Cardiotoxicity anthracycline-induced

Dexrazoxane (Zinecard) [Chelating Agent] Uses Prevent anthracycline-induced (eg, doxorubicin) cardiomyopathy Action Chelates heavy metals binds intracellular iron prevents anthracycline-induced free radicals Dose 10 1 ratio dexrazoxane doxorubicin 30 min prior to each dose, 5 1 ratio w/ CrCl <40 mL/min Caution [C, ] Contra Component sensitivity Disp Inj SE -1-BM (esp leukopenia), fever, Infxn, stomatitis, alopecia, NA /D Interactions t Length of muscle relaxation Wf succinylcholine EMS Given concurrent w/a chemo agent for treating CA to prevent cardiotox monitor for Infxn and reduced cardiac Fxn use caution w/ succinylcholine, reduced doses may be needed OD May cause extreme BM suppression symptomatic and supportive... 

The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2-3 days and presents as arrhythmias or conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and is asymptomatic in most cases. The chronic form results in a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of free radicals within the myocardium. This effect is rarely seen at total doxorubicin dosages below 500-550 mg/m2. Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m2. All anthracyclines can produce "radiation recall reaction," with erythema and desquamation of the skin observed at sites of prior radiation therapy. 

The development of anthracycline-induced cardiomyopathy is closely related to the cumulative lifetime dose of the anthracycline. The recommended maximum cumulative lifetime dose of doxorubicin is 450-550 mg/m (7) and of daunorubicin 400-550 mg/m intravenously in adults (1,2). About 5% of doxorubicin-treated patients develop congestive cardiac failure at this dose however, the incidence approaches 50% at cumulative doses of 1000 mg/m (7-9). These figures are derived from experience with doxorubicin administered as a bolus or by infusion of very short duration (under 30 minutes). The incidence of clinical cardiotoxicity falls dramatically with other schedules of administration (that is weekly doses or continuous infusion for more than 24 hours). 

Anesthesia is difficult in patients with cumulative anthracycline-induced cardiotoxicity, and it has proved fatal on occasions (20). 

Severe anthracycline-induced cardiotoxicity is generally considered irreversible, and it is associated with a poor prognosis and high mortality. However, in four cases the advanced cardiac dysfunction associated with doxorubicin recovered completely after withdrawal (45). Of 19 patients with anthracycline-induced congestive... 

Is this patient at risk for anthracycline-induced cardiotox-icity How should she be monitored ... 

Visscher H, Ross CJ, Rassekh SRet al (2012) Canadian Pharmacogenomics Network for Drug Safety Consortium. Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J Clin Oncol 30 1422-1428... 

Erkus, B., S. Demirtas, A. A. Yarpuzlu, M. Can, Y. Gene, and L. Karaca. 2006. Early prediction of anthracycline induced cardiotoxicity. Acta Paediatrica 96 506-509. 

K. Conklin, Coenzyme Qio for Prevention of Anthracycline-Induced Cardiotoxicity, Integrative Cancer Therapies 4, no. 2 (2005) 110-130 (2005). Abstract accessed online at http ict. sagepub.com/cgi/content/abstract/4/2/110. 

Shan K. Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996 125 47-58. 

While several oncologic drugs have been associated with cardiomyopathy, anthracyclines such as daunorubicin and doxorubicin are salient examples. Anthracycline-induced cardiotoxicity may be defined as acute, early-onset chronic, and late-onset chronic (Cardinale et al. 2015). Acute cardiotoxicity occurs after a single dose, or a single course, of anthracyclines, and the onset of clinical manifestations is within 2 weeks from the end of treatment. Early-onset chronic toxicity develops within 1 year, and is the most frequent and clinically relevant form of cardiotoxicity. It usually presents as a dilated and hypokinetic cardiomyopathy leading to heart failure. Late-onset chronic cardiotoxicity develops years, or even decades, after the end of chemotherapy (Cardinale et al. 2015). 

Ewer MS, Martin FJ, Henderson C, Shapiro CL, Benjamin RS, Gabizon AA (2004) Cardiac safety of liposomal anthracyclines. Semin Oncol 31 161—181 Ferreira AL, Matsubara LS, Matsubara BB (2008) Anthracycline-induced cardiotoxicity. 

Cranial irradiation has also been shown to be a risk factor for anthracycline-induced cardiotoxicity in children. One hundred and thirty children (aged 6-37) treated with an anthracycline-containing combination for a variety of cancers had LV mass measured a mean of 10 years after diagnosis, with 59 of these children also having cranial irradiation. Those exposed to cranial irradiation had a 12% decrease in LV mass and a 3.6% decrease in LV dimension [27 ]. 

EHtok A, Oz F, Cizgici AY, Kilic L, Ciftci R, Sen F, et al. Effect of carvedilol on silent anthracycline-induced cardiotoxicity assessed by strain imaging a prospective randomized controlled study with 6-month follow-up. Cardiol J 2014. http //dx.doi.org/10.5603/CJ.a2013.0150. [Epub ahead of print],... 

Simunek T, Sterba M, Popelova O, Adamcova M, Hrdina R, Gersl V. Anthracycline-induced cardiotoxicity overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep 2009 61(1) 154-71. 

There are various pathways for free radical-mediated processes in microsomes. Microsomes can stimulate free radical oxidation of various substrates through the formation of superoxide and hydroxyl radicals (the latter in the presence of iron) or by the direct interaction of chain electron carriers with these compounds. One-electron reduction of numerous electron acceptors has been extensively studied in connection with the conversion of quinone drugs and xenobiotics in microsomes into reactive semiquinones, capable of inducing damaging effects in humans. (In 1980s, the microsomal reduction of anticancer anthracycline antibiotics and related compounds were studied in detail due to possible mechanism of their cardiotoxic activity and was discussed by us earlier [37], It has been shown that semiquinones of... 

Minotti, G. et al. (1995) Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines novel linkage between anthracycline metabolism and iron-induced cardiotoxicity, J. Clin. Invest. 95, 1595-605. 

Using a similar approach to our studies of cisplatin-induced ototoxicity, we have identified a series of SNPs associated with anthrac-yline-induced cardiotoxicity in children with cancer in Canada, a finding that we have verified in a replication cohort from the Netherlands [69, 70]. We identified a series of risk and protective alleles that can be related at least in good part to the known pharmacology of the anthracyclines these variants include protective variants characterized by loss-of-function for influx transporters for anthracyclines as well as risk variants characterized by loss-of-function for efflux transporters for anthracyclines (Table 2, Fig. 5) [69],... 

Circulating cardiac troponin (cTn) is the most widely used biomarker for detection of myocardial injury (Newby et al. 2011). With regard to its employment in the context of drug-induced cardiotoxicity, most data to date have examined anthracycline-based chemotherapy, and so the broader applicability of these data is currently nncertain (Christenson et al. 2015). However, a notable 2004 publication from the Expert Working Gronp on Biomarkers of Drug-induced Cardiac Toxicity (Wallace et al. 2004) reported that troponin I (cTnl) and troponin T (cTnT) are sensitive, specific, and robust biomarkers of drug-induced cardiotoxicity. 

---