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Some people with aggressive lymphoma are given extra methotrexate, into the spine or into a vein, to stop the lymphoma reaching the brain. It has been standard for decades, and the best evidence now available suggests it does not work.
Relapse in the brain or the spinal fluid after R-CHOP happens in roughly 2 to 5 per cent of people with diffuse large B-cell lymphoma, usually within the first year, and is hard to treat. The CNS-IPI, derived from 2,164 patients in the German High-Grade Non-Hodgkin Lymphoma Study Group and MabThera International Trial studies and validated in 1,597 British Columbia patients, puts the five IPI factors together with kidney or adrenal involvement to give three groups: low risk (46 per cent of patients, 2-year CNS disease 0.6 per cent), intermediate (41 per cent, 3.4 per cent) and high (12 per cent, 10.2 per cent). Testicular, breast, uterine and epidural sites, and certain molecular subgroups, raise the risk independently.
The practice that grew up around that risk was to give intrathecal methotrexate with each cycle, or two to four doses of systemic high-dose methotrexate at 3 to 3.5 g per square metre, to high-risk patients. Both routes now have evidence against them. A retrospective study across 21 United States academic centres of 1,162 adults who all received single-route prophylaxis found CNS relapse in 5.7 per cent, with no difference between intrathecal (5.4 per cent) and systemic high-dose methotrexate (6.8 per cent, p 0.4), and the observed relapse rate was almost identical to the rate predicted by CNS-IPI alone (5.7 against 5.8 per cent expected). In other words, the prophylaxis did not move the number it was given to move. Several large international retrospective series have since reported the same. There has never been a randomised trial.
Where that leaves practice in 2026: intrathecal prophylaxis has largely been abandoned in the United Kingdom and much of Europe; systemic high-dose methotrexate is still offered to some patients with a high CNS-IPI, testicular involvement or high-grade B-cell lymphoma, and is increasingly discussed as a choice rather than given as a rule, because it carries renal and mucosal toxicity and delays the chemotherapy it is interleaved with. Anyone offered it is entitled to ask what the absolute benefit is believed to be, and the honest answer is that it has not been demonstrated.
Showing the molecule this term concerns: Methotrexate.
Shares R-CHOP (lymphoma chemoimmunotherapy), Primary CNS lymphoma, Methotrexate, Diffuse large B-cell lymphoma.
Shares Cytarabine, Burkitt lymphoma, Methotrexate, Diffuse large B-cell lymphoma.
Shares International Prognostic Index (IPI), British and American lymphoma practice: where they differ, and why, Non-Hodgkin lymphoma (all types), Diffuse large B-cell lymphoma.
Shares Burkitt lymphoma, Non-Hodgkin lymphoma (all types), Diffuse large B-cell lymphoma.
Shares CNS penetration (brain-penetrant drugs), Intrathecal therapy (lumbar puncture, Ommaya reservoir).
Shares Cytarabine, Primary CNS lymphoma, Methotrexate.
Shares International Prognostic Index (IPI), Diffuse large B-cell lymphoma.
Shares Cytarabine, Primary CNS lymphoma, Methotrexate, Non-Hodgkin lymphoma (all types).