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      Dexrazoxane for the treatment of chemotherapy-related side effects

      Cancer Management and Research

      Dove Medical Press

      anthracyclines, cardiomyopathy, extravasation

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          Abstract

          For more than half a century, the different properties of dexrazoxane have captured the attention of scientists and clinicians. Presently, dexrazoxane is licensed in many parts of the world for two different indications: prevention of cardiotoxicity from anthracycline-based chemotherapy, and prevention of tissue injuries after extravasation of anthracyclines. This article reviews the historical, preclinical, and clinical background for the use of dexrazoxane for these indications.

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          Most cited references 65

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          Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood.

          Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission. Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography. Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress-velocity index). The cumulative dose of doxorubicin was the most significant predictor of abnormal cardiac function (P less than 0.002). Seventeen percent of patients who received one dose of doxorubicin had slightly elevated age-adjusted afterload, and none had decreased contractility. In contrast, 65 percent of patients who received at least 228 mg of doxorubicin per square meter had increased afterload (59 percent of patients), decreased contractility (23 percent), or both. Increased afterload was due to reduced ventricular wall thickness, not to hypertension or ventricular dilatation. In multivariate analyses restricted to patients who received at least 228 mg of doxorubicin per square meter, the only significant predictive factors were a higher cumulative dose (P = 0.01), which predicted decreased contractility, and an age of less than four years at treatment (P = 0.003), which predicted increased afterload. Afterload increased progressively in 24 of 34 patients evaluated serially (71 percent). Reported symptoms correlated poorly with indexes of exercise tolerance or ventricular function. Eleven patients had congestive heart failure within one year of treatment with doxorubicin; five of them had recurrent heart failure 3.7 to 10.3 years after completing doxorubicin treatment, and two required heart transplantation. No patient had late heart failure as a new event. Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload sometimes accompanied by reduced contractility. We hypothesize that the loss of myocytes during doxorubicin therapy in childhood might result in inadequate left ventricular mass and clinically important heart disease in later years.
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            American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants.

            To update a clinical practice guideline on the use of chemotherapy and radiation therapy protectants for patients with cancer. An update committee reviewed literature published since the last guideline update in 2002. Thirty-nine reports met the inclusion criteria: palifermin and dexrazoxane, three reports (two studies) each; amifostine, 33 reports (31 studies); and mesna, no published randomized trials identified since 2002. Dexrazoxane is not recommended for routine use in breast cancer (BC) in adjuvant setting, or metastatic setting with initial doxorubicin-based chemotherapy. Consider use with metastatic BC and other malignancies, for patients who have received more than 300 mg/m(2) doxorubicin who may benefit from continued doxorubicin-containing therapy. Cardiac monitoring should continue in patients receiving doxorubicin. Amifostine may be considered for prevention of cisplatin-associated nephrotoxicity, reduction of grade 3 to 4 neutropenia (alternative strategies are reasonable), and to decrease acute and late xerostomia with fractionated radiation therapy alone for head and neck cancer. It is not recommended for protection against thrombocytopenia, prevention of platinum-associated neurotoxicity or ototoxicity or paclitaxel-associated neuropathy, prevention of radiation therapy-associated mucositis in head and neck cancer, or prevention of esophagitis during concurrent chemoradiotherapy for non-small-cell lung cancer. Palifermin is recommended to decrease severe mucositis in autologous stem-cell transplantation (SCT) for hematologic malignancies with total-body irradiation (TBI) conditioning regimens, and considered for patients undergoing myeloablative allogeneic SCT with TBI-based conditioning regimens. Data are insufficient to recommend use in the non-SCT setting.
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              Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease.

              Pediatric Oncology Group (POG) studies 9426 and 9425 evaluated dexrazoxane (DRZ) as a cardiopulmonary protectant during treatment for Hodgkin's disease (HD). We evaluated incidence and risk factors of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and second malignant neoplasms (SMNs). Treatment for low- and high-risk HD with doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC), respectively, was followed by low-dose radiation. The number of chemotherapy cycles was determined by rapidity of the initial response. Patients were assigned randomly to receive DRZ (n = 239) or no DRZ (n = 239) concomitantly with chemotherapy to evaluate its potential to decrease adverse cardiopulmonary outcomes. Ten patients developed SMN. Six of eight patients developed AML/MDS, and both solid tumors (osteosarcoma and papillary thyroid carcinoma) occurred in recipients of DRZ. Eight patients with SMN were first events. With median 58 months' follow-up, 4-year cumulative incidence rate (CIR) for AML/MDS was 2.55% +/- 1.0% with DRZ versus 0.85% +/- 0.6% in the non-DRZ group (P = .160). For any SMN, the CIR for DRZ was 3.43% +/- 1.2% versus CIR for non-DRZ of 0.85% +/- 0.6% (P = .060). Among patients receiving DRZ, the standardized incidence rate (SIR) for AML/MDS was 613.6 compared with 202.4 for those not receiving DRZ (P = .0990). The SIR for all SMN was 41.86 with DRZ versus 10.08 without DRZ (P = .0231). DRZ is a topoisomerase II inhibitor with a mechanism distinct from etoposide and doxorubicin. Adding DRZ to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS.
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                Author and article information

                Journal
                Cancer Manag Res
                Cancer Manag Res
                Cancer Management and Research
                Cancer Management and Research
                Dove Medical Press
                1179-1322
                2014
                15 September 2014
                : 6
                : 357-363
                Affiliations
                Thoracic and Neuroendocrine Section, Department of Oncology, Copenhagen University Hospital, Copenhagen, Denmark
                Author notes
                Correspondence: Seppo W Langer, Thoracic and Neuroendocrine Section, Department of Oncology 5073, Copenhagen University Hospital, Rigshospitalet Blegdamsvej 9, DK-2100 Copenhagen, Denmark, Email seppo.langer@ 123456regionh.dk
                Article
                cmar-6-357
                10.2147/CMAR.S47238
                4168851
                © 2014 Langer. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Oncology & Radiotherapy

                anthracyclines, cardiomyopathy, extravasation

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