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Therapeutic use 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, followed by 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.
  • Doses between 50 and 500 mg/m2, as used for malignant gestational trophoblastic disease (GTD), are considered intermediate-dose MTX. In general, these patients do not require aggressive hydration or urinary alkalinization. Leucovorin rescue is rarely needed with doses ≤250 mg/m2 unless unexpected toxicity is encountered. (See "Malignant gestational trophoblastic disease: Staging and treatment", section on 'Methotrexate with and without leucovorin'.)
  • Low-dose MTX (<50 mg/m2) is used intravenously for the treatment of bladder and breast cancer and desmoid tumors, and orally for patients with T-cell large granular lymphocyte (LGL) leukemia, ALL, acute promyelocytic leukemia, mycosis fungoides, and various nonmalignant immune-mediated disorders (table 2).

                                         

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Literature review current through: Apr 2012. | This topic last updated: Apr 30, 2012.
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