Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
Department of Oncology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
Int J Radiat Oncol Biol Phys. 2024 Jun 1;119(2):640-654. doi: 10.1016/j.ijrobp.2023.07.025. Epub 2023 Sep 29.
A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors.
A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated.
The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs.
This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors.
本研究通过对已发表的儿童癌症幸存者接受放射治疗（RT）后中枢神经系统（CNS）继发肿瘤（SNs）、继发肉瘤和继发肺癌的文献进行儿科正常组织效应在临床中的（PENTEC）分析，以评估 RT 剂量对 SNs 风险的影响，并评估宿主和治疗因素对这种风险的影响。
本研究进行了一项系统的文献综述，以确定自 1975 年至 2022 年期间，在儿童癌症幸存者中，在接受 RT 治疗后发生 SNs 的研究数据。在摘要审查后，从 83 项关于 CNS SNs、118 项关于继发肉瘤和 10 项关于肺 SNs 的研究中提取了可用的定量和定性数据，另外 4 项研究（3 项关于 CNS SNs 和 1 项关于肺 SNs）在后期也被添加进来。提取 SNs 的发生率、RT 剂量、年龄、性别、原发癌诊断、化疗暴露和从原发诊断到 SNs 的潜伏期，以评估影响 SNs 风险的因素。使用逆方差加权线性回归分析 SNs 发展的超额相对比（ERR），并估计 ERR/Gy。还计算了超额绝对风险。
随后脑膜瘤的 ERR/Gy 估计值为 0.44（95%置信区间，0.19-0.68）；恶性 CNS 肿瘤为 0.15（95%置信区间，0.11-0.18）；肉瘤为 0.045（95%置信区间，0.023-0.067）；肺癌为 0.068（95%置信区间，0.03-0.11）。在原发性诊断时年龄较小与随后发生脑膜瘤和肉瘤的风险较高有关，而在接受辐射时年龄对恶性 CNS 肿瘤风险没有显著影响，且关于肺癌风险的年龄数据不足。女性患随后脑膜瘤的风险高于男性（比值比，1.46；95%置信区间，1.22-1.76；P<0.0001），而恶性 CNS 肿瘤、肉瘤 SNs 或肺癌 SNs 的风险在性别上没有统计学上的显著差异。化疗的接受（特别是烷化剂和蒽环类药物）与随后发生的肉瘤风险之间存在关联，而特定的化疗药物与 CNS SNs 和肺癌 SNs 的风险之间没有明确的关联。
本 PENTEC 系统综述显示 CNS SNs、肉瘤和肺癌存在显著的放射剂量反应关系。鉴于线性剂量反应，限制高剂量体积的目标体积周围的一致性改善可能是降低 RT 后 SNs 风险的一种有前途的策略。其他宿主和治疗相关因素，如年龄和化疗，在 SNs 的发展中起着重要的作用，在估计儿童癌症幸存者接受 RT 后 SNs 的风险时应予以考虑。
