Promising Outcomes With R-MPV Followed by Consolidation Reduced-Dose Whole-Brain Radiotherapy and Cytarabine in Newly Diagnosed Primary CNS Lymphoma
In a phase II trial reported in the Journal of Clinical Oncology, Patrick G. Morris, MD, of Memorial Sloan-Kettering Cancer Center, and colleagues assessed the efficacy of rituximab (Rituxan), methotrexate, procarbazine (Matulane), and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in primary central nervous system (CNS) lymphoma. They found that the strategy produced high response rates, prolonged progression-free and overall survival, and minimal neurotoxicity.
Study Details
In the study, 52 patients with newly diagnosed primary CNS lymphoma received induction chemotherapy with five to seven 14-day cycles of R-MPV, consisting of rituximab at 500 mg/m2 on day 1, methotrexate at 3.5 g/m2 over 2 hours and vincristine at 1.4 mg/m2 on day 2, and procarbazine at 100 mg/m2 per day on days 1 to 7 in odd cycles only. After grade 4/5 neutropenia was observed in two of the first five patients enrolled, all patients received prophylactic filgrastim (Neupogen) after each cycle. Patients achieving a complete response received reduced-dose whole-brain radiotherapy (23.4 Gy), with standard whole-brain radiotherapy (45 Gy) otherwise being offered. After radiotherapy, all patients received two 28-day high-dose cytarabine cycles at 3 g/m2/d on days 1 and 2 of each cycle. Prophylactic filgrastim/pegfilgrastim (Neulasta) was given after each cytarabine cycle.
The primary endpoint was 2-year progression-free survival in patients receiving reduced-dose whole-brain radiotherapy. Exploratory endpoints included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient as a prognostic factor. Three cognitive domains were evaluated: executive (Trail Making Test, Brief Test of Attention), verbal memory (Hopkins Verbal Learning Test), and motor speed (Grooved Pegboard Test). Quality of life was examined using the Functional Assessment of Cancer Therapy-Brain Cancer, and mood was evaluated with the Beck Depression Inventory.
Patients had a median age of 60 years (range, 30–79 years), 58% were men, and median Karnofsky performance score was 70 (range, 50–100).
Efficacy Outcomes
Overall, 31 patients (60%) achieved complete response after R-MPV and received reduced-dose whole-brain radiotherapy. In this group, 2-year progression-free survival was 77%, and median progression-free survival was 7.7 years. Median overall survival was not reached after median follow-up of 5.9 years for survivors, and 3-year overall survival was 87%. Among all 52 patients, median progression-free survival was 3.3 years and median overall survival was 6.6 years.
Cognitive impairment was present in several domains at baseline. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and there was no evidence of significant cognitive decline during follow-up except in motor speed (P < .05). Minor fluctuations were observed in memory performance over time. There was no evidence of depressed mood, and self-reported quality of life remained stable during follow-up.
All 28 examined MRIs had a Fazekas score of ≤ 3, with no patients developing scores of 4 to 5. Differences in apparent diffusion coefficient values did not predict response (P =.15), progression-free survival (P = .27), or overall survival (P = .33).
Toxicities
Neutropenia was the main dose-limiting toxicity. Four patients discontinued study treatment due to toxicity before completing five cycles of R-MPV, one with grade 3 renal impairment, one with grade 3 ileus, one with grade 5 febrile neutropenia, and one with grade 4 perforated diverticulum. In addition, one patient had grade 5 neutropenia after the fifth cycle of R-MPV and one patient had grade 5 febrile neutropenia/pneumonitis after the second cycle of cytarabine. Three deaths (6%) were considered possibly/probably related to toxicity.
The investigators concluded: “R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity…. Our study adds to the existing therapeutic arsenal for newly diagnosed patients, providing an alternative treatment option that could potentially benefit patients of all ages.”
The Radiation Therapy Oncology Group (RTOG) is conducting a randomized study to confirm and and build on the results of this trial. RTOG 1114 will compare the R-MPV regimen with or without reduced-dose whole-brain radiotherapy, and the authors noted that the findings of this upcoming trial “could ultimately guide the individualization of treatment choices to achieve optimal outcomes.”
Antonio Omuro, MD, of Memorial Sloan-Kettering Cancer Center is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Memorial Sloan-Kettering Cancer Center Department of Neurology Research and Development funds. Genentech provided rituximab and partial financial support.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
