Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience

Abstract

PURPOSE Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved. PATIENTS AND METHODS This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age > or = 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis. Results The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age < 60 years and KPS > or = 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae. CONCLUSION This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens.

Fig 1.

Progression-free survival (yellow line; median, 1.8 years; 95% CI, 1.3 to 2.8 years) from date of first intra-arterial/blood-brain barrier disruption treatment (149 patients, 93 have experienced disease progression) with 95% CI (blue lines). Symbols on lines indicate censored observations.

Fig 2.

Overall survival (yellow line; median, 3.1 years; 95% CI, 2.2 to 5.0 years) from date of first intra-arterial/blood-brain barrier disruption treatment (149 patients, 96 deaths) with 95% CI (blue lines). Symbols on lines indicate censored observations.

Fig 3.

(A) Overall survival according to proposed risk groups. Survival from date of first intra-arterial/blood-brain barrier disruption treatment stratified by age and Karnofsky performance score (KPS). Low risk, age younger than 60 years with KPS ≥ 70 (47 patients); moderate risk, age older than 60 years with any KPS or age younger than 50 years with KPS less than 70 (89 patients); and high risk, age 50 to less than 60 years with KPS less than 70 (13 patients). Symbols on lines indicate censored observations. (B) Progression-free survival according to proposed risk groups. Progression-free survival from date of first intra-arterial/blood-brain barrier disruption treatment stratified by age and KPS. Low risk, age 50 to less than 60 years with KPS greater than 70, or age less than 50 years with any KPS (65 patients); moderate risk, age ≥ 60 years with any KPS (71 patients); and high risk, age 50 to less than 60 years with KPS less than 70 (13 patients). Symbols on lines indicate censored observations.