Therapeutic use and toxicity of high-dose methotrexate

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 anti-inflammatory 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 (eg, rheumatologic) conditions are covered elsewhere. (See appropriate topic reviews.)

DEFINITION OF HIGH-DOSE METHOTREXATE — 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, and require 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 "Initial management of low-risk gestational trophoblastic neoplasia", section on 'Methotrexate as the preferred option'.)

●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).

The side effect profile of chronic low-dose oral MTX, as used for the treatment of nonmalignant disorders, differs from that of cyclical parenteral administration in the setting of cancer, particularly with regard to myelosuppression, hepatic fibrosis, and pulmonary toxicity. The major side effects of low-dose oral MTX for nonmalignant disorders are addressed in detail elsewhere. (See "Major side effects of low-dose methotrexate".)

Low doses of MTX (typically 12 mg total dose) also can be given intrathecally for treatment of leptomeningeal metastases or CNS prophylaxis in patients with leukemia or high-risk lymphoma. In this setting, the major toxicities are neurologic; there is a very small risk of myelosuppression because MTX is eliminated from the cerebrospinal fluid by slow passive diffusion into the systemic circulation. Because of this, some experts recommend a short course of leucovorin rescue in this situation, particularly for patients with renal dysfunction. (See "Treatment of leptomeningeal disease from solid tumors".)

CLINICAL PHARMACOLOGY — MTX enters the cell via the same energy-dependent, saturable carrier protein that transports naturally occurring folates and leucovorin [3-6]. Some tumors have reduced or no transport capability; in such cases, high extracellular concentrations of MTX permit the drug to enter the cell by passive diffusion [7,8]. A third mechanism of MTX entry is through endocytosis, mediated by folate binding proteins, which may be overexpressed in malignant as compared with normal cells [3].

Mechanism of action

Interference with folate metabolism — The antiproliferative activity of antifolates such as MTX results from interference with folate metabolism. A normal dividing cell uses large amounts of reduced folates to maintain ongoing purine and thymidine synthesis (figure 1); demand is even greater for rapidly dividing malignant cells.

Several key enzymes of these synthetic pathways are targets of MTX:

●The critical factor for the cell's ongoing production of thymidylate, and to a lesser extent the purines, is its ability to regenerate reduced folates from the oxidized forms. The key enzyme in this process is dihydrofolate reductase (DHFR), which converts dihydrofolate to tetrahydrofolate, thus continuously replenishing the cell's supply of reduced folates. Competitive inhibition of DHFR represents the main mechanism of action for antifolates such as MTX, but other synthetic enzymes are also inhibited by polyglutamated forms of MTX. (See 'Importance of polyglutamation' below.)

●Within the thymidine synthetic pathway, the enzyme thymidylate synthetase (TS) uses a methyl group from the reduced folate, 5-methylenetetrahydofolate, to synthesize deoxythymidylate monophosphate (dTMP) from deoxyuridylate monophosphate (dUMP).

●Within the purine synthetic pathway, the enzymes glycinamide ribonucleotide transformylase (GARFT) and aminoimidazole carboxamide transformylase (AICARFT) both use the formyl groups of the reduced folate N(10)-formyltetrahydrofolate to initiate synthesis of adenosine and guanosine.

Intracellularly, MTX competitively inhibits DHFR because it has a higher affinity for the enzyme than the naturally occurring dihydrofolate. The depletion of reduced folates (tetrahydrofolates) causes an abrupt cessation of thymidine synthesis, DNA synthesis, and eventually cell death. This process is accentuated in rapidly dividing cells (ie, those in the S-phase of the cell cycle), which require more DNA precursors. As a result, MTX is considered an S-phase specific cytotoxic drug.

The level of DHFR in any given cell is in great excess of what is needed to provide normal levels of reduced folates [3]. Furthermore, tetrahydrofolate synthesis continues until more than 95 percent of DHFR activity has been inhibited [7]. As a result, high levels of MTX are required to successfully compete with other folates for DHFR binding [7,9,10].

Importance of polyglutamation — As part of normal cellular physiology, multiple glutamate residues are added to carboxyfolates by the enzyme folyl polyglutamate synthetase (FPGS), a process referred to as polyglutamation (figure 1). Polyglutamation increases the intracellular pool of folates, as polyglutamated folates are not easily transported out of the cell because of their size and charge. Folate polyglutamation also influences the equilibrium balance in favor of continual cellular uptake of folates [5,11].

When significant intracellular levels are present, MTX is polyglutamated by the same enzyme [12]. However, in most cell lines studied, conversion to polyglutamated MTX (PGMTX) does not occur until cells have been exposed to the drug for at least six hours at concentrations of at least 2 micromoles/liter (2 microM, 2 X 10 [-6] M) [8,9]. These concentrations are easily achievable in plasma with high-dose MTX (HDMTX) but not with intermediate or low-dose regimens.

The accumulation of PGMTX metabolites serves to further amplify and prolong the antiproliferative effects of MTX:

●Intracellular accumulation and decreased efflux of PGMTX enhances and prolongs inhibition of DHFR, since PGMTX is less readily dissociable from the enzyme than is free MTX [8,10].

●Polyglutamated forms of MTX also bind to other enzymes involved in DNA synthesis such as TS, AICARFT, and GARFT; this further depletes intracellular thymidine and inhibits purine synthesis [13-15]. Inhibition of TS also leads to accumulation of dUMP, which cannot be incorporated into DNA, further disrupting DNA synthesis and repair [16].

Besides being a main determinant of antitumor activity, MTX polyglutamation is also thought to be mainly responsible for the greater incidence and severity of all HDMTX-related side effects when there is prolonged MTX excretion or if leucovorin rescue is delayed beyond 36 hours [10,16-18]. Higher plasma MTX concentrations and longer exposure times increase the formation of longer polyglutamated MTX molecules [8,13,19,20]. When the polyglutamated tail has a larger number of glutamic acid residues (ie, greater than five), there is greater affinity for DHFR and TS, and degradation and diffusion out of the cell is slowed [13,14].

Finally, variability in polyglutamation between tumor cells and normal (nonmalignant) cells is thought to provide at least part of the explanation for why leucovorin can selectively rescue normal cells from the effects of HDMTX but does not compromise tumor cell cytotoxicity.

Other mechanisms — In addition to involvement of pathways involved in folate metabolism, newer data suggest that upregulation of mitochondrial enzymes involved in the metabolism of serine and glycine may also influence tumor cell sensitivity to MTX [21]. Whether this finding is relevant to all tumors, especially osteosarcoma, is unclear.

Rationale for leucovorin rescue — As with many other anticancer drugs, MTX has little selectivity for tumor cells, and its effectiveness is limited by toxicity to normal tissue, particularly the gastrointestinal (GI) epithelium and bone marrow. To improve the therapeutic index of MTX, Goldin developed the concept of rescuing normal cells from toxicity by providing reduced folates (leucovorin, also called folinic acid, N5-formyl-tetrahydrofolate, citrovorum factor) to bypass the metabolic block induced by MTX [22]. In these pioneering experiments, administration of leucovorin within 24 to 36 hours after administration of MTX was able to prevent MTX-induced host toxicity without diminishing antitumor activity.

The reason why leucovorin selectively rescues normal but not malignant cells is incompletely understood. The original premise that providing reduced folate would circumvent the metabolic block produced by MTX is not easily explained except in situations where folate transport is deficient in the malignant cells. In such cases, leucovorin cannot be transported into the malignant cell, but it can enter normal cells and compete with MTX for binding sites on DHFR because they retain a normal folate carrier protein [6,23]. If leucovorin is present in sufficient quantities, the enzyme is reactivated, and purine and thymidine synthesis can be reinitiated. This situation is thought to be relatively uncommon.

As noted above, cellular differences in polyglutamation have been suggested as an alternative explanation for selective leucovorin rescue. Intracellularly, leucovorin is able to compete with free but not polyglutamated MTX for binding to DHFR [23]. In contrast to tumor cells, comparatively little PGMTX synthesis occurs in normal gut epithelium and bone marrow precursors under similar conditions [18,24]. It is hypothesized that because of the lower levels of intracellular PGMTX, leucovorin can more effectively curtail DHFR inhibition in normal as compared with malignant cells [11,14,18,24-26].

Leucovorin can only rescue normal cells that have not already had lethal DNA damage from the toxic effects of MTX. Thus, to be effective, treatment with leucovorin must be initiated within 24 to 36 hours of starting HDMTX [7]. Issues relevant to the dose, route of administration, and duration of leucovorin rescue after HDMTX are discussed below. (See 'Leucovorin administration' below.)

Resistance to methotrexate — Neoplastic cells may be innately resistant or acquire resistance to MTX. As an example, MTX is not a useful agent for treatment of acute myeloid leukemia because the leukemic cells cannot polyglutamate the drug once it enters the cell [27].

More often resistance is acquired through one or more of the following mechanisms [3,27-29]:

●Decreased drug transport due to gene mutations or a change in the rate of transcription of the folate carrier

●Increased DHFR activity, typically due to gene amplification

●Mutations in the DHFR protein, which decrease its affinity for MTX

●Decreased cellular polyglutamation of MTX due to increased folyl polyglutamate hydrolase activity or decreased FPGS activity

●Decreased TS activity or affinity for the folate antagonists

Because of the frequent development of acquired resistance, MTX is not typically used as a single agent for treatment of aggressive malignancy with the exception of primary CNS lymphoma, head and neck cancer, and malignant GTD. (See "Initial management of low-risk gestational trophoblastic neoplasia".)

Pharmacokinetics, metabolism, and excretion

●Pharmacokinetics – Even when given identical doses of HDMTX, patients vary significantly in their pharmacokinetics, patterns of toxicity and in response to therapy. This diversity can, to some extent, be linked to sequence variations in genes involved in drug absorption, metabolism, excretion, cellular transport, and/or effector targets or target pathways [30]. A review of advances in the individual prediction of MTX toxicity and the impact of genetic polymorphisms on MTX efficacy and toxicity is beyond the scope of this review. (See "Overview of pharmacogenomics", section on 'Drug transport'.)

Following intravenous (IV) administration, MTX is widely distributed through the body. In the serum, approximately 50 percent is protein/albumin-bound [10]. Peak serum levels following MTX doses >1000 mg/m² are in the range of 500 to 1500 microM (50 to 150 X 10 [-5] M) [31]. The overall half-life following IV administration is between 8 and 12 hours.

The decay curve varies widely: 30 to 300 microM (3 to 30 X 10 [-5] M) at 24 hours; 3 to 30 microM (3 to 30 X 10 [-6] M) at 48 hours; <0.3 microM (<3 x 10 [-7] M) at 72 hours. Levels in excess of 5 to 10 microM (5 to 10 x 10 [-6] M) at 24 hours, 1 microM (1 x 10 [-6] M) at 48 hours, and 0.1 micro M (1 x 10 [-7] M) at 72 hours portend greater toxicity, and must be managed by increasing IV hydration and augmenting the dose of leucovorin. (See 'Management of patients with renal failure and prolonged high plasma methotrexate levels' below.)

Because MTX is not a lipophilic compound, it penetrates only slowly across intact cellular barriers such as the vascular endothelium. Third-space fluid collections (eg, ascites, pleural effusions) can accumulate high levels of the drug that slowly leak back into the circulation long after the initial dose. Particularly if renal function is impaired, this can result in prolonged drug elimination and severe delayed toxicity. If possible, these fluid collections should be drained prior to administration of HDMTX.

MTX also crosses the blood-brain barrier (BBB). The level of cerebrospinal fluid (CSF) penetration is variable but CSF levels are approximately 3 to 10 percent of plasma concentrations. Thus, high serum levels (typically requiring IV administration of MTX doses ≥1000 mg/m²) are required to achieve therapeutic concentrations in the CSF.

●Excretion and metabolism – Almost 90 percent of MTX is excreted unchanged in the urine, the bulk within 12 hours of administration. Although the mechanism of MTX excretion in the human kidney has not been completely elucidated, the finding that MTX clearance exceeds creatinine clearance in several studies suggests that there is active tubular secretion [32,33].

Although most MTX is excreted unchanged in the urine, a small amount of the administered dose is excreted unchanged into the bile and undergoes enterohepatic circulation; this is neither clinically relevant nor harmful.

Approximately 10 percent of the parent drug is metabolized to 7-hydroxymethotrexate by hepatic aldehyde oxidase. This metabolite is a less potent inhibitor of DHFR but can contribute to renal toxicity due to its lower water solubility [10]. Due to its longer half-life, the serum concentration of 7-hydroxymethotrexate may exceed that of MTX [5].

A less important metabolite, 4-amino-4-deoxy-N10-methylpteroic acid (DAMPA), is produced by bacteria in the intestine as a very small percentage of the administered dose and is not clinically relevant [34].

Causes of delayed clearance — Clearance of MTX may be delayed by impaired kidney function, genetic variability, and drug-drug interactions. Delayed clearance increases risk for treatment-related toxicity. (See 'Management of patients with renal failure and prolonged high plasma methotrexate levels' below.)

As examples:

●Kidney impairment – Given that most MTX is excreted in the urine, all patients with pre-existing chronic or acute kidney impairment are at risk for delayed clearance and require MTX dose adjustment. (See 'Pretreatment assessment' below.)

During HDMTX infusion, rapid drug excretion leads to high MTX concentrations in the urine. These concentrations, approaching 10 microM, exceed the solubility of the drug below pH 7 and are thought responsible for intrarenal precipitation of the drug and acute kidney injury. This further interferes with MTX excretion, predisposing patients to potentially severe mucosal toxicity and myelosuppression. In order to prevent intrarenal precipitation, hydration and urinary alkalinization are recommended for HDMTX regimens. (See 'Renal toxicity' below and 'Hydration and urinary alkalinization' below.)

●Patients with Down syndrome – Trisomy 21 cells (ie, those of patients with Down syndrome) appear to have increased cellular accumulation of MTX because of the presence of extra copies of the reduced folate carrier SLC19A1, which is located on chromosome 21. This increases susceptibility to the systemic toxicity of MTX. As a result, protocols using HDMTX for treatment of diseases such as acute lymphoblastic leukemia in patients with Down syndrome generally recommend a reduced MTX dose [35]. (See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults", section on 'Patients with Down syndrome'.)

●Drug-drug interactions that impact clearance – Many drugs inhibit renal excretion of MTX and may increase treatment-related toxicity [11,36]. These include sulfa drugs and trimethoprim [37], nonsteroidal anti-inflammatory drugs (NSAIDs) [38], phenytoin, ciprofloxacin, penicillin-type drugs [39] probenecid, amiodarone, proton pump inhibitors [40,41], and tyrosine kinase inhibitors such as imatinib and dasatinib [42,43]. Coadministration of these drugs should be avoided, if possible, during HDMTX treatment. (See 'Potential drug-drug-interactions' below.)

Case reports also suggest that levetiracetam might also alter renal clearance, but the available data are conflicting [44-47]. The United States Prescribing Information for levetiracetam recommends close monitoring of methotrexate levels when the drugs are coadministered.

OVERVIEW OF ADVERSE EFFECTS — High-dose MTX (HDMTX) can be associated with multiple potential adverse effects, some of which are related to both drug dose and duration of drug exposure; some are idiosyncratic.

Hepatotoxicity — MTX has the potential for hepatotoxicity at all doses. The association between MTX and hepatic dysfunction has been studied most extensively in patients receiving chronic oral low-dose MTX for psoriasis and rheumatoid arthritis. Hepatotoxicity can be manifested as a mild transaminitis, but patients are at risk for fibrosis and cirrhosis when the total dose exceeds 1.5 to 2 grams. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

HDMTX can cause an acute elevation in the serum transaminases from 2- to 20-fold normal levels, even in patients who receive leucovorin rescue. Acute transaminitis occurs in as many as 60 to 80 percent of patients and typically resolves spontaneously within one to two weeks. If the level of alanine transferase (ALT) has not returned to less than 180 international units/L by the beginning of the next treatment cycle, the next dose should be reduced and/or delayed.

Rarely, HDMTX causes a temporary elevation in serum bilirubin, which usually normalizes within a few days. Subsequent cycles do not require dose reduction unless the peak serum bilirubin level exceeds 3 mg/dL [11].

Among patients receiving intravenous (IV) MTX for treatment of cancer, hepatic fibrosis (with a subsequent risk for hepatocellular cancer) is reported only rarely. All cases have been in children receiving MTX for acute lymphoblastic leukemia. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Methotrexate'.)

Other hepatotoxic medications and alcohol should be avoided during HDMTX therapy, if at all possible.

Nausea, vomiting, and stomatitis — MTX doses above 250 mg/m² are considered moderately emetogenic; smaller doses have low or minimal emetogenic potential (≤30 percent risk of emesis). In keeping with guidelines from the American Society of Clinical Oncology (ASCO), patients receiving MTX ≥250 mg/m² should be pretreated with a serotonin receptor antagonist and dexamethasone, with or without aprepitant [48]. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Prevention of chemotherapy-induced nausea and vomiting in adults".)

Mucositis is typically avoided in patients who undergo successful leucovorin rescue. Mucositis may be severe after HDMTX if leucovorin rescue is delayed or in the setting of prolonged elevated serum levels. (See 'Rationale for leucovorin rescue' above.)

Renal toxicity — At low doses, MTX is not nephrotoxic. However, HDMTX can affect the kidneys in two different ways [49]:

●The main cause is that MTX can precipitate in the tubules and directly induce tubular injury. The risk is increased in the presence of acidic urine (since MTX and its two major metabolites are poorly soluble at an acid pH), with volume depletion (which decreases urine flow rate and increases the concentration of MTX in tubular fluid) and when high plasma MTX concentrations are sustained.

●MTX also causes a transient decline in glomerular filtration rate (GFR) after each dose, with complete recovery within six to eight hours. The mechanism responsible for this functional renal impairment involves afferent arteriolar constriction or mesangial cell constriction. The effect can be exacerbated when additional nephrotoxic drugs (eg, cisplatin) are administered.

MTX-induced acute renal failure is typically nonoliguric and is reversible in almost all cases. Plasma creatinine levels usually peak within the first week and return toward baseline levels within one to three weeks. (See "Crystal-induced acute kidney injury", section on 'Methotrexate'.)

The major risk with MTX-induced renal dysfunction is that MTX clearance is severely compromised, resulting in delayed excretion of the drug, higher than expected plasma concentrations, and increased systemic toxicity.

The likelihood of MTX-induced renal dysfunction in patients receiving HDMTX can be minimized (but not eliminated) by hydration both to maintain a high urine flow and to lower the concentration of MTX in the tubular fluid and by alkalinization of the urine to a pH above 7.0. Raising the urine pH from 5.0 to 7.0 increases the solubility of MTX 10-fold [49,50]. (See 'Hydration and urinary alkalinization' below.)

Despite these measures, the risk of renal failure after HDMTX is still approximately 2 percent. In a review of the literature and clinical trial reports of children treated with HDMTX for osteosarcoma after 1980, a time during which hydration and alkalinization were administered routinely, the incidence of renal dysfunction was 1.8 percent and the mortality among patients who developed renal dysfunction was 4.4 percent [51]. The incidence may be higher in adults, especially those treated for hematologic malignancies [52].

If the patient develops HDMTX-related nephrotoxicity during treatment, the serum creatinine should be serially monitored, and subsequent doses held until the serum creatinine has returned to baseline. Management of patients with renal failure and prolonged excretion of MTX is discussed below. (See 'Management of patients with renal failure and prolonged high plasma methotrexate levels' below.)

Hematologic toxicity — In contrast to the situation with low-dose oral MTX, in which hematologic toxicity can be the major dose-limiting side effect, there is usually little evidence of treatment-related myelosuppression following HDMTX with leucovorin rescue. Myelosuppression may become evident if rescue is delayed or in the setting of prolonged elevated serum levels. (See 'Rationale for leucovorin rescue' above and "Major side effects of low-dose methotrexate".)

Pulmonary toxicity — The pattern of lung toxicity most frequently seen in patients treated with MTX is a hypersensitivity pneumonitis. Although this most often occurs after long-term oral therapy, pulmonary toxicity can occur following HDMTX. In contrast to bone marrow and GI epithelial toxicity, the repletion of folate stores does not reduce the risk for MTX pulmonary toxicity, suggesting that it results from an idiosyncratic mechanism unrelated to folate antagonism.

The majority of patients who develop pulmonary toxicity do so within the first year of therapy, although cases are reported as early as 12 days and as late as 18 years after drug initiation. The presentation may be acute, subacute, or chronic. Subacute presentations are most common, manifesting with dyspnea, nonproductive cough, fever, crackles on auscultation of the lungs, hypoxemia, and peripheral blood eosinophilia in up to one-half of affected patients. Widespread interstitial lung opacities are the earliest radiographic findings and may progress rapidly to patchy acinar consolidation.

For patients who develop pulmonary findings during treatment, the drug should be discontinued and an infectious etiology for the pulmonary findings excluded. If symptoms, radiographic findings, or physiologic abnormalities persist despite drug discontinuation or if the patient is severely ill, glucocorticoids are indicated, although they have varying degrees of success. This topic is discussed in more detail elsewhere. (See "Methotrexate-induced lung injury".)

Neurologic toxicity — Acute or subacute encephalopathy is the most important neurotoxicity of HDMTX. This complication is characterized by somnolence, confusion, and seizures within 24 hours of treatment. Symptoms usually resolve spontaneously without sequelae, and retreatment is often possible. Neurologic toxicity of MTX is discussed in detail separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Methotrexate'.)

Dermatologic toxicity — A variety of dermatologic side effects are described. Approximately 14 to 15 percent of patients develop a nonspecific morbilliform drug rash, which is usually erythematous, macular, pruritic, and often confined to the neck and trunk [53,54]. In severe cases, it can progress to bullous formation or desquamation. MTX can also cause photoreactivation and photoenhancement as well as skin hyperpigmentation, and photoreactivation may be magnified by concomitant use of other drugs such as voriconazole. (See "Cutaneous adverse effects of conventional chemotherapy agents".)

Alopecia is occasionally encountered but is usually not complete. (See "Alopecia related to systemic cancer therapy".)

Hypersensitivity — True hypersensitivity reactions to MTX are rare [55]. Successful rechallenge has been reported using a desensitization protocol. (See "Infusion reactions to systemic chemotherapy".)

ONCOLOGIC INDICATIONS FOR HIGH-DOSE METHOTREXATE — High-dose MTX (HDMTX) is a component of modern treatment protocols for certain leukemias, high-risk peripheral as well as central nervous system lymphomas, osteosarcoma, and is an alternative to intrathecal (IT) MTX for treatment of leptomeningeal metastases.

The specific dose and schedule of HDMTX vary according to the disease and the specific regimen and are discussed in depth under the specific disorders. The following sections provide a brief overview as to how HDMTX is incorporated into the treatment of these conditions.

Leukemia and lymphoma — Leukemic and lymphomatous meningitis are fairly common at presentation; the incidence is between 3 and 5 percent. Furthermore, central nervous system (CNS) relapse develops in 5 to 10 percent of patients.

For non-Hodgkin lymphomas, the risk of CNS disease is greatest in patients with highly aggressive lymphomas (eg, Burkitt's lymphoma) and in patients with aggressive lymphomas who have advanced disease. Specific risk factors for CNS lymphoma, which may involve the brain parenchyma and/or the leptomeninges, include a high International Prognostic Index (IPI), multiple extranodal sites, renal or adrenal disease, disease involving the testes and possibly the bone marrow (this is quite controversial), and the presence of human immunodeficiency virus (HIV) disease. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

Acute lymphoblastic leukemia — At least in part due to the gradual shift away from radiation therapy for CNS prophylaxis, many if not all protocols for treating acute lymphoblastic leukemia (ALL) incorporate HDMTX to provide systemic and CNS cytotoxic effects.

There is no "standard" method of administering HDMTX for ALL. The dose, infusion duration, and timing of leucovorin rescue vary markedly among various protocols. A major area of controversy is whether higher peak plasma MTX levels (as can be achieved with higher doses given over a shorter period of time) or greater AUC (area under the concentration x time curve, achieved with longer infusion times and lower doses) correlate best with clinical outcomes [56,57].

As noted above, patients with trisomy 21 (Down syndrome) are at risk for excessive toxicity from HDMTX due to presence of extra copies of the folate transporter SLC191A, and doses should be reduced in these patients. (See 'Causes of delayed clearance' above.)

Specific protocols that incorporate HDMTX into treatment are discussed in detail elsewhere. (See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults" and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

Primary central nervous system lymphoma — HDMTX is the mainstay of most treatment regimens for primary and secondary CNS lymphoma. (See "HIV-related lymphomas: Primary central nervous system lymphoma", section on 'High-dose methotrexate' and "Secondary central nervous system lymphoma: Treatment and prognosis", section on 'Methotrexate-based induction regimens'.)

Systemic non-Hodgkin lymphoma — HDMTX is an integral component of therapeutic regimens for the highly aggressive Burkitt lymphomas to treat and/or prevent CNS involvement. (See "Treatment of Burkitt leukemia/lymphoma in adults".)

HDMTX (or intrathecal MTX) is also employed for CNS prophylaxis in patients with certain diffuse large B cell lymphomas that are associated with a high risk of CNS relapse, as well as in patients with known CNS involvement, although its value is uncertain. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'CNS management'.)

Osteosarcoma — With the recognition that almost all osteosarcomas have micrometastatic disease at diagnosis even if they appear localized, systemic chemotherapy has become an integral part of curative therapy for this disease. The majority of pediatric protocols include HDMTX at doses range from 8 to 12 g/m². Many studies indicate a correlation between peak MTX plasma levels, tumor response, and long-term outcome. (See "Chemotherapy and radiation therapy in the management of osteosarcoma", section on 'Role of high-dose methotrexate'.)

The role of adjuvant HDMTX is more controversial in adults with osteosarcoma because randomized studies have failed to show an advantage for higher as compared with intermediate doses of MTX or for HDMTX plus doxorubicin and cisplatin versus doxorubicin/cisplatin alone. (See "Chemotherapy and radiation therapy in the management of osteosarcoma", section on 'Chemotherapy in adults'.)

HDMTX is also an important agent for metastatic osteosarcoma; response rates, when used as a single agent in the metastatic setting, are in the range of 30 to 40 percent [58]. (See "Chemotherapy and radiation therapy in the management of osteosarcoma", section on 'Patients with metastatic disease at diagnosis'.)

Leptomeningeal metastases — MTX is the chemotherapeutic agent most commonly used for IT chemotherapy in patients with leptomeningeal metastases. Furthermore, systemic administration of HDMTX is the most widely used alternative to IT chemotherapy in this setting and achieves higher CSF concentrations than does IT administration. The level of cerebrospinal fluid (CSF) penetration is variable but CSF levels are approximately 3 to 10 percent of plasma concentrations. (See "Treatment of leptomeningeal disease from solid tumors".)

PRACTICAL TIPS FOR MANAGING HIGH-DOSE METHOTREXATE — As noted above, the specific details of MTX dose, infusion duration, and leucovorin rescue are generally disease- and protocol-specific. However, there are some general aspects of high-dose MTX (HDMTX) administration and posttreatment management that are common to all regimens.

Pretreatment assessment — HDMTX requires central venous access or excellent large-caliber peripheral venous access and at least two to three days of inpatient care. Although outpatient administration of HDMTX is feasible [59], it requires a highly motivated and reliable patient, daily outpatient visits, and rigorous attention to hydration status, urinary output, and urine pH. The development of nausea or diarrhea leading to volume depletion renders outpatient management unsuitable.

Exclude a third-space fluid collection — As noted above, patients with ascites or pleural effusions can accumulate MTX in these "third spaces," which can lead to delayed elimination as the MTX slowly leaches out of the fluid collection, particularly if renal function is impaired. Clearance may also be delayed in those with anasarca, in the absence of obvious third-space fluid collections.

If present, third-space fluid collections should be treated and/or drained prior to the first dose of MTX. If this is not feasible, the possibility that plasma MTX levels may remain elevated for longer than 72 hours should be anticipated. (See 'Pharmacokinetics, metabolism, and excretion' above.)

Kidney function — Because MTX is cleared predominantly by the kidney, assessment of renal function is necessary prior to each dose of HDMTX. If the serum creatinine is initially high, we would hydrate the patient and recheck the value. If the serum creatinine is still elevated, dose reduction may be warranted. There is no consensus as to which of the several dose reduction schema are optimal (for children and adults), and institutional practice varies. In practice, particularly if treatment is being administered with curative intent, dose reductions are rarely performed for baseline altered renal function. On the other hand, if the patient develops HDMTX-related nephrotoxicity during treatment, serum creatinine should be serially monitored and subsequent dosing held until the serum creatinine has returned to baseline. (See 'Renal toxicity' above.)

There are no universally agreed upon guidelines for dose reduction based on baseline renal function; the US Food and Drug Administration (FDA)-approved manufacturer's product labeling does not include recommendations. The following dose reduction schema have been suggested by expert groups:

Aronoff recommends the following dose modifications for adults [60]:

●Creatinine clearance (CrCl) 10 to 50 mL/min – Reduce dose to 50 percent of usual dose

●CrCl <10 mL/min – Avoid use of MTX

●Hemodialysis/continuous renal replacement therapy – Administer 50 percent of the dose (others suggest that only 25 percent of the dose be administered after hemodialysis [61])

Kintzel provided slightly different recommendations [62]:

●CrCl 46 to 60 mL/min – Reduce dose to 65 percent of usual dose

●CrCl 31 to 45 mL/min – Reduce dose to 50 percent of usual dose

●CrCl <30 mL/min – Avoid use of MTX

Others suggest that the MTX dose be reduced by the percentage reduction of the measured CrCl below 100 mL/min (eg, for a CrCl 60 mL/min, the dose would be reduced by 40 percent) [63].

One published trial of adults receiving HDMTX for acute leukemia recommended that the HDMTX dose be based on serum creatinine on the day of treatment [64]:

●Serum creatinine <1.5 mg/dL – 100 percent

●Serum creatinine 1.5 to 2.0 mg/dL – Reduce dose to 75 percent of usual dose

●Serum creatinine >2.0 mg/dL – Reduce dose to 50 percent of usual dose

There is no consensus as to which one of these dose reduction schema are optimal (for children and adults), and institutional practice is variable. In practice, particularly if treatment is being administered with curative intent, dose reductions are rarely performed for baseline altered renal function. On the other hand, if the patient develops HDMTX-related nephrotoxicity during treatment, the serum creatinine should be serially monitored, and subsequent dosing held until the serum creatinine has returned to baseline. (See 'Renal toxicity' above.)

There is also no consensus on how best to periodically assess CrCl during treatment regimens that include drugs that are dependent on renal elimination. Some protocols require 24-hour urine collection and measurement of CrCl as an obligatory part of each pre-dose evaluation. However, it is not clear that 24-hour urine collection is necessary or sufficient for all patients [65]. Some studies suggest greater accuracy for estimating CrCl (and therefore, GFR) using the Wright formula [66], the Cockcroft-Gault formula [63], or by use of the simplified modification of diet in renal disease (MDRD) equation (calculator 1 and calculator 2) [65].

However, any estimation of GFR based on either a 24-hour urine collection or calculated from the serum creatinine is imprecise, and a patient may be incorrectly labeled as having a low GFR. This must be considered when weighing the potential risk of increased drug toxicity in a patient with reduced GFR against the potential benefit to be derived from therapy. These issues are addressed in detail elsewhere (see "Nephrotoxicity of chemotherapy and other cytotoxic agents"). The K/DOQI clinical practice guidelines for CKD, as well as other K/DOQI guidelines, can be accessed through the National Kidney Foundation's website.

Issues specific to older patients — There is potential for overestimation of the CrCl for older adult patients, as well as others with cachexia, if they have abnormally low serum creatinine levels. Consensus-based guidelines from the National Comprehensive Cancer Network propose using minimal value of 0.7 for the serum creatinine for calculations [67].

While many studies have shown that older adults are able to tolerate and derive benefit from high dose methotrexate [68,69], close adherence to dose reductions as determined by the calculated CrCl before each cycle is needed as some studies have shown higher levels of acute kidney injury in older patients [70] as well as those with diabetes mellitus [71].

Baseline hepatic impairment — Dose adjustment is not provided in the manufacturer's labeling. The following dose reductions have been suggested by one expert group [72]:

●Serum bilirubin 3.1 to 5 mg/dL or transaminases >3 times the upper limit of normal – Administer 75 percent of the usual dose

●Serum bilirubin >5 mg/dL – Avoid use

Obesity — ASCO guidelines for appropriate chemotherapy dosing in persons with obesity who have cancer recommend use of the patient's actual body weight for calculation of body surface area, particularly when the intent of therapy is curative [73]. (See "Dosing of anticancer agents in adults", section on 'Dosing for overweight/obese patients'.)

Potential drug-drug-interactions — As noted above, many drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), phenytoin, ciprofloxacin, sulfa drugs, trimethoprim, penicillin-type drugs, probenecid, amiodarone, tyrosine kinase inhibitors (including imatinib and dasatinib), and proton pump inhibitors, inhibit excretion of MTX. Their use should be avoided, if possible, during HDMTX treatment. (See 'Causes of delayed clearance' above.)

Case reports also suggest that levetiracetam might also alter renal clearance, but the available data are conflicting. The United States Prescribing Information for levetiracetam recommends close monitoring of methotrexate levels in patients receiving levetiracetam.

Prevention and management of high-dose methotrexate toxicity — The guiding principles for prevention of HDMTX toxicity, namely maintaining urine output, urinary alkalinization, monitoring serum creatinine, electrolytes, and plasma MTX concentrations, and pharmacokinetically guided leucovorin rescue, are also the cornerstones of management for patients who develop early signs of renal dysfunction and delayed MTX elimination.

Hydration and urinary alkalinization — Maintaining adequate hydration and urine output is essential for rapid clearance of MTX. Most protocols recommend at least 2.5 to 3.5 liters/m² of intravenous (IV) fluid hydration per day, starting 4 to 12 hours prior to the initiation of the MTX infusion.

The pH of the urine should be measured at baseline. As noted above, MTX precipitates in acid urine; maintaining the urine pH 7.0 or higher increases MTX solubility, prevents drug precipitation in renal tubules, and drastically decreases the chance of renal damage. In clinical practice, it is customary to begin the MTX infusion only after the urine pH is ≥7.0 and to maintain it in this range until plasma MTX levels have declined to less than 0.1 microM.

Urinary alkalinization is most easily accomplished by adding ampules of sodium bicarbonate to each liter of IV fluid hydration. This accomplishes both fluid hydration and urinary alkalinization.

A typical choice is IV D5W with 100 to 150 mEq of sodium bicarbonate per liter, administered by continuous infusion at 125 to 150 mL/hour. A cation concentration of 80.5 mEq/L is roughly equivalent to one-half normal saline. The amount of bicarbonate in each liter and the IV fluid composition can then be modified according to the urine pH and serum sodium. If only 50 mEq of sodium bicarbonate is added to each liter of IV fluid, clinicians should be aware that the resultant fluid will be hypotonic if D5W is used. (See "Maintenance and replacement fluid therapy in adults", section on 'Replacement fluid therapy'.)

Alternatively, sodium bicarbonate dosing can be accomplished intermittently either by the IV or oral route:

●50 mL of D5W containing sodium bicarbonate 1 mEq/kg can be infused IV over 30 minutes every four or six hours.

●Oral sodium bicarbonate can also be given although the dose is variable. At our institution, we start with 3250 mg (five tablets) every six hours, and escalate to five tablets every two to four hours as needed; once the urine pH is ≥7, the 24 hour daily dose can usually be divided into four doses, every six hours. An alternative oral protocol is available [74].

As with continuous administration of IV bicarbonate-containing fluid, the urine pH should be ≥7.0 before the MTX infusion is begun, and urine pH must be monitored closely until serum MTX levels are below 0.1 microM to ensure that the urine is still adequately alkalinized. (See 'Laboratory monitoring during treatment' below.)

Frequent measurement of urine pH and urine output (recommended at least every two to four hours) will ensure that the urine remains alkalinized and diuresis is appropriate to prevent nephrotoxicity [75,76]. Oral sodium bicarbonate can be added if the urine pH decrease to <7.

Interference with urinary alkalinization — Few foods or beverages are known to be associated with delayed MTX clearance or toxicity. However, at least some evidence suggests that intake of cola beverages during MTX treatment may lead to urinary acidification (due to the phosphoric acid content) and delayed MTX clearance [77].

Although some protocols restrict dietary intake of colas and other acidic foods (eg, orange juice, tomato products) during HDMTX treatment until levels are below 0.1 microM. Others recommend avoidance of aspirin and other NSAIDs and vitamins (particularly vitamin C) until plasma MTX levels are less than 0.1 microM. In our view, as long as urine pH can be maintained above 7.0, dietary and medication restriction is unnecessary.

Leucovorin administration — Leucovorin rescue should be started within 24 to 36 hours of the start of the MTX infusion. Most American patients receive a racemic mixture of d,l-leucovorin (leucovorin or leucovorin calcium). However, the l-isomer is the biologically active moiety (ie, has the capacity to rescue cells from MTX toxicity [75]), and an IV preparation of l-leucovorin is now commercially available in the United States (LEVOleucovorin, Fusilev, Khapzory). It is dosed at one-half that of d,l leucovorin.

A variety of dosing schedules have been published for leucovorin, but most administer 10 mg/m² IV or 15 mg/m² of leucovorin calcium orally (or 5 mg/m² of levoleucovorin IV) every six hours until plasma MTX levels are less than 0.05 to 0.1 microM [78].

The size and number of leucovorin doses do not appear to be critical in patients who have normal MTX clearance [7]. Even doses of 10 to 15 mg/m² are often in excess of those required to achieve rescue in such patients [79]. By contrast, higher concentrations of leucovorin are needed if rapid elimination of MTX is compromised by renal insufficiency. Management of leucovorin dosing in patients with delayed elimination and prolonged elevated plasma MTX levels is discussed below. (See 'Increased dose and frequency of leucovorin' below.)

Oral versus intravenous — Orally administered leucovorin can successfully reverse MTX toxicity. The inactive d-isomer has a longer plasma half-life than the active l-isomer [80], and at least in theory, repeated parenteral administration of the d,l racemic mixture may result in selective accumulation of the inactive d-isomer, which could, at least in theory, compete with the active isomer for cellular uptake, compromising efficacy. Since the active l-isomer is preferentially absorbed from the intestinal tract, oral rather than IV administration of leucovorin calcium may be preferred in this setting as long as the dose is 25 mg or less (oral bioavailability is reduced at doses 40 mg and above [81,82]). LEVOleucovorin is not available as an oral preparation.

For doses higher than 25 mg, oral bioavailability of the active l-isomer is significantly decreased, and IV administration of either the d,l racemic mixture or levoleucovorin is preferred.

Laboratory monitoring during treatment — Laboratory monitoring during treatment with HDMTX is mandatory. Serum creatinine and electrolytes as well as plasma MTX levels should be followed daily. A rise in the serum creatinine above normal values indicates acute renal dysfunction and the potential for delayed MTX elimination, which may prompt an increase in the dose and duration of leucovorin rescue, and consideration for use of glucarpidase. (See 'Increased dose and frequency of leucovorin' below and 'Glucarpidase (carboxypeptidase G2)' below.)

Early studies conducted in the 1970s revealed that the following drug levels after MTX infusion indicated a high risk for bone marrow and gastrointestinal mucosal toxicity [79,83-86]:

●Levels above 5 to 10 microM at 24 hours

●Levels above 0.9 to 1 microM at 48 hours

●Levels above 0.1 microM at 72 hours

These studies also showed that the risk of MTX-associated toxicity is minimal in the absence of elevated MTX concentrations, and that in most circumstances, the development of MTX-associated toxicities can be ameliorated or prevented when patients with MTX drug levels in this range at these time points receive pharmacokinetically guided doses of leucovorin rescue.

As a result, it is mandatory that all patients receiving HDMTX have plasma MTX levels determined after dosing. Monitoring of serum creatinine alone is inadequate since there are large interindividual variations in MTX clearance and a poor correlation between serum creatinine and MTX clearance [83,87,88].

It is customary to assay plasma MTX levels at 24, 48, and 72 hours after the start of the MTX infusion; more frequent monitoring may be needed. Consensus-based recommendations for the timing of MTX levels following HDMTX are available [89]:

●For infusions over six hours or less glucarpidase may be indicated if the 24-hour concentration is above 50 microM, the 36-hour concentration is above 30 microM, the 42-hour concentration is above 10 microM, or the 48-hour concentration is above 5 microM and the serum creatinine is elevated relative to baseline measurement (indicative of HDMTX-induced acute kidney injury).

●For 24- to 42-hour infusional regimens, the initial MTX measurement should be at 24 hours; if the level is >120 microM at that time, or the creatinine has increased ≥50 percent over baseline, this warrants additional monitoring at 36, 42, and 48 hours. If the 36-hour MTX concentration is above 30 microM, the 42-hour MTX concentration is above 10 microM, or the 48-hour concentration is above 5 microM and the serum creatinine is elevated relative to baseline measurement (indicative of HDMTX-induced acute kidney injury), glucarpidase rescue may be indicated. (See 'Glucarpidase (carboxypeptidase G2)' below.)

Most sites monitor plasma MTX concentrations until they are <0.1 to 0.2 microM.

Leucovorin doses should be adjusted based on the MTX drug levels, and hydration/alkalinization is continued or increased provided that adequate urine output can be maintained [90]. (See 'Management of patients with renal failure and prolonged high plasma methotrexate levels' below.)

Management of patients with renal failure and prolonged high plasma methotrexate levels — Delayed renal elimination can result in elevated plasma MTX levels for as long as two to three weeks, which increases systemic toxicity. Risk factors contributing to renal failure and delayed clearance of MTX include urine pH <7, less than 3 L/m² of IV fluid hydration per 24 hours, high body mass index, use of concomitant medications with nephrotoxic potential or known interference with MTX elimination (eg, salicylates, nonsteroidal anti-inflammatory drugs, beta-lactam antibiotics, sulfonamides, aminoglycosides, and proton pump inhibitors), pre-existing hepatic or renal dysfunction, and the presence of third-space fluid collections [91].

In this setting, the risk of treatment-related toxicity may be diminished by the following maneuvers:

Augmenting urine output — Since the rate of MTX elimination is dependent on urine output, hydration and urinary alkalinization should be continued or increased, provided that adequate urine output can be maintained.

Increased dose and frequency of leucovorin — Because the reversal of MTX action by leucovorin is competitive, proportionately higher leucovorin concentrations are required to achieve rescue in the presence of high MTX levels [7,79,92]. In one study, five of 12 patients with 48-hour MTX levels >0.9 microM who were treated with leucovorin doses 6 to 30 mg/m² developed toxicity, compared with none of those who received 50 to 150 mg/m² every six hours [79]. Others have observed occasional patients with delayed MTX clearance and sustained plasma levels >10 microM in whom toxicity seemed to improve when large doses of leucovorin were given [93].

Specific dose modification schema for leucovorin varies broadly among protocols and institutions. The following table shows guidelines for dose and schedule adjustment for leucovorin (the d,l racemic mixture) recommended by the manufacturer (table 3). Guidelines for dose and schedule adjustments for LEVOleucovorin in patients with delayed MTX clearance recommended by the manufacturer are outlined in the table (table 4). Higher-dose leucovorin dosing nomograms have been developed [10,94] and are in use in some institutions [49,95]. However, there is no evidence to suggest that these higher-dose regimens are more effective than the guidelines provided in the United States prescribing information.

The dosing interval for leucovorin has been derived empirically; the half-life of its primary active metabolite is approximately four to six hours [81]. The benefit of dosing every three to four as compared with every six hours has not been proven, although mean plasma levels are two to three times higher with every three hour administration [96]. The duration of leucovorin rescue is often more critical than the dose or dosing interval, since elevated plasma levels may persist for several days [7].

As noted previously, leucovorin selectively rescues normal but not malignant cells from the effects of MTX (see 'Rationale for leucovorin rescue' above). It is not clear that there is any dose of leucovorin that is sufficiently high to interfere with antitumor efficacy. Although leucovorin "overrescue" has rarely been described in children receiving HDMTX for childhood ALL or osteosarcoma [97,98], its clinical relevance is debated [99].

Alternative rescue techniques for patients with renal failure — Whether higher doses of leucovorin alone are sufficient in the setting of renal failure and severe MTX intoxication is debated. In vitro data suggest that rescue of the toxic effects of MTX by leucovorin is not observed when cells are exposed to MTX concentrations ≥100 microM [100]. Clinical data are scarce. In a retrospective review of 13 patients with MTX levels >100 microM at 24 hours and >10 microM at 48 hours after HDMTX, all patients recovered with the use of high-dose leucovorin alone in conjunction with hydration and alkalinization, but short-term morbidity (myelosuppression, mucositis, diarrhea) was prominent [101]. Thus, these data support the view that leucovorin alone is not optimal.

Alternative rescue techniques have been utilized in an attempt to enhance MTX clearance and/or minimize severe systemic toxicity. These include extracorporeal removal of MTX by means of peritoneal dialysis, hemodialysis, hemoperfusion, and/or charcoal hemofiltration [49,51,102-108], administration of leucovorin in conjunction with thymidine [109], use of cholestyramine to bind MTX in the gut and aid in MTX clearance [110], and administration of the metabolizing enzyme carboxypeptidase G2 (glucarpidase, Voraxaze).

Glucarpidase (carboxypeptidase G2) — Glucarpidase rescue may be indicated in specific circumstances, as outlined in the table (table 5).

When renal dysfunction severely compromises clearance of MTX, exogenous administration of the recombinant bacterial enzyme carboxypeptidase G2 (CPDG2, glucarpidase, Voraxaze) can rapidly lower serum MTX levels that remain unacceptably high despite adequate hydration and urinary alkalinization [91,111-115]. Glucarpidase metabolizes folic acid (and leucovorin) and chemically similar antifolates such as MTX to inactive metabolites. In the case of MTX, the molecule is cleaved at the c-terminal glutamate residue into glutamate and the inactive metabolite DAMPA (2,4-diamino-N-methylpteroic acid). (See 'Pharmacokinetics, metabolism, and excretion' above.)

After a single dose of 50 units per kg by bolus IV injection over five minutes, glucarpidase rapidly decreases plasma MTX levels by 98 percent in the first 30 minutes, which in the majority of patients, is sustained [91,112,113,115]. In a series of 43 adult patients treated with glucarpidase for renal dysfunction and delayed MTX elimination, only three required a second dose, which was administered 24 to 48 hours after the first dose [91].

The importance of early administration of glucarpidase was shown in a study of 100 patients who had either a MTX concentration ≥10 micromolar ≥42 hours after the start of the HDMTX infusion or HDMTX-induced renal dysfunction (creatinine ≥1.5 times the upper limit of normal or CrCl ≤60 mL/min and plasma MTX concentration ≥2 standard deviations above the mean ≥12 hours after MTX administration) [116]. All patients received leucovorin and glucarpidase at one of three dose schedules (single dose, two doses 24 hours apart, or three doses every four hours of 50 U/kg/dose). The initial cohort of 35 patients also received IV thymidine for 48 hours or longer after the last dose of glucarpidase, and subsequent patients received thymidine prior to glucarpidase only if there was >96 hour exposure to high levels of MTX, or if the patients had substantial MTX toxicity at the time of the request for glucarpidase.

Glucarpidase was administered at a median of 96 hours in the 44 patients who received thymidine and at 66 hours in the 56 patients who did not receive thymidine. Plasma MTX concentrations decreased by 99 percent within 15 minutes of glucarpidase. Six of the 12 patient deaths were directly attributable to irreversible MTX toxicity. All deaths occurred among the 14 patients with grade 4 toxicity prior to glucarpidase administration, and five of them occurred in patients who received insufficient leucovorin rescue and delayed administration of glucarpidase after 96 hours.

Adverse effects are minimal. In a report of data on 290 patients with markedly delayed MTX clearance secondary to renal dysfunction who were treated in two single-arm open-label multicenter trials, the most common adverse reactions that were not hematologic, hepatic, or renal events included paresthesias, flushing, and nausea and vomiting, which each occurred in 2 percent of patients; infusional-related allergic reactions are reported but are uncommon (<1 percent) [117].

Glucarpidase was approved in the United States in January 2012 for treatment of toxic MTX plasma concentrations (>1 microM) in patients with delayed MTX clearance due to impaired renal function [117]. The indications for glucarpidase are not well established. Recommendations are available from a year 2018 consensus guideline for use of glucarpidase in patients with HDMTX-induced acute kidney injury and delayed MTX clearance (table 5) [89]. However, clinical interpretation of laboratory results that do not directly correspond to the algorithm is a limitation of its use.

A clinical decision support tool (available at MTXPK.org) has been developed at the Cincinnati Children's Hospital that allows clinicians to utilize individual demographics, serum creatinine, and real-time MTX plasma concentrations to predict the elimination profile for HDMTX and facilitate decision-making for glucarpidase [118]. We agree with the use of this clinical decision support tool.

Importantly, leucovorin (either the d,l racemic mixture or l-leucovorin [LEVOleucovorin]) must be continued for two days beyond glucarpidase administration [49,80]. However, because leucovorin is a substrate for glucarpidase, leucovorin doses should not be administered within two hours before or after the dose of glucarpidase.

MTX concentrations within 48 hours following administration of glucarpidase can only be reliably measured by a chromatographic method, as the inactive metabolite that results from cleavage of the MTX molecule, DAMPA, interferes with measurement of MTX levels by immunoassay. (See 'Laboratory monitoring during treatment' above.)

Issues related to cost — The cost of glucarpidase is high enough (Average Wholesale Price $42,000.00 USD per 1000 units) that access and rapid availability are problematic even in large academic medical centers because the drug is used infrequently and not kept "in stock." Most pharmacies need at least a 24 hour notice to procure the agent. This is challenging to the principle of administration as early as possible.

Given the high cost, there is some intriguing research that perhaps a half dose may be sufficient [119], but this is not yet a standard approach.

Rechallenge — It is possible to safely resume HDMTX after glucarpidase treatment. This was shown in a series of 20 children who received glucarpidase for HDMTX-induced acute kidney injury, 13 of whom were rechallenged after recovery of renal function [120]. Twelve received a reduced dose (33 to 75 percent of the original dose that was associated with acute kidney injury), while one patient with osteosarcoma received the full recommended dose (12 g/m²). The maximal serum creatinine after the initial rechallenge was 0.8 mg/dL, and none of the patients required further glucarpidase with subsequent HDMTX courses. These data support the view that use of glucarpidase is associated with complete renal recovery and that resumption of HDMTX is safe after glucarpidase, with close monitoring of renal function and plasma MTX levels.

Dialysis — Removal of MTX by peritoneal dialysis is ineffective [121], and other dialysis methods are of limited effectiveness. This was illustrated in a review of the efficacy of dialysis-based methods of MTX removal in 49 patients with HDMTX-induced renal dysfunction [51]. The most frequently used methods were hemodialysis (n = 10), high-flux hemodialysis (n = 9), and charcoal hemofiltration (n = 7); 16 patients were treated with multiple modalities. High-flux hemodialysis resulted in the greatest decrease in plasma MTX concentration (median 76 percent) within the shortest period of time (median four hours). However, only three patients had a >90 percent decrease in MTX drug concentration with the use of a single method in one dialysis session.

A major limitation to the use of dialysis-based methods to remove MTX is the marked rebound in plasma MTX concentration that occurs once dialysis is stopped [104-108]. Further limitations of these methods are the accompanying risks for complications, which can include bleeding, thrombocytopenia, hypokalemia, and severe hypophosphatemia [102,106].

Overall, these techniques are best utilized temporarily, when combined with higher doses of leucovorin rescue, while awaiting the initiation of glucarpidase therapy.

Thymidine — There is no indication for thymidine supplementation. Thymidine supplementation can restore DNA synthesis, even at low serum levels. Unlike leucovorin, thymidine does not compete with MTX for uptake into cells. Several older clinical trials and case reports documented the success of thymidine (continuous IV infusion of 8 gm/m²/day) as a rescue agent, often in combination with higher doses of leucovorin [109,122-125]. However, thymidine was not effective in the previously discussed series of 100 consecutive patients with HDMTX-induced nephrotoxicity [116].

SUMMARY AND RECOMMENDATIONS

●Definition, indications, and clearance

•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. (See 'Definition of high-dose methotrexate' above and 'Oncologic indications for high-dose methotrexate' above.)

•Almost 90 percent of MTX is excreted unchanged in the urine. When given at high doses, MTX can precipitate in the renal tubules and directly induce tubular injury, especially in the presence of acidic urine and volume depletion. This may severely compromise MTX clearance, resulting in delayed excretion, higher than expected plasma levels, and increased systemic toxicity. (See 'Renal toxicity' above and 'Pharmacokinetics, metabolism, and excretion' above.)

●Prevention of HDMTX toxicity – The guiding principles for preventing HDMTX toxicity include maintaining urine output and urinary alkalinization; close monitoring of serum creatinine, electrolytes, and plasma MTX concentrations; and pharmacokinetically guided leucovorin rescue. (See 'Practical tips for managing high-dose methotrexate' above.)

•Pretreatment assessment

-Pretreatment assessment of renal function is needed prior to each dose; if feasible, third-space fluid collections (pleural effusions, ascites) should be drained prior to treatment, as they provide a drug reservoir that prolongs MTX excretion. (See 'Pretreatment assessment' above.)

-A number of drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), phenytoin, ciprofloxacin, penicillin-type drugs, probenecid, amiodarone, proton pump inhibitors, tyrosine kinase inhibitors, and possibly levetiracetam, may delay elimination, and their use should be avoided, if possible, during HDMTX treatment. (See 'Potential drug-drug-interactions' above.)

•Maintaining urinary output and urine alkalinization during HDMTX

-Maintaining adequate hydration and urine output is essential for rapid clearance of HDMTX. Aggressive hydration (2.5 to 3.5 liters of intravenous [IV] fluid/m² per day) should start 4 to 12 hours before the MTX infusion is begun and should continue until plasma MTX levels are ≤0.1 microM. (See 'Hydration and urinary alkalinization' above.)

-Urinary alkalinization, usually with sodium bicarbonate added to each liter of IV fluid hydration (or oral sodium bicarbonate), is required to maintain the urine pH ≥7.0 until plasma MTX levels are below 0.1 microM.

•Monitoring creatinine, electrolytes, and plasma MTX levels – Serum creatinine, electrolytes, and plasma MTX concentrations should be monitored at least daily. (See 'Laboratory monitoring during treatment' above.)

•Leucovorin rescue

-Leucovorin rescue is promptly initiated within 24 to 36 hours of the start of the MTX infusion, with continued leucovorin until MTX plasma levels are <0.1 microM. (See 'Leucovorin administration' above.)

-Leucovorin doses are modified if plasma MTX levels are ≥5 to 10 microM at 24 hours, ≥1.0 microM at 48 hours, and/or ≥0.1 microM at 72 hours (table 4). (See 'Laboratory monitoring during treatment' above.)

●Management of acute kidney failure during HDMTX – Even when these preventive guidelines are strictly followed, approximately 2 percent of patients will develop acute kidney failure following HDMTX. Early recognition of renal dysfunction should prompt the following maneuvers (see 'Management of patients with renal failure and prolonged high plasma methotrexate levels' above):

•Increase hydration and urinary alkalinization, provided that adequate urine output can be maintained. (See 'Augmenting urine output' above.)

•Increase doses of d,l leucovorin or LEVOleucovorin based on the measured plasma MTX levels (table 3 and table 4). (See 'Increased dose and frequency of leucovorin' above.)

•Glucarpidase rescue may be indicated in specific circumstances, as outlined in the table (table 5). We utilize a clinical decision support tool (available at MTXPK.org) that was developed at the Cincinnati Children's Hospital and allows clinicians to utilize individual demographics, serum creatinine, and real-time MTX plasma concentrations to predict the elimination profile for HDMTX and facilitate decision-making for glucarpidase. (See 'Glucarpidase (carboxypeptidase G2)' above.)

Administration of glucarpidase should optimally occur within 48 to 60 hours from the start of the HDMTX infusion because life-threatening toxicities may not be preventable beyond this time point.

•Removal of MTX by dialysis techniques is of limited effectiveness, and dialysis is best utilized temporarily, combined with higher doses of leucovorin rescue, while awaiting the initiation of glucarpidase therapy. (See 'Dialysis' above.)