Safety Of High-dose Methotrexate Research Articles

First-line induction chemotherapy with high-dose methotrexate versus teniposide in patients with newly diagnosed primary central nervous system lymphoma: a retrospective, multicenter cohort study

BackgroundThis study aimed to compare the efficacy and safety of high-dose methotrexate (HD-MTX) versus teniposide (TEN) in patients with newly diagnosed immunocompetent primary central nervous system lymphomas (PCNSLs).MethodsThe study included immunocompetent, adult patients with newly diagnosed PCNSL at 22 centers in China from 2007 to 2016. The patients received HD-MTX or TEN as first-line induction therapy. The objective response rate, progression-free survival, and overall survival were analyzed for each patient cohort.ResultsA total of 96 patients were eligible: 62 received HD-MTX, while 34 received teniposide. The overall response rate was 73.2% and 72.7% in the MTX and the TEN cohorts, respectively (P = 0.627). The median progression-free survival was 28.4 months [95% confidence interval (CI): 13.7–51.2] in the MTX cohort and 24.3 months (95% CI: 16.6–32.1) in the TEN cohort (P = 0.75). The median overall survival was 31 months (95% CI: 26.8–35.2) in the MTX cohort and 32 months (95% CI: 27.6–36.4) in the TEN cohort (P = 0.77). The incidence of any grade of coagulopathy/deep-vein thrombosis and gastrointestinal disorders was significantly higher in the MTX cohort than in the TEN cohort; no significant difference was found in the incidence of other adverse events between the two cohorts.ConclusionsThis was the first multicenter study using TEN as the main agent compared with HD-MTX in newly diagnosed primary CNS lymphoma. The TEN-based regimen was non-inferior to the HD-MTX-based regimen with similar overall responses.Classification of evidenceThis study provided Class III evidence that the teniposide-based regimen was non-inferior to high-dose methotrexate − based regimen with similar overall responses and long-time survival in immunocompetent patients with PCNSL.

Evaluation of Hepatic Complications for High Dose Methotrexate in Children: 10 Years after Treatment of Malignancy

Background Methotrexate is a chemotherapy drug used in high doses to treat malignancies that can lead to serious liver damage, especially cirrhosis in a dose-dependent manner. We aimed to evaluate the hepatic complications, 10 years after treating children with hematologic malignancies by high-dose Methotrexate regimen. Materials and Methods: In a descriptive-analytical study, all children with hematologic malignancies who received high-dose methotrexate for treating cancer and who were hospitalized in Tabriz Children’s Hospital, Tabriz, Iran, from 2008 to 2009 were included. Demographic data were extracted from medical records. Liver enzyme tests, ultrasonography, as well as a Doppler ultrasound of the portal vein were performed for all participants in the Tabriz Children’s Hospital. Data were analyzed using descriptive statistics. The Chi-Square test was used to examine the relationship between variables using SPSS software version 22.0. Results: Out of 30 patients, 18 cases (60%) were boys and 23 (76.67%) of patients had Acute Lymphoblastic Leukemia. ALT, Total BILL, and Direct BILL levels were increased by 13.33%, 13.33%, and 10% of cases, respectively. AST, PT, and PTT levels were normal in all patients. The liver and spleen spans were larger than normal in 26.67% and 40% of cases, respectively and 5 patients (16.67%) had grade 1 fatty liver. Port vein diameter was normal in all patients. Conclusion Based on the results of the study, it is possible to consider the long-term safety of high dose Methotrexate in terms of the development of severe liver disease following treating malignancies in children. However, patient follow-up is recommended to identify complications for years after discontinuing treatment.

Systemic high-dose intravenous methotrexate in patients with central nervous system metastatic breast cancer

BackgroundInfusion of high-dose intravenous methotrexate (MTX) has been demonstrating to penetrate the blood-brain barrier. The aim of this present study was to assess the efficacy and safety of high dose MTX in patients with central nervous system (CNS) metastases of breast cancer.MethodsTwenty-two patients with CNS metastases treated by MTX (3 g/m2) between April 2004 and October 2009 were enrolled. Clinical response rate, time to progression (TTP), overall survival (OS), and safety were assessed.ResultsIn terms of brain metastases, 2 patients (9%) achieved a partial response, 10 patients (45%) had disease stabilization, and 10 patients (45%) had disease progression. In others metastatic sites, 7 patients (39%) achieved a disease stabilization, and 11 patients (61%) had disease progression. TTP and OS were 2.1 (95%CI 1.4–2.9) and 6.3 (95%CI 1.8–10) months, respectively.ConclusionHigh-dose MTX demonstrated a moderate activity at 3 g/m2. Nonetheless, the favorable toxicity profile should suggest the possibility to increase the dosage and further study are planned.

Hypoalbuminemia Is Significantly Associated with Increased Clearance Time of High Doses of Methotrexate

Introduction: Methotrexate is an antimetabolite chemotherapeutic agent used for over 50 years. The inclusion of high dose methotrexate with leucovorin rescue has enhanced lymphoma and acute leukemia regimens' efficacy. As a weak acid, methotrexate has variable protein binding and about 50% of the drug binds to serum albumin. Animal models suggest that methotrexate conjugated to albumin may improve anti-tumor effects by accumulating in tumor cells through endocytosis, decreasing its clearance. Further, greater methotrexate toxicity has been reported in patients with hypoalbuminemia. Our purpose was to assess serum albumin's impact on methotrexate pharmacokinetics by comparing methotrexate clearance and toxicities between patients with normal serum albumin and hypoalbuminemia.Methods: This IRB approved single-center retrospective study at Memorial Sloan Kettering Cancer Center included patients who were ≥18 years of age, received methotrexate at a dose of ≥1 gram/m2 between January 2007- November 2014, and admitted to the inpatient leukemia or lymphoma service. Patients admitted to other services or who had prior methotrexate exposure were excluded. Patients were identified through the pharmacy database and electronic medical records. Patients were categorized based on their most recent serum albumin level prior to methotrexate administration. Hypoalbuminemia was defined as serum albumin ≤ 3.4 g/dL. The relationship between hypoalbuminemia and clinical variables was assessed with Fisher's exact and Wilcoxon Rank Sum tests. Kaplan Meier methods were used to visualize the relationship between hypoalbuminemia with time to methotrexate clearance. Methotrexate clearance was defined as the first documented time the methotrexate level ≤0.05 micromolar. Univariate and multivariate associations between predictors and clearance were assessed with Cox proportional hazards regression. Clinical variables considered for the Cox model included hypoalbuminemia, urine acidity, renal function, fluid retention, presence of drug interactions, methotrexate dose, and nephrotoxic agents. Any variables significant at p<0.05 were considered for multivariate analysis.Results: Of 523 patients identified, 167 patients were evaluable. Of them 126 had lymphoma (75.4%) and 41 patients had leukemia (24.6%). The most common chemotherapy regimens used were R-CODOX/M-IVAC (21%), pediatric inspired acute lymphoblastic leukemia regimens (15%), HyperCVAD (12%), SMILE (11.4%), and MR-CHOP (10%). 135 patients had normal serum albumin and 32 had hypoalbuminemia. Baseline characteristics were similar between cohorts. Hypoalbuminemia was associated with a higher proportion of patients with fluid retention (34% vs. 12%, p=0.006) and concomitant use of nephrotoxic agents (41% vs. 20%, p=0.02). Hypoalbuminemia was associated with a significantly longer time to methotrexate clearance (median: 96 hours, 95% CI: 72-132 hours) vs normal serum patients (median 72 hours, 95% CI: 63-72 hours), p=0.004) (Figure 1). In univariate analysis, hypoalbuminemia, methotrexate dose, and nephrotoxic agents were significantly associated with time to clearance. In our multivariate model, hypoalbuminemia (p=0.009), methotrexate dose (p=0.002) and nephrotoxic agents (p=0.02) remained significantly associated with methotrexate clearance time. In addition, patients with hypoalbuminemia had a higher proportion of hyperbilirubinemia (28% vs. 13%, p=0.001) and significantly longer hospitalization (median 14 days vs. 5 days, p<0.001). There was no significant difference in the proportion of patients who experienced transaminitis, nephrotoxicity, mucositis, leukopenia, neutropenia, or pneumonitis.Conclusions: Hypoalbuminemia was associated with prolonged methotrexate clearance, and it remained significant after adjusting for the methotrexate dose and concomitant use of nephrotoxic agents. Patients with hypoalbuminemia were more likely to have bilirubin elevation, both markers of synthetic liver function. There were no differences in the toxicities of high dose methotrexate between groups owing to appropriate leucovorin rescue and good supportive care, demonstrating the safety of high dose methotrexate in patients with hypoalbuminemia, despite differences in the clearance time. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Primary CNS Lymphoma Treated with HD-Methotrexate, HD-Busulfan/Thiotepa, Autologous Stem Cell Transplantation and Response-Adapted Whole-Brain Radiotherapy: Results of the Multicenter OSHO-53 Phase II - Study.

Purpose:This multicenter study investigated the efficacy and safety of high-dose methotrexate (HD-MTX) induction followed by high-dose busulfan/thiotepa with autologous stem-cell transplantation (HD-BuTT) and response-adapted whole-brain radiotherapy (WBRT) in patients with newly diagnosed primary CNS lymphoma.Patients and methods:23 patients (median age 55 years) were treated in five centres. Patients received HD-MTX (4h-infusion; 8g/m2; >60y: 6g/m2) on d1 and d10 followed by leucapheresis. Then patients were stratified according to their results on neuroimaging: In case of at least a partial response, HD-BuTT consisting of 16mg busulfan / 10mg thiotepa per kg body weight followed by peripheral stem cell transplantation was given. Patients without response to induction or without complete response after high-dose therapy received WBRT (45Gy) as further treatment.Results:16 patients received the planned treatment with HD-MTX followed by HD-BuTT. CR / PR rates for these patients were 19 % / 69 % after HD-MTX, 69 % / 13 % after HD-BuTT, 81 % / 6 % after HD-BuTT plus WBRT, respectively. Included the patients with early WBRT due to toxicity (n=2) and non-responders to HD-MTX induction (n=4) the overall response rate for all 23 patients was 83 % (intention-to-treat). Outcome was significantly influenced by the response to MTX-induction. There were three treatment-related deaths. Irradiated patients (n=9) had a high incidence of severe neurotoxicity leading to death in 3 patients. At a median follow-up of 15 months the median EFS and OS for all patients were 17 and 20 months, after HD-BuTT 27 months and “not reached”, respectively. Patients older than 60 years and younger patients have achieved similar outcomes.Conclusion:This study showed that HD-methotrexate induction followed by HD-BuTT is a feasible treatment option for newly diagnosed primary CNS lymphoma. Patients achieving CR after HD-BuTT show no signs of clinical neurotoxicity with median survival not reached yet. Time on treatment is 2–3 months only, but the induction treatment needs improvement to be more effective. WBRT in this study was associated with a high incidence of severe neurotoxicity and should therefore be avoided.