Departments of Radiation Oncology and.
Pediatrics, University of Minnesota, Minneapolis, Minnesota.
Int J Radiat Oncol Biol Phys. 2024 Jun 1;119(2):625-639. doi: 10.1016/j.ijrobp.2023.02.037. Epub 2023 Mar 26.
Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS.
A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data.
Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process.
This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.
肺并发症，特别是特发性肺炎综合征（IPS），是造血细胞移植（HCT）后可能改变生命或致命的后遗症。全身照射（TBI）作为预处理方案的一部分与 IPS 有关。进行了全面的 PENTEC（儿科正常组织在临床中的应用）审查，以增加我们对 TBI 在急性、非传染性 IPS 发展中的作用的理解。
使用 MEDLINE、PubMed 和 Cochrane 图书馆数据库对描述接受 HCT 治疗的儿童肺毒性的文章进行了系统的文献检索。提取与 TBI 和肺终点相关的数据。分析 IPS 风险与患者年龄、TBI 剂量、分割、剂量率、肺屏蔽、时间和移植类型的关系，目的是更好地了解儿童接受 HCT 时与该并发症相关的因素。使用具有可比移植方案和足够 TBI 数据的子集研究开发了逻辑回归模型。
有 6 项研究符合建模 TBI 参数与 IPS 相关性的标准；所有研究均包括接受环磷酰胺为基础的化疗方案的异基因 HCT 的儿科患者。IPS 的定义各不相同，但所有报告 IPS 的研究均包括在本分析中。移植后 IPS 的平均发生率为 16%（范围，4%-41%）。发生 IPS 时的死亡率很高（中位数为 50%；范围，45%-100%）。分割 TBI 处方剂量范围狭窄，为 9 至 14 Gy。报告了许多不同的 TBI 方法，并且缺乏对肺阻挡技术的 3 维剂量分析。因此，无法对 IPS 与总 TBI 剂量、剂量分割、剂量率或 TBI 技术之间进行单变量相关性分析。然而，基于使用等效 2-Gy 分数剂量的归一化剂量参数（EQD2）的这些研究构建的模型表明，与 IPS 的发展存在相关性（P=.0004）。模型预测的 IPS 比值比为 24.3 Gy（95%置信区间，7.0-84.3）。TBI 肺剂量指标（例如，中肺点剂量）的使用无法成功建模，这可能是由于实际给予的体积肺剂量的剂量学不确定性和我们建模过程的不完美所致。
本 PENTEC 报告是对接受异基因 HCT 分割 TBI 方案的儿科患者 IPS 的全面综述。IPS 与 1 个 TBI 因素没有明确关联。使用剂量率调整的 EQD2 进行建模显示，使用环磷酰胺为基础的化疗方案进行异基因 HCT 时与 IPS 存在相关性。因此，该模型表明 IPS 缓解策略不仅可以关注剂量和剂量分割，还可以关注 TBI 中的剂量率。需要更多的数据来证实该模型，并确定化疗方案和移植物抗宿主病的贡献。存在影响风险的混杂变量（例如全身化疗）、文献中发现的分割 TBI 剂量范围狭窄以及其他报告数据（例如肺点剂量）的限制，可能阻止了 IPS 与总剂量之间更直接的联系被观察到。
