Real-world survival, cognitive, and quality of life outcomes of methotrexate/ifosfamide plus whole brain radiotherapy for newly diagnosed primary central nervous system lymphoma.

Background: Outcomes for primary central nervous system lymphoma (PCNSL) have been improved with high-dose methotrexate (HD-MTX)/Thiotepa-based chemotherapy followed by autologous stem cell transplantation. In limited-resource settings, HD-MTX/Ifosfamide plus whole brain radiotherapy (WBRT) has become the local standard of care. Objectives: This study investigated the real-world effectiveness, neurocognitive functions, and health-related quality of life (HRQoL) of HD-MTX/Ifosfamide in newly diagnosed PCNSL patients. Design: A single-center retrospective and prospective study. Methods: Newly diagnosed PCNSL patients treated with HD-MTX (±Ifosfamide) between 2011 and 2024 were analyzed for treatment effectiveness using binary logistic regression and a Cox regression model. The age range- and education-matched PCNSL and non-central nervous system (CNS) lymphoma patients in first remission were assessed using standardized cognitive tests and European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/BN20 questionnaires. The categorical data and continuous data were calculated with the Chi-square test or Fisher's exact test and analysis of variance, respectively. Results: Among 94 PCNSL patients, 56 patients received HD-MTX/Ifosfamide (median age 56 (range 16-69) years; 68% Eastern Cooperative Oncology Group (ECOG) 0-1) and 38 patients received HD-MTX monotherapy (median age 66 (range 51-82) years; 63% ECOG ⩾2). HD-MTX/Ifosfamide demonstrated a significantly longer event-free survival (39 months vs 8 months, p = 0.021) than HD-MTX monotherapy. Poor performance status (ECOG ⩾2) was associated with inferior response (54.8% vs 78.8%, p = 0.013) and overall survival (hazard ratio 2.4 (95% confidence interval 1.57-4.56), p = 0.007). Patients who received WBRT consolidation had a superior 2-year progression-free survival (74.5% vs 35.6%, p < 0.001). Comparing neurocognitive tests in 20 PCNSL and 20 non-CNS lymphoma survivors showed no difference in overall scores, but trends toward lower attention and executive function scores in the PCNSL group. Most (16/20) PCNSL survivors received WBRT. Compared to non-CNS lymphoma survivors, PCNSL survivors reported significantly lower HRQoL, particularly in physical functioning, which might be attributed to residual neurological deficits. Conclusion: This study supports HD-MTX/Ifosfamide as an effective, well-tolerated regimen for younger, fit PCNSL patients. WBRT remains a valuable consolidation therapy to prevent recurrence without a pronounced decline in cognitive function. However, PCNSL survivors may experience subtle declines in attention, executive function, and HRQoL.