儿童肿瘤学组 III 期临床试验：化疗联合低剂量、小体积放疗治疗新诊断的中危型髓母细胞瘤。
Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.
机构信息
Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
出版信息
J Clin Oncol. 2021 Aug 20;39(24):2685-2697. doi: 10.1200/JCO.20.02730. Epub 2021 Jun 10.
PURPOSE
Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume.
METHODS
ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time.
RESULTS
Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm ( = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS ( = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; = .021).
CONCLUSION
Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.
目的
对于患有中危髓母细胞瘤（MB）的儿童，通过降低颅脊髓照射（CSI）剂量和体积来减轻治疗的不良反应，使他们的生存率达到≥80%。
方法
ACNS0331（临床试验.gov 标识符：NCT00085735）将年龄在 3-21 岁的中危 MB 患儿随机分为接受 CSI 后行全后颅窝放疗（PFRT）或累及野放疗（IFRT）的两组。年龄较小的患儿（3-7 岁）也随机分为接受标准剂量 CSI（SDCSI；23.4Gy）或低剂量 CSI（LDCSI；18Gy）的两组。根据已知的生物亚组（Wingless、Sonic Hedgehog、group 3 和 group 4）和遗传生物标志物，对患儿进行事后分子分类和突变分析，以确定预后。通过监测神经认知变化和耳毒性来评估患儿的长期预后。
结果
共有 549 名患儿入组，其中 464 名患儿符合入组标准并可用于比较 IFRT 与 PFRT 方案，226 名患儿符合入组标准并可用于比较 SDCSI 与 LDCSI 方案。IFRT 与 PFRT 方案的 5 年无事件生存率（EFS）分别为 82.5%（95%CI，77.2-87.8）和 80.5%（95%CI，75.2-85.8），LDCSI 与 SDCSI 方案的 5 年 EFS 分别为 71.4%（95%CI，62.8-80）和 82.9%（95%CI，75.6-90.2）。IFRT 方案并不劣于 PFRT 方案（风险比，0.97；94%置信区间，1.32）。LDCSI 方案劣于 SDCSI 方案（风险比，1.67%；80%置信区间，2.10）。Sonic Hedgehog MB 患儿随机分组至 IFRT 组后，EFS 明显提高（ =.018）。接受 LDCSI 治疗的 group 4 MB 患儿 EFS 明显降低（ =.047）。接受 SDCSI 治疗的患儿智商（IQ）后期下降更明显（估计值=5.87； =.021）。
结论
在中危 MB 患儿中降低放射量是安全的，不会影响生存率。在中危 MB 患儿中降低 CSI 剂量可能会降低疗效，尤其是在亚组中，但会改善神经认知预后。基于分子信息的患儿选择可能为 MB 患儿提供新的治疗机会，以便减少不良反应。
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