Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目的：对已发表的中枢神经系统（CNS）后续肿瘤（SNs）研究的临床小儿正常组织效应（PENTEC）分析，随后的肉瘤，对接受放射治疗(RT)的儿童癌症幸存者和随后的肺癌进行评估,以评估RT剂量对SNs风险的影响,以及宿主和治疗因素对该风险的改变.
方法：进行了系统的文献综述，以确定1975年至2022年在儿童癌症幸存者中进行放疗后SNs的数据。经过抽象审查，从83项中枢神经系统SNs研究中提取了可用的定量和定性数据，随后的肉瘤118，肺SNs为10，随后增加了4项其他研究（CNSSNs为3项，肺SNs为1项）。SNs的发生率，RT剂量，年龄,性别,原发性癌症诊断，化疗暴露，提取从初次诊断到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了发展SNs的过量相对比（ERR）作为剂量的函数，并估计了ERR/Gy。还计算了超额绝对风险。
结果：随后的脑膜瘤的ERR/Gy估计为0.44（95％CI，0.19-0.68）；对于恶性中枢神经系统肿瘤，0.15（95%CI，0.11-0.18）；对于肉瘤，0.045（95%CI，0.023-0.067）；对于肺癌，0.068（95%CI，0.03-0.11）。初次诊断时年龄较小与随后脑膜瘤和肉瘤的风险较高有关。而暴露年龄对中枢神经系统恶性肿瘤风险没有显著影响，关于肺癌年龄的数据不足.女性患脑膜瘤的风险更高(比值比，1.46；95%CI，1.22-1.76；P<0.0001)相对于男性，然而，在恶性中枢神经系统肿瘤的风险方面没有发现统计学上显著的性别差异，肉瘤SNs，或肺SN。接受化疗（特别是烷化剂和蒽环类药物）与随后的肉瘤风险之间存在关联。而特定的化疗药物与CNSSNs和肺SNs的风险之间没有明确的关联。
结论：本PETEC系统评价显示CNSSNs存在显著的辐射剂量-反应关系，肉瘤,和肺SNs。鉴于线性剂量反应，改善限制高剂量体积的目标体积周围的保形性可能是降低RT后SNs风险的有前景的策略.其他与主机和治疗相关的因素，如年龄和化疗在SNs的发展中起着重要的作用，在评估儿童癌症幸存者RT后SNs的风险时应考虑。
方法：进行了系统的文献综述，以确定1975年至2022年在儿童癌症幸存者中进行放疗后SNs的数据。经过抽象审查，从83项中枢神经系统SNs研究中提取了可用的定量和定性数据，随后的肉瘤118，肺SNs为10，随后增加了4项其他研究（CNSSNs为3项，肺SNs为1项）。SNs的发生率，RT剂量，年龄,性别,原发性癌症诊断，化疗暴露，提取从初次诊断到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了发展SNs的过量相对比（ERR）作为剂量的函数，并估计了ERR/Gy。还计算了超额绝对风险。
结果：随后的脑膜瘤的ERR/Gy估计为0.44（95％CI，0.19-0.68）；对于恶性中枢神经系统肿瘤，0.15（95%CI，0.11-0.18）；对于肉瘤，0.045（95%CI，0.023-0.067）；对于肺癌，0.068（95%CI，0.03-0.11）。初次诊断时年龄较小与随后脑膜瘤和肉瘤的风险较高有关。而暴露年龄对中枢神经系统恶性肿瘤风险没有显著影响，关于肺癌年龄的数据不足.女性患脑膜瘤的风险更高(比值比，1.46；95%CI，1.22-1.76；P<0.0001)相对于男性，然而，在恶性中枢神经系统肿瘤的风险方面没有发现统计学上显著的性别差异，肉瘤SNs，或肺SN。接受化疗（特别是烷化剂和蒽环类药物）与随后的肉瘤风险之间存在关联。而特定的化疗药物与CNSSNs和肺SNs的风险之间没有明确的关联。
结论：本PETEC系统评价显示CNSSNs存在显著的辐射剂量-反应关系，肉瘤,和肺SNs。鉴于线性剂量反应，改善限制高剂量体积的目标体积周围的保形性可能是降低RT后SNs风险的有前景的策略.其他与主机和治疗相关的因素，如年龄和化疗在SNs的发展中起着重要的作用，在评估儿童癌症幸存者RT后SNs的风险时应考虑。
