Very Low Dose Radiotherapy (VLDRT) with 4 Gy for Potentially-Curable Indolent Non-Hodgkin Lymphomas
Authors: Mankuzhy Nikhil P. , Imber Brandon S. , Pammer Paige , Fregonese Beatrice , Cajo Adriana , Cederquist Gustav , Dreyfuss Alexandra , Lapen Kaitlyn , Patel Roshal R. , Moore Zachary R. , Hajj Carla , Salles Gilles , Yahalom Joachim 
Published: December 2024

Introduction: Radiotherapy (RT) is the guideline-recommended treatment for localized, indolent non-Hodgkin lymphoma (iNHL). The FoRT analysis established 24 Gy as the standard of care dose particularly for curable patients (pts) given superior local control vs. very low dose radiotherapy (VLDRT) of 4 Gy. Despite this, enthusiasm remains for VLDRT for curable pts due to: a) VLDRT's relatively high local control potential with negligible toxicity b) the primary risk of distant progression in iNHL and c) favorable Phase II outcomes for orbital and gastric iNHL. At our institution, we implemented an adaptive approach for use of VLDRT in iNHL. After VLDRT, pts undergo short-interval assessment to consider additional RT. Our initial analysis reported a 9% 2-year incidence of local progression (LP) for 52 potentially-curable pts with median follow up of 1.7 years. Here, we present an expanded series of curable iNHL pts with longer follow up treated with 4 Gy in 2 fractions with an adaptive approach.

Methods: We identified pts with potentially curable iNHL treated with VLDRT defined as 4 Gy in 2 fractions through April 2024. Pts were considered curable if they had stage I, II, or localized (for cutaneous) disease, were treated comprehensively with VLDRT to all sites of disease, had not received any prior systemic therapy for iNHL, and did not undergo an oncologic resection. Pts were excluded if they lacked a post-VLDRT response assessment evaluation. Progression or recurrence within the RT field was considered LP and any other disease recurrence was considered out-of-field progression. Progression free survival (PFS) included any progression event or death. Overall survival (OS) and PFS were measured from date of RT on a patient level. Cumulative incidence of LP was analyzed on a lesion level from date of RT with death as a competing risk.

Results: From 2010-2024, 157 potentially curable pts treated to 165 lesions were analyzed. Median age at VLDRT was 62 (range 24-91) and histology was follicular lymphoma (FL) in 70 (45%), marginal zone lymphoma in 73 (46%) and low-grade iNHL not specified in 14 (8.9%). 17 (11%) pts were stage II. PET staging was completed in all but 2 patients and 46 patients underwent bone marrow biopsy. 26 pts underwent excisional biopsy. For pts with FL, four patients had grade 3A disease and the remainder grade 1-2. Just over half of treated lesions (52%) were extranodal, with 37 (22%) purely nodal and 43 (26%) cutaneous. Extranodal sites included eye/orbit (38), parotid (13), gastrointestinal (11), head/neck (7), breast (6), liver (4), lung (4), kidney (1), and vulvovaginal (1). Of the primary cutaneous cases, 30 were lesions on the head and neck. For pts with reported SUV values, median pre-VLDRT maximum was 5.4 (range 0.9-17.6). For patients with radiographically-measured disease, median diameter was 2.1 cm (0.1-7.8 cm). Prior to VLDRT, 18 pts (11%) were initially observed.

The median follow up was 27.5 months (range 1.6-167). After VLDRT, median time to first response assessment was 2.5 months (0.7-6.6). PET was used for 104 lesions, clinical exam in 40 patients, and endoscopy in 9 patients. At this response assessment, 127 (77%) had a complete response (CR) and 30 (18%) had a partial response (PR) for an overall response rate of 95%. Based on insufficient response and after evaluation, 7 patients received additional RT to the index lesions with 20-30 Gy. One had PR and 6 had CR after additional RT and none experienced subsequent LP. At 2 and 5 years, cumulative incidence of LP was 8% (95% confidence interval [CI] 4-14%) and 18% (CI 10-26%) respectively. At 2 and 5 years, PFS was 70% (CI 62-79%) and 58% (CI 48%-69%) and OS was 99% and 92%. In the entire series, 4 patients developed transformation to large cell lymphoma at an out of field site and received rituximab and chemotherapy. One patient with out-of-field progression received rituximab.

Conclusions: For potentially curable patients, VLDRT with 4 Gy in 2 fractions with a response-adapted approach offers excellent local control over 5 years with progression primarily occurring outside of the treated field. Need for subsequent systemic therapies and transformation risks are low. Relatively few patients required additional local RT following VLDRT and PFS rates are similar to use of higher RT doses. Given a superior toxicity profile and patient convenience, we advocate for further investigation of a VLDRT-anchored approach for all potentially curable patients.