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Cardio-Oncology: A Focus on Chemotherapy-Induced Cardiomyopathy

Allison Karabinos, PharmD
PGY-2 Oncology Pharmacy Resident
Levine Cancer Institute
Charlotte, NC

Advances in oncology treatment and supportive care have led to the conversion of numerous cancers from a terminal illness into a chronic disease state. Nevertheless, cancer remains the second leading cause of death in the United States behind cardiovascular disease.1 Certain cancer therapies, including chemotherapy, targeted therapy, and radiation therapy, may result in treatment-related cardiovascular complications; therefore, efforts to identify patient-specific risk factors prior to beginning cancer treatment and to recognize cardiac dysfunction during therapy have been given priority in order to lessen cardiovascular risks and their effects on cancer outcomes. The field of cardio-oncology has emerged as a new area of clinical practice, intertwining cardiology and oncology principles with the purpose of providing optimal oncology care to cancer patients without compromising cardiovascular health. Long-term cardiovascular complications related to cancer treatment may have an impact on survivorship; thus it is vital to incorporate cardio-oncology into clinical oncology patient care in order to optimize efficacy and survival outcomes and improve quality of life for patients.

Clinical presentations of cardiovascular complications from chemotherapy, targeted therapy, and radiation therapy include heart failure (HF), myocardial ischemia, myocarditis, hypertension, pericardial diseases, thromboembolic disorders, QTc prolongation and arrhythmias, and pulmonary hypertension.2 Cancer therapy–induced cardiomyopathy is a historically recognized adverse event, and relevant cardio-oncology data are discussed below.

Heart Failure

The lifetime risk of developing HF is 20% for all adults 40 years of age or older in the United States, and patients with HF secondary to doxorubicin therapy have had significantly worse survival rates compared to patients with idiopathic cardiomyopathy.3,4 As defined by the American College of Cardiology Foundation and the American Heart Association (ACCF/AHA), HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood.3 It is recognized as a progressive disorder, and onset during cancer therapy is of particular importance because it may result in the interruption or discontinuation of therapy, which may have a negative impact on oncology-related outcomes. Although no definition for HF in the cardio-oncology setting has been established, package labeling of known cardiotoxic cancer therapies, including anthracyclines and antihuman epidermal growth factor receptor (HER2)–targeted therapies, has characterized it as an absolute decrease in left ventricular ejection fraction (LVEF) of at least 16%–20% from baseline, a decline in LVEF by 10% or more from baseline to below the lower limit of normal, or an absolute LVEF of no more than 40%–45%.5-9 The definition established by the Common Terminology Criteria for Adverse Events version 5.0 includes symptoms and their responsiveness to intervention as a standardized qualitative method for reporting HF and left ventricular (LV) systolic dysfunction in clinical trials.10

Diagnostic Workup

Although cardiac dysfunction may present as systolic or diastolic dysfunction or both, LVEF via echocardiogram (ECHO) remains the primary technique to assess cardiac structure and function during and after completion of anthracycline and anti-HER2 targeted therapy. Multigated acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI) are alternative monitoring approaches but may be limited by their high cost. When an ECHO cannot be performed, cardiac MRI is preferred over MUGA because it provides cardiac structural and functional information without exposing the patient to radiation.2,11 All patients receiving cardiotoxic cancer therapy should undergo baseline LVEF measurement and periodic monitoring during and after completion of therapy based on package labeling recommendations and as clinically indicated, using the same method at each time point throughout treatment.11

Other surveillance tools for monitoring LVEF include myocardial strain and serum biomarkers, but evidence to provide guidance on monitoring strategies for these tools is lacking.11 Global longitudinal strain has detected preclinical changes in LV systolic function prior to quantifiable declines in LVEF and was shown to predict subsequent toxicity prior to the onset of HF symptoms.12,13 Monitoring cardiac biomarkers such as troponin and brain natriuretic peptide may offer opportunities to identify early signs of myocardial damage: positive troponin I has been correlated with a higher incidence of HF and asymptomatic LV dysfunction.14 Although still being investigated, these strategies may in the future offer benefit in detecting subclinical HF prior to detection on ECHO and allowing for earlier intervention to avoid long-term complications of cardiotoxicity.

Risk Factors

Risk factors for cardiac dysfunction in the form of LVEF decline in patients treated with an anthracycline or trastuzumab or both are well established. Modifiable risk factors include hypertension, diabetes, dyslipidemia, and smoking, all of which have had a significant association with cardiac dysfunction in this patient population, with hypertension being the most common risk factor. Patients with two or more modifiable risk factors have an added risk of HF. Patients 60 years of age and older have demonstrated 1.6- to 6.8-fold increased risks of cardiac dysfunction, and those with preexisting compromised cardiac function, including LVEF of 50%–55% at baseline or history of myocardial infarction or coronary artery disease, have demonstrated 3.6- to 11.8-fold increased risks of cardiac dysfunction.11 Obesity and metabolic syndrome are other modifiable risk factors recognized by the ACCF/AHA as important risk factors for HF and should also be considered in patients treated with an anthracycline or anti-HER2 targeted agent.3 Cancer therapy–related risk factors include exposure to anthracycline and anti-HER2 targeted agents and prior exposure to radiation therapy in which the heart was in the treatment field.11 Specifically, the coadministration of doxorubicin and trastuzumab is not recommended because rates of cardiac dysfunction have been reported to be as high as 27% when doxorubicin and trastuzumab are given with cyclophosphamide.15 It is recommended that patients with underlying cardiovascular risk factors be carefully evaluated prior to oncology treatment to ensure that the benefit outweighs the harm of therapy. Cancer patient populations at greatest risk include females with breast cancer because anthracyclines are commonly used for most breast cancer patients, and they are used in conjunction with trastuzumab if a patient has HER2-positive disease.

Anthracyclines

The association between anthracycline exposure and risk of LVEF decline is well established and is hypothesized to occur as a result of their interaction with topoisomerase 2β in cardiomyocytes, leading to three hallmarks of anthracycline-induced cardiotoxicity: apoptosis of myocytes, generation of reactive oxygen species, and mitochondriopathy.2 Anthracycline-induced HF is related to cumulative drug exposure; may be irreversible; and may occur during therapy  or months to years after discontinuation of therapy.5 The American Society of Clinical Oncology recognizes high-dose anthracycline therapy—defined as doxorubicin in doses of 250 mg/m2 or greater or epirubicin in doses of 600 mg/m2 or greater—as placing recipients at increased risk for cardiac dysfunction, with the risk for delayed cardiotoxicity estimated to range from 1% to 2% at cumulative lifetime doses of doxorubicin 300 mg/m2, 3%–5% at 400 mg/m2, 5%–8% at 450 mg/m2, and 6%–20% at 500 mg/m2.5,11 However, subclinical cardiac events have occurred in patients who have received cumulative doses of doxorubicin 240 mg/m2, which highlights the individual susceptibility to anthracyclines as well as the importance of regular ECHO monitoring during and after therapy.16 Although no standardized conversion table exists, oncology cooperative groups have investigated anthracycline toxicity equivalence ratios to quantify cumulative doxorubicin lifetime doses and stratify patients who have received multiple anthracyclines based upon risk for HF, which is intended to guide future treatment strategies.17

Nonspecific recommendations for LVEF monitoring exist for anthracyclines, with increased frequency of assessments suggested for cumulative doxorubicin doses over 300 mg/m2. Any clinical sign or symptom of HF warrants discontinuation of anthracycline therapy.5

Anti-HER2 Targeted Agents

Although the mechanism of cardiotoxicity is not fully elucidated, HER2 is a protein expressed on the surface of cardiomyocytes and is essential for their survival.2 Trastuzumab is recognized to be the most cardiotoxic of the four U.S. Food and Drug Administration (FDA)-approved anti-HER2 targeted agents (the others are pertuzumab, ado-trastuzumab emtansine, and lapatinib); however, all have package-label warnings for cardiotoxicity.6-9 Unlike the anthracyclines, LVEF decline with anti-HER2 targeted agents is not dose related and is normally reversible with termination, with improvements observed in LVEF within 4–6 weeks of discontinuation.6,18

Specific intervals of LVEF monitoring are recommended for trastuzumab: every 3 months during therapy, at 4-week intervals if the drug is withheld for significant cardiac dysfunction, and every 6 months for at least 2 years following completion of therapy. An absolute decrease in LVEF of 16% or more from baseline or LVEF below institutional limits of normal and a 10% or higher absolute decrease in LVEF from baseline is an indication for withholding trastuzumab.6 It is safe to readminister anti-HER2 targeted agents after withholding them for LVEF decreases after heart function has recovered.

Guidance provided for trastuzumab requires that the LVEF return to within normal limits within 4–8 weeks of withdrawal, with an absolute decrease from baseline of 15% or less.6,18 Trastuzumab should be permanently discontinued for LVEF decline that does not recover within 8 weeks or when trastuzumab has been discontinued because of cardiomyopathy on more than three occasions.6

The use of combination HER2 blockade with trastuzumab and pertuzumab has become routine in treating HER2-positive breast cancer without demonstrating an increased risk of cardiotoxicity.19,20 LVEF should be monitored every 12 weeks for patients receiving pertuzumab in combination with trastuzumab. Recommendations for withholding and resuming pertuzumab and trastuzumab therapy are stratified by the metastatic or early breast cancer treatment setting and take into account absolute LVEF values as well as LVEF percent decline, allowing lower LVEF measurements in the metastatic setting. Pertuzumab should be discontinued if trastuzumab therapy is terminated. It is important to note that any delays in treatment secondary to withholding for cardiotoxicity require that patients receive a repeat loading dose of pertuzumab if the time between two sequential infusions is 6 weeks or more and of trastuzumab if the dose has been held for longer than 1 week.6,8 However, when the pharmacokinetics of trastuzumab are taken into account, a repeat loading dose may be necessary only after a dose delay of more than 6 weeks.21

Other Chemotherapeutic Agents

Although more robust literature exists on anthracyclines and anti-HER2 targeted agents, other chemotherapeutic agents, including carfilzomib, high-dose cyclophosphamide, and vascular endothelial growth factor (VEGF) inhibitors, are also associated with cardiomyopathy. Carfilzomib is the only proteasome inhibitor with reported cardiac failure events, including LVEF decline and congestive HF, which occurred in 7% of patients.22 High-dose cyclophosphamide was associated with congestive HF in 28% of patients treated with doses of 180 mg/kg over 4 days within 3 weeks of administration.23 Although this is a higher administered dose than may be observed in clinical practice in adults, cyclophosphamide package labeling lists cardiotoxicity, including HF, as a warning, with risk factors including high doses, advanced age, and prior radiation when the heart was in the treatment field.24 Mechanisms of VEGF inhibitor–induced cardiomyopathy include uncontrolled hypertension, which is associated with cardiovascular disease, and impairment of cardiomyocyte survival and proliferation.2,25

LVEF decline occurred in 4.1% of patients treated with sunitinib, and development of HF has been reported in 2%–4% of patients treated with bevacizumab.26-28 VEGF inhibitors have been associated with hypertension in 30%–80% of patients treated with these agents, and blood pressure control may play an important role in mitigating the risk of secondary HF.28 As with anthracyclines and anti-HER2 targeted agents, symptomatic HF warrants immediate discontinuation of therapy.

Prevention and Management

Angiotensin-Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor Blockers (ARBs), and Beta Blockers
ACE inhibitors, ARBs, and beta blockers improve morbidity and mortality rates and are mainstays of traditional HF management.3 Primary prevention strategies using these agents against anthracycline- and trastuzumab-induced cardiotoxicity are ongoing areas of research. Enalapril initiated 1 month after chemotherapy and continuing for 1 year following initiation of anthracycline-containing chemotherapy regimens demonstrated benefit in preserving LVEF in patients with troponin I elevation after chemotherapy.29 Evidence on the use of candesartan in the prophylactic setting has been conflicting. Compared to metoprolol and placebo, candesartan demonstrated a benefit in LVEF preservation in females receiving adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, although no benefit was observed in protecting LVEF in a second study in a similar patient population.30,31

Prophylactic use of beta blockers has also yielded conflicting evidence in protecting LV function. A small study in patients who received an anthracycline and carvedilol for 6 months demonstrated that patients were able to maintain preserved LVEF.32 Similarly, patients with hematologic malignancies who received both enalapril and carvedilol at the start of chemotherapy and continued for 6 months maintained preserved LVEF.33 However, in the largest randomized prospective study to date, treatment-naive breast cancer patients receiving an anthracycline, cyclophosphamide, and a taxane were randomized to receive incremental 3-week dosing of carvedilol or placebo as tolerated until completion of chemotherapy. Carvedilol had no impact on the primary endpoint, an early-onset reduction in LVEF of at least 10% at 6 months.34

The current literature highlights a need for further studies to investigate the use of agents known to improve mortality rates in traditional HF so that outcomes for managing cancer therapy–induced HF can be improved. Although both beta blockers and inhibitors of the renin-angiotensin-aldosterone system have demonstrated LVEF protection when initiated at multiple time points in relation to initiation of anthracycline- or trastuzumab-containing regimens, inconsistencies in cardiac benefit seen with these agents show the need to determine the optimal initiation time and duration of use. Further, possible adverse events such as dehydration or weakness secondary to chemotherapy also present a challenge to cancer patients and may limit the initiation of cardiac agents because of blood pressure intolerance. Any presentation of overt symptomatic and asymptomatic HF should be managed according to ACCF/AHA HF guidelines.

Other Prevention Strategies
Other preventive pharmacologic strategies are recommended to reduce the risk of cardiovascular complications prior to initiation of anthracycline therapy and during its administration.11 Dexrazoxane, an antidote for anthracycline extravasation, is also a cardioprotectant, acting as an intracellular chelating agent to disrupt iron-mediated oxygen free radical generation, a component of anthracycline-induced cardiomyopathy.35 When administered in a 10:1 ratio of dexrazoxane to doxorubicin or equivalents, dexrazoxane resulted in reduced rates of LVEF decline without compromising antitumor efficacy.36-39 The FDA-approved indication for dexrazoxane for the prevention of doxorubicin-induced cardiomyopathy specifies its use for patients who have received a cumulative doxorubicin dose of 300 mg/m2 and will continue anthracycline therapy.35 Limitations to routine use with anthracyclines outside this setting include package-label warnings for myelosuppression and secondary malignancies; however, clinical evidence has demonstrated that dexrazoxane is associated with reversible myelosuppression, and exposure is not associated with increased risks of secondary malignancies.35,40 Dexrazoxane has not been shown to affect survival when coadministered with anthracyclines.40 Guidelines for dexrazoxane use at lower cumulative anthracycline dosing thresholds may be institution specific.

Pegylated liposomal doxorubicin has demonstrated a lower risk of clinical cardiotoxicity compared to conventional anthracyclines without affecting efficacy outcomes, so it is another preventive strategy for mitigating the risk of cardiomyopathy in patients with advanced cancers requiring anthracyclines.41-43 Adjustment of the rate of anthracycline administration is another preventive strategy; administration of anthracycline via intravenous bolus has been associated with an increased risk of clinical cardiotoxicity, more than four times that seen with continuous infusion.42

The most conservative strategy is the avoidance of a potentially cardiotoxic agent in the patient’s cancer therapy; however, this decision should recognize the intent of therapy and the possibility that the antitumor efficacy of the alternative agent could compromise cancer-specific outcomes. Considering each individual patient’s clinical scenario is vital to ensure that strategies for preventing cardiotoxicity are selected for the patient populations at highest risk. High-risk patients include those receiving high-dose anthracyclines, recognized as doses equivalent to doxorubicin of 250 mg/m2 and greater.11

Conclusion

Management and prevention of cardiotoxicity induced by cancer therapies is an ongoing area of research aimed to balance cancer therapy efficacy with cardiovascular safety. Trastuzumab transformed the landscape of HER2-positive breast cancer treatment, and anthracyclines remain a backbone of hematologic and solid tumor chemotherapy regimens; however, their impact on long-term cancer outcomes can be limited by their cardiotoxicity profiles.44 LVEF monitoring via ECHO remains the mainstay method for assessing the cardiotoxicity of cancer therapies; however, ongoing research with serum biomarkers and myocardial strain may allow for earlier detection of subclinical HF and intervention to combat cardiotoxicity. Every patient receiving any cancer therapy with cardiotoxic potential must be approached individually, with particular focus on the intent of cancer therapy and pre-existing cardiac risk factors. Institutions fortunate to have providers specialized in cardio-oncology should consider referring high-risk patients early in the treatment course for assistance in cardiac management. All cardiovascular complications of oncology therapy have the potential to affect the efficacy of cancer treatment, reduce quality of life, and affect long-term survival. An integrated approach is therefore necessary to optimize long-term outcomes in this unique patient population.

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