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Methotrexate May Cure up to 20% of Patients With Rare Brain Tumor

Caroline Cassels

New research shows that high-dose methotrexate is the most effective drug for primary central nervous system lymphoma (PCNSL), with up to 20% of patients achieving a long-term remission with monotherapy.

In a follow-up study of the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium, investigators at the Massachusetts General Hospital Cancer Center, in Boston, found that of the original 25 PCNSL patients, 12 (52%) achieved complete remission after a minimum follow-up of 6.5 years. Of these individuals, 5 (40%) have not relapsed after a median follow-up of 6.8 years.

“In this small, multicenter study we found that at almost 7 years of follow-up, 5 of the original 25 patients were still in remission after treatment with high-dose methotrexate alone and that toxicity was modest,” principal investigator Tracy Batchelor, MD, told Medscape Neurology & Neurosurgery.

The study is published in the January 29 issue of Neurology.

Neurotoxicity

A rare non-Hodgkins lymphoma, PCNSL is confined to the nervous system and accounts for approximately 3% of all primary brain tumors. In the United States, there are approximately 1500 new cases annually.

The incidence of PCNSL has risen 3-fold over the last 30 years, an increase that in part is attributed to the human immunodeficiency virus (HIV) epidemic.

“It was felt that a lot of this increased incidence was driven by the HIV pandemic, because immunosuppression is a risk factor for developing a CNS lymphoma. The current data indicate that the incidence of the disease is beginning to stabilize, which likely reflects improved HIV treatment,” said Dr. Batchelor.

The disease is most commonly seen among individuals age 60 years and older, and whole brain radiation therapy (WBRT) was the traditional standard of care — initially alone and subsequently in combination with chemotherapy. However, neurotoxicity associated with WBRT, particularly in older patients, led researchers to consider other, potentially less detrimental, therapies.

“Most patients over the age of 60 will develop neurotoxicity [with WBRT] that is akin to a dementing illness and includes memory failure, cognitive loss, and difficulties with balance,” he said.

Equally Effective, Less Toxic

With initial 2-year results published in 2003 in the Journal of Clinical Oncology (Batchelor T et al. J Clin Oncol. 2003;21:1044-1049), the aim of the initial study was to determine whether methotrexate monotherapy could offer patients an equally effective, less toxic, alternative.

According to Dr. Batchelor, clinicians began to use methotrexate to treat PCNSL because, unlike many other chemotherapeutic agents, at high doses it had the ability to cross the blood-brain barrier and appeared to be effective and well tolerated.

“We found [in the first study] that we were able to achieve comparable remission rates with methotrexate without incurring the same kind of neurotoxicity associated with whole brain radiation,” said Dr. Batchelor.

The current study examined long-term outcomes of the original 25 adults with newly diagnosed, non–HIV-related PCNSL who received an intravenous infusion of 8 g/m2 of methotrexate every 2 weeks for 4 months or until they achieved a complete response (CR) as determined by radiographic criteria.

With an average follow-up of 6.5 years, investigators found the average survival among the study group was 4.5 years. In contrast, they note, the average survival rate for patients who receive WBRT is approximately 1 year.

Eleven patients died of progressive disease or unknown causes, and 3 died from other medical illnesses, for a total of 14 deaths. Methotrexate was well tolerated, with more than half the study subjects experiencing no dose-limiting adverse effects.

First-Line Therapy

While the study did not measure cognitive outcomes, the anecdotal experience is that methotrexate does not have the same detrimental impact on cognition as WBRT, he added.

“This is more evidence that methotrexate is important — perhaps the most important drug in the treatment of CNS lymphoma. This research shows that a subset of patients can achieve a long-term remission with methotrexate and that it is better tolerated than some of the other, more toxic therapies we use for this disease,” said Dr. Batchelor.

Plans for another prospective, phase 2, multicenter study that will include approximately 40 PCNSL patients are currently under way. This time, the investigators will look at outcomes of methotrexate in combination with 3 other agents — temozolomide, rituximab, and topotecan.

In addition to remission and survival, the next study will also measure cognitive outcomes, which Dr. Batchelor said are vitally important in a disease where treatment has the potential to affect brain function.

The study was supported by the National Cancer Institute. The authors report no conflicts of interest.

Neurology. 2008;70:401-402.

Thanks to Medscape Medical News 2008. www.medscape.com
January 2008


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