Subsequent Neoplasm Risk After Modern Mediastinal Radiation Therapy for Pediatric Hodgkin Lymphoma: Insights From a Multi-Institutional Children’s Oncology Group Trial

Purpose: The reported incidence of subsequent malignant neoplasms (SMNs) in long-term survivors of pediatric classic Hodgkin lymphoma (cHL) is based on patients treated with outdated radiation therapy (RT) doses and techniques. The risk associated with modern mediastinal RT in pediatric cHL is unknown. Methods and Materials: We modeled the risk of SMN in children with cHL who enrolled in the multi-institutional Children’s Oncology Group AHOD1331 trial (2015-2019) and received mediastinal RT. Results: Among 587 trial patients, 296 (50%) received mediastinal RT and were eligible for this analysis. Proton therapy was used for 25%, photon intensity modulated RT (IMRT) for 46%, and photon 3-dimensional conformal RT (3D-CRT) for 28%. The RT prescription dose was 21 Gy in 83% and 30 Gy in 16%. The estimated mean lifetime attributable risk at 70 years of age of breast carcinoma (females) was 2.92% (1.45% proton; 4.36% IMRT; 1.82% 3D-CRT; P <.0001), lung carcinoma was 5.37% (4.15% proton; 6.24% IMRT; 5.07% 3D-CRT; P <.0001), and thyroid carcinoma was 0.17% (0.25% proton; 0.17% IMRT; 0.12% 3D-CRT; P =.271). The predicted risk of breast carcinoma was higher among female patients treated with their arms raised versus arms down (P <.0001). Conclusions: Normal tissue doses associated with contemporary mediastinal RT produce lower predicted SMN risks than were observed in cohorts treated with historical RT approaches, with substantial variation among individuals. On average, proton therapy is associated with a lower predicted risk. These findings have implications for the selection of therapies, counseling of patients, planning of RT, and recommendations for SMN screening.