Researchers involved in a multicenter European-South American study have reported that the addition of high-dose cytarabine to high-dose methotrexate improves the response rate in patients with primary central nervous system lymphoma (PCNSL). The details of this study were published early online on September 20, 2009 in The Lancet.[1]

Primary central nervous system lymphoma is a relatively uncommon form of non-Hodgkin’s lymphoma (NHL) that has been increasing in incidence during the past three decades. Unlike the progress made in the general treatment of NHL, there has been little progress in the treatment of PCNSL NHL. The standard treatment is high-dose methotrexate and whole-brain radiotherapy, which has improved outcomes. However, relapse rates are high with standard approaches, and studies continue to evaluate new approaches to treating PCNSL.

Researchers from Harvard have recently updated results from a trial referred to as the NABITT trial, which included 25 patients with newly diagnosed PCNSL. Patients were treated with high-dose methotrexate every two weeks until there was no detectable cancer for a minimum of four months. With a median follow-up of seven years, the median overall survival was 4.6 years. Median disease-specific survival has not yet been reached.

The current study included 79 patients with PCNSL treated in 24 centers in six countries. All patients received four courses of high-dose methotrexate and folinic acid followed by whole brain radiotherapy. The median age was 58 years, with the oldest patient being 74 years old. Half the patients were randomly allocated to receive cytarabine for three days in each course of treatment. The overall response rate was 40% for the methotrexate-alone group and 69% for the cytarabine group. The complete response rate was 18% for the methotrexate alone group compared with 46% in the cytarabine group. Hematologic toxicities were more frequent and more severe in the cytarabine group. The three-year failure-free survival was 21% for the methotrexate-alone group and 38% for the cytarabine group. The three-year overall survival was 32% for the methotrexate-alone group and 46% for the cytarabine group (P=0.07). Twenty-three patients in the methotrexate group received salvage therapy compared with 10 in the cytarabine group; responses in both groups were 48% and 56%, respectively. There were three toxic deaths in the cytarabine group and one in the methotrexate-alone group.

These authors concluded: “The addition of high-dose cytarabine to high-dose methotrexate is associated with a remarkable outcome benefit in patients with primary CNS lymphoma. This combination could be used as an upfront approach in patients aged 75 years and younger and with adequate hepatic and renal function, with appropriate antimicrobial prophylaxis. The combination of methotrexate and cytarabine might be considered as the control group for future randomised trials, as it is supported by the best level of evidence available in the field of primary CNS lymphoma.”

Comments: This is one of the very few randomized, controlled trials evaluating treatment for PCNSL. Whether of not cytarabine and methotrexate will become standard therapy remains to be determined with further studies.

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