Modeling Radiation Therapy-Related Risk of Heart Failure in Survivors of Pediatric Malignancy: Early Results from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Group

Abstract

Cardiac disease is the most common cause of non-cancer mortality among long-term survivors of pediatric cancer; radiation therapy (RT) is a risk factor for late cardiotoxicity. The PENTEC cardiovascular task force aims to quantify radiation dose effects and the impact of critical risk factors. Through systemic review, including a meta-analysis of the available literature, we describe the relationships between heart failure (HF) and RT, as well as the influence of anthracycline chemotherapy, age, and gender. We conducted PubMed searches of peer-reviewed manuscripts published January 1, 1995, to October 2, 2017, evaluating HF among survivors of childhood cancer who received RT. Overall, 1,496 reports were identified, 148 were fully reviewed, and 5 had adequate data for modelling as described herein (Table). Patients were treated between 1966 and 1998, before the age of 18 years. HF diagnosis was based on CTCAE criteria, physician diagnosis, or patient reporting; all patients diagnosed were symptomatic. Heart dose was determined by either dose reconstruction or prescribed dose to an RT field including the heart. Meta-analysis hazard ratios for RT dose, anthracycline dose, gender, and age were determined using the inverse variance method based on multivariate, mutually adjusted models in the contributing reports. The population analyzed included 32,395 survivors; 614 events of HF were identified. The population-weighted mean incidence of HF at 20 years was 2.2%. For each 10 Gy increase in mean cardiac dose, the relative increase in HF risk was 50% (hazard ratio [HR] = 1.50; 95% CI = 1.41 – 1.60). Similarly, for each 100 mg/m2 increase in cumulative anthracycline dose, relative HF risk increased by 60% (HR = 1.60; 95% CI = 1.55 – 1.66). Younger age at diagnosis was associated with increased HF risk; every 5 years below 15 years of age increased the relative HF risk by 83% (HR = 1.83; 95% CI = 1.52 – 2.20). Female gender also increased HF risk (HR = 1.61; 95% CI = 1.35 – 1.93). This meta-analysis quantifies the dose relationship between cardiac RT and late HF, and identifies anthracycline dose, young age, and female gender as risk factors. Each 10 Gy of mean cardiac RT and each 100 mg/m2 of cumulative anthracycline dose results in a similar increase in the risk of HF. Further knowledge of the impact of these variables, especially the age-related vulnerabilities, helps inform clinical shared decision-making between providers, patients, and their families. This information will also inform future treatment protocols to minimize the late cardiac toxicity of cancer therapies.Abstract 105; TableIncluded StudiesCalculated HR per 10 Gy RT95% CIMulrooney, et al (2009)1.51.3 – 1.6Van der Pal, et al (2012)1.41.1 – 2.0Green, et al (2001)1.81.1 – 2.7Chow, et al (2015)1.71.5 – 1.9Schellong, et al (2010)––Meta-Value1.51.4 – 1.6 Open table in a new tab