Elsevier

The Lancet Oncology

Volume 11, Issue 11, November 2010, Pages 1036-1047
The Lancet Oncology

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High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial

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Summary

Background

High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival.

Methods

Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m2) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m2) on days 3–5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530.

Findings

551 patients (median age 63 years, IQR 55–69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8–39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5–46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80–1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6–25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3–16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%).

Interpretation

No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.

Funding

German Cancer Aid.

Introduction

Primary CNS lymphoma is a rare brain tumour with a yearly incidence of 0·5 cases per 100 000 people. The incidence of primary CNS lymphoma is supposed to be rising in immunocompetent individuals, whereas it seems to be decreasing in patients with HIV infection. Median age at diagnosis is 60–65 years, and median survival is 10–20 months, with survival of less than 20–30% at 5 years.1, 2, 3, 4, 5, 6

Standards of care have not been well defined. Surgical measures outside a stereotactic biopsy sample to confirm diagnosis are not recommended. Whole brain radiotherapy induces complete response defined by neuroimaging in up to 60% of patients, but the duration of remission is usually short and median survival is only 12–18 months.7 High-dose methotrexate, given at doses above 3·5 g/m2 in intervals of 2–3 weeks, is the most active drug for primary CNS lymphoma. Combination of a chemotherapy regimen based on high-dose methotrexate and whole brain radiotherapy, with or without intrathecal chemotherapy, induced high response rates and extended survival to up to 30–60 months in phase 2 studies,8, 9, 10, 11 but was associated with intolerable long-term neurotoxicity, especially in elderly people.12, 13 Accordingly, various strategies maintaining treatment efficacy, but reducing toxic effects, were explored, including the use of high-dose methotrexate alone.14, 15, 16 However, the German NOA-03 trial did not confirm adequate response rates and survival times with high-dose methotrexate alone as the first-line treatment for primary CNS lymphoma.17, 18 The response rate increased when high-dose cytarabine was added to high-dose methotrexate as part of first-line chemotherapy.19 The role of whole brain radiotherapy added to high-dose methotrexate in first-line treatment of primary CNS lymphoma has been identified as the most important issue to address.20 Accordingly, the German Primary CNS Lymphoma Study Group (G-PCNSL-SG) designed a randomised trial in 1999 to test the hypothesis that first-line treatment with a chemotherapy regimen based on high-dose methotrexate was not inferior to the same first-line chemotherapy followed by whole brain radiotherapy for patients with newly diagnosed primary CNS lymphoma (figure 1). Preliminary data have been reported for HLA associations in 82 patients,21 treatment tolerability in 154 elderly patients,22 relapse patterns in 227 patients,23 cerebrospinal fluid (CSF) findings in 116 patients,24 and occurrence of leptomeningeal dissemination in 282 patients.25

Section snippets

Patients

Patients were enrolled from 75 centres in Germany and treated between May, 2000, and May, 2009. Patients were eligible for inclusion in the study if they met the following criteria: 18 years or older; primary CNS lymphoma confirmed by histology or by cytology or immunocytochemistry from CSF; no previous cytostatic treatment; no evidence of extra-CNS involvement; life expectancy of more than 2 months; neutrophil count of more than 1500 cells per μL; platelet count of more than 100 000 per μL;

Results

551 patients, with a median age of 63 years (IQR 55–69), were enrolled and randomly allocated to receive treatment, but 14 patients were excluded before the first dose of first-line chemotherapy because they did not meet inclusion criteria (another histological diagnosis, severe systemic infection or pulmonary embolism before chemotherapy, or proof of systemic lymphoma manifestations) or they refused to participate (figure 2). A further 11 patients were excluded during first-line chemotherapy

Discussion

Although overall survival was similar in both treatment groups, our findings did not prove our primary hypothesis that omission of whole brain radiotherapy is non-inferior to whole brain radiotherapy for overall survival in patients with newly diagnosed primary CNS lymphoma who are receiving first-line chemotherapy based on high-dose methotrexate (panel).

Primary CNS lymphoma has remained a major challenge in neuro-oncology for decades. Unresolved issues include the cell of origin, the lymphoma

References (38)

  • NS Kadan-Lottick et al.

    Decreasing incidence rates of primary central nervous system lymphoma

    Cancer

    (2002)
  • LM DeAngelis et al.

    Combined modality therapy for primary CNS lymphoma

    J Clin Oncol

    (1992)
  • LM DeAngelis et al.

    Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10

    J Clin Oncol

    (2002)
  • LE Abrey et al.

    Treatment for primary CNS lymphoma: the next step

    J Clin Oncol

    (2000)
  • LE Abrey et al.

    Long-term survival in primary CNS lymphoma

    J Clin Oncol

    (1998)
  • IT Gavrilovic et al.

    Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma

    J Clin Oncol

    (2006)
  • N Guha-Thakurta et al.

    Intravenous methotrexate as initial treatment for primary central nervous system lymphoma. Response to therapy and quality of life of patients

    J Neurooncol

    (1999)
  • S Hiraga et al.

    Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas

    J Neurosurg

    (1999)
  • T Batchelor et al.

    Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07

    J Clin Oncol

    (2003)
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