Fast track — ArticlesHigh-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial
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
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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
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2023, Critical Reviews in Oncology/HematologyRecent advances in the diagnosis and the treatment of primary CNS lymphoma
2023, Revue Neurologique
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These authors contributed equally