Current Status of Liposomal Anthracycline Therapy in Metastatic Breast Cancer (original) (raw)
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Annals of Oncology, 2004
Background: This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYX™ [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC). Patients and methods: Women (n = 509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m 2 (every 4 weeks) or doxorubicin 60 mg/m 2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose. Results: PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR) = 1.00; 95% confidence interval (CI) 0.82-1.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR = 3.16; 95%CI 1.58-6.31; P <0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR = 0.94; 95%CI 0.74-1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin. Conclusions: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.
Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin
British journal of cancer, 1999
Cardiotoxicity represents the major side-effect limiting the clinical use of anthracyclines, especially doxorubicin, in cancer chemotherapy. The use of non-toxic prodrugs, or of liposome-encapsulated drugs, allows a better targeting of the tumours and may, therefore, improve the tolerance to the treatment. Using the model of isolated perfused rat heart, we have evaluated the cardiotoxicity of a novel prodrug of doxorubicin, HMR-1826, which consists of the association of doxorubicin to glucuronic acid. We have compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by HMR-1826 to those induced by doxorubicin and Doxil, a liposomal form of doxorubicin. HMR-1826 was administered intravenously every other day for 11 days at doses of 50-200 mg kg(-1) per injection while doxorubicin was administered according to the same protocol at doses of 1-3 mg kg(-1) per injection. Doxorubicin strongly decreased the cardiac functional parameters a...
Doxorubicin-induced congestive heart failure in adults
Cancer, 1985
The prognosis of doxorubicin-induced congestive heart failure (CHF) is reported to be poor. To define the clinical course of doxorubicin-induced CHF, the authors reviewed their experience with 43 patients with this diagnosis. The median age of the total group was 55 years (range, 23-69); the median cumulative dose of doxorubicin was 450 mg/m2 (range, 200 mg/m2-1150 mg/m2). A majority of the patients had a diagnosis of breast cancer. The median survival of the whole group estimated by means of a Kaplan-Meier plot was 112 weeks. Twelve of 43 patients (28%) died of CHF, 7 of them (16%) because of fulminant failure in less than 8 weeks and the remaining 5 because of a more protracted course with recurrent episodes of cardiac decompensation. Twenty-five of the 43 patients (58%) achieved complete control of CHF. In the remaining 6 patients (14%), CHF had improved but was not completely controlled at the time of death, which was secondary to progressive tumor. Treatment consisted of standard therapy with digitalis and diuretics. Survival was significantly shorter in patients who presented with class IV dyspnea and in those who developed CHF less than 4 weeks after administration of the last dose of doxorubicin. The authors conclude that in a majority of patients, doxorubicin-induced CHF is easily treatable and frequently controlled with digitalis and diuretics.
Cancer Chemotherapy and Pharmacology, 2010
Purpose Anthracyclines and fluoropyrimidines are very active in breast cancer, while liposomal doxorubicin has low cardiotoxicity. We conducted a dose-finding study of the combination of liposomal doxorubicin and capecitabine in patients with pretreated metastatic breast cancer. Patients and methods Patients received liposomal doxorubicin 60 mg/m2 on day 1 plus capecitabine 825 mg/m2 bid (level 0) or 1,000 mg/m2 bid (level 1) on days 1–14 of each 21-day cycle to establish the maximum tolerated dose (MTD) and cardiac safety. Results Nine patients were enrolled and a total of 52 courses were delivered (median 6 cycles per patient [range 4–7]). Grade 4 neutropenia occurred in 15% of cycles, with one episode of febrile neutropenia; most nonhematological toxicities were mild or moderate. No formal MTD was established, and the study was closed because two cardiac events were observed at dose level 1 and another at dose level 0 in patients pretreated with epirubicin ≥ 560 mg/m2. Conclusions The recommended dose for phase II studies is liposomal doxorubicin 60 mg/m2 on day 1 plus capecitabine 825 mg/m2/bid on days 1–14 of each 21-day cycle. Despite the lower cardiotoxicity of liposomal doxorubicin, the risk of cardiac damage persists in anthracycline-pretreated individuals and mandates close cardiac monitoring and careful evaluation of the overall cumulative dose.
Doxorubicin-Induced Cardiotoxicity: From Bioenergetic Failure and Cell Death to Cardiomyopathy
Medicinal Research Reviews, 2014
Doxorubicin (DOX) is an anticancer anthracycline that presents a dose-dependent and cumulative cardiotoxicity as one of the most serious side effects. Several hypotheses have been advanced to explain DOX cardiac side effects, which culminate in the development of life-threatening cardiomyopathy. One of the most studied mechanisms involves the activation of DOX molecule into a more reactive semiquinone by mitochondrial Complex I, resulting in increased oxidative stress. The present review describes and critically discusses what is known about some of the potential mechanisms of DOX-induced cardiotoxicity including mitochondrial oxidative damage and loss of cardiomyocytes. We also discuss alterations of mitochondrial metabolism and the unique characteristics of DOX delayed toxicity, which can also interfere on how the cardiac muscle handles a "second-hit stress." We also present pharmaceutical and nonpharmaceutical approaches that may decrease DOX cardiac alterations in animal models and humans and discuss the limitations of each strategy. C 2013 Wiley Periodicals, Inc. Med. Res. Rev., 00, No. 0, 1-30, 2013 2 r CARVALHO ET AL.