Treatment of primary central nervous system lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ was safe, with the best 2-year overall survival rate and progression-free survival achieved in any Radiation Therapy Oncology Group primary CNS lymphoma trial, according to studies published in the Journal of Clinical Oncology.1

The phase 1 study was performed to determine the maximum tolerated dose of TMZ. The phase 2 trial’s endpoint was the 2-year overall survival rate. Secondary endpoints included preirradiation response rates, progression-free survival, neurologic toxicities, and quality of life.

For the phase 1 study, 12 patients received increased TMZ doses from 100 to 150 to 200 mg/m2. Patients were treated with rituximab 375 mg/m2 3 days prior to cycle 1; methotrexate 3.5 mg/m2 with leucovorin on weeks 1, 3, 5, 7, and 9; TMZ daily for 5 days on weeks 4 and 8; hWBRT 1.2 Gy twice daily on weeks 11 to 13 (38 Gy); and TMZ 200 mg/m2. A total of 53 patients were treated in the phase 2 trial.

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Results from the phase 1 trial showed that the maximum tolerated dose was 100 mg/m2 for TMZ and dose-limiting toxicities were hepatic and renal.

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In the phase 2 trial, 2-year overall survival was 80.8% and progression-free survival was 63.6% at a median follow-up of 3.6 years. Objective response rate was 85.7%. A total of 66 patients had grade 3 and 4 toxicities prior to hWBRT and 45% had grade 3 and 4 toxicities related to post-hWBRT.  Quality of life and cognitive function improved or stabilized post HWBRT.


  1. Glass J, Won M, Schultz CJ, et al. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227 [published online ahead of print March 28, 2016]. J Clin Oncol. doi: 10.1200/JCO.2015.64.8634.