The chemotherapy agents most commonly associated with the development of cardiomyopathy are anthracyclines and trastuzumab. The development of cardiomyopathy is clinically significant for two main reasons:

1. It may limit or preclude potentially life-saving chemotherapy.
2. Among cancer survivors, progressive chemotherapy-induced cardiomyopathy can lead to significant clinical symptoms and limit life expectancy, independent of oncologic prognosis.

Early detection and treatment of both anthracycline^1,2 and trastuzumab^3,4 mediated cardiomyopathy can lead to improvements in cardiac function in the majority of patients. Additionally, in the case of trastuzumab cardiotoxicity, re-introduction of trastuzumab after interruption of therapy and treatment with cardiac medications is often well-tolerated.⁵ However, screening to look for asymptomatic cardiac dysfunction, especially in the case of anthracyclines, is not routinely conducted in patients who have been exposed to these agents. Consequently, the diagnosis of cardiotoxicity is delayed until symptomatic heart failure (HF) develops, at which point interventions are less effective. Therefore, emphasis has been placed on investigating preventive strategies for the development of chemotherapy-induced cardiomyopathy.

Risk Factors for Cardiotoxicity

Anthracyclines cause a dose-dependent cardiotoxicity that ranges from subtle changes in myocardial strain or biomarkers to overt left ventricular (LV) systolic dysfunction and clinical HF. Although there are many proposed mechanisms by which anthracyclines induce cardiotoxicity, most studies identify increased oxidative stress and inhibition of topoisomerase 2 as the two major mechanisms involved in mediating myocardial cell death and apoptosis.⁶ Risk factors for anthracycline cardiotoxicity include cumulative dose, concurrent mediastinal radiation, extremes of age, female gender, and cardiac risk factors or pre-existing cardiovascular disease.⁷ In contrast, trastuzumab prevents activation of ErbB2-4 receptors, thus disrupting cellular repair pathways, and promotes myocardial dysfunction rather than cell death.⁸ In patients treated with trastuzumab, adjuvant anthracyclines, increasing age, hypertension, diabetes, coronary artery disease, atrial fibrillation, and chronic renal insufficiency have been shown to increase the risk of cardiotoxicity.⁹

Strategies to Reduce Risk of Cardiotoxicity

Dosing and Administration

There is no threshold anthracycline dose below which cardiotoxicity does not occur, but it is recommended that the cumulative lifetime anthracycline dose be limited to minimize cardiotoxicity (450-550 mg/m² doxorubicin or 800-1000 mg/m² epirubicin).¹⁰ In patients with pre-existing cardiovascular risk factors or cardiac disease, attempts should be made to optimize cardiac medications prior to initiating cancer therapy. These patients constitute a high-risk group that may also benefit from closer monitoring of cardiac function before, during, and after chemotherapy. Lastly, in these high-risk patients, different dosing schedules to lower peak anthracycline concentrations or use of alternative chemotherapeutic agents that are less cardiotoxic may be considered. A recent meta-analysis of 7 studies showed a significantly lower rate of clinical HF with an anthracycline infusion duration ≥ 6 hours compared with shorter infusion durations (relative risk [RR] 0.27; 95% confidence interval [CI], 0.09-0.81).¹¹ However, prolonged infusions, rather than bolus administration, to reduce anthracycline cardiotoxicity remain controversial due to the increased risk of extravasation and tissue necrosis. Compared with conventional doxorubicin, liposomal doxorubicin has been shown to reduce the incidence of both asymptomatic and symptomatic cardiomyopathy (odds ratio = 0.46; 95% CI, 0.23-0.92; p = 0.03) without reducing progression-free or overall survival.¹² The routine use of liposomal doxorubicin, however, has been limited by increased skin toxicity (hand-foot syndrome) and higher cost. Mitoxantrone and epirubicin are also believed to be less cardiotoxic than conventional doxorubicin;¹³ however, there are no prospective or systematic trials comparing the cardiac effects of these agents. Newer human epidermal growth factor receptor 2 (HER-2) targeted therapies including lapatinib, pertuzumab, trastuzumab emtansine, neratinib, and afatinib have all been shown to have decreased cardiotoxicity relative to trastuzumab¹⁴ and may be considered in certain patients with HER-2 positive metastatic breast cancer and cardiomyopathy who need long-term treatment with HER-2 antagonists.

Dexrazoxane

Dexrazoxane is a potent intracellular chelating agent that interferes with iron-mediated oxygen free radical generation and is thought to be responsible, in part, for anthracycline-induced cardiotoxicity. In a meta-analysis of 5 randomized clinical trials (RCTs) of anthracyclines ± dexrazoxane, use of dexrazoxane reduced the incidence of both asymptomatic and symptomatic cardiomyopathy (RR 0.29; 95% CI, 0.2-0.4; p < 0.00001).¹⁵ Furthermore, dexrazoxane has been shown to be effective in reducing cardiotoxicity even when administered after receipt of 300 mg/m² of anthracyclines.¹⁶ Widespread use of dexrazoxane has been limited by concerns of decreased tumor response rates in one breast cancer trial¹⁷ and by a perceived increase in the risk of secondary hematologic malignancies in children treated with dexrazoxane.¹⁸ Meta-analyses reveal that there is no difference in oncologic response rates or oncologic survival between patients treated with or without dexrazoxane.^15,19 Furthermore, a recent RCT of dexrazoxane added to anthracycline-based chemotherapy in children with T-cell acute lymphoblastic leukemia or lymphoblastic non-Hodgkin lymphoma did not show a significant increase in secondary malignancies with dexrazoxane.²⁰ Nonetheless, dexrazoxane is currently approved only in the United States for use in adult patients with metastatic breast cancer who have received ≥ 300 mg/m² and need additional anthracycline therapy.

Cardioprotectant Agents

Patients with cancer receiving cardiotoxic chemotherapy are at risk for developing cardiomyopathy and are designated as having Stage A HF.²¹ The efficacy of renin-angiotensin-aldosterone inhibition and sympathetic nervous system blockade has been proven only in patients with established systolic cardiac dysfunction (Stages B-D HF),²¹ but there have been several pre-clinical studies suggesting that humoral factors including angiotensin II²² and endothelin I²³ are involved in mediating anthracycline cardiotoxicity. Similarly, in animals exposed to anthracyclines, beta-1 activation appears to be cardiotoxic, whereas beta-2 activation is cardioprotective.²⁴ Furthermore, certain beta-blockers, such as carvedilol and nebivolol that have additional antioxidant properties, have been shown to attenuate the histopathologic changes seen in anthracycline-mediated cardiomyopathy.²⁵ Accordingly, there have been several RCTs evaluating the role of neurohormonal antagonists as cardioprotective agents in patients receiving cardiotoxic chemotherapy (Table 1). Many of these studies suggest that prophylactic neurohormonal blockade in patients exposed to anthracyclines or trastuzumab is associated with a smaller decrement in LV ejection fraction. However, they have all been underpowered to detect a difference in clinical HF events. This, combined with the reluctance to introduce blood-pressure-lowering medications in patients with a predisposition to hypotension (such as from dehydration and neutropenic fever secondary to chemotherapy), has prevented widespread use of prophylactic neurohormonal blockade in patients exposed to anthracyclines and trastuzumab. Serial monitoring for changes in global longitudinal strain or elevations of troponin I can identify a subset of high-risk patients who might benefit from targeted use of neurohormonal antagonists to prevent an overt decline in LV systolic function.^4,26-28 Larger, multi-center clinical trials are needed to conclusively assess the efficacy of neurohormonal blockade to prevent chemotherapy-induced cardiotoxicity.

Table 1: RCTs of Prophylactic Treatment With Neurohormonal Antagonists to Prevent Anthracycline- and Trastuzumab-Induced Cardiomyopathy

Study	Treatment	Prophylaxis Agent (Daily dose)	Control (n)	Treatment (n)	Follow Up	Primary Endpoint	Imaging Modality	Result (Treatment vs. Control)
Positive Trials
Kalay et al.29	Anthracycline	Nebivolol (5 mg)	27	18	6 months	Mean ejection fraction at 6 months	Echo	63.8 ± 3.9% vs. 57.5 ± 5.6%, p = 0.01
Bosch et al.30	Anthracycline	Enalapril (8.6 ± 5.9 mg) + Carvedilol (23.8 ± 17 mg)	45	45	6 months	Δ ejection fraction from baseline)	Echo; cardiac magnetic resonance imaging	-0.17 vs. -3.28, p = 0.04 0.36 vs. -3.04, p = 0.09
Kalay et al.29	Anthracycline	Carvedilol (12.5 mg)	25	25	5.2 ± 1.2 months	ejection fraction < 50%	Echo	RR: 0.2 (0.03-1.59)
Janbabai et al.31	Anthracycline	Enalapril (17.94 ± 4.10 mg)	34	35	6 months	Δ ejection fraction from baseline @ 6 mths	Echo	0.55 vs. -13.3, p < 0.001
Cardinale et al.32	Anthracycline	Enalapril (16±6 mg)	56	58	12 months	↓ ejection fraction >10% from baseline and <50%	Echo	0 vs. 43%, p<0.001
Akpek et al.33	Anthracycline	Spironolactone (25 mg)	43	40	6 months	Δ ejection fraction from baseline @ 6 mths	Echo	67 ± 6.1→65.7 ± 7.4 vs. 67.7 ± 6.3→53.6 ± 6.8, p < 0.001
Gulati et al.34	Anthracycline ± Trastuzumab	Candesartan (32 mg)	60	60	10-61 weeks	Δ ejection fraction from baseline	Cardiac magnetic resonance imaging	-0.8 vs. -2.6%, p = 0.026
Negative Trials
Gulati et al.34	Anthracycline ± Trastuzumab	Metoprolol (100 mg)	58	62	10-61 weeks	Δ ejection fraction from baseline	Cardiac magnetic resonance imaging	-1.6 vs. -1.8%, p=0.77
Georgakopoulos et al.35	Anthracycline	Metoprolol	40	42	31 months	HF	Clinical	1 vs. 3, p = not significant
Georgakopoulos et al.35	Anthracycline	Enalapril	40	43	31 months	HF	Clinical	2 vs. 3, p = not significant
Pituskin et al.36	Trastuzumab	Perindopril (8 mg)	33	30	12 months	Δ LV end diastolic volume index from baseline	Cardiac magnetic resonance imaging	7 vs. 4 ml/m2, p = not significant
PItuskin et al.36	Trastuzumab	Bisoprolol (10 mg)	31	30	12 months	Δ LV end diastolic volume index from baseline	Cardiac magnetic resonance imaging	8 vs. 4 ml/m2, p = not significant
Nakamae et al.37	Anthracycline	Valsartan (80 mg)	20	20	7 days	Δ ejection fraction from baseline @ 7 days	Echo	p = 0.07 vs. p = 0.07

Statins

Anthracycline cardiotoxicity is mediated in part by an increase in reactive oxygen species. Because statins exert their "pleotropic effects" by decreasing oxidative stress and inflammation, it is postulated that statins may have cardioprotective effects. In a propensity-matched analysis, 67 women with newly diagnosed breast cancer who were on concomitant statins during anthracycline-based chemotherapy were compared with 134 non-statin treated controls.³⁸ In this study, incidental statin treatment was associated with a significantly decreased risk of HF hospitalizations (hazard ratio 0.3; 95% CI, 0.1-0.9; p = 0.03).³⁸ Another small study evaluated LV function using cardiac magnetic resonance imaging in 51 patients receiving anthracycline-based chemotherapy.³⁹ In this analysis, the 14 patients who were taking statins for cardiovascular reasons during chemotherapy experienced no decline in LV function at 6 months, while the remaining 37 patients who were not taking a statin had a significant decline in their mean LV ejection fraction (from 57.5 ± 1.4% to 52.4 ± 1.2%, p = 0.0003) after anthracycline treatment.³⁹ A RCT of 40 patients undergoing anthracycline treatment compared 6 months of prophylactic atorvastatin (40 mg daily) to placebo.⁴⁰ Although there was no significant difference in the primary endpoint of LV ejection fraction < 50% after 6 months of anthracycline chemotherapy between the 2 groups, statin therapy resulted in a smaller decline in mean LV ejection fraction (1.3 ± 3.8% vs. -7.9 ± 8.0%, p < 0.001) and a lesser increase in mean LV end-systolic (p < 0.001) and end-diastolic (p = 0.02) dimensions compared with placebo.⁴⁰ Further prospective RCTs of statin therapy are currently underway.

Other Agents

Several other agents with putative antioxidant effects including metformin, resveratrol, febuxostat, bioflavinoids, L-carnitine, and alpha-linoleic acid have been shown to be effective in ameliorating the cardiotoxic effects of anthracyclines in animal models.^15,41-43 Other agents such as ranolazine that limit intracellular calcium influx have also been shown to decrease anthracycline cardiotoxicity in pre-clinical models.⁴⁴ It is hopeful that ongoing efforts will identify agents that are both cardioprotective and well-tolerated from a hemodynamic standpoint.

Conclusion

In summary, anthracyclines and trastuzumab can cause cardiomyopathy, particularly in high-risk individuals. Efforts should be made to identify and optimize cardiovascular risk factors in patients prior to treatment with these agents. Furthermore, dose reduction and the use of alternative agents with reduced cardiotoxicity should be considered to minimize the risk of cardiotoxicity, particularly in high-risk patients. The use of cardioprotective therapies such as dexrazoxane, initiated prior to and maintained during chemotherapy, can allow successful administration of life-saving chemotherapies while limiting adverse cardiovascular events. Ongoing efforts suggest that neurohormonal antagonists, such as renin-angiotensin-aldosterone inhibitors and beta-blockers, may also be effective in reducing cardiotoxicity. Nonetheless, routine use of these agents has not yet been adopted in clinical practice. Larger clinical trials are needed to verify the efficacy and tolerability of these agents in patients with cancer.

References

1. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55:213-20.
2. Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-8.
3. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005;23:7820-6.
4. Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 2010;28:3910-6.
5. Yu AF, Yadav NU, Lung BY, et al. Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat 2015;149:489-95.
6. Sawyer DB. Anthracyclines and heart failure. N Engl J Med 2013;368:1154-6.
7. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710-7.
8. Chen MH, Kerkelä R, Force T. Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation 2008;118:84-95.
9. Ezaz G, Long JB, Gross CP, Chen J. Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc 2014;3:e000472.
10. Barrett-Lee PJ, Dixon JM, Farrell C, et al. Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk. Ann Oncol 2009;20:816-27.
11. van Dalen EC, van der Pal HJ, Kremer LC. Different dosage schedules for reducing cardiotoxicity in people with cancer receiving anthracycline chemotherapy. Cochrane Database Syst Rev 2016;3:CD005008.
12. Xing M, Yan F, Yu S, Shen P. Efficacy and Cardiotoxicity of Liposomal Doxorubicin-Based Chemotherapy in Advanced Breast Cancer: A Meta-Analysis of Ten Randomized Controlled Trials. PloS One 2015;10:e0133569.
13. Smith LA, Cornelius VR, Plummer CJ, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer 2010;10:337.
14. Sendur MA, Aksoy S, Altundag K. Cardiotoxicity of novel HER2-targeted therapies. Curr Med Res Opin 2013;29:1015-24.
15. van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2011:CD003917.
16. Swain SM, Whaley FS, Gerber MC, Ewer MS, Bianchine JR, Gams RA. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 1997;15:1333-40.
17. Swain SM, Whaley FS, Gerber MC, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997;15:1318-32.
18. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 2007;25:493-500.
19. Shaikh F, Dupuis LL, Alexander S, Gupta A, Mertens L, Nathan PC. Cardioprotection and Second Malignant Neoplasms Associated With Dexrazoxane in Children Receiving Anthracycline Chemotherapy: A Systematic Review and Meta-Analysis. J Natl Cancer Inst 2016;108.
20. Asselin BL, Devidas M, Chen L, et al. Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol 2016;34:854-62.
21. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.
22. Toko H, Oka T, Zou Y, et al. Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy. Hypertens Res 2002;25:597-603.
23. Bien S, Riad A, Ritter CA, et al. The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. Cancer Res 2007;67:10428-35.
24. Bernstein D, Fajardo G, Zhao M, et al. Differential cardioprotective/cardiotoxic effects mediated by beta-adrenergic receptor subtypes. Am J Physiol Heart Circ Physiol 2005;289:H2441-9.
25. Oliveira PJ, Bjork JA, Santos MS, et al. Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 2004;200:159-68.
26. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004;109:2749-54.
27. Sawaya H, Sebag IA, Plana JC, et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol 2011;107:1375-80.
28. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014;27:911-39.
29. Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258-62.
30. Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 2013;61:2355-62.
31. Janbabai G, Nabati M, Faghihinia M, Azizi S, Borhani S, Yazdani J. Effect of Enalapril on Preventing Anthracycline-Induced Cardiomyopathy. Cardiovasc Toxicol 2016 Mar 22 [Epub ahead of print].
32. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474-81.
33. Akpek M, Ozdogru I, Sahin O, et al. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail 2015;17:81-9.
34. Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J 2016;37:1671-80.
35. Georgakopoulos P, Roussou P, Matsakas E, et al. Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up. Am J Hematol 2010;85:894-6.
36. Pituskin E, Mackey JR, Koshman S, et al. Prophylactic beta blockade preserves left ventricular ejection fraction in HER2-overexpressing breast cancer patients receiving trastuzumab: Primary results of the MANTICORE randomized controlled trial. San Antonio Breast Cancer Symposium 2015:S1-05.
37. Nakamae H, Tsumura K, Terada Y, et al. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 2005;104:2492-8.
38. Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol 2012;60:2384-90.
39. Chotenimitkhun R, D'Agostino R Jr, Lawrence JA, et al. Chronic statin administration may attenuate early anthracycline-associated declines in left ventricular ejection function. Can J Cardiol 2015;31:302-7.
40. Acar Z, Kale A, Turgut M, et al. Efficiency of atorvastatin in the protection of anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2011;58:988-9.
41. Kobashigawa LC, Xu YC, Padbury JF, Tseng YT, Yano N. Metformin protects cardiomyocyte from doxorubicin induced cytotoxicity through an AMP-activated protein kinase dependent signaling pathway: an in vitro study. PLoS One 2014;9:e104888.
42. Lou Y, Wang Z, Xu Y, et al. Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway. Int J Mol Med 2015;36:873-80.
43. Krishnamurthy B, Rani N, Bharti S, et al. Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats. Chem Biol Interact 2015;237:96-103.
44. Tocchetti CG, Carpi A, Coppola C, et al. Ranolazine protects from doxorubicin-induced oxidative stress and cardiac dysfunction. Eur J Heart Fail 2014;16:358-66.

Keywords: Cardiotoxicity, Aldosterone, Angiotensin II, Anthracyclines, Antibodies, Monoclonal, Humanized, Antioxidants, Atrial Fibrillation, Breast Neoplasms, Cardiomyopathies, Cardiotonic Agents, Cardiovascular Diseases, Coronary Artery Disease, Diabetes Mellitus, Heart Failure, Hypertension, Hypotension, Magnetic Resonance Imaging, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Reactive Oxygen Species, Receptor, ErbB-2, Renal Insufficiency, Chronic, Risk Factors, Spironolactone, Sympathetic Nervous System, Tetrazoles, Troponin I

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