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 Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
Int J Radiat Oncol Biol Phys. 2021 Jun 1;110(2):596-608. doi: 10.1016/j.ijrobp.2020.12.041. Epub 2021 Jan 4.
Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy.
The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models.
Late rectal α/β ratio estimates (without DMF) ranged from bleeding (G1 + α/β = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 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 = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus 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.
We estimated α/β ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy.
外照射放疗的分次剂量变化对后续毒性有非线性影响。通常用线性二次模型来描述，正常组织的分次剂量敏感性由α/β 比值表示。我们试图研究前列腺外照射放疗后不同晚期直肠效应的个体α/β 比值。
CHHiP 试验（ISRCTN97182923）将非转移性前列腺癌患者以 1:1:1 的比例随机分为 3 组，分别接受 74 Gy/37 分次（Fr）、60 Gy/20 Fr 或 57 Gy/19 Fr。研究中的患者有完整的剂量学数据和零基线毒性。毒性量表被合并为 6 个肠终点：出血、腹泻、疼痛、直肠炎、肛门括约肌控制和狭窄。通过终点的对数似然拟合 Lyman-Kutcher-Burman 模型，评估 α/β 比值，模型带有或不带有 2 Gy/Fr 剂量修正因子（DMF）的等效剂量。通过逐步纳入剂量修正因子（DMF），评估α/β 比值估计值的敏感性：年龄、糖尿病、高血压、炎症性肠病或憩室病（IBD/憩室病）和痔疮。95%置信区间（CI）通过自举法获得。比较了 632 个估计对数似然的似然比检验。
晚期直肠α/β 比值估计值（无 DMF）范围从出血（G1+α/β=1.6 Gy；95%CI，0.9-2.5 Gy）到肛门括约肌控制（G1+α/β=3.1 Gy；95%CI，1.4-9.1 Gy）。肠痛模型拟合效果较差（α/β，3.6 Gy；95%CI，0.0-840 Gy）。将 IBD/憩室病作为 DMF 纳入显著改善了大便频率 G2+（P=0.00041）和直肠炎 G1+（P=0.00046）的拟合效果。然而，在这些无 DMF 与 DMF 模型中，大便频率 G2+（α/β 2.7 Gy 与 2.5 Gy）和直肠炎 G1+（α/β 2.7 Gy 与 2.6 Gy）的α/β 比值相似。对终点α/β比值进行频率加权平均，得到：G1+α/β 比值=2.4 Gy；G2+α/β 比值=2.3 Gy。
我们估计了直肠放疗后几种常见晚期不良反应的α/β 比值。在比较剂量分割方案时，我们建议使用晚期直肠α/β 比值≤3 Gy。
