Methotrexate is an antimetabolite that interferes with intracellular folate metabolism by binding to the enzyme dihydrofolate reductase. This inhibits conversion of folic acid to tetrahydrofolate. The result is cellular depletion of reduced folates and inhibition of DNA synthesis. This drug is active only during the S phase of the cell cycle. It selectively affects tissues with more rapid cell turnover. The side effects of methotrexate can be minimized by supplying reduced folates in the form of leucovorin within 36 hours after exposure to the drug. As a single agent, methotrexate usually is given in weekly doses of 40 to 50 mg/m2. Toxic reactions include myelosuppression, mucositis, dermatitis, nausea, vomiting, diarrhea, and hepatic fibrosis. These toxicities are exacerbated with high-dose regimens unless leucovorin rescue is administered. Renal injury occurs with high-dose schedules.
Methotrexate produces a partial response rate of approximately 10% (9,10); the response duration ranges from 1 to 6 months. Improved response and survival rates are not consistently achieved with high-dose methotrexate regimens, but toxicity increases. Therefore, high-dose methotrexate is not used. Although single-agent methotrexate sometimes is used, other drugs or combinations, especially those containing 5-FU, paclitaxel, or cisplatin lead to higher response rates. Survival rate is not clearly improved with these combinations, and toxicity can be greater than that of single-agent therapy. Thus, methotrexate is the minimal standard treatment of patients having chemotherapy (8). Although it is sometimes still used as a control arm in randomized trials, currently it is not generally used as first-line therapy.
Methotrexate produces a partial response rate of approximately 10% (9,10); the response duration ranges from 1 to 6 months. Improved response and survival rates are not consistently achieved with high-dose methotrexate regimens, but toxicity increases. Therefore, high-dose methotrexate is not used. Although single-agent methotrexate sometimes is used, other drugs or combinations, especially those containing 5-FU, paclitaxel, or cisplatin lead to higher response rates. Survival rate is not clearly improved with these combinations, and toxicity can be greater than that of single-agent therapy. Thus, methotrexate is the minimal standard treatment of patients having chemotherapy (8). Although it is sometimes still used as a control arm in randomized trials, currently it is not generally used as first-line therapy.
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