title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD. jon.glass@jefferson.edu.
authors.forename: Jon
authors.initials: J
authors.lastname: Glass
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Minhee
authors.initials: M
authors.lastname: Won
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schultz
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brat
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Bartlett
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: John H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Maria
authors.initials: M
authors.lastname: Werner-Wasik
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Barbara Jean
authors.initials: BJ
authors.lastname: Fisher
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Marcia K
authors.initials: MK
authors.lastname: Liepman
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Mark
authors.initials: M
authors.lastname: Augspurger
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Felix
authors.initials: F
authors.lastname: Bokstein
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Bovi
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Solhjem
authors.affiliation: Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D008223:Lymphoma / Q000188:drug therapy* / Q000532:radiotherapy*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D000069283:Rituximab / Q000008:administration & dosage / Q000009:adverse effects; D000077204:Temozolomide; D014916:Whole-Body Irradiation; D055815:Young Adult
chemical_list: D000069283:Rituximab; D003606:Dacarbazine; D000077204:Temozolomide; D008727:Methotrexate