Evaluation of methotrexate clearance with an enteral urine alkalinization protocol for patients receiving high-dose methotrexate

Abstract

Purpose High-dose methotrexate is a cytotoxic agent used to treat several malignancies. Urine alkalinization with sodium bicarbonate and hyperhydration are given with methotrexate to prevent drug precipitation in the kidneys. Due to a nationwide intravenous sodium bicarbonate shortage, an enteral-based urine alkalinization protocol was instituted. This study compared outcomes and adverse effects between the previously used intravenous and newly implemented enteral protocols. Methods Single center retrospective cohort study comparing parenteral and enteral urine alkalinization for patients that received methotrexate doses ≥ 500 mg/m2 between 1 April 2016 and 1 October 2018. The primary endpoint was time to methotrexate clearance. Secondary outcomes included length of stay, time to administration of methotrexate, amount of sodium bicarbonate utilized, toxicities of methotrexate, and protocol-associated adverse effects. Results There were 67 patients included in the study for a total of 195 infusions. The average time to methotrexate clearance between the two cohorts was similar (parenteral 88 h vs. enteral 98 h p = 0.06). Likewise, length of stay was not different between the two cohorts (p = ns). The enteral cohort methotrexate’s doses were initiated faster and received significantly less intravenous sodium bicarbonate when compared to the parenteral cohort (p = 0.04). Rates of acute kidney injury, neutropenia, hepatotoxicity, and mucositis were similar between the two groups. There were higher rates of diarrhea and low serum bicarbonate values in the enteral cohort. Conclusion This study supports the ability to conserve intravenous sodium bicarbonate by using an enteral-based urine alkalization regimen for HD methotrexate, with no difference in outcomes or toxicity.

Evaluation of an oral sodium bicarbonate protocol for high-dose methotrexate urine alkalinization

“…Similar to the results reported by Roy, et al, Kramer et al, and Rouch, et al, this study did not nd a signi cant difference in the rates of renal dysfunction, or mucositis between our PO and IV cohorts [9][10][11]. As well, no difference in the rates of neurologic complications, or hypernatremia were seen.…”

“…These adverse effects, however, rarely led to administration issues such as refusal of doses or a need to change sodium bicarbonate formulation. Both Kramer, et al, and Rouch et al found higher rates of diarrhea in their cohorts receiving enteral urine alkalinizing therapy [10,11]. In our study, the rates of diarrhea were similar between our cohorts.…”

“…While they also used a higher PO sodium bicarbonate dose than our protocol, a higher MTX level of 0.1 µmol/L was used to de ne MTX clearance than our local standard and may explain their shorter time to MTX clearance. Another retrospective cohort study by Kramer et al compared a predominantly enteral protocol with combination sodium bicarbonate and acetazolamide to a predominately parenteral protocol in adult patients receiving HDMTX [10]. Time to MTX clearance was not found to be statistically different between the enteral protocol, 98 ± 38 hours, and the parenteral protocol, 88 ± 36 hours; p=0.06.…”

“…In our study, the rates of diarrhea were similar between our cohorts. This discrepancy may be explained by the use of acetazolamide and higher doses of PO sodium bicarbonate administered by Kramer, et al [10].…”

“…Despite the lower sodium bicarbonate dose, no differences in time to MTX clearance or the rates of increased serum creatinine were seen between the two cohorts. This nding of an overall lower enteral sodium bicarbonate dose being comparable to a higher IV sodium bicarbonate dose is re ected in the literature, both in the pediatric and adult populations [9][10][12][13]. Consideration to whether lower IV sodium bicarbonate doses have comparable outcomes to those currently prescribed may be of interest.…”