Pulmonary Complications of Total Body Irradiation in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: Results from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Initiative

Abstract

Pulmonary toxicity is a potential complication of total body irradiation (TBI) delivered as part of hematopoietic cell transplantation (HCT) conditioning. The PENTEC stem cell task force aims to systematically determine the incidence and severity of TBI-associated acute and chronic lung injury and to quantify TBI related risk factors among pediatric HCT patients. A systematic literature search was conducted using Medline, PubMed, and Cochrane library databases from 1980 through 2016 for all articles describing pulmonary toxicity in children treated with HCT. Only English language reports where patients were either all ≤21 years old, or had a median age ≤21 years with patients stratified by age were included. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of acute and chronic lung injury was analyzed in relation to patient age, TBI dose, fractionation, lung shielding, timing, and type of transplant. Of 3,049 identified studies, 3,025 were excluded due to inappropriate age and lack of details related to TBI or pulmonary toxicity. The endpoint of acute, non-infectious idiopathic pneumonitis (IP) was reported in 17 papers with incidences ranging from 0-33% (median 11%). Mortality, when reported, was high (median 78%, range 37.5-100%). IP rates among reports with median patient ages <10 years was not significantly different than in reports with median ages >10 (8.5% vs. 12.5%). Total TBI doses ranged from 7.5 to 17 Gy given in 1.2-10 Gy per fraction at dose rates between 5 and 26 cGy/minute. TBI factors associated with a higher rate of IP were difficult to discern as variables were often reported in combination. Dose rate of <15 cGy minute was associated with a lower incidence of IP in a single report. The effect of lung shielding was inconclusive as was the protective effect of fractionation. Long-term pulmonary function abnormalities were present in 40-100% of patients based on 7 evaluable studies, but usually of a mild or moderate degree. Restrictive abnormalities were more frequent than obstructive disorders and many patients were asymptomatic despite a decline in pulmonary function testing (PFT). Pulmonary toxicity is a potentially serious complication following TBI in the setting of HCT. Based on a limited number of evaluable studies, the rates of IP were low among pediatric patients. While PFT abnormalities were common, few patients became symptomatic. Lower dose rate of TBI may be protective of IP, but the effects of other practices, such as lung blocking and fractionation are unclear.