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      Complications of 5-azacytidine: Three cases of severe ischemic colitis in elderly patients with myelodysplastic syndrome

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          Abstract

          5-Azacytidine (5-AZA) was the first drug to be approved for the treatment of high-risk myelodysplastic syndrome (MDS). The adverse event profile of this drug appears favorable compared with the conventional intensive chemotherapy that is used for MDS or acute myeloid leukemia. However, uncommon adverse events may have remained undetected in the limited number of patients that have been treated to date. The present study describes three cases/66.8 person-years (4,491 cases/100,000 person-years) of severe ischemic colitis in a single center cohort of 95 patients who were consecutively treated using subcutaneous 5-AZA. The results demonstrated a much higher incidence of colitis compared with the rates in the general population or in patients of greater ages and co-morbidities. The present study investigated whether the combination of anemia and constipation due to the co-medication of 5-HT 3 receptor antagonists may explain the three cases of ischemic colitis.

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          Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.

          Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments. Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
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            International scoring system for evaluating prognosis in myelodysplastic syndromes.

            Despite multiple disparate prognostic risk analysis systems for evaluating clinical outcome for patients with myelodysplastic syndrome (MDS), imprecision persists with such analyses. To attempt to improve on these systems, an International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems. A global analysis was performed on these patients, and critical prognostic variables were re-evaluated to generate a consensus prognostic system, particularly using a more refined bone marrow (BM) cytogenetic classification. Univariate analysis indicated that the major variables having an impact on disease outcome for evolution to acute myeloid leukemia were cytogenetic abnormalities, percentage of BM myeloblasts, and number of cytopenias; for survival, in addition to the above, variables also included age and gender. Cytogenetic subgroups of outcome were as follows: "good" outcomes were normal, -Y alone, del(5q) alone, del(20q) alone; "poor" outcomes were complex (ie, > or = 3 abnormalities) or chromosome 7 anomalies; and "intermediate" outcomes were other abnormalities. Multivariate analysis combined these cytogenetic subgroups with percentage of BM blasts and number of cytopenias to generate a prognostic model. Weighting these variables by their statistical power separated patients into distinctive subgroups of risk for 25% of patients to undergo evolution to acute myeloid leukemia, with: low (31% of patients), 9.4 years; intermediate-1 (INT-1; 39%), 3.3 years; INT-2 (22%), 1.1 years; and high (8%), 0.2 year. These features also separated patients into similar distinctive risk groups for median survival: low, 5.7 years; INT-1, 3.5 years; INT-2, 1.2 years; and high, 0.4 year. Stratification for age further improved analysis of survival. Compared with prior risk-based classifications, this International Prognostic Scoring System provides an improved method for evaluating prognosis in MDS. This classification system should prove useful for more precise design and analysis of therapeutic trials in this disease.
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              Antiemetics: American Society of Clinical Oncology clinical practice guideline update.

              To update the American Society of Clinical Oncology (ASCO) guideline for antiemetics in oncology. A systematic review of the medical literature was completed to inform this update. MEDLINE, the Cochrane Collaboration Library, and meeting materials from ASCO and the Multinational Association for Supportive Care in Cancer were all searched. Primary outcomes of interest were complete response and rates of any vomiting or nausea. Thirty-seven trials met prespecified inclusion and exclusion criteria for this systematic review. Two systematic reviews from the Cochrane Collaboration were identified; one surveyed the pediatric literature. The other compared the relative efficacy of the 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists. Combined anthracycline and cyclophosphamide regimens were reclassified as highly emetic. Patients who receive this combination or any highly emetic agents should receive a 5-HT(3) receptor antagonist, dexamethasone, and a neurokinin 1 (NK(1)) receptor antagonist. A large trial validated the equivalency of fosaprepitant, a single-day intravenous formulation, with aprepitant; either therapy is appropriate. Preferential use of palonosetron is recommended for moderate emetic risk regimens, combined with dexamethasone. For low-risk agents, patients can be offered dexamethasone before the first dose of chemotherapy. Patients undergoing high emetic risk radiation therapy should receive a 5-HT(3) receptor antagonist before each fraction and for 24 hours after treatment and may receive a 5-day course of dexamethasone during fractions 1 to 5. The Update Committee noted the importance of continued symptom monitoring throughout therapy. Clinicians underestimate the incidence of nausea, which is not as well controlled as emesis.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                December 2013
                15 October 2013
                15 October 2013
                : 6
                : 6
                : 1756-1758
                Affiliations
                Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncological Center, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Medical University of Salzburg, Salzburg A-5020, Austria
                Author notes
                Correspondence to: Professor Alexander Egle, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncological Center, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Medical University of Salzburg, Muellner Hauptstrasse 48, Salzburg A-5020, Austria, E-mail: a.egle@ 123456salk.at
                Article
                ol-06-06-1756
                10.3892/ol.2013.1629
                3834563
                f08fe424-ba4f-4b22-a9fd-aecc3cd040cc
                Copyright © 2013, Spandidos Publications

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 12 March 2013
                : 05 September 2013
                Categories
                Articles

                Oncology & Radiotherapy
                5-azacytidine,myelodysplastic syndrome,colitis,vascular complications
                Oncology & Radiotherapy
                5-azacytidine, myelodysplastic syndrome, colitis, vascular complications

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