PATIENTS AND METHODS

Patient selection

Thirty-seven pediatric patients diagnosed with ALL, NHL, or osteosarcoma, undergoing 165 courses of HD-MTX containing a chemotherapy regimen at the Division of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand, from January 2010 to December 2016, were retrospectively reviewed. Written informed consent and assent forms to review medical records were obtained from all participants including children and their parents or guardians prior to enrollment in the study. The study protocol was approved by the Institutional Review Board of Phramongkutklao Hospital and College of Medicine and adhered to the ethical principles of the Declaration of Helsinki of 1975 and its revision. The inclusion criteria included patients who were diagnosed with ALL, NHL, or osteosarcoma, were younger than 18 years, received intravenous hydration during their hospital admission for HD-MTX administration, and had plasma methotrexate levels measured at least one time point at 72 hours after the initiation of HD-MTX. Patients who had incomplete data, including progress clinical summary notes during their admission for HD-MTX administration, HCO3 level assessment, and evaluation of urine specific gravity, and had no plasma methotrexate level recorded at 72 hours after initiating HD-MTX were excluded from the study.

HD-MTX regimens

Patients with ALL were treated according to the Thai Pediatric Oncology Group (ThaiPOG) protocols, in which treatment is stratified according to risk groups. For low-risk ALL protocol (ThaiPOG ALL-01-05), HD-MTX is administered during the consolidation phase at a dose of 1.5 g/m2 over 24 hours every 2 weeks for a total of four cycles on days 1, 15, 29, and 43 of treatment. For high-risk ALL protocol (ThaiPOG ALL-02-05), HD-MTX is administered during the consolidation phase at a dose of 1.5 g/m2over 24 hours every 2 weeks for a total of four cycles on days 29, 43, 57, and 71 of treatment. Patients with NHL were treated according to the ThaiPOG protocols depending on lymphoma subtypes. Following mature B-cell lymphoma protocol (ThaiPOG NHL-04-05) for diffuse large B-cell lymphoma and Burkitt lymphoma, HD-MTX is administered during induction, consolidation, and maintenance phases at a dose of 3 g/m2 over 4 hours on the first day of each cycle for a total of five cycles. Patients with lymphoblastic lymphoma were treated with HD-MTX 1.5 g/m2 as in ThaiPOG ALL protocol. Patients with osteosarcoma are treated according to ThaiPOG protocol consisting of HD-MTX 10–12 g/m2 given over 4 hours on weeks 4, 5, 9, 10, 13, 16, 19, 22, 25, and 28 of treatment. Regarding HD-MTX-containing chemotherapy regimens for ALL, NHL, and osteosarcoma in this study, the starting dose of leucovorin (folinic acid) in all regimens was similar at 15 mg/m2/dose administered every 6 hours. The timing to start leucovorin rescue in NHL and osteosarcoma regimens was at 24 hours after the initiation of HD-MTX, and the timing to start leucovorin rescue in ALL regimen was at 36 hours after the initiation of HD-MTX. All patients enrolled in this study were given intravenous leucovorin at the exact time point without delay. In addition, the dose and frequency of intravenous leucovorin (folinic acid) administration were adjusted according to plasma methotrexate nomogram.

Intravenous hydration strategy

According to our institutional methotrexate administration and monitoring guidelines, the amount of aggressive intravenous hydration administered was between 2,500 and 3,500 mL/m2/day depending on individual oncologist’s decisions based on patients’ clinical status at the time of HD-MTX administration; therefore, patients received a different exact amount of intravenous fluid within the instructed range between 2,500 and 3,500 mL/m2/day on each course of HD-MTX regimen. In this study, the intravenous hydration administrations were grouped as <3,000 and ≥3,000 mL/m2/day. In addition, potential adverse events from aggressive hydration including clinical symptoms of volume overload were also reviewed.

Methotrexate levels and laboratory monitoring during HD-MTX administration

All patients treated with HD-MTX were carefully followed up according to our institutional methotrexate administration and monitoring guidelines including adjusting of the dose and monitoring the frequency of intravenous leucovorin (folinic acid) administration based on the methotrexate level obtained at different time points (plasma methotrexate nomogram). In addition, the bicarbonate in intravenous fluid was adjusted based on serial urine pH monitoring to keep urine pH between 7 and 8 at all times. Plasma methotrexate levels collected at 72 hours after the initiation of HD-MTX from all patients were reviewed and analyzed. A 72-hour methotrexate level of <0.1 μmol/L was considered complete methotrexate clearance and a level ≥0.1 μmol/L indicated delayed methotrexate clearance. In addition, blood HCO3 and urine specific gravity during HD-MTX administration were reviewed and their average levels were used to evaluate the usefulness of serving as predictive factors for delayed methotrexate clearance.

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Adverse complications from HD-MTX administration

Adverse complications such as mucositis, bone marrow suppression, renal toxicity, and liver toxicity were reviewed among all patients during and after each course of the HD-MTX regimen. Bone marrow suppression was defined as an absolute neutrophil count of <500 cell/mm3 within 3 days and/or platelet count of <75,000 cell/mm3 within 1 week after the course of HD-MTX regimen. Renal toxicity was defined as an elevated serum creatinine level of >2 SD of the upper limit of normal in the reference population of the same age. Liver toxicity was defined as an elevated level of serum aspartate aminotransferase and/or serum alanine aminotransferase of >2 SD of the upper limit of normal in the reference population of the same age.

Statistical analysis

Baseline values of selected variables were calculated as mean and SD or as median (range) for continuous variables and were expressed using frequency and percentage for categorical variables. The chi-squared test and Fisher’s exact test were used to analyze the categorical variables for data with a parametric distribution and nonparametric distribution, respectively. SPSS Version 23 Software (IBM, Armonk, NY, USA) was used for statistical analysis, and P-values <0.05 were considered significant.