Pulmonary Acute and Late Effects after Radiation for Childhood Cancer: A Report From the PENTEC (Pediatric Normal Tissue Effects in the Clinic) Initiative

Abstract

The PENTEC pulmonary task force aims to quantify radiation dose-volume effects among children treated for cancer, taking into account impact of multimodality therapy (radiation therapy [RT], chemotherapy, and surgery). This report focuses on acute and late radiation pneumonitis (RP), lung fibrosis, abnormal pulmonary function tests (PFTs), supplemental oxygen need, dyspnea, chronic cough and impaired exercise tolerance. A comprehensive search of PubMed databases from 1965-2017 was conducted using key words related to acute and late effects of pulmonary radiation in cancer patients < 21y. The identified papers were reviewed to develop a predictive model of lung injury following radiation in this vulnerable population. RP grade was based on Common Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) criteria, and other clinical outcomes were reported using CTCAE and questionnaires. For RP analysis, lung dose was calculated from dose-volume histogram (DVH) data. The search identified > 2,300 publications, from which 432 papers with detailed treatment and toxicity data were selected for further review. DVH data was extracted from 9 papers for modeling. The cohorts analyzed for acute and late RP included 139 and 254 patients, respectively, aged 0.04-22.7y, treated from 2000-2013. Clinical outcomes data included 14,985 patients, aged 0-21.9y, treated from 1970-2009. RP in pediatric patients receiving RT to all or part of the thorax was minimal, with 4% acute (range, 0-4%) and 4% late (range, 1.6-17.4%) grade 2 RP from the pooled analysis. No higher grade RP was reported. Abnormal PFTs correlated with dose, but patients were often asymptomatic; however, cooperation with pulmonary function and exercise testing was challenging in the pediatric cohort. Large multi-institutional studies showed relationship between doses > 10 Gy and abnormal PFTs, clinical outcomes (dyspnea, chronic cough, supplemental oxygen need, lung fibrosis, recurrent pneumonia), and pulmonary deaths at ≥ 10-y follow-up. Multivariate analyses (MVA) in two studies demonstrated that bleomycin does not contribute to adverse pulmonary outcomes at doses used in contemporary treatment regimens (n=510, RR: 1.2, CI: 0.8-1.8 and n=64, p=0.14, respectively). Extent of thoracic surgery showed variable impact on lung function in this cohort. Pediatric RT to the thorax results in low frequency and severity of both acute and late pulmonary toxicity. Unlike lung toxicity studies for adults, single-institution pediatric cohorts are often small, making MVA difficult. Larger multi-institutional trials and registries with DVH data and long-term follow-up are needed to determine correlations between RT and acute and late lung toxicity in children treated for cancer.