High-Dose Methotrexate (HDMTX)
Use in Cancer Treatment
Methotrexate: A Potent and Powerful Cancer Therapy
Methotrexate (MTX) is an antifolate therapeutic agent that possesses potent anticancer activity against both solid tumors and leukemia.
What Is Considered High-Dose Methotrexate?
High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers, including :
- Diffuse large B-cell lymphoma
- Burkitt lymphoma
- Adult acute lymphoblastic leukemia (ALL)
- Pediatric ALL
- Primary central nervous system (CNS) lymphoma
- Osteosarcoma
High-Dose MTX (HDMTX)–Associated Acute Kidney Injury (AKI)
For patients with healthy renal function, HDMTX may be safely administered with appropriate supportive care; however, despite standard support measures, HDMTX carries the risk of severe toxicity :
- MTX is primarily cleared by the kidneys but is poorly soluble, and pH changes within the kidneys can promote its precipitation, which can result in AKI.
- HDMTX-induced AKI leads to delayed MTX clearance, resulting in prolonged, elevated plasma MTX concentrations.
An Oncologic Emergency
Up to 12% of patients who receive HDMTX will experience delayed MTX clearance due to AKI. Delayed MTX clearance due to AKI is an oncologic emergency that can lead to potentially irreversible life-threatening systemic toxicity and organ damage.
Patients who survive an episode of AKI have :
- Double the risk of death
- Triple the risk of end-stage renal disease
- Ten times the risk of developing incident or progressive chronic kidney disease
The rate of cardiovascular events is as high as 22% and mortality related to cardiovascular events is 33% in patients with AKI.
Inadequate Elimination of MTX Due to AKI Increases the Risk of Severe Toxicities and Death
Grade 3-4 toxicities in 43 patients with delayed MTX clearance due to HDMTX-induced AKI included hematologic, renal, hepatic, and CNS toxicity as well as mucositis (all in >10% of patients). Grade 3-4 hematologic toxicity occurred in 60% of patients.
|
Toxicity |
Patients, n (%) |
|---|---|
|
Hematologic |
26 (60%) |
|
Mucositis |
15 (35%) |
|
Renal |
8 (19%) |
|
Liver |
7 (16%) |
|
CNS |
6 (14%) |
|
Skin |
1 (2%) |
Assessing the Risk of Acute Kidney Injury From High-Dose Methotrexate
There are many factors associated with MTX that can increase the risk of AKI, including :
- Dose and schedule of MTX
- Preexisting renal insufficiency
- Host factors including patient age and cancer type
|
Tumor types |
Incidence of AKI |
|---|---|
|
Lymphoma (N=194) |
9.1% |
|
Primary CNS lymphoma (N=154) |
3-7% |
|
Pediatric acute lymphoblastic leukemia (N=1286) |
3.6% |
|
Osteosarcoma (N=3887) |
1.8% |
*Tumor types included acute lymphoblastic leukemia, lymphoma, CNS lymphoma germ cell tumor, and osteosarcoma.
Patients who have one or more of the following risk factors may experience delayed MTX clearance :
- Nephrotoxic comedication (NSAIDs, PPIs, etc)
- BMI ≥25 kg/m2
- Renal insufficiency prior to HDMTX (i.e., CrCl <60 mL/min)
- Prior toxicity with HDMTX
- Adult and elderly patients, as many as 60% of whom may have some degree of renal dysfunction
- Third spacing (pleural effusions, ascites, intracranial fluid)
- Volume depletion due to vomiting, diarrhea, or other factors
- Polyuria
- Urine pH <7
BMI, body mass index; CrCl, creatinine clearance; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor.