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

A significant body of experimental evidence supports the notion that a deficiency of either vitamin B12 or folic acid enhances the activity of various carcinogens. Unifying mechanisms are proposed to explain this cocarcinogenic role.

Role of Vitamin B12 and Folate Deficiencies in Carcinogenesis

Thirty-six patients with nonlymphoid solid tumors who were undergoing therapy with cytosine arabinoside (ara-C) or methotrexate (MTX) were immunized withEscherichia coliVi antigen and teta...

Immunosuppressive effects of cytosine arabinoside and methotrexate in man.

Single agent chemotherapy employing either hydroxyurea, cyclophosphamide, bleomycin, or methotrexate has been reported to produce objective remissions in 30–40% of patients with advanced epidermoid carcinoma of the head and neck region. Responses are usually incomplete with remission durations of a few months. Methotrexate, the most extensively studied agent, appears to be most effective when used in an intermittent (every 4–7 day) dosage schedule or when used in high dosage followed by leucovorin “rescue.” In some reports, the intra-arterial administration of these drugs achieved better response rates, but the value of this approach is diminished by the high frequency of lesions that extend beyond the infused arterial supply and the high complication rate of catheterization procedures. Initial studies with dichlo-romethotrexate, an equipotent analog of methotrexate which is hydroxylated to an inactive form by the liver, suggest that intra-arterial use of this unique compound may be of value. Several studies indicate that the use of drugs in combination with radiotherapy may achieve greater tumor regression and longer response durations than radiotherapy alone; however, more controlled studies will be needed to establish this. The availability of effective agents with diverse mechanisms of action strongly suggests that major gains in chemotherapy of these tumors will be made in the next decade using combinations of drugs.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197305%2931%3A5%3C1141%3A%3AAID-CNCR2820310515%3E3.0.CO%3B2-R

Chemotherapy of cancer of the head and neck

Cancer research: from folate antagonism to molecular targets.

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