Reduced-Dose Hypofractionated Radiation Therapy (3 Gy × 3 Fractions) for Indolent Non-Hodgkin’s lymphoma (POSEIDON): A Multisite Phase 2 Randomized Trial Protocol

Indolent non-Hodgkin's lymphoma, including follicular and marginal zone lymphoma, is highly radiosensitive, with radiation therapy (RT) serving as an effective treatment. Although standard RT doses (24 Gy in 12 fractions) provide excellent disease control, they are associated with toxicity. Emerging evidence suggests that lower RT doses may maintain efficacy while reducing toxicity; however, prior prospective randomized attempts to reduce the dose to 4 Gy in 2 fractions have demonstrated inferior disease control. This phase 2 randomized trial aims to determine whether reduced-dose hypofractionated RT can achieve comparable disease control while minimizing toxicity and treatment burden. Patients will be randomized 1:1 to receive experimental arm treatment with 8 to 10 Gy in 2 to 5 fractions or standard of care treatment with 24 Gy in 12 fractions. The primary endpoint is acute toxicity (grade ≥ 2). Secondary endpoints include patient-reported quality of life (FACIT-Fatigue scale), response rate at 3 months posttreatment (Lugano criteria), local control, relapse-free survival, and overall survival. Exploratory analyses will evaluate financial toxicity (COST-FACIT questionnaire), health care expenditure, late toxicity, and the prognostic value of preradiation metabolic imaging parameters, including metabolic tumor volume, total lesion glycolysis, and maximum standardized uptake value, as well as molecular biomarkers such as <i>TP53, MYC</i>, and Ki-67.