A single institution, prospective cohort study was designed to evaluate patients admitted to a tertiary academic center receiving either IV or PO alkalization for administration of HDMTX during the period of May 2017 to March 2018. According to the Declaration of Helsinki, this study was approved by the Institutional Review Board for Health Sciences Research at the University of Virginia Health System. This study was deemed as quality improvement research. The University of Virginia Health System Institutional Review Board approved this study to be filed as Exempt Determination, which does not require written consent. Two cohorts were a part of this study: patient encounters initiated on PO alkalization observed from May 2017 to October 2017 and a control group of encounters who received IV alkalization from November 2017 to March 2018. All medications were obtained from a commercial wholesaler. The initial IV sodium bicarbonate and PO sodium bicarbonate plus acetazolamide regimens for urine alkalization are detailed in Table 1. In addition, encounters in both the PO and IV alkalization cohorts could receive up to 50 mEq of IV sodium bicarbonate admixed with the MTX infusion bag, which is standard practice for 2-hr infusion protocols at our institution. After starting alkalization, regimens could be modified as necessary to achieve urine pH or output goals—including starting IV sodium bicarbonate continuous infusion in the patients originated on the PO regimen—based upon the clinical judgment of the treating physician. No patient received oral alkalization prior to admission as this is not a standard practice at the University of Virginia.
Inclusion criteria consisted of patients ≥18 years of age scheduled to receive HDMTX for hematologic malignancies. HDMTX was administered as 2.8–3.5 g/m2 over 2 hrs for the treatment or prophylaxis of CNS disease for non-Hodgkin’s lymphoma, including primary CNS lymphoma. Patients with acute lymphoblastic leukemia were treated on HDMTX regimens administered over 24 hrs based upon either Hyper-CVAD (1 g/m2) or Children’s Oncology Group study AALL0232 (5 g/m2).9,10 Patients who received HDMTX doses greater than 5 g/m2 were excluded from this analysis.
Data including patient demographics, treatment regimens, lab values, and safety parameters were collected through review of the electronic medical record. Co-primary outcomes assessing safety included incidence of AKI, incidence of decreased MTX clearance, and change in the liver function tests aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin; these were assessed from the time of HDMTX infusion until hospital discharge. AKI was defined according to criteria defined by the Kidney Disease Improving Global Outcomes (KIDGO) practice guidelines.11 Creatinine clearance was also calculated by the Cockcroft–Gault formula utilizing actual body weight.12 A case of delayed MTX clearance was defined by failure to meet any protocol-specific goal for MTX plasma concentrations (Table S1; see original article). The secondary outcomes included length of hospital stay and time from hospital admission to initiation of MTX infusion, to meeting urine pH goal of 7, and to meeting urine output goal of greater than or equal to 125 mL/hr. All laboratory procedures were performed with commercial instruments in the core inpatient laboratory or FDA approved point-of-care medical devices on the oncology unit. Total quantity of IV and PO sodium bicarbonate and PO acetazolamide were also collected. Finally, a cost analysis was completed to determine if there were any financial consequences to using the PO alkalization regimen. For each medication, the lower end of the Average Wholesale Price range as published by Medi-Span was used to estimate costs associated with each regimen (Table S3; see original article).13
The statistical analysis made unadjusted comparisons of PO and IV alkalization using Student’s t-test for continuous variables and chi-square analysis for categorical variables. Statistical significance was defined at a two-sided alpha at 0.05. Descriptive statistics were done for continuous variables. All analyses used SPSS Statistics, version 22.214.171.124.
Overall, 56 patients and 162 encounters were analyzed for inclusion. On average, patients had around three encounters for the treatment regimen. Twelve encounters were excluded due to receipt of HDMTX greater than 5 g/m2, and 24 encounters were excluded for receiving a planned, initial urine alkalization regimen that combined both PO sodium bicarbonate tablets and IV sodium bicarbonate as continuous infusion. Twenty patients were identified to meet inclusion criteria in the IV alkalization group and 28 patients met inclusion criteria in the oral alkalization group. One hundred twenty-six patient encounters were included in the study: 83 patient encounters in the PO alkalization and 43 patient encounters in the IV sodium bicarbonate cohorts. The PO alkalization encounters were older although not statistically significant than the IV cohort with a median age of 55 years (range 21–77) and 52 years (range 21–74), respectively (P=0.90). Patient cases from encounters utilizing the PO alkalization regimen had similar median weight compared to the IV alkalization group. Baseline characteristics of the two cohorts are described in Table 2 and Table 3.
In the safety analysis, there was a non-statistically significant trend toward higher AKI incidence with the PO regimen (14.5% vs 9.3%, P=0.41). However, there was no difference in the incidence of delayed methotrexate (26.5% for PO vs 37.2% for IV, P=0.21) or absolute change in AST, ALT, or total bilirubin (Table 4).
In order to consistently calculate time to HDMTX (as the first chemotherapy received), time to urine output >125 mL/hr, time to urine pH >7, and hospital length of stay, a subset of patient encounters (n=66) were analyzed. These encounters were scheduled admissions with the plan to initiate HDMTX—as a single agent or as the first in a multi-agent chemotherapy regimen—immediately upon achievement of urine output and pH parameters. Unplanned HDMTX encounters for new or progressive disease or those with plans to start HDMTX later in the admission following other chemotherapy were excluded from these time-sensitive assessments. Results of these analyses are summarized in Table 5. Time to MTX was not statistically significant between alkalization regimens (7.9 hrs for PO vs 8.0 hrs for IV, P=0.6). Time to urinary output goal of 125 mL/hr was markedly reduced, but without statistical significance, with PO alkalization (5.9 hrs vs 9.2 hrs, P=0.1). Length of stay was also not statistically different; however, it was longer in encounters utilizing PO alkalization (3.8 days vs 3.1 days, P=0.3).
The IV regimen for urine alkalization was associated with an average of 25.8 vials of 50-mEq IV sodium bicarbonate per HDMTX encounter, while the PO regimen utilized 90.7 sodium bicarbonate tablets, 13.8 acetazolamide tablets, and 1.6 vials of IV sodium bicarbonate per case. For the 83 patients administered the PO regimen, it is estimated 2002 vials of IV sodium bicarbonate were saved during the shortage. Furthermore, the PO regimen was approximately US$226 less expensive per HDMTX encounter ($57.87 vs $283.44). The estimated cost savings for all 83 patients in the PO cohort were $18,722. These data are described in Tables S2 and S3 (see original article).