Therapeutic use and toxicity of high-dose methotrexate

Therapeutic use and toxicity of high-dose methotrexate

Author
Ann S LaCasce, MD
Section Editors
Robert Maki, MD, PhD
Arnold S Freedman, MD
Alberto S Pappo, MD
Deputy Editor
Diane MF Savarese, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Mar 2013. | This topic last updated: Mar 21, 2013.

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 antiinflammatory 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 conditions
are covered elsewhere. (See appropriate topic reviews).

DEFINITION OF HIGH-DOSE MTX — 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/m 2 ,
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, followed by 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/m 2 , 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/m 2 unless unexpected toxicity is encountered. (See
"Gestational trophoblastic neoplasia: Staging and treatment", section on 'Methotrexate
with and without leucovorin' .)
 Low-dose MTX (<50 mg/m 2 ) 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 metastases (carcinomatous meningitis)" .)

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 to 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)-
formyltetrahydofolate 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 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 methotrexate [ 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 to 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 MTX — 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 "Gestational trophoblastic
neoplasia: Staging and treatment" .)

Pharmacokinetics, metabolism, and excretion — Even when given identical doses of

HDMTX, patients vary significantly in their response and pattern of toxicity. This diversity
can, to some extent, be linked to sequence variations in genes involved in drug absorption,
metabolism, excretion, cellular transport, and effector targets or target pathways. 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 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/m 2 are in the range of 500 to 1500 microM (50 to 150 X 10 [-5] M) [ 30 ].
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 intravenous hydration and augmenting the dose of leucovorin . (See
'Management of patients with renal failure and prolonged high plasma MTX 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/m 2 ) 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 [ 31,32 ].

Patients with renal insufficiency require MTX dose adjustment. (See 'Pretreatment
assessment' below.)

Many drugs inhibit renal excretion of MTX and may increase treatment-related toxicity.
These include NSAIDs, phenytoin , ciprofloxacin , penicillin-type drugs, probenecid ,
amiodarone , and proton pump inhibitors [ 11,33,34 ].

Concurrent use of the antibiotic trimethoprim-sulfamethoxazole increases treatment-related

toxicity and, at least in theory, may also interfere with antitumor efficacy [ 35-37 ]. Sulfa
drugs inhibit MTX renal excretion, while trimethoprim (also an antifolate) can compete with
MTX for binding sites on the DHFR molecule.

During HDMTX infusion, rapid drug excretion leads to high MTX concentrations in the
urine. These concentrations, approaching 10 mM, exceed the solubility of the drug below pH
7.0 and are thought responsible for intrarenal precipitation of the drug and renal failure. Renal
failure 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.)

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 [ 33 ].

OVERVIEW OF ADVERSE EFFECTS — 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 oral
methotrexate for nonmalignant disease" .)

HDMTX can cause an acute elevation in the serum transaminases from two to twenty-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 IU/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 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", 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/m 2 are considered
moderately emetogenic; smaller doses have low or minimal emetogenic potential ( table 3 ).
In keeping with guidelines from the American Society of Clinical Oncology (ASCO), patients
receiving MTX ≥250 mg/m 2 should be pretreated with a serotonin receptor antagonist and
dexamethasone , with or without aprepitant [ 38 ]. (See "Pathophysiology and prediction of
chemotherapy-induced nausea and vomiting" and "Prevention and treatment of
chemotherapy-induced nausea and vomiting" .)

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 [ 39 ]:

 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 (acute renal failure)",
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 ten-fold [ 39,40 ].
(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 [ 41 ]. The incidence may
be higher in adults.

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 MTX
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 "Neurologic complications of non-platinum cancer chemotherapy", section on
'Methotrexate' .)

Dermatologic toxicity — Between 5 to 10 percent of patients develop a nonspecific

morbilliform drug rash, which is usually erythematous, pruritic, and often confined to the
neck and trunk. In severe cases, it can progress to bullous formation or desquamation. MTX
can also cause photoreactivation and photoenhancement as well as skin hyperpigmentation.
(See "Cutaneous complications of conventional chemotherapy agents" .)

Alopecia is occasionally encountered but is usually not complete. (See "Chemotherapy-

induced alopecia" .)

Hypersensitivity — True hypersensitivity reactions to MTX are rare [ 42 ]. Successful

rechallenge has been reported using a desensitization protocol. (See "Infusion reactions to
systemic chemotherapy" .)

ONCOLOGIC INDICATIONS FOR HDMTX — High-dose methotrexate (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 lymphomatous meningitis include
aggressive histologic features, a high International Prognostic Index (IPI), multiple extranodal
sites, disease involving the sinuses, testes, and possibly the bone marrow (this is quite
controversial), and in patients with HIV disease. (See "Secondary involvement of the central
nervous system by non-Hodgkin lymphoma" .)

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 ( table 4 ).
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 [ 43,44 ].
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 "Overview of the treatment of acute lymphoblastic leukemia in children" .)

Primary CNS lymphoma — HDMTX is the mainstay of most treatment regimens for primary
CNS lymphoma. It has been used as the sole therapeutic agent as well as in multi-agent
chemotherapy regimens, with or without radiotherapy. Response rates and outcomes are
superior when HDMTX is combined with radiation therapy, but toxicity rates are higher,
especially in elderly patients who receive both MTX and radiotherapy. (See "Treatment and
prognosis of primary central nervous system lymphoma", section on 'Initial Treatment' .)

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. (See "Secondary involvement of the central
nervous system by non-Hodgkin lymphoma" .)

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/m 2 ( table 5 ). 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
'Adjuvant chemotherapy' .)

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 to 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 'Choice of regimen' .)

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 [ 45 ]. (See
"Chemotherapy and radiation therapy in the management of osteosarcoma", section on
'Treatment of 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. 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
metastases (carcinomatous meningitis)" .)

PRACTICAL TIPS FOR MANAGING HDMTX — 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 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 [ 46 ], 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.

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. If present, these effusions 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.)

Renal function — Because MTX is cleared predominantly by the kidney, assessment of renal
function is necessary prior to each dose of HDMTX. Dose reduction may be warranted for
GFR (as estimated by the creatinine clearance, CrCl) <80 mL/min:

 CrCl 61 to 80 mL/minute — Reduce dose to 75 percent of usual dose

 CrCl 51 to 60 mL/minute — Reduce dose to 70 percent of usual dose
 CrCl 10 to 50 mL/minute — Reduce dose to 30 to 50 percent of usual dose
 CrCl <10 mL/minute — Avoid use of MTX

There is 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 [
47 ]. Some studies suggest greater accuracy for estimating CrCl (and therefore, GFR) using
the Wright formula [ 48 ], the Cockcroft-Gault formula [ 49 ], or by use of the simplified
MDRD (modification of diet in renal disease) equation ( calculator 1 and calculator 2 ) [ 47 ].

However, any estimation of GFR based upon 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 "Chemotherapy-related nephrotoxicity and dose
modification in patients with renal insufficiency", section on 'Estimation of GFR for possible
dose adjustment' .) 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.

Use of proton pump inhibitors — Coadministration of proton pump inhibitors (PPIs) such as
such as omeprazole , esomeprazole , and pantoprazole appears to be a major risk factor for
delayed elimination of MTX [ 34,50,51 ]. Although the mechanism underlying this interaction
is unclear, PPIs should be avoided, if possible, during HDMTX treatment.

Prevention and management of HDMTX 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 are
essential for rapid clearance of MTX. Most protocols recommend at least 2.5 to 3.5 liters/m 2
of IV fluid hydration per day, starting four 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 starting with two x 650 mg tablets, and
increased up to five tablets every two to four hours.

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.)

Some protocols restrict dietary intake of acidic foods (eg, orange juice, tomato products)
during HDMTX treatment until levels are below 0.1 microM. There are no data to support
benefit from this practice, and as long as urine pH can be maintained above 7.0, dietary
restriction is unnecessary. Others recommend avoidance of aspirin and other NSAIDs and
vitamins (particularly vitamin C) until plasma MTX levels are less than 0.1 microM.

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 [ 52 ]), and an
intravenous preparation of l-leucovorin is now commercially available in the US (
LEVOleucovorin , Fusilev). It is dosed at one-half that of d,l leucovorin.
A variety of dosing schedules have been published, but most administer 10 mg/m 2 IV or 15
mg/m 2 of leucovorin calcium orally (or 5 mg/m 2 of levoleucovorin IV) every six hours until
plasma MTX levels are less than 0.05 to 0.1 microM. 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/m 2 are often in excess of those required to achieve rescue in such
patients [ 53 ]. In contrast, higher concentrations of leucovorin are needed if rapid elimination
of MTX is compromised by renal insufficiency. Management of leucovorin in patients with
delayed elimination and prolonged elevated plasma MTX levels is discussed below. (See
'Increased dose and frequency of leucovorin' below.)

Oral versus IV — Orally administered leucovorin can successfully reverse MTX toxicity.
The inactive d-isomer has a longer plasma half-life than the active l-isomer [ 54 ], 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 [ 55 ], oral rather than IV administration of leucovorin
calcium may be preferred in this setting as long as the dose is less than 50 mg.
LEVOleucovorin is not available as an oral preparation.

For doses higher than 50 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 — Serum creatinine and electrolytes as well as

plasma MTX levels should be followed daily. A rise in the serum creatinine above normal
values indicates renal dysfunction and the potential for delayed MTX elimination [ 53 ]. 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 [ 56-58 ].

It is customary to assay plasma MTX levels at 24, 48, and 72 hours after the start of the MTX
infusion. For 24-hour infusional regimens, the initial MTX measurement may be at 36 hours
(ie, 12 hours after the completion of the infusion). Leucovorin doses are then adjusted based
upon the MTX drug levels, and hydration/alkalinization is continued or increased provided
that adequate urine output can be maintained [ 59 ]. Drug levels should continue to be
monitored with ongoing alkaline hydration and leucovorin rescue until they are <0.05 to 0.1
microM (<0.05 to 0.1 microgram/mL). (See 'Management of patients with renal failure and
prolonged high plasma MTX levels' 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 [
53,57,60-62 ]:

 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.

Management of patients with renal failure and prolonged high plasma MTX 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/m 2 of IV fluid hydration per 24
hours, high body mass index, use of comedications with nephrotoxic potential or known
interference with MTX elimination (eg, salicylates, nonsteroidal antiinflammatory drugs,
beta-lactam antibiotics, sulfonamides, aminoglycosides, and proton pump inhibitors),
preexisting hepatic or renal dysfunction, and the presence of third-space fluid collections [ 63
].

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 [ 7,53,64 ]. 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/m 2 developed toxicity, compared to none of those who received 50 to 150 mg/m 2
every six hours [ 53 ]. 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 [ 65 ].

Specific dose modification schema for leucovorin varies broadly among protocols and
institutions. The following table shows a typical pharmacokinetically-guided schedule for
dose adjustment of leucovorin (the d,l racemic mixture) based upon plasma MTX levels used
in our institutions ( table 6 ). Guidelines for dose and schedule adjustments for
LEVOleucovorin in patients with delayed methotrexate clearance recommended by the
manufacturer are outlined in the table ( table 7 ).

The dosage interval for leucovorin has been derived empirically; the half-life of its primary
active metabolite is approximately four to six hours [ 55 ]. The benefit of dosing every three
to four as compared to every six hours has not been proven, although mean plasma levels are
two to three times higher with every three hour administration [ 66 ]. 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 [ 67,68 ], its clinical relevance is debated [ 69 ].
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 [ 70 ]. 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 [ 71 ]. 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 [
39,41,72-78 ], administration of leucovorin in conjunction with thymidine [ 79 ], and
administration of the metabolizing enzyme carboxypeptidase G2 ( glucarpidase , Voraxaze®).

Glucarpidase (carboxypeptidase G2) — 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 [
39,63,80-83 ]. 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 [ 63,81,82 ]. 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 [ 63 ].

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 creatinine clearance ≤60 mL/min and plasma MTX concentration ≥2 standard
deviations above the mean ≥12 hours after MTX administration) [ 84 ]. 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) [ 85 ].

Glucarpidase was approved in the US in January 2012 for treatment of toxic methotrexate
plasma concentrations (>1 micromol/L [>1 microM]) in patients with delayed methotrexate
clearance due to impaired renal function [ 85 ]. Although the indications for glucarpidase are
not well established, it is reasonable to consider use of this drug in a patient with early renal
dysfunction if the serum MTX level is still greater than 10 microM beyond 42 to 48 hours.
Leucovorin (either the d,l racemic mixture or l-leucovorin [ LEVOleucovorin ]) must be
continued for two days beyond glucarpidase administration [ 39,54 ]. 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.)

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 [ 86 ]. 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/m 2 ). 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 [ 87 ], 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 [ 41 ]. 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 [ 74-78 ]. Further
limitations of these methods are the accompanying risks for complications, which can include
bleeding, thrombocytopenia, hypokalemia, and severe hypophosphatemia [ 72,76 ].

Overall, these techniques are best utilized temporarily, when combined with higher doses of
leucovorin rescue, while awaiting glucarpidase .
Thymidine — 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/m 2 /day) as a rescue agent, often in combination with higher doses of
leucovorin [ 79,88-91 ]. However, thymidine was not effective in the previously discussed
series of 100 consecutive patients with HDMTX-induced nephrotoxicity [ 84 ]. Thus, there is
no indication for thymidine in this setting.

SUMMARY AND RECOMMENDATIONS — High-dose methotrexate (HDMTX) is an

integral component of therapy for a variety of malignant conditions. When given at high
doses, MTX can precipitate in the renal tubules and directly induce tubular injury. The risk is
increased in the presence of acidic urine and with volume depletion. 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 guiding principles for prevention of HDMTX toxicity are as follows (see 'Practical tips
for managing HDMTX' above):

 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.)

Concomitant use of proton pump inhibitors may delay elimination, and their use
should be avoided, if possible, during HDMTX treatment. (See 'Use of proton pump
inhibitors' above.)
 Maintaining adequate hydration and urine output are essential for rapid clearance of
HDMTX. Aggressive hydration (2.5 to 3.5 liters of IV fluid/m 2 per day) should start
four to 12 hours before the MTX infusion is begun and 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, should be used to maintain the urine pH ≥7.0 until plasma MTX levels are
below 0.1 microM.
 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.)
 Serum creatinine, electrolytes, and plasma MTX concentrations are monitored daily,
with modification of the leucovorin dose 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. (See 'Laboratory
monitoring during treatment' above.)

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

 Hydration and urinary alkalinization should be increased, provided that adequate urine
output can be maintained.
  Doses of d,l leucovorin or LEVOleucovorin should be increased based upon the
measured plasma MTX levels ( table 6 ).
 If plasma MTX levels are greater than 10 microM beyond 42 to 48 hours, a single
dose of the recombinant enzyme glucarpidase (carboxypeptidase G2) can rapidly
decrease plasma MTX levels by 98 percent within 15 to 30 minutes. Early
administration is crucial to preventing severe toxicity and death. (See 'Glucarpidase
(carboxypeptidase G2)' above.)

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