Methotrexate:

Potent and Powerful
Cancer Therapy2,6

Methotrexate (MTX) is an antifolate therapeutic agent that possesses potent anticancer activity against both solid tumors and leukemia.

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:

  • Osteosarcoma
  • Adult acute lymphoblastic leukemia (ALL)
  • Pediatric acute lymphoblastic leukemia (ALL) • Primary CNS lymphoma
  • Primary CNS lymphoma
doctor and patient

Appropriate
Supportive Care2,6

For patients with normal renal function, HDMTX may be safely administered with appropriate supportive care, including:

  • Vigorous hydration and alkalinization to enhance the solubility of MTX in the patient’s urine
  • Pharmacokinetically guided leucovorin rescue therapy to aid MTX clearance and to prevent systemic and potentially fatal onset of MTX toxicity

HDMTX Toxicity

Despite standard support measures, HDMTX carries the risk of severe toxicity2,6

  • As MTX is primarily cleared by renal excretion, HDMTX-induced renal dysfunction leads to delayed MTX elimination resulting in sustained, elevated plasma MTX concentrations.6
  • Exposure to millimolar concentrations of MTX for minutes to hours may lead to acute renal toxicity and other serious systemic adverse reactions.6
forest in flames

Inadequate elimination of MTX due to impaired renal function increases the risk of severe toxicities7

Grade 3-4 toxicities post-HDMTX in 43 patients with
delayed MTX clearance due to impaired renal function7
Toxicity Patients, n (%)
Hematological 26 (60%)
Mucositis 15 (35%)
Renal 8 (19%)
Liver 7 (16%)
CNS 6 (14%)
Skin 1 (2%)

CNS=central nervous system.
*Tumor types included acute lymphoblastic leukemia, lymphoma, CNS lymphoma germ cell tumor, and osteosarcoma.

  • When renal dysfunction becomes acute and other toxicities are present, standard doses of leucovorin may no longer be an effective rescue intervention.5
  • Voraxaze® may be indicated to bring MTX levels down quickly and avoid further systemic damage.5
Consensus Guidelines recommend early administration with Voraxaze®.
Learn more here.

Assessing the risk of
acute kidney injury

There are many factors associated with MTX that can increase the risk of acute kidney injury (AKI), including:2,7

  • Dose and schedule of MTX
  • Pre-existing renal insufficiency
  • Host factors including patient age cancer type
Types of tumors associated with higher risk for AKI8-11
Tumor types Incidence
of AKI
Osteosarcoma (N=3887)8 1.8%
Pediatric acute lymphoblastic leukemia
(n=445)9
3.3%
Adult acute lymphoblastic leukemia (n=31)10 6.4%
Primary CNS lymphoma in patients >70 years (n=154)11 3% to 7%

References

  1. Voraxaze® [prescribing information]. BTG International Inc; 2013.
  2. Howard SC, et al. Preventing and managing toxicities of high-dose methotrexate. The Oncologist 2016; 21:1-12.
  3. Widemann BC, Balis FM, Kim A, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol. 2010; 28:3979-3986.
  4. 2013 Annual Meeting of the North American Congress of Clinical Toxicology (NACCT), Clinical Toxicology 2013; 51(7):575-724. doi:10.3109/15563650.2013.817658.
  5. Ramsey L, Balis FM, O’Brien MM, et al. Consensus guidelines for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance. Durham, NC. The Oncologist. 2017 Oct 27. doi: 10.1634/theoncologist.2017-0243
  6. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11:694-703
  7. Schwartz S, Borner K,Müller K, et al. Glucarpidase (carboxypeptidase G2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007;12:1299-1308.
  8. Widemann BC, Balis FM, Kempf-Bielack B, et al. High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma. Cancer. 2004;100:2222-2232
  9. Data on file. BTG International Inc. 2012.
  10. de Miguel D, García-Suárez J Martín Y, Gil-Fernández JJ, Burgaleta C. Severe acute renal failure following high-dose methotrexate therapy in adults with haematological malignancies: a significant number result from unrecognized co-administration of several drugs. Nephrol Dial Transplant. 2008;23:3762-3766.
  11. Jahnke K, Korfel A, Martus P, et al; on behalf of the German Primary Central Nervous System Lymphoma Study Group (G-PCNSL-SG). High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma. Ann Oncol. 2005;16:445-449
  12. Flombaum C, Meyers P. High-dose leucovorin as sole therapy for methotrexate toxicity. Journal of Clinical Oncology 1999; 17(5): 1589-1594.
  13. Murashima M, et al. Methotrexate clearance by high-flux hemodialysis and peritoneal dialysis: a case report. Am J Kidney Dis 2009; 53:781-874.
  14. Wall S, Johansen M, et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis 1996; 28(6):846-854.
  15. Green JM. Glucarpidase to combat toxic levels of methotrexate in patients. Ther Clin Risk Manag. 2012;8:403-4
  16. Glucarpidase (Voraxaze®) National Drug Monograph and Considerations for Use. U.S. Department of Veterans Affairs website. 2014. http://www.pbm.va.gov/clinicalguidance/drugmonographs/Glucarpidase_ Drug_Monograph_and_Considerations_for_Use.doc. Published June 2014. Accessed November 04, 2016.
  17. Leucovorin [prescribing information]. Bedford Laboratories; 2011.