Incorporating a checklist and a chart for tracking urine pH into a standard operating procedure (SOP) for supportive care of patients with cancer treated with high-dose methotrexate (HD-MTX) led to a decrease in risk of MTX-associated adverse events, according to results of a study reported in The Oncologist.

Methotrexate is a folate analogue that inhibits DNA synthesis. High-dose methotrexate is a dose exceeding 500 mg/m2. HD-MTX is a key component of treatment regimens for patients with a variety of cancers, including acute lymphoblastic leukemia.

Use of HD-MTX has been associated with a range of toxicities including mucositis, bone marrow suppression, liver injury, neurotoxicity, and kidney damage. Methotrexate is primarily eliminated by the kidneys, therefore, patients with methotrexate-associated acute kidney injury are at increased risk of reduced MTX renal clearance and prolonged exposure to toxic levels that can lead to other adverse effects, which can be life threatening. Supportive care approaches to decrease this risk include increased hydration and alkalinization of urine to a pH of 7.5 to limit methotrexate precipitation in renal tubules. In addition, leucovorin administration is a means of rescuing patients from the toxic effects of HD-MTX.

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Other key elements of supportive care for patients treated with HD-MTX include avoiding coadministation with other drugs, such as nonsteroidal anti-inflammatory agents, and ruling out the presence of fluid accumulation in third spaces, such as ascites and pleural effusions, which are known to prolong methotrexate elimination.

“Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD-MTX. Therefore, strict adherence to supportive measures during HD-MTX is vital for patient safety,” the study investigators noted.

For this study, they evaluated the impact of documenting key elements of supportive care in combination with standard supportive care (intervention) on the risk of methotrexate-associated adverse events compared with standard supportive care alone. The intervention included a standardized checklist covering key elements of supportive care and a chart for recording urine pH and administration of sodium bicarbonate at key time intervals.  

The intervention group included 118 patients treated with 414 cycles of HD-MTX, and the standard care group included 108 patients treated with 332 cycles of HD-MTX. Average MTX dose per treatment cycle was 2.1 g/m2 in the intervention group and 2.7 g/m2 for those receiving standard supportive care alone.

Key findings included a delay in MTX clearance for 2.6% and 15.2% of patients in the intervention group and standard care group, respectively (P <.001). Acute kidney injury occurred during 0.7% of cycles in the intervention group, whereas this adverse effect was observed during 6.3% of cycles in the standard care group (P <.001).

The average MTX dose per treatment cycle was slightly lower in the intervention group compared with the standard care group, and more patients in the intervention group underwent 24-hour infusions of HD-MTX. However, “although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances,” commented the investigators.

“The use of a standardized, checklist-based documentation for supportive care significantly improves the safety of HD-MTX treatment,” the study authors noted. “These tools are able to minimize the risk of pharmacokinetic drug-drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events.”

Disclosures: Multiple authors declared affiliation with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Alsdorf WH, Karagiannis P, Langebrake C, Bokemeyer C, Frenzel C. Standardized supportive care documentation improves safety of high-dose methotrexate treatment. Oncologist. Published online November 20, 2020. doi:10.1002/onco.13603

This article originally appeared on Oncology Nurse Advisor