Leucovorin (folinic acid) rescue for high‐dose methotrexate: A review

Abstract

High‐dose methotrexate (HDMTX) is active against various malignancies; it possesses serious toxicities and is associated with patient characteristics, dosage regimens, comedications, and physiological status. There are many strategies to overcome HDMTX‐induced toxicities, such as hydration, alkalization, leucovorin rescue, and haemodialysis. Leucovorin rescue is a cornerstone for toxicity prevention in HDMTX treatment. However, the leucovorin dose adjustment and the existence of leucovorin overrescue are still controversial. At present, various methods for calculating leucovorin doses in different tumour types have been proposed, including empirical calculations based on MTX plasma concentration, the Bleyer nomogram, and other methods. Nonetheless, leucovorin rescue protocols differ greatly across tumour types and medical institutions. Further studies are needed to investigate the optimal dosage regimen for leucovorin rescue in various tumours using HDMTX.

Target concentration achievement for efficacy and safety of patients with osteosarcoma treated with high‑dose methotrexate based on individual pharmacokinetics: A retrospective study

“…The serum concentration was the highest immediately after completion of loading infusion (at 1 h), and the coefficient of variation was 26.7% in the BSA method and 17.4% in the PK method. Similarly, for C max and C mean (1)(2)(3)(4)(5)(6) , the coefficients of variation of the BSA method were 23.2 and 18.5%, and those of the PK method were 17.2 and 16.3%, respectively. MTX clearance varied from 2.74-8.14 l/h in the first course administered by the BSA method, with a 0.74-2.84-fold change in MTX clearance after the second course compared to the first course (Fig.…”

“…The following characteristics were surveyed: age, sex, height, weight, BSA, diagnosis, site of onset, MTX dose, serum MTX concentration (a total of 10 points at 1, 2, 4, 6, 7, 9, 12, 24, 48, and 72 h after the start of MTX treatment, as C 1 -C 72 ), number of courses of HD-MTX therapy, laboratory data [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum creatinine levels], and treated patients with toxic MTX levels. As an efficacy index, the achievement of the MTX effective concentration (700-1,000 µmol/l) at C max and the mean concentration during maintenance dose [C mean (1)(2)(3)(4)(5)(6) ] were evaluated. The achievement of the safety range (C 24 <10 µmol/l, C 48 <1 µmol/l, C 72 <0.1 µmol/l), and the incidence of hepatic and renal dysfunction within 1 week after MTX administration were assessed to determine safety.…”

“…Adverse events are also a major problem in HD-MTX therapy, and even with leucovorin rescue, HD-MTX therapy remains highly toxic. For safety, serum MTX concentrations of less than 10, 1, and 0.1 µmol/l at 24, 48, and 72 h, respectively, after starting MTX administration are recommended (1,6,21,(26)(27)(28)(29)(30)(31). Delayed MTX excretion not only causes serious adverse events such as myelosuppression, renal dysfunction, hepatic dysfunction, and mucositis but also makes it difficult to continue the treatment and worsens patient prognosis (1,10).…”

“…However, administration of HD-MTX to the body causes severe toxicity in normal cells, resulting in lethal side effects. Therefore, leucovorin, an active folate, is administered to reduce this toxicity (3)(4)(5)(6). Inhibition of the folate cycle of MTX in cancer cells is not compensated by leucovorin because cancer cells do not have a mechanism for leucovorin uptake (4,(6)(7)(8).…”

“…Therefore, leucovorin, an active folate, is administered to reduce this toxicity (3)(4)(5)(6). Inhibition of the folate cycle of MTX in cancer cells is not compensated by leucovorin because cancer cells do not have a mechanism for leucovorin uptake (4,(6)(7)(8). Due to this advantage, HD-MTX therapy is widely used at present and exhibits high efficacy in various carcinomas, especially osteosarcoma (9)(10)(11)(12)(13)(14).…”