The role of chemotherapy additional to high-dose methotrexate for treatment of patients with primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a malignant disease of the lymphatic system that accounts for about 2% to 5% of all primary intracranial tumours in immunocompetent patients. It is a form of extranodal non-Hodgkin lymphoma (NHL) and appears at a median age of 62 years. PCNSL is a rare disease with an incidence of 2.7 cases per million population per year, but since the 1990s the occurrence of it has increased in immunocompetent as well as immunocompromised (mostly human immunodeficiency virus (HIV)-infection related) populations. Symptoms of PCNSL can present manifold though the usual signs are neurological deficits, neuropsychiatric symptoms and raised intracranial pressure. Despite improved treatment strategies, overall survival is still poor and a standard of care for PCNSL patients has not been defined yet. However, high-dose methotrexate (HD-MTX) with additional chemotherapy is considered to increase overall survival although the value of additional chemotherapy remains unclear, as there is evidence of a higher risk of adverse events. In this systematic review we summarised and analysed the evidence from randomised controlled trials (RCTs) on efficacy and safety of methotrexate combined with additional chemotherapy in the treatment of adult, immunocompetent PCNSL patients regarding overall survival, progression-free survival, response rate, adverse events, treatment-related mortality and quality of life. We searched several important medical databases such as CENTRAL and MEDLINE and found one RCT with 79 patients that fulfilled our inclusion criteria. As a result, this review shows that patients treated with methotrexate plus cytarabine compared to high-dose methotrexate alone have a statistically significant improvement in progression-free survival and response rate. No statistically significant difference is shown for overall survival. Adverse events, especially infections, hepatotoxicity and haematological toxicities are more common in patients undergoing therapy with methotrexate plus cytarabine, although there are no differences in terms of treatment-related mortality. Owing to the small number of included trials and patients, the findings in this review remain uncertain and more RCTs with enlarged numbers of patients and longer follow-up periods are needed. However, the one analysed study demonstrated that RCTs are feasible on patients with this rare disease and should concentrate on overall survival.

Authors' conclusions: 

Owing to the small number of included trials and patients, the findings in this review remain uncertain. In summary, the presently available evidence (one small trial) showed a benefit in terms of PFS, ORR and CRR but no statistically significant difference regarding OS for patients with PCNSL treated with HD-MTX plus cytarabine compared to HD-MTX alone. However, the risk of severe infections and toxicity was significantly higher in patients treated with combined chemotherapy. More RCTs with additional chemotherapy to HD-MTX therapy with higher numbers of patients and longer follow-up periods are needed to confirm the results of this review and determine whether the PFS benefit will translate into an OS advantage. At least the one included study shows that RCTs of moderate quality and with valuable outcomes for this malignant disease are feasible.

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Background: 

Primary central nervous system lymphoma (PCNSL) is a variant of extranodal non-Hodgkin lymphoma (NHL) that accounts for about 2% to 5% of all primary intracranial tumours with immunocompetent patients. It appears at a median age of 62 years. A standard of care for PCNSL patients has not been defined yet, but high-dose methotrexate (HD-MTX) is considered to be a beneficial chemotherapy in PCNSL treatment. Currently, HD-MTX is combined with numerous other chemotherapy drugs to improve outcomes of HD-MTX monotherapy. However, the impact of additional chemotherapy remains unclear, as there is evidence of a higher risk of adverse events (AEs) such as infective complications.

Objectives: 

We performed a systematic review of randomised controlled trials (RCTs) to assess the efficacy and safety of additional chemotherapy to HD-MTX in the treatment of immunocompetent PCNSL patients.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5) and MEDLINE (from 1950 to May 2012) as well as conference proceedings for RCTs. Two review authors (NB, NS) independently screened search results.

Selection criteria: 

We included RCTs comparing HD-MTX in combination with additional chemotherapy to mono-chemotherapy with HD-MTX in immunocompetent patients off all ages in first-line treatment of PCNSL.

Data collection and analysis: 

As an effect measure we used hazard ratios (HR) and 95% confidence intervals (CI) for overall survivals (OS) and progression-free survival (PFS). For effect measure of complete remission rate (CRR), partial response rate (PRR), treatment-related mortality (TRM) and AEs we used risk ratios (RR). Two review authors (NB, NS) independently extracted data and assessed the quality of trials.

Main results: 

Our search strategies led to 699 potentially relevant references. Of these, one RCT involving 79 patients was included. We judged the quality of the trial as moderate. The study was reported as a randomised open-label study and published as a full-text article.

Even though PFS was statistically significantly improved for patients treated with HD-MTX plus cytarabine (HR 0.54; 95% CI 0.31 to 0.92; P = 0.01), this did not translate to a statistical significant OS benefit (HR 0.65; 95% CI 0.38 to 1.13; P = 0.07). AEs, especially infective complications, hepatotoxicity and haematological toxicities, were assessed more often in patients undergoing HD-MTX therapy combined with cytarabine. However, there were no statistically significant differences in terms of TRM (RR 3.08; 95% CI 0.33 to 28.32; P = 0.35).

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