Radiotherapy Utilization and Outcomes on a Contemporary Trial for Pediatric High-Risk Hodgkin Lymphoma Study

Contemporary trials in pediatric Hodgkin lymphoma (cHL) evaluate strategies to reduce radiotherapy (RT) utilization while maintaining excellent progression-free survival (PFS). An alternative strategy is to irradiate selective sites at higher risk of relapse, and/or use proton therapy (PT) to minimize exposure to healthy tissue. We investigated the use of PT and photon therapy (XRT) and associated early outcomes among patients receiving involved site RT (ISRT) to high-risk sites on the Children's Oncology Group (COG) trial AHOD1331 (NCT021664643).This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated cHL: stages IIB + bulk, IIIB, IVA, IVB. Patients were randomized to 5 cycles of either ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) or the brentuximab vedotin (BV) containing regimen BV-AVE-PC given every 21 days. ISRT to 21 Gy was given to bulky mediastinal adenopathy and slow responding lesions (SRL) defined by 5-point score 4 or 5 on PET-CT after 2 cycles. ISRT could be delivered as 3D conformal XRT (3D), intensity modulated XRT (IMRT), or proton therapy (PT). Utilization of RT was compared by mode and by study enrollment midpoint among irradiated patients. Severe acute toxicity assessment included any incident grade 3 or higher toxicity during the ISRT period, except for neuropathy.Among 587 eligible patients who were enrolled across 153 institutions between March 2015 and August 2019 with a median follow up of 43.1 months, the 3-yr PFS was 82.5% (90% CI, 78.3%-85.9%) with ABVE-PC and 92.5% (90% CI 89.5%-94.6%) with BV-AVE-PC (p = 0.0002). There was no difference in ISRT receipt or modality by study arm (p = 0.33). Among those who received RT 69.7% received it due to bulky mediastinal adenopathy, 6.6% due to SRL, and 23.7% for both. Overall, 317 (54.0%) patients received protocol RT of which 28.7% received 3D, 44.8% received IMRT, and 26.5% received PT. PT utilization increased over the course of the study from 21.5% among the first 50% of irradiated patients to 31.5% in the second half of irradiated patients (p = 0.045). The 3-yr progression-free survival rates overall by RT were comparable: PT (88.0%, 90% CI 80.6% - 92.7%%); XRT (87.1%, 90% CI 82.9%-90.4%) (p = 0.85). No difference in PFS was observed between 3D versus IMRT (p = 0.65). No differences were observed in severe acute toxicities (8.33% vs. 8.15%, p = 0.96) between PT and XRT.Selective use of RT results in excellent outcomes for pediatric patients with high-risk HL and combination chemotherapy inclusive of the novel agent BV. Over the course of the study, PT utilization increased as an RT modality. Early results suggest that PT does not compromise disease control and has similar acute toxicity as XRT. Long term follow-up (>10 years) is needed to evaluate for secondary malignancies and cardiac toxicity among the different RT modalities.