Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome

Abstract

Purpose: A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma.

Patients and methods: Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor.

Results: Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33).

Conclusion: R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

Trial registration: ClinicalTrials.gov NCT00594815.

Fig 1.

CONSORT diagram. (*) One patient was ineligible because of evidence of systemic non-Hodgkin lymphoma, and two had rapid progression of disease before initiation of any protocol therapy. (†) One patient had a CR and received reduced-dose WBRT off protocol; the other had a PR and received standard-dose WBRT. (‡) Includes one patient who developed renal impairment and only received six cycles of treatment. He achieved a CR, completed the rest of treatment per protocol, and is alive and progression-free 4.5 years later. (§) One patient died as a result of toxicity and one as a result of unknown causes. CR, complete response; PD, progressive disease; PR, partial response; R-MPV, rituximab, methotrexate, procarbazine, and vincristine; SD, stable disease; WBRT, whole-brain radiotherapy.

Fig 2.

Progression-free survival (PFS) and overall survival (OS). (A) PFS and OS in patients who received reduced-dose radiotherapy (n = 31). The 1-, 2-, and 3-year PFS was 84% (95% CI, 71% to 97%), 77% (95% CI, 63% to 92%), and 71% (95% CI, 55% to 87%), respectively. The 1-, 2-, 3-, and 5-year OS was 94% (95% CI, 85% to 100%), 90% (95% CI, 80% to 100%), 87% (95% CI, 75% to 99%), and 80% (95% CI, 66% to 94%), respectively. (B) PFS by age in patients who received reduced-dose radiotherapy (n = 31). The 1-, 2-, and 3-year PFS for patients younger than 60 years was 94% (95% CI, 82% to 100%), 94% (95% CI, 82% to 100%), and 88% (95% CI, 71% to 100%), respectively. The 1-, 2-, and 3-year PFS for patients ≥ 60 years of age was 73% (95% CI, 51% to 96%), 60% (95% CI, 35% to 85%), and 53% (95% CI, 28% to 79%), respectively. (C) Intent-to-treat PFS and OS in entire cohort (n = 52). The 1-, 2-, and 3-year PFS was 65% (95% CI, 52% to 78%), 57% (95% CI, 44% to 71%), and 51% (95% CI, 38% to 65%), respectively. The 1-, 2-, 3-, and 5-year OS was 85% (95% CI, 75% to 94%), 81% (95% CI, 70% to 91%), 77% (95% CI, 65% to 88%), and 70% (95% CI, 57% to 83%), respectively. (D) Intent-to-treat PFS by age in entire cohort (n = 52). The 1-, 2-, and 3-year PFS for patients younger than 60 years was 68% (95% CI, 50% to 86%), 64% (95% CI, 45% to 83%), and 64% (95% CI, 45% to 83%), respectively. The 1-, 2-, and 3-year PFS for patients ≥ 60 years of age was 63% (95% CI, 45% to 81%), 47% (95% CI, 28% to 66%), and 38% (95% CI, 19% to 57%), respectively.