Prevention of Cardiomyopathy in Patients With Cancer

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 anthracycline1,2 and trastuzumab3,4 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

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Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Magnetic Resonance Imaging, Hypertension

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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