51: Chemotherapeutics: Methotrexate

Methotrexate (MTX) is commonly used in the treatment of cancers and noncancerous conditions. Its immunosuppressive activity allows it to also be used for rheumatoid arthritis, organ transplantation, psoriasis, trophoblastic diseases, and therapeutic abortion.^12,33

Risk factors for MTX toxicity include impaired kidney function (primary route of drug elimination), third compartment spacing, ascites and pleural effusions, concurrent use of nephrotoxins (such as nonsteroidal antiinflammatory drugs (NSAIDs) aminoglycosides⁴²) and certain intravenous (IV) radiologic contrast dyes^18,26, age, folate deficiency, and concurrent infection.⁶⁵ MTX toxicity depends on the dose but even more on the duration of exposure.

The therapeutic and toxic effects of MTX are based on its ability to limit DNA and RNA synthesis by inhibiting dihydrofolate reductase (DHFR) and thymidylate synthetase (Fig. 51–1). Thymidylate synthesis is inhibited by polyglutamic derivatives of MTX. DHFR reduces folic acid to tetrahydrofolate (FH4), which serves as an essential cofactor in the synthesis of purine nucleotides. Reduced folate is also required by thymidylate synthetase to serve as a methyl donor in the formation of thymidylate. Thymidylate is then used for DNA synthesis. MTX, a structural analog of folate, competitively inhibits DHFR by binding to the enzymatic site of action. This inhibits reduced folate production, which is necessary for nucleotide formation and DNA/RNA synthesis.

The bioavailability of MTX appears to be limited by a saturable intestinal absorption mechanism. At oral doses less than 30 mg/m², the absorption is 90%; at doses greater than 80 mg/m², the total absorption is less than 10% to 20%.⁹ The weekly adult dose used for the treatment of psoriasis and rheumatoid arthritis is low and can be administered orally. However, the dose used to induce abortion is higher (50 mg/m²) and must be administered parenterally to achieve an effective drug concentration. MTX dosing regimens for chemotherapy are variable but can be generally classified as low (40 mg/m²), moderate range, and high doses (1000 mg/m²). Conventional IV doses of up to 100 mg/m² can be administered without leucovorin rescue. Doses of 1000 mg/m² are considered potentially lethal. Much higher doses (2–3 g/m²) can be given when MTX is followed by leucovorin to prevent life-threatening toxicity. The mortality rate from high-dose MTX is approximately 6% and occurs primarily when MTX concentrations are not closely monitored.^65,68

Methotrexate has a triphasic plasma clearance. The initial plasma distribution half-life is short at 0.75 hours. The second half-life is 2 to 3.4 hours and represents renal clearance of the drug. The third phase has a half-life of about 8 to 10.4 hours and represents tissue redistribution into the plasma. This third phase can be prolonged in the setting of kidney failure and is associated with bone marrow and gastrointestinal (GI) toxicity. The volume of distribution is 0.6 to 0.9 L/kg, and protein binding is 50%. Healthy kidneys eliminate 50% to 80% of MTX unchanged within 48 hours of administration. When the creatinine clearance is less than 60 mL/min, MTX clearance is delayed.^58,70

At high doses, drug and insoluble drug metabolites (7-hydroxy methotrexate {7-OH-MTX} and 2,4-diamino-N10-methylpteroic acid {DAMPA}) accumulate and may precipitate in the renal tubules, causing reversible acute tubular necrosis. MTX is one-tenth as soluble at a pH of 5.5 as it is at a pH of 7.5.^9,59 Expressed another way, the serum concentration threshold for nephrotoxicity is 2.2 mmol/L when the urine pH is 5.5 and 22 mmol/L when the urine pH is 6.9. Thus, patients who are either inadequately hydrated or have not had urinary alkalinization are at risk for acute kidney failure from high-dose MTX treatment.^3,34 MTX is excreted unchanged in the urine by both glomerular filtration and active tubular secretion. Folic acid blocks renal MTX reabsorption and can enhance elimination during leucovorin rescue.²⁷ A small amount of MTX is metabolized intracellularly to polyglutamate derivatives, which inhibit DHFR and thymidylate synthetase and are believed to be responsible for the persistent cytotoxic effect of MTX because they do not easily diffuse outside of the cell.

In the course of MTX therapy, a variety of disorders can occur, resulting from either increased patient susceptibility to toxicity or excessive administration. The clinical manifestations of MTX toxicity include stomatitis, esophagitis, kidney failure, myelosuppression, hepatitis, and central nervous system dysfunction. In a group of 23 patients who received 45 courses of high-dose MTX therapy with leucovorin rescue, the most commonly observed signs included increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT) (81%), nausea and vomiting (66%), mucositis (33%), dermatitis (18%), leukopenia (11%), thrombocytopenia (9%), and creatinine elevation (7%).⁵⁵

Nausea and vomiting, considered rare after low-dose cancer therapy (40 mg/m²), typically begin 2 to 4 hours after high-dose therapy (1000 mg/m²)and last for about 6 to 12 hours. Mucositis, characterized by mouth soreness, stomatitis, or diarrhea, usually occurs in the first week of therapy, continues to evolve in the second week of therapy, and can last for 4 to 7 days. Other GI effects resulting from MTX therapy include pharyngitis, anorexia, GI hemorrhage, and toxic megacolon.⁶ Hepatocellular toxicity, as identified as increased AST (>1000 IU/L) or ALT (>1000 IU/L), and hyperbilirubinemia, can occur with both acute and chronic therapy.^47,49 It is usually associated with high dose regimens. Laboratory abnormalities improve within 1 to 2 weeks of discontinuation of MTX. The mechanism is incompletely understood, but toxicity is attributed to reduced liver folate stores.⁷ Factors associated with hepatotoxicity include sustained high serum concentrations, increased cumulative dosages, chronic therapy, and host factors such as an increase in age, obesity, diabetes, and alcoholism.⁷¹

Pancytopenia usually occurs within the first 2 weeks after an acute exposure. Pancytopenia can also occur with chronic MTX therapy for rheumatoid arthritis and psoriasis.^16,40,47,57

When used in low-dose IV doses of 40 to 60 mg/m², MTX is not associated with appreciable nephrotoxicity. However, at doses greater than 5000 mg/m² (~130 mg/kg for an adult), several investigators report severe kidney damage, with oliguria, azotemia, and kidney failure.⁸ The kidney function can normalize over time. Patients at risk for nephrotoxicity include elderly adults; those with underlying kidney disease defined as a glomerular filtration rate of less than 50 mL/min; and those who receive concurrent drug therapy that can delay MTX excretion, which includes xenobiotics that reduce renal blood flow such as NSAIDs, nephrotoxins such as cisplatin and the aminoglycosides, and weak organic acids such as salicylates and piperacillin that inhibit renal secretion.^32,65

The neurologic complications associated with either high-dose systemic MTX therapy or intrathecal administration are the most consequential manifestations. The incidence of neurologic toxicity from high-dose MTX therapy is approximately 5% to 15%.³⁵ The manifestations of toxicity usually occur from hours to days after the initiation of therapy and include hemiparesis, paraparesis, quadraparesis, seizures, and dysreflexia.^35,46,66,69 These events are reversible to varying degrees.² Clinical findings occurring within several hours (usually within 12 hours) of therapy are attributed to chemical arachnoiditis, and they include acute onset of fever, meningismus, pleocytosis, and increased cerebrospinal fluid (CSF) protein ­concentration.²⁸ Leukoencephalopathy is associated with the onset of behavioral disorders and progressive dementia from months to years after treatment and is irreversible, although manifestations presenting soon after treatment can be reversible depending on the extent of involvement.^5,74 Patients with increased age and prior cranial radiation are at increased risk for this disorder.²³ Patients with leukoencephalopathy have findings consistent with edema and demyelination or necrosis of the white matter on computed tomography (CT) and magnetic resonance imaging (MRI) of the brain.⁵

Serum MTX concentrations are monitored during therapy to limit toxicity. For example, patients with a serum concentration greater than 1.0 μmol/L at 48 hours after treatment are considered at risk for bone marrow and mucosal toxicities.⁶⁵ The measurement of MTX concentrations in the clinical setting is routinely conducted using an enzyme immunoassay or fluorescence polarization immunoassay (FPIA). These measurements can be performed on serum, plasma, and CSF. The presence of MTX metabolites, such as 7-OH-MTX and DAMPA, folic acid, and certain drugs, such as trimethoprim and aminopterin, can diminish the specificity of the analytical method for MTX.^{4,11,19,53,60} The amount by which these xenobiotics affect the MTX concentration depends on the assay. Leucovorin demonstrated a crossreactivity for MTX of less than 1% at a concentration of 1000 μmol/L with the FPIA (monoclonal antibody {MAB}) method¹ and approximately 8% at a concentration of 1.69 µmol/L with a modified enzyme immunoassay method.¹⁰ The advantages of high-performance liquid chromatography (HPLC) over these other methods include improved sensitivity, specificity, and ability to detect metabolites; however, HPLC takes longer to run than the routine clinical methods because it is not an automated procedure. When patients are treated with glucarpidase (carboxypeptidase) (Antidotes in Depth: A11), it is preferable to use the HPLC method to measure MTX because of the presence of metabolites. The FPIA method with MABs is not recommended for use in patients who have developed antibodies to mouse MABsor elevated concentrations of DAMPA.⁴¹

An elevated CSF MTX concentration (>100 µmol/L) is indicative of an excessive intrathecal dose or delayed CSF outflow obstruction.⁵⁰ Radiologic imaging of the brain, such as CT and MRI, can be obtained to evaluate for meningeal inflammation, demyelination and necrosis of the white matter, or other pathologies such as a cerebrovascular accident.

In the event of an oral overdose of MTX, the initial concern should be GI decontamination. Activated charcoal adsorbs MTX and should be administered as soon as possible to limit absorption.²⁴ The administration of multiple-­dose activated charcoal or cholestyramine^17,62 can significantly decrease the elimination half-life of MTX by interrupting the enterohepatic circulation.^21,24 This approach can increase MTX clearance but is of most benefit to patients with diminished creatinine clearance.

Adequate hydration with 0.9% sodium chloride solution as well as urinary alkalinization with IV sodium bicarbonate (to urine pH of 7 to 8) (Antidotes in Depth: A5) is also important to prevent kidney failure that results from the precipitation of MTX and metabolites.¹³ The complete blood count should be monitored on days 7, 10, and 14 to assess the impact on the bone marrow.⁴³ Granulocyte-macrophage colony-stimulating factor (GM-CSF) was used in a patient with a chronic MTX overdose and pancytopenia.⁶⁴ The patient had a serum MTX concentration of 1.25 μmol/L on admission and was in kidney failure. Bone marrow biopsy showed promyelocytes but no mature white cells and a marked reduction of megakaryocytes. Because of deteriorating conditions, GM-CSF (125 µg/m²/d) was administered when the MTX concentration fell below the reference limit for toxicity. Seven days after the initiation of GM-CSF, the white blood cell count rose and reached normal values within 10 days.

Patients presenting with meningismus or altered mental status after MTX therapy require an initial MRI of the brain and then CSF analysis for infection.³⁸ Although not considered standard, the CSF can be assayed for MTX if excessive exposure to this compartment is suspected. The CSF MTX concentration is about 0.1 mol/L (1 × 10⁵µmol/L) and lasts for 48 hours after an IV MTX dose of 1500 mg/m² and 100 mol/L (1 × 10⁸µmol/L) for the peak therapeutic concentration after a 12-mg intra­thecal MTX dose.⁵¹ MRI of the brain can demonstrate a high signal throughout the pachymeningeal (dura mater) region, which is consistent with chemical meningitis,²⁰ or a high signal of the white matter with a decreased diffusion coefficient in a diffusion-weighted image to indicate the presence of edema, which is an early finding of leukoencephalopathy.

The available rescue agents for MTX toxicity include folinic acid (leucovorin) (Antidotes in Depth: A10) and glucarpidase (carboxypeptidase) (Antidotes in Depth: A11). The effectiveness of these therapies depends on both the timing of administration and the dose, which warrants the monitoring of serum MTX concentrations during the use of these antidotes. Folinic acid rescue therapy limits bone marrow and GI toxicity by allowing essential biochemical processes that are dependent on reduced folates to continue. The purpose of the initial dose of leucovorin is to achieve a serum concentration equal to the MTX; subsequent doses should be adjusted according to serum MTX concentrations at 12, 24, and 48 hours after exposure (Fig. 51–1).^39,60 Leucovorin treatment is continued until the MTX concentration is less than 0.01 µmol/L.¹² In patients with marrow toxicity and no cancer, leucovorin therapy should be continued until marrow recovery occurs even if serum MTX is no longer detectable⁴⁵ because intracellular MTX activity can still be ongoing because of the presence of cytosolic MTX polyglutamates. Among 36 patients undergoing MTX therapy (the amount varied from 2.0–13.0 mg of MTX per week) for rheumatoid arthritis, all of these patients had indirectly detectable MTX polyglutamates in their red blood cells and nondetectable MTX in the serum (FPIA, MAB).^29,30

Glucarpidase (carboxypeptidase G₂, Voraxaze) is a recombinant bacterial enzyme that is used as a rescue therapy to inactivate MTX by hydrolyzing it to DAMPA and glutamte. Glucarpidase is available for use as an adjunctive therapy in patients receiving high-dose MTX and those experiencing MTX toxicity or who are at risk for MTX toxicity (diminished kidney function or delayed MTX clearance based on serum MTX concentrations). After glucarpidase therapy, serum MTX concentrations need to be monitored because residual concentrations of MTX in the blood after initial enzymatic therapy can result from an inadequate dose of glucarpidase. This occurs in patients with large MTX exposures or the redistribution of MTX from tissue stores to the blood compartment.^11,60,72 Glucarpidase can also be successfully administered intrathecally to reduce elevated MTX concentrations in the cerebrospinal space (Special Considerations: SC3).⁷³

There are several reports of the use of hemodialysis or hemoperfusion (or both) for patients with MTX toxicity.^{37,48,56,67,70} Although the volume of distribution (0.6–0.9 L/kg) and protein binding (50% that is not concentration dependent) suggest that MTX is dialyzable, older clinical evidence suggested otherwise.⁶⁴ In one report, less than 10% of an initial 700 mg dose of MTX was cleared in 12 sessions of hemodialysis.⁶⁷ The measured clearance was only 38 mL/min, which can be compared with 5 mL/min for peritoneal dialysis,²⁵0.28 to 24 mL/min for continuous venovenous hemodiafiltration,^36,39 and 180 mL/min for normal renal clearance.⁴⁴ Using plasma exchange transfusion to remove MTX is not recommended because MTX has limited protein binding, limiting any potential efficacy of this procedure.^8,39,52,67

Acute intermittent hemodialysis with a high-flux dialyzer membrane (F-80B Fresenius Dialyzer) yielded an effective mean serum MTX clearance of 92 ± 10.3 mL/min in six patients with kidney failure that was a result of either chronic disease or high-dose MTX therapy.⁷⁰ These patients received high-dose MTX therapy and had predialysis serum MTX concentrations ranging from 1.45 to 1813 µmol/L. The time of dialysis initiation after MTX treatment was from 1 hour to 6 days in these patients. A postdialysis serum MTX concentration of 0.3 µmol/L was used as an end point for dialysis. The reported MTX clearance by this technique closely approximates normal renal MTX clearance and is indicated to enhance the clearance of MTX in patients with diminished renal clearance and an elevated serum MTX concentration.⁵⁸

Charcoal hemoperfusion removed more than 50% of MTX in four patients with impaired renal MTX clearance during high-dose MTX ­therapy.¹⁵ This was thought to have prevented severe skin and mucosal toxicity. Sequential hemodialysis and hemoperfusion were used for a patient with substantial MTX toxicity.²⁴ These procedures decreased the half-life of elimination from 45 hours to 7.6 hours. In experimental animals, hemoperfusion significantly reduced the terminal half-life of MTX. In surgically anephric dogs, hemoperfusion decreased the half-life from more than 20 hours to 1.3 hours.³¹ Consequently, hemoperfusion is recommended over hemodialysis when it is available; otherwise, high-flux hemodialysis is preferred.⁵⁶

In vitro studies indicate that the toxic effects of 100 µmol/L of MTX cannot be reversed by 1000 µmol/L of folinic acid.⁵⁴ This suggests the need for extracorporeal elimination after massive doses or enzymatic cleavage (or both) to lower persistent serum MTX concentrations of greater than 100 µmol/L.⁵⁶ It is important to perform high-flux hemodialysis early before distribution into tissues. Rebound of MTX concentrations from tissues can be expected after hemodialysis, which can begin at 2 hours after dialysis and plateau at 16 hours.^22,25,70 Patients who are at the greatest risk for developing MTX toxicity despite folinic acid treatment should be considered for glucarpidase therapy. This includes patients with progressively diminishing renal clearance.⁶⁵ High-flux hemodialysis can offer the additional benefit of correcting fluid and electrolyte disorders resulting from kidney failure. Other treatment options to limit additional organ toxicity, including leucovorin and urinary alkalinization, should be continued during extracorporeal MTX removal. Folic acid is water soluble and can be removed by hemodialysis.^14,56,61,63 This is probably also applicable for folinic acid, and replacement doses of leucovorin postdialysis should be considered.

• The number of patients with MTX exposures and resultant toxicity is anticipated to increase because of the expanding therapeutic indications and available multiple formulations of this antineoplastic.

• Clinicians need to have a greater awareness of the clinical presentations, acute and chronic, and management of MTX toxicity to improve outcomes.

• Patients with associated chronic illnesses, diminished renal clearance, and chronic toxicity are at greatest risk for increased morbidity from overwhelming sepsis.

• Management includes supportive care, monitoring serum MTX concentrations, urinary alkalinization to limit kidney toxicity, enhanced elimination, and antidotal therapy with leucovorin and enzymatic cleavage with glucarpidase when indicated.

• The early recognition of these patients and institution of these therapies can offer the patient the best outcome.

Disclaimer

The findings and conclusions in this chapter are those of the author and do not necessarily represent the views of Centers for Disease Control and Prevention.

References