Omission of Radiation Therapy is Associated with Inferior Disease Control in High Risk Early-Stage Hodgkin Lymphoma:

Early-stage classical Hodgkin lymphoma (HL) is highly curable, yet optimal frontline treatment remains contested. Combined modality therapy (CMT) with chemotherapy followed by radiotherapy (RT) has been the standard, but concern over RT-associated toxicities has driven adoption of chemotherapy-alone approaches despite randomized trials failing to demonstrate noninferiority with RT omission. We analyzed 810 adult patients treated across eight academic centers for stage I/II HL between 1/2012 and 1/2022, comparing outcomes with CMT and chemotherapy alone. Primary endpoints were progression-free (PFS) and overall survival (OS); propensity-score matching was conducted to homogenize baseline characteristics between the groups, and subgroup analyses were conducted to identify clinical features associated with differential benefit. Among 480 propensity-matched patients, five-year OS was 98.6% with CMT versus 97.3% with chemotherapy alone (p=0.620); five-year PFS was 87.2% vs 81.4% (p=0.053). CMT conferred significantly superior PFS in patients with bulky disease (91.8% vs 73.0%; HR 3.77; p=0.005) and interim (iPET)-positive disease (Deauville score (DS)≥4; 74.9% vs 51.9%; HR 2.97; p=0.020). iPET response was the strongest independent predictor of both progression (HR 7.02) and mortality (HR 6.97), with PFS declining markedly across DS groups (DS1-2: 92.2%; DS3: 79.4%; DS4-5: 46.4%). Among iPET-positive patients, those receiving unplanned consolidative RT required less salvage therapy than those managed with chemotherapy escalation alone (29.0% vs. 45.2%; p=0.037). Late toxicities were more frequent with CMT, though 69% of second malignancies occurred outside the RT field. These findings support risk-adapted, biomarker-driven treatment selection and the need for prospective trials incorporating modern RT techniques and iPET-adapted algorithms.