Division of Clinical Studies, Institute of Cancer Research, London, United Kingdom; The Royal Marsden Hospital, London, United Kingdom.
The Royal Marsden Hospital, London, United Kingdom; Radiotherapy Trials Quality Assurance Group, London, United Kingdom.
Int J Radiat Oncol Biol Phys. 2020 Apr 1;106(5):928-938. doi: 10.1016/j.ijrobp.2020.01.003. Epub 2020 Jan 24.
The CHHiP trial randomized 3216 men with localized prostate cancer (1:1:1) to 3 radiation therapy fractionation schedules: 74 Gy in 37 fractions over 7.4 weeks; 60 Gy in 20 fractions over 4 weeks; and 57 Gy in 19 fractions over 3.8 weeks. Literature-based dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively collected clinician-reported outcomes (CROs) and patient-reported outcomes (PROs) and to assess the added predictive value of spatial dose metrics.
A case-control study design was used; 7 CRO and 5 PRO bowel symptoms were evaluated. Cases experienced a moderate or worse symptom 1 to 5 years after-radiation therapy and did not have the symptom before radiation therapy. Controls did not experience the symptom at baseline or between 1 to 5 years after radiation therapy. The anorectum was recontoured from the anal verge to the rectosigmoid junction; dose/volume parameters were extracted. Univariate logistic regression, atlases of complication indices, and bootstrapped receiver-operating-characteristic analysis (1000 replicates, balanced outcomes) were used to derive dose constraints for the whole cohort (hypofractionated schedules were converted to 2-Gy equivalent schedules using α/β = 3 Gy) and separate hypofractionated/conventional fractionation cohorts. Only areas under the curve with 95% confidence interval lower limits >0.5 were considered statistically significant. Any constraint derived in <95% to 99% of bootstraps was excluded.
Statistically significant dose constraints were derived for CROs but not PROs. Intermediate to high doses were important for rectal bleeding, whereas intermediate doses were important for increased bowel frequency, fecal incontinence, and rectal pain. Spatial dose metrics did not improve prediction of CROs or PROs. A new panel of dose constraints for hypofractionated schedules to 60 Gy or 57 Gy are V20Gy <85%, V30Gy <57%, V40Gy <38%, V50Gy <22%, and V60Gy <0.01%.
Dose constraints differed among symptoms, indicating potentially different pathogenesis of radiation-induced side effects. Derived dose constraints were stricter than those used in CHHiP and may reduce bowel symptoms after radiation therapy.
CHHiP 试验将 3216 名局限性前列腺癌男性患者（1:1:1）随机分为 3 种放射治疗分割方案：74 Gy/37 次/7.4 周；60 Gy/20 次/4 周；57 Gy/19 次/3.8 周。应用文献基础剂量限制，并对分割剂量进行了算术调整。本研究旨在利用前瞻性收集的临床医生报告的结局（CRO）和患者报告的结局（PRO）得出直肠剂量限制，并评估空间剂量指标的额外预测价值。
采用病例对照研究设计；评估了 7 项 CRO 和 5 项 PRO 肠症状。病例组在放疗后 1 至 5 年内出现中度或更严重的症状，且在放疗前没有该症状。对照组在基线或放疗后 1 至 5 年内均未出现该症状。将肛门直肠从肛门缘到直肠乙状结肠交界处进行再勾画，提取剂量/体积参数。采用单变量逻辑回归、并发症指数图谱和自举接收者操作特征分析（1000 次重复，平衡结果），为整个队列（将低分割方案转换为 2-Gy 等效方案，α/β=3 Gy）和单独的低分割/常规分割队列推导出剂量限制。只有曲线下面积的 95%置信区间下限>0.5 的区域被认为具有统计学意义。任何在 95%至 99%自举中得出的限制都被排除在外。
CRO 有统计学意义的剂量限制，但 PRO 没有。中高剂量对直肠出血很重要，而中剂量对增加排便频率、粪便失禁和直肠疼痛很重要。空间剂量指标并不能提高 CRO 或 PRO 的预测能力。新的低分割至 60 Gy 或 57 Gy 方案的剂量限制为 V20Gy<85%，V30Gy<57%，V40Gy<38%，V50Gy<22%，V60Gy<0.01%。
不同症状的剂量限制不同，表明放射诱导副作用的发病机制可能不同。得出的剂量限制比 CHHiP 中使用的更严格，可能会减少放疗后的肠道症状。
