目的:再照射越来越多地用于患有复发性原发性中枢神经系统肿瘤的儿童和青少年/年轻人(AYA)。临床儿科正常组织效应(PENTEC)再照射工作组旨在量化再照射后脑和脑干坏死的风险。
方法:使用PubMed和Cochrane数据库对1975年至2021年的同行评审文章进行了系统的文献检索,确定了92项关于儿童/AYA复发性肿瘤再照射的研究。代表449名患者的17项研究报告了再次照射后脑和脑干坏死,其中包含了足够的分析数据。虽然所有17项研究都描述了用于再照射的技术和剂量,他们缺乏对后期效应的剂量-反应建模所必需的临床显著剂量-体积指标的必要细节.我们,因此,用精确的95%CI和定性描述的数据估计坏死的发生率。通过从个别研究中获取报告的粗率的加权平均值来汇集来自多个研究的结果。
结果:治疗的癌症包括室管膜瘤(n=279例;7项研究),髓母细胞瘤(n=98例;6项研究),任何中枢神经系统肿瘤(n=62例;3项研究),和幕上高级别胶质瘤(n=10例;1项研究)。初始和再照射之间的中位间隔为2.3年(范围,1.2-4.75年)。2-Gy分数(EQD22;假设α/β值=2Gy)的等效剂量的累积处方剂量中位数为103.8Gy(范围,55.8-141.3Gy)。在449名接受再照射的儿童/AYA中,22例(4.9%;95%CI,3.1%-7.3%)发生脑坏死,14例(3.1%;95%CI,1.7%-5.2%)发生脑干坏死,加权中位随访时间为1.6年(范围,0.5-7.4年)。累积处方EQD22中位数为111.4Gy(范围,55.8-141.3Gy)用于任何坏死的发展,107.7Gy(范围,55.8-141.3Gy)用于脑坏死,和112.1Gy(范围,100.2-117Gy)用于脑干坏死。再照射和坏死发展之间的中位潜伏期为5.7个月(范围,4.3-24个月)。尽管儿童/AYA接受小分割和常规分割再照射的事件更多,差异无统计学意义(P=0.46).
结论:现有报告表明,在患有复发性脑肿瘤的儿童/AYA中,在中位随访1.6年后,总EQD22为约112Gy的再照射与约5%~7%的脑/脑干坏死发生率相关(初始放射治疗疗程采用常规处方剂量≤2Gy/分数,第二疗程采用可变分数).我们建议采用统一的方法报告剂量测定终点,以得出再辐照后晚期毒性的可靠预测模型。
OBJECTIVE: Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation.
METHODS: A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies.
RESULTS: Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46).
CONCLUSIONS: Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.