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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. J Clin Oncol 2016 05 10;34(14):1620-5



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Scopus ID

2-s2.0-84969916579   50 Citations


PURPOSE: This study investigated the treatment of primary CNS lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Secondary end points were preirradiation response rates, progression-free survival (PFS), neurologic toxicities, and quality of life.

PATIENTS AND METHODS: The phase I study increased TMZ doses from 100 to 150 to 200 mg/m(2). Patients were treated with rituximab 375 mg/m(2) 3 days before cycle 1; methotrexate 3.5 g/m(2) 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 (36 Gy); and TMZ 200 mg/m(2) daily for 5 days every 28 days on weeks 14 to 50.

RESULTS: Thirteen patients (one ineligible) were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m(2). Dose-limiting toxicities were hepatic and renal. In phase II, 53 patients were treated. Median follow-up for living eligible patients was 3.6 years, and 2-year OS and PFS were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG-9310, 2-year OS and PFS were significantly improved (P = .006 and .030, respectively). In phase II, the objective response rate was 85.7%. Among patients, 66% (35 of 53) had grade 3 and 4 toxicities before hWBRT, and 45% (24 of 53) of patients experienced grade 3 and 4 toxicities attributable to post-hWBRT chemotherapy. Cognitive function and quality of life improved or stabilized after hWBRT.

CONCLUSION: This regimen is safe, with the best 2-year OS and PFS achieved in any Radiation Therapy Oncology Group primary CNS lymphoma trial. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies.

Author List

Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP


Joseph A. Bovi MD Professor in the Radiation Oncology department at Medical College of Wisconsin
Christopher J. Schultz MD Chair, Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Combined Chemotherapy Protocols
Central Nervous System Neoplasms
Disease-Free Survival
Induction Chemotherapy
Middle Aged
Whole-Body Irradiation
Young Adult
jenkins-FCD Prod-478 d1509cf07a111124a2d122fd3df854cc0b993c00