Central Nervous System (CNS) Prophylaxis

The CNS-IPI tool predicts which patients have a CNS relapse risk exceeding 10%.[43,44] It was developed by the German Lymphoma Study Group and validated by the British Columbia Cancer Agency database. The presence of four to six of the CNS-IPI risk factors (age >60 years, performance status ≥2, elevated LDH, stage III or IV disease, >1 extranodal site, or involvement of the kidneys or adrenal glands) was used to define a high-risk group for CNS recurrence (a 12% risk of CNS involvement by 2 years).[44]

CNS prophylaxis (usually with four to six doses of intrathecal methotrexate) is often recommended for patients with testicular involvement.[45-47][Level of evidence C3] A retrospective analysis of the German RICOVER studies compared intrathecal methotrexate with no prophylaxis in patients with DLBCL. This study was completed during the R-CHOP treatment era. With the possible exception of patients with testicular involvement, the analysis showed that intrathecal methotrexate did not reduce the risk of CNS disease.[48][Level of evidence C3]

Some clinicians use high-dose intravenous (IV) methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[43,49] Five retrospective studies and one network meta-analysis evaluating high-dose methotrexate alone in patients with high-risk DLBCL also showed no improvement in CNS relapse rate.[50-55][Level of evidence C3] Patients deemed at high risk for CNS relapse (e.g., patients with testicular, renal, or adrenal disease and three or more extranodal sites) may receive intrathecal methotrexate or high-dose IV methotrexate, but the lack of confirmatory randomized studies calls this standard into question and shows an urgent need for better therapeutics verified in clinical trials.[43,43] While there is insufficient evidence to support a significant benefit for CNS prophylaxis in most high-risk patients, the perceived risk of not treating for CNS relapse has often outweighed the lack of evidence for its efficacy.[43] Although patients with testicular involvement or kidney/adrenal involvement are considered an exception, there is only anecdotal benefit from intrathecal or high-dose IV methotrexate in reducing CNS recurrence.[45-47][Level of evidence C3]

In retrospective analyses, the addition of rituximab to CHOP-based regimens has significantly reduced the risk of CNS relapse.[48,56][Level of evidence C3] Patients with CNS dissemination at diagnosis or at relapse usually receive rituximab and high doses of methotrexate and/or cytarabine followed by autologous SCT, but this approach has not been assessed in randomized trials.[57,58][Level of evidence C3]