, Gao Annie, Syndikus Isabel, Dearnaley David P, van As Nicholas, Hall Emma, Gulliford Sarah, Tree Alison C
Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom; Urology Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom; Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.
Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland; Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland.
Int J Radiat Oncol Biol Phys. 2023 Feb 1;115(2):327-336. doi: 10.1016/j.ijrobp.2022.08.030. Epub 2022 Aug 17.
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 α/β ratio. Few α/β ratio estimates exist for human late genitourinary endpoints; here we provide estimates derived from a hypofractionation trial.
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 ≥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.
The LKB-EQD2 model significantly improved performance over LKB-NoEQD2 for just 3 endpoints: dysuria G1+ (α/β = 2.0 Gy; 95% confidence interval [CI], 1.2-3.2 Gy), hematuria G1+ (α/β = 0.9 Gy; 95% CI, 0.1-2.2 Gy) and hematuria G2+ (α/β = 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 α/β ratio estimates remained stable.
Inclusion of EQD2-correction significantly improved model fitting for dysuria and hematuria endpoints, where fitted α/β 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 α/β ratio assumptions of 3 to 5 Gy.
中度低分割外照射调强放射治疗（RT）目前是前列腺癌的标准治疗方法。正常组织对分割剂量改变的毒性反应是非线性的：线性二次模型是一个广泛使用的框架，通过α/β比值来解释这一现象。关于人类晚期泌尿生殖系统终点的α/β比值估计很少；在此我们提供来自一项低分割试验的估计值。
CHHiP试验将3216例局限性前列腺癌男性患者按1:1:1随机分为常规分割调强放疗组（74 Gy/37次分割（Fr））和2种中度低分割方案组（60 Gy/20 Fr和57 Gy/19 Fr）。对2206例男性患者进行了RT计划和合适的随访评估。将3个前瞻性评估的临床医生报告的毒性量表合并用于常见的泌尿生殖系统终点：排尿困难、血尿、尿失禁、尿流减少/尿道狭窄和尿频。对于每个终点，仅纳入基线毒性为零的患者。拟合了3个终点分级≥1（G1+）和G2+毒性的模型：未进行2 Gy/Fr等效剂量（EQD2）校正的莱曼·库彻-伯曼（LKB）模型[LKB-NoEQD2]；进行EQD2校正的LKB模型[LKB-EQD2]；纳入剂量修正因子（DMF）的LKB-EQD2模型[LKB-EQD2-DMF]。DMF包括年龄、糖尿病、高血压、盆腔手术、既往经尿道前列腺切除术（TURP）、总治疗时间和急性泌尿生殖系统毒性（G2+）。通过自助法生成95%置信区间和无偏性能估计值。通过似然比检验比较模型。
LKB-EQD2模型仅在3个终点上显著优于LKB-NoEQD2模型：排尿困难G1+（α/β = 2.0 Gy；95%置信区间[CI]，1.2 - 3.2 Gy）、血尿G1+（α/β = 0.9 Gy；95% CI，0.1 - 2.2 Gy）和血尿G2+（α/β = 0.6 Gy；95% CI，0.1 - 1.7 Gy）。对于这3个终点，进一步纳入2个DMF在LKB-EQD2模型基础上有所改进：急性泌尿生殖系统毒性和既往TURP（仅血尿G1+），但α/β比值估计值保持稳定。
纳入EQD2校正显著改善了排尿困难和血尿终点的模型拟合，其中拟合的α/β比值估计值较低：0.6至2 Gy。这表明通过低分割治疗，临床医生报告的泌尿生殖系统毒性的治疗获益可能低于典型的晚期α/β比值假设（3至5 Gy）所预期的。
