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Therapeutic use and toxicity of high-dose methotrexate

Topic Outline

GRAPHICS

CALCULATORS

INTRODUCTION

Folate antagonists were among the first antineoplastic agents to be developed. In 1948, aminopterin was used to induce remission in childhood acute lymphoblastic leukemia (ALL), and the related agent methotrexate (MTX) is still an important component of modern treatment for ALL as well as a number of other hematologic malignancies [1]. MTX was the first drug shown to cure a cancer when given as monotherapy, and single agent MTX remains a cornerstone of treatment for malignant gestational trophoblastic disease [2].

The broad range of antitumor activity seen with MTX is reflected in the large number of malignant conditions for which MTX is a component of the treatment regimen (table 1). Furthermore, in addition to antiproliferative activity, MTX also has antiinflammatory and immunomodulating properties, leading to its use in a wide range of doses for a broad range of therapeutic indications across multiple specialties (table 2).

This topic review will cover the clinical use of high-dose MTX for treatment of malignancy, focusing on the prevention and management of toxicity. Intrathecal use of MTX and clinical use of low-dose and intermediate-dose MTX for both malignant and nonmalignant conditions are covered elsewhere. (See appropriate topic reviews).

DEFINITION OF HIGH-DOSE MTX

The side effect profile of MTX varies markedly according to dose. Regimens containing MTX are classified as high, intermediate, or low-dose:

Most clinicians reserve the term high-dose MTX (HDMTX) for doses ≥500 mg/m2, as are used for central nervous system (CNS) prophylaxis in patients with leukemia and high-risk lymphoma, and for the treatment of leptomeningeal metastases, primary CNS lymphoma, and osteosarcoma. These regimens deliver an otherwise lethal dose of MTX in a 4 to 36 hour infusion, and require a two to three day period of multiple leucovorin doses to terminate the toxic effect of MTX (termed leucovorin "rescue"). Successful rescue by leucovorin depends on rapid elimination of MTX by the kidneys, which requires aggressive pretreatment as well as posttreatment hydration and urinary alkalinization. The main toxicities of HDMTX are elevated serum transaminase levels and renal insufficiency, which can delay drug clearance.

                                              

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Literature review current through: Aug 2014. | This topic last updated: Sep 12, 2014.
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