METHOTREXATE, the most widely used antimetabolite in cancer chemotherapy, has an essential role in the treatment of such diverse diseases as acute lymphocytic leukemia, non-Hodgkin's lymphoma, oste...

The pharmacology and clinical use of methotrexate

High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. Implications for practice High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.

Preventing and Managing Toxicities of High-Dose Methotrexate

High-dose methotrexate (HDMTX) with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology for more than a decade. Administration of HDMTX results in tumoricidal plasma concentrations of the drug without significant host toxicity, provided that plasma MTX levels are monitored and LV rescue is properly administered. The original premise of LV rescue was that the provision of reduced folate to normal cells would circumvent the metabolic block produced by MTX and allow resumption of DNA synthesis, although the presumed therapeutic selectivity of leucovorin has not yet been adequately explained. Despite a strong pharmacologic rationale and a vast clinical experience, HDMTX with leucovorin rescue has not been shown to be unequivocally superior to conventional doses of MTX in any clinical situation except, perhaps, for treatment of osteogenic sarcoma and childhood acute leukemia. While HDMTX is an important component of effective treatment regimens for these diseases, its precise contribution to the success of these regimens remains undefined. Although HDMTX can theoretically overcome all known mechanisms of MTX resistance, no data exist to suggest that this can be accomplished in the clinic. Thus, this well-known but poorly understood treatment regimen must remain a subject of clinical investigation rather than a part of routine clinical practice.

High-dose methotrexate: a critical reappraisal.

Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease.

Gastrointestinal toxicity of chemotherapeutic agents

Summary The effect of “leucovorin rescue” on the therapeutic index of methotrexate in epidermoid carcinomas of the head and neck was studied. Sixteen patients received maximally tolerated doses of methotrexate alone as 30-hr i.v. infusions at 2-week intervals and 44% responded. Significant hematological toxicity and 4 drug-related deaths were incurred. Twenty-five patients received higher doses of methotrexate followed by leucovorin rescue as 36- to 42-hr i.v. infusions every 2 weeks. This group experienced a response rate of 60% with fewer cases of severe toxicity. Seventeen of this group received more than 500 mg/sq m as a maximal dose and had a response rate of 76% with two drug-related deaths, while those receiving smaller doses had a response rate of only 25%. Serum methotrexate levels were proportional to the dose of drug. Leucovorin rescue enhances the therapeutic index of high-dose methotrexate infusions in epidermoid carcinomas of the head and neck.

https://cancerres.aacrjournals.org/content/canres/33/7/1729.full.pdf

Improved therapeutic index of methotrexate with "leucovorin rescue".

Summary Nineteen patients with recurrent carcinoma of the head and neck were treated with three 24-hour infusions of Methotrexate (2 mg/kg) followed by Leucovorin. Maintenance therapy consisted of weekly injections of 0.8 to 1.0 mg/kg of Methotrexate. Nine of 19 patients had objective regression of the disease in the primary site of the tumor and in regional lymph nodes, of which three responses were complete or nearly complete. The mean duration of remission was approximately five months. Mucositis (stomatitis) occurred in five of the nineteen patients, and of these only two were 3rd degree (moderately severe). Leukopenia and thrombocytopenia also generally were mild, although severe depression occurred in three patients, one of whom had a marrow already compromised prior to treatment. High-dose intermittent infusions of Methotrexate followed by Leucovorin seems to be a safe, effective way to induce regression of tumor masses in epidermoid carcinomas of the head and neck.

https://cancerres.aacrjournals.org/content/canres/28/6/1088.full.pdf

Effectiveness of High-Dose Infusions of Methotrexate Followed by Leucovorin in Carcinoma of the Head and Neck

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Improved therapeutic index of methotrexate with "leucovorin rescue".

Effectiveness of High-Dose Infusions of Methotrexate Followed by Leucovorin in Carcinoma of the Head and Neck