Salvage whole brain radiotherapy after methotrexate failure in primary cns lymphoma

Abstract Introduction: Primary CNS lymphoma (PCNSL) is a rare and aggressive subtype of mostly B-cell non-Hodgkin lymphoma. While high-dose methotrexate (HD-MTX)-based regimens have significantly improved first-line outcomes, no consensus salvage strategy exists for relapsed or refractory disease. Whole brain radiotherapy (WBRT) is guideline-supported for consolidation, but its role after MTX failure remains poorly defined. Given the known radiosensitivity of PCNSL, we hypothesized that WBRT could provide meaningful survival benefit independent of MTX response. Methods We conducted a retrospective cohort study of adults with PCNSL treated at Memorial Sloan Kettering Cancer Center with WBRT following failure of an HD-MTX containing regimen. Patients were included if they received WBRT for radiographically persistent or progressive disease at any time following an HD-MTX–containing regimen. Overall survival (OS) was calculated from WBRT start using Kaplan-Meier estimates and reported with 95% confidence intervals. Subgroup analyses were performed to assess the impact of age ≤50 vs. >50 years) and normalized WBRT dose (<40 Gy BED10 vs. ≥40 Gy BED10). Results 52 patients treated between 2007-2024 met inclusion criteria. Median age at WBRT start was 59 years (range: 23–76) and median Karnofsky Performance Status (KPS) at diagnosis was 80 (range: 40–100). Patients received WBRT at a median of 8.7 months (range: 1.2–57.7 months) after initial diagnosis. Common WBRT doses included 45 Gy in 25 fractions (19%), 36 Gy in 20 fractions (17%), and 30 Gy in 10 fractions (10%). 27% received low dose WBRT (<40 Gy BED10). Median follow-up was 42.8 months among survivors and was 12.2 months among all patients. Median OS was 17.5 months (95% CI: 9–51 months). Patients aged ≤50 had significantly improved OS compared to patients >50 years (2-year OS 70% vs. 37%, p = 0.006). There was no significant OS difference when comparing patients who received <40 Gy BED10 vs. ≥40 Gy BED10 (p = 0.9). Discussion Amid evolving systemic therapy options for relapsed PCNSL, including immunomodulators, BTK inhibitors, and novel immunotherapies, the role of radiotherapy is uncertain. Our series provides the largest contemporary benchmark for salvage WBRT in methotrexate-refractory patients. We observed survival outcomes that compare favorably with systemic strategies, particularly for younger patients. Radiation dose was not associated with OS suggesting that traditional, higher doses of WBRT may be unnecessary to achieve adequate and durable disease control. These data reaffirm WBRT as a practical, effective salvage option and highlight the need for prospective studies to refine dose–fractionation, explore synergy with modern systemic agents, and incorporate neuroprotective strategies.