Challenges in defining a new standard of care in Primary CNS Lymphoma

In May 2016, Glass et al. published in the Journal of Clinical Oncology the results of a phase I/II study into the efficacy of methotrexate, temozolomide (TMZ) with rituximab, proceeded by hyperfractionated Whole-Brain Radiotherapy (hWBRT) in patients with Primary CNS Lymphoma (PCNSL), followed by maintenance treatment with TMZ. The reported 2-year OS and PFS were 80.8% and 63.6%, respectively.

In a more recent correspondence, also in the Journal of Clinical Oncology, Marc C. Chamberlain, of the University of Washington and Fred Hutchinson Cancer Research Center, Seattle, responded to these results explaining potential issues with the study. The key points of concern were:

  • Due to timing of assessments, it was unclear if rituximab, dosed at 5 intervals alongside HD-MTX, provided an additional benefit
  • TMZ has limited data as a single-agent treatment in this setting
  • TMZ dose was lower than other studies, potentially leading to undertreatment with TMZ
  • Use of dose-reduced hWBRT to reduce late neurotoxicity, however no significant evidence of late neurotoxicity was reported since the measure of cognitive dysfunction used was poor
  • Myeloablative conditioning chemotherapy and ASCT are more frequently being suggested as alternatives to consolidation WBRT
  • Value of 10 cycles of TMZ maintenance therapy, following hWBRT, was not shown


In conclusion, both the authors of the original study and Marc Chamberlain state that randomized trials are needed to elucidate the value of these protocol modifications for treatment of PCNSL. Marc Chamberlain also suggested that deciding upon which regimen a patient should follow is based on “interpretation of a confusing literature”, and the physician’s familiarity with and subjective opinions of therapies, amplifying the need for more randomized, multi-arm studies.

References:
  1. Chamberlain M.C. Immunochemotherapy, the New Standard of Care for Primary CNS Lymphoma: However, Which One? Journal of Clinical Oncology. 2016 Oct; 34(33):4056–4057. doi: 10.1200/JCO.2016.68.9018.
  2. Glass J. 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. Journal of Clinical Oncology. 2016 May; 34(14):1620–5. doi: 10.1200/JCO.2015.64.