Elsevier

The Lancet

Volume 374, Issue 9700, 31 October–6 November 2009, Pages 1512-1520
The Lancet

Articles
High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial

https://doi.org/10.1016/S0140-6736(09)61416-1Get rights and content

Summary

Background

Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma.

Methods

This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18–75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3·5 g/m2 on day 1 (n=40) or methotrexate 3·5 g/m2 on day 1 plus cytarabine 2 g/m2 twice a day on days 2–3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00210314.

Findings

All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6–30) and 46% (31–61), respectively, (p=0·006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25–55) and 69% (55–83), respectively, (p=0·009). Grade 3–4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one).

Interpretation

In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone.

Funding

Swiss Cancer League.

Introduction

Present therapeutic knowledge of primary CNS lymphomas results from several single-group phase 2 trials, meta-analyses, and large retrospective studies. So far, only one randomised trial has been undertaken, which has been stopped early because of unsatisfactory accrual.1 The rarity of primary CNS lymphomas makes randomised trials difficult to do, and different opinions on many therapeutic aspects result in no consensus about the overall strategy and the main endpoints to be investigated in a randomised setting. The assessment of new first-line chemotherapy combinations in non-randomised trials, with divergent study designs and entry criteria, does not allow proper comparisons between different regimens, and has produced modest therapeutic progress.2, 3

Chemotherapy with high-dose methotrexate followed by whole-brain radiotherapy is the most commonly used approach for patients with newly diagnosed primary CNS lymphomas,3, 4 resulting in a 5-year survival of 20–35%.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 Several drugs have been combined with high-dose methotrexate to improve outcome; however, none had been previously assessed as effective single agents in patients with relapsed or refractory primary CNS lymphomas. Conversely, these drugs were selected on the basis of their capability to penetrate the blood–brain barrier and on their efficacy against systemic lymphomas. Findings from a meta-analysis of 19 prospective trials22 of primary CNS lymphomas and an international retrospective study of 378 patients4 suggested a survival improvement resulting from the addition of high-dose cytarabine to high-dose methotrexate. The rationale for the administration of high-dose cytarabine after high-dose methotrexate is the continuance of the exposure of proliferating cells to S-phase cytostatics and the increase of cytarabine-CTP formation and DNA incorporation, with a consequent increased cytotoxicity. Different combinations based on methotrexate and cytarabine have been used in patients with primary CNS lymphoma, mostly with promising results,17, 20, 23 but the assessment of this combination in a randomised setting remains crucial to clarify its risk–benefit ratio.

We examined the feasibility and activity of high-dose methotrexate alone and in combination with high-dose cytarabine as upfront chemotherapy in patients with newly diagnosed primary CNS lymphoma.

Section snippets

Study design and patients

This was a multicentre, open-label, randomised phase 2 trial undertaken in 24 centres in six countries (Argentina, Greece, Italy, Peru, Portugal, and Switzerland) between March 25, 2004, and Dec 20, 2007. Selection criteria for the trial were diagnosis of non-Hodgkin lymphoma made on stereotactic or surgical biopsy, cerebrospinal fluid (CSF) cytology examination, or vitrectomy; disease exclusively localised in the CNS, cranial nerves, or eyes; no previous treatment apart from steroids; at least

Results

Figure 1 shows the trial profile. 79 patients with primary CNS lymphoma were recruited and enrolled. 40 patients were randomly allocated to receive methotrexate alone and 39 to receive methotrexate plus cytarabine. Distribution of patients' characteristics between groups was similar (table 1).

There were no major protocol deviations related to chemotherapy. 231 (73%) of the 316 planned courses were delivered: 112 (70%) in methotrexate group and 119 (76%) in methotrexate plus cytarabine group. In

Discussion

Findings from this study show that the addition of high-dose cytarabine to high-dose methotrexate is associated with improved activity and efficacy compared with monochemotherapy with high-dose methotrexate in patients with primary CNS lymphoma. Moreover, this study shows that randomised trials in these patients are feasible, in a reasonable time-frame, and might provide useful information for improving the evidence-based management of these malignant diseases. To our knowledgde, this is the

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