Chemotherapy for Primary Central Nervous System Lymphoma

Antonio M. P. Omuro, MD; Lauren E. Abrey, MD

Disclosures

Neurosurg Focus. 2006;21(5) 

In This Article

Abstract and Introduction

Abstract

Chemotherapy, with or without radiotherapy, is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, and it is used in doses of 1 to 8 g/m2, either as a single agent or in combination with other drugs such as corticosteroid agents, cytarabine, procarbazine, vincristine, carmustine, lomustine, thiotepa, cyclophosphamide, temozolomide, and rituximab. To date, an overwhelming number of different regimens in which high-dose MTX is used have been reported. Given the lack of randomized trials, however, the optimal treatment remains controversial. Varying methodology makes the comparison of available studies extremely difficult, yet some common themes can be found throughout the literature. Treatment paradigms vary considerably according to the patient's age. Most studies support the use of chemotherapy-only treatments for elderly patients (> 60 years), given the high risks of neurotoxicity associated with radiotherapy. Nevertheless, the prognosis remains poor regardless of the chemotherapy chosen, and less toxic regimens might be preferable for such elderly patients. Conversely, in younger patients (< 60 years), there is growing evidence that commonly used chemotherapy-only regimens are associated with increased relapse rates that may not justify deferral of radiotherapy. Thus, a significant focus of research has been the development of intensified chemotherapy regimens that could replace radiotherapy. In this article, the authors discuss the principles guiding the use of chemotherapy for PCNSL, and critically review the available literature, including the most recent trials.

Introduction

Primary CNS lymphoma is a non-Hodgkin lymphoma that arises with in the brain, eyes, leptomeninges, or spinal cord in the absence of systemic disease. Histological analysis discloses a B-cell lymphoma in more than 90% of patients, and the lesion usually has large cell or immunoblastic features. Despite being a relatively rare tumor, its incidence has been increasing among immunocompetent patients over the past several decades.[33]

The first attempts to treat PCNSL were based on WBRT and corticosteroid drugs. This approach achieved limited results, with a median OS duration of 10 to 18 months, and 5-year survival rates of less than 5%.[30] Subsequently, it was demonstrated in numerous reports that adding certain chemotherapy regimens to WBRT could decrease relapse rates and improve survival.[12,17,19] The majority of active regimens include the use of high-dose MTX, which has become a standard component in the treatment of PCNSL. Nevertheless, the recognition of delayed neurotoxicity as a devastating and relatively frequent complication of combined chemo- and radiotherapy[34] prompted investigators to explore the possibility of deferring radiotherapy and treating patients with chemotherapy alone.[5,23,25,36,37,39]

Unfortunately, in most trials researchers have suggested that such an approach may compromise PFS, although some patients can be successfully treated with salvage therapy.[5,31,36,37] This fact has introduced significant controversy in the field, which is divided on the question of what constitutes an acceptable risk of radiotherapy-related dementia when attempting to achieve prolonged disease-free survival. Such controversy, aggravated by the lack of randomized trials defining the standard of care, has created a situation in which any regimen including high-dose MTX may be considered acceptable, whether or not it is combined with radiotherapy or other drugs ( Table 1 ). When confronted with the available literature, physicians and patients are overwhelmed by the wide range of different treatment approaches, and it is difficult to make an informed treatment decision. In this article, we discuss the principles guiding chemotherapy for PCNSL and critically review the available literature; our aim is to provide the necessary elements for better informed clinical decisions.

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