New drug combo for primary central nervous system lymphoma

20 Sep 2009

Combining cytarabine with conventional monochemotherapy (high-dose methotrexate) improves remission rates in patients with primary central nervous system lymphoma. (primary CNS lymphoma). The findings are discussed in an article published in an upcoming edition of The Lancet,written by Dr Andrés J. M. Ferreri, San Raffaele H Scientific Institute, Milan, Italy, and colleagues from the International Extranodal Lymphoma Study Group (IELSG).

Primary CNS lymphoma typically occurs in individuals with a median age of 60 years old, with a similar prevalence between men and women. In this randomised phase 2 trial, the researchers assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma. This is the first worldwide randomised trial to be successfully completed; an earlier randomised study was stopped due to insufficient recruitment.

The trial took place in 24 centres in six countries; 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18–75 years were given four courses of either methotrexate 3·5 g/m² on day 1 (40 patients) or methotrexate 3·5 g/m² on day 1 plus cytarabine 2 g/m² twice a day on days 2 and 3 (39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation (also a standard treatment). The primary endpoint was complete remission rate after chemotherapy.

The researchers found that, after chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% and 46%, respectively. Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% and 69%, respectively. As expected, a higher, but manageable, blood toxicity rate was observed in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs. six [15%]), and four patients died of toxic effects (three vs. one). Importantly, the drugs combination was associated with a significantly lower proportion of patients experiencing lymphoma relapse with respect to methotrexate alone, with a 20% improvement in the progression-free survival at 3 years.

The authors conclude: “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 liver and kidney function, with appropriate antimicrobial prophylaxis.”

In an accompanying Comment, Dr Peter O’Brien, Department of Radiation Oncology, Calvary Mater Oncology, Newcastle, NSW, Australia, and Dr John Seymour, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, say that rather than confirming these results, future investigators' efforts would be better spent investigating the benefits other aspects of treatment, such as contemporary biological agents and radiotherapy, the place of which they describe as 'uncertain'. They conclude: “The IELSG, and more latterly the International Primary CNS Lymphoma Study Group, have set the standard for a continuing international cooperative approach to improving the outcome for the diverse group of patients with this rare but potentially curable cancer.”