Introduction

Since the first description of anthracycline-induced heart failure (HF) in the 1960s, a number of other cancer therapies have been linked to left ventricular (LV) dysfunction, including HER-2 antagonists, anti-angiogenic agents, proteasome inhibitors, and radiation therapy, alone or in combination. Multiple studies have shown that the cardiovascular (CV) effect of cancer regimens has a significant impact on the short- and long-term outcomes in patients with cancer, with CV events being the leading competing cause of morbidity and mortality with the underlying cancer.¹ In addition, LV dysfunction can lead to discontinuation or dose adjustments of the patient's life-saving cancer therapy during treatment itself, potentially contributing to reduced cancer survival. Thus, optimally managing cancer-therapy-induced LV dysfunction is essential in the short term to reduce discontinuation of cancer treatment and in the long term to improve patient quality of life and overall survival.

Over the last several years, many guidelines and position statements have been published to help guide the practitioner in the identification and treatment of LV dysfunction from cancer therapy, including those from the International Society of Geriatric Oncology in 2010,² European Society for Medical Oncology (ESMO) in 2012,³ the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) in 2014,⁴ the European Society of Cardiology in 2016,⁵ and the American Society of Clinical Oncology (ASCO) in 2017.⁶ Although not specific to cardiotoxicity, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of HF also provide a relevant overview to the treatment of HF from stage A (high risk but without structural heart disease) to stage D (refractory HF).⁷ The ACC/AHA has also endorsed the more specific ASCO guidelines for care of patients with cancer.

Taken together, the available guidelines do provide a helpful framework for the prevention and management of cancer-therapy-induced LV dysfunction. However, it is important to realize that the cancer-specific recommendations are not based on strong evidence, and guidelines for the management of LV dysfunction have been largely extrapolated from management of HF in the general population (i.e., non-cancer patients) in which the pathophysiology of the LV dysfunction may differ significantly. Clinicians should apply the available guidelines to their patients with an understanding of these limitations until further high-quality evidence can better inform our approach.

The two most complete and relevant guidelines for prevention, screening, and management of LV dysfunction in patients with cancer are those from ESMO and ASCO. Comparatively, the ESMO guidelines were generally more willing to make specific recommendations such as screening interval in an attempt to aid the practicing clinician, and the ASCO guidelines were more likely to refrain from making a specific recommendation without more direct supporting evidence. The two sets of guidelines were written 5 years apart, which may have influenced the different approaches taken by the guideline panels. Once LV dysfunction is present, the ACC/AHA general HF guidelines likely provide the most comprehensive and robust recommendations for management even though they are not specific to cardio-oncology.

In this article, we will review the major questions addressed by the guidelines (Table 1), touching on prevention, screening and early diagnosis, and management of asymptomatic LV dysfunction, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF). We will also highlight some important areas that need further research.

Table 1: Selection of Major Topics Addressed by the Guidelines for Management of LV Dysfunction

1. Identifying patients at elevated risk for cardiac dysfunction

2. Treatment of patients' CV risk factors to reduce their risk

3. Modifications in anthracycline and radiation delivery to reduce risk of LV dysfunction

4. Use of dexrazoxane to help prevent cardiotoxicity

5. Screening options during and after cancer treatment

6. Management of patients at risk for LV dysfunction (stage A HF)

7. Medical therapy for asymptomatic LV dysfunction, HFrEF, and HFpEF

Prevention

Major Points

• All patients should receive a baseline risk assessment with optimization of CV risk factors. Baseline risk assessment should include history, physical examination, and echocardiogram.
• All patients receiving cardiotoxic medications should be considered stage A HF.
• Specific cancer therapy regimens that place patients at notable long-term risk for cardiac dysfunction include the following:
  • High-dose anthracyclines (equivalent to ≥250 mg/m² of doxorubicin or ≥600 mg/m² of epirubicin)
  • Radiation with the heart in the treatment field at a dose of 30 Gray or more
  • A combination of anthracyclines and radiation even at lower dosages
  • A combination of anthracycline followed by trastuzumab
  • Low-dose anthracycline and other CV risk factors
  • Trastuzumab and other CV risk factors
• For patients at high risk for cardiotoxicity, continuous anthracycline infusion and the liposomal formulation of doxorubicin can be considered.
• Methods to reduce radiation field to the heart are recommended.
• Dexrazoxane is the only universally recommended medication for the prevention of LV dysfunction.
• Renin-angiotensin system inhibitors and beta-blockers may also be beneficial in high-risk patients.

Baseline Risk Assessment

The optimal management of any disease will always start with prevention, and LV dysfunction is no exception. It has been recommended across multiple cardio-oncology guidelines and position statements to identify patients at increased risk for LV dysfunction at initial cancer diagnosis by screening for traditional CV risk factors (hypertension, diabetes, dyslipidemia, obesity, and smoking) and treating them accordingly to minimize risk during cancer treatment.^3,6 Certainly, any patient undergoing potentially cardiotoxic therapy should be considered stage A HF. For these patients, the 2013 HF guidelines give Class I recommendations to controlling hypertension, lipid disorders, and other CV risk factors.⁷ In childhood cancer survivors, traditional CV risk factors, especially hypertension, have been shown to significantly compound the risk of cardiotoxicity from the patient's cancer therapy,⁸ highlighting the potential importance of identification and treatment.

Beyond the traditional CV risk factors, the guidelines highlight specific cancer therapy regimens that place patients at notable long-term risk for cardiac dysfunction, including high-dose anthracyclines (equivalent to ≥250 mg/m² of doxorubicin or ≥600 mg/m² of epirubicin), radiation with the heart in the treatment field at a dose of 30 Gray or more, a combination of anthracyclines and radiation even at lower dosages, and anthracyclines followed by trastuzumab.⁶ In addition, patients treated with low-dose anthracyclines or singe-agent trastuzumab were also considered at risk if they had other CV risk factors (including age over 60). The ASCO guidelines made no recommendation on the risk of cardiac dysfunction for kinase inhibitors or newer regimens due to lack of sufficient evidence available at the time in cancer survivors, but the treating clinician should be aware of the reported 10-15% incidence of LV dysfunction with anti-angiogenic kinase inhibitors. Contemporary evaluation of acute toxicity from other drug classes is beyond the scope of the available guidelines (e.g., specific kinase inhibitors, checkpoint inhibitors, and proteasome inhibitors).

In addition to a complete history and physical exam, echocardiography or equivalent, with or without global longitudinal strain, is also recommended for baseline assessment to screen for asymptomatic LV dysfunction or other structural abnormalities in patients before potential cardiotoxic cancer treatment.^3,6

Pharmacotherapy and Other Preventive Strategies

The 2017 focused update of the HF guidelines recommends treating hypertension in stage A HF to a goal of <130/80,⁹ consistent with the 2017 ACC/AHA guidelines for the management of high blood pressure.¹⁰ The HF guidelines do not recommend specific antihypertensive therapy for stage A HF, but they do highlight that diuretic-based antihypertensive therapy has been shown to prevent HF in a variety of patient cohorts.⁷ The HF guidelines also cite the potential benefit of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), and beta-blockers, including ACEI or ARB in patients with vascular disease or diabetes mellitus.⁷ The 2017 hypertension guidelines also do not give specific recommendations for antihypertensive treatment in stage A HF, although ACEI or ARB can be considered in patients with chronic kidney disease or diabetes mellitus with albuminuria.¹⁰

For patients undergoing cancer treatment, trials have been conducted to attempt to identify specific therapies that are best able to prevent incidence and severity of LV dysfunction in the setting of cardiotoxic therapy. Dexrazoxane is the only current medication uniformly endorsed by the ASCO and ESMO guidelines for cardio-protection, with the ASCO guidelines recommending its consideration for patients with planned high-dose anthracyclines (equivalent to ≥250 mg/m² of doxorubicin or ≥600 mg/m² of epirubicin),⁶ and the ESMO guidelines considering its use for all patients at high risk of cardiotoxicity without further specificity.³ With low level of evidence (Level III), the 2012 ESMO guidelines also recommend considering beta-blockers, ACEI, and ARB as potential cardioprotective regimens for high-risk patients as well.³ Determination of what constitutes high-risk is not specified and left to the treating clinician.

Trials of potential cardioprotective regimens have used different inclusion and exclusion criteria, with variability in the ability to prevent LV dysfunction or similar outcome. Many are limited by short follow-up, and all are likely underpowered. All trials were fewer than 210 patients. A full review of trials is beyond the scope of this document, but some of the larger trials are worth mentioning, many of which were conducted after the 2012 ESMO guidelines.

In the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial, candesartan, but not metoprolol, was found to help protect against decline in LV function in patients receiving anthracyclines with or without trastuzumab and radiation therapy.¹¹ A later study in 210 patients undergoing trastuzumab therapy, as opposed to anthracycline-based therapy, did not find a cardioprotective benefit in preventing LVEF decline with candesartan compared to placebo.¹² In the OVERCOME (Prevention of Left Ventricular Dysfunction With Enalapril and Carvedilol in Patients Submitted to Intensive Chemotherapy for the Treatment of Malignant Hemopathies) trial, patients receiving combined treatment with enalapril and carvedilol had preserved LV ejection fraction (EF) compared with controls in patients receiving intensive chemotherapy (82% received anthracyclines).¹³ In the MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) trial, perindopril and bisoprolol both helped protect against declines in LVEF during therapy with trastuzumab, though there was no difference in the primary outcome for prevention of LV remodeling (as measured by indexed LV volume).¹⁴ More recently, in CECCY (Carvedilol Effect in Preventing Chemotherapy - Induced Cardiotoxicity), a study of 192 patients undergoing anthracycline therapy for HER2-negative breast cancer, carvedilol did not protect against a drop in LVEF by greater than 10% (the primary outcome), though there was a decrease in troponin elevations and abnormal diastolic function.¹⁵

Taken together, these studies strongly suggest that, in certain patient groups, there may be benefit for cardioprotective medications, including enalapril, carvedilol, candesartan, and possibly perindopril and bisoprolol. Yet the degree of that benefit is unclear with the available studies and limited follow-up. Patients most likely to benefit in studies to date are patients receiving anthracycline-based treatment. There have not been trials for specific cardioprotective strategies done in newer cancer therapies such as inhibitors of the vascular endothelial growth factor signaling pathway.

Other recommended strategies to reduce risk of cardiotoxicity in patients with planned high-dose anthracyclines include using a continuous anthracycline infusion (as opposed to bolus dosing) as well as the liposomal formulation of doxorubicin.⁶ For patients with planned mediastinal radiation, techniques to reduce exposure to the heart including deep-inspiration breath-hold and intensity-modulated radiotherapy are recommended.⁶

Screening and Early Diagnosis

Major Points

• Consider use of echocardiography (or magnetic resonance imaging), global longitudinal strain, and biomarkers for surveillance for asymptomatic LV dysfunction.^3,4,6,9
• There is no clear recommended screening interval.
• Diagnosis of asymptomatic LV dysfunction has been variably described:
  • Classifications of asymptomatic LV dysfunction in trastuzumab clinical trials have included a drop in LVEF by more than 10 percentage points to less than 55%¹⁶ or to below the lower limit of normal, as well as any drop of ≥15 percentage points.¹⁷
  • Cancer Treatment Related Cardiac Dysfunction was defined in the 2014 imaging expert consensus statement as a drop of LVEF of 10% or more to a level <53%.⁴
• Subclinical LV dysfunction has also been defined as a relative drop in the absolute global longitudinal strain of more than 15%.⁴

Imaging

The 2012 ESMO guidelines provide the most specific guidelines for screening for early detection of asymptomatic LV dysfunction, recommending serial monitoring with echocardiogram of patients receiving anthracyclines and/or trastuzumab at baseline and at 3, 6, 9, 12, and 18 months. Other patients with metastatic disease were recommended to have a baseline assessment and infrequent monitoring thereafter. ASCO, on the other hand, simply recommended that clinicians may use echocardiogram for monitoring of patients deemed at increased risk, including those receiving trastuzumab, at unspecified intervals during cancer treatment and at 6 and 12 months post-treatment.⁶ ASCO does recommend appropriate work-up of anyone with signs or symptoms of cardiac dysfunction with consideration for imaging, biomarkers, and referral to a cardiologist. The general HF guidelines generally endorse screening with echocardiography in patients receiving cardiotoxic medications without specific recommendations.⁷ Unfortunately, there are no high-quality studies to help determine the optimal screening interval for imaging of patients receiving cardiotoxic medications.

Global Longitudinal Strain

When performing an echocardiogram, the use of global longitudinal strain to help detect subclinical LV dysfunction is endorsed by the 2014 expert consensus for multimodality imaging by the ASE and EACVI as well as the ASCO guidelines.^4,6 Subclinical LV dysfunction is defined by a relative decrease in the absolute value of strain by more than 15% in those not meeting criteria for Cancer Treatment Related Cardiac Dysfunction (LVEF drop by 10% or more to <53%).⁴ The use of strain can also be used to help subclinical LV dysfunction at baseline prior to cancer treatment.⁴

Biomarkers

ESMO recommends consideration for measurement of biomarkers at baseline and as often as every cycle for early detection of LV dysfunction with treatment involving cardiotoxic medications.³ The ASCO guidelines only specifically recommend use of biomarkers as part of the work-up for patients with clinical signs or symptoms of CV disease.⁶ The most recent guidelines, the 2017 HF focused update, includes a Class IIa recommendation that it is reasonable to check biomarkers in screening of patients who are asymptomatic but at risk (stage A HF) based on the STOP-HF (St. Vincent's Screening To Prevent Heart Failure Study) and PONTIAC (Nt-proBNP Guided Primary Prevention of CV Events in Diabetic Patients) trials in patients with CV risk factors and diabetes, respectively.^9,18,19 No screening interval is specified.

The successful use of biomarkers as a screening test in patients undergoing high-dose chemotherapy was best illustrated by a randomized-controlled study (n = 114) by Cardinale et al.²⁰ Treatment with enalapril (versus no treatment) was able to prevent development of LV dysfunction in patients with positive troponins discovered on screening. The study was a single center and limited by lack of placebo administration.

Management of LV Dysfunction

Major Points

• There is no recommendation on the appropriateness to continue or hold cancer therapy if LV dysfunction is diagnosed.
• Nondihydropyridine calcium channel blockers should be avoided in patients with systolic dysfunction.
• All patients should have their blood pressure effectively controlled and other risk factors optimized.
• Patients with stage B HF (asymptomatic LV dysfunction) should be treated with renin-angiotensin system inhibitors and beta-blockers. Statins should be used in patients after myocardial infarction.
• ACEI or ARB or angiotensin receptor-neprilysin inhibitor in conjunction with evidence-based beta-blockers, and aldosterone antagonists in selected patients, should be used in patients with stage C HFrEF.
• Ivabradine can be beneficial to patients with New York Heart Association (NYHA) Class II-III stage C HFrEF on maximum-dose beta-blockers in normal sinus rhythm with heart rate >70.
• In African Americans with NYHA Class III-IV on optimal guideline-directed medical therapy, the combination of hydralazine and isosorbide is also recommended.
• In patients with HFpEF, spironolactone may be considered to decrease hospitalization.

Once LV dysfunction develops, the most relevant treatment guidelines remain the general ACC/AHA HF guidelines published in 2013, with a focused update published in 2016 and then revised in 2017.^7,9 There are no specific trials or evidence to warrant a significant change in approach for patients undergoing cancer treatment. Management of patients with cancer and HF, though, may often be hindered by relative hypotension during cancer treatment reducing tolerance of guideline-directed medical therapy.

Continuation of Cancer Therapy

The ASCO guidelines make sure to mention that they could not make a recommendation regarding the continuation or discontinuation of cancer therapy in patients with evidence of cardiac dysfunction.⁶ It is important to be aware that there is currently no compelling evidence to determine the optimal selection of patients who can continue cancer therapy despite LV dysfunction. Recent observational evidence suggests that patients can safely be continued on treatment with trastuzumab despite some evidence of asymptomatic LV dysfunction,²¹ though not necessarily symptomatic HFrEF. The current evidence is limited by its retrospective nature and cannot be extrapolated to other forms of cancer therapy such as anthracyclines. In general, it seems counterproductive to always permanently discontinue cancer therapy when cardiotoxicity is encountered; rather, optimal treatment for HF should be the rule. Any decision to discontinue cancer therapy should be multidisciplinary and weigh the benefits and risks of the current treatment plan as well as alternative regimens. Other causes of the LV dysfunction, including ischemia, need to be considered.

Asymptomatic LV Dysfunction

For patients with asymptomatic, stage B HF with any reduction in LVEF or evidence of LV remodeling, the 2013 HF guidelines give a Class I recommendation to the use of ACEI (strong Level A evidence) and beta-blockers (weak Level C evidence).⁷ In addition, statins should be used post-myocardial infarction, implantable cardioverter-defibrillators should be considered in patients with ischemic cardiomyopathy and LVEF of <30%, and calcium channel blockers should be avoided due to negative inotropic effects. In addition, all recommendations for stage A HF carry over, including optimal management of patient risk factors. The HF guidelines also reference the stable ischemic heart disease/percutaneous coronary intervention/acute coronary syndromes/valvular heart disease guidelines for consideration of revascularization or valve repair/replacement in appropriate patients. There were no additional recommendations for stage B HF in the 2017 focused update.

Stage C HF

Stage C, or symptomatic HF, encompasses all ranges of LVEF including those with HFrEF (LVEF ≤40%), HFpEF (LVEF ≥50%), and an intermediate group consisting of patients with a mid-range or borderline LVEF of 41-49% (HFmrEF).

HFrEF (LVEF ≤40%)

The most robust and extensive guidelines focus on patients with symptomatic reduction in LV systolic function with an LVEF ≤40% (HFrEF). ACEI or ARB or angiotensin receptor-neprilysin inhibitor should be used in conjunction with evidence-based beta-blockers in all patients, as well as aldosterone antagonists in selected patients (LVEF ≤35%, NYHA Class II-IV, K < 5.0 meq/dL, estimated glomerular filtration rate >30 mL/min/1.73 m²). Ivabradine may also be helpful in patients on maximum dose beta-blockers in normal sinus rhythm with heart rate greater than 70. In African Americans with NYHA Class III-IV on optimal guideline directed medical therapy, the combination of hydralazine and isosorbide is also recommended (see the 2013 guidelines and 2017 focused update for full recommendations^7,9).

HFpEF (LVEF ≥50%)

Over the years, many previous clinical trials had failed to identify any specific treatment for HFpEF, likely due to a wide variation in etiology of HF among patients with vastly different phenotypes. The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial more recently found benefit of spironolactone in preventing HF hospitalization,²² which was subsequently endorsed by the guidelines.⁹ There was a potential signal of improved mortality as well in certain patient groups within the trial (e.g., those with elevated B-type natriuretic peptide and those enrolled in Western countries).

Additionally, the guidelines recommend use of diuretics to reduce symptoms of volume overload, consideration of coronary revascularization for those with contribution of myocardial ischemia, and appropriate guideline management of atrial fibrillation. ACEI, ARB, and beta-blockers can be used to help control hypertension, and ARB might be considered for decrease in hospitalization. Nitrates should not be routinely used to help with symptoms due to lack of benefit.⁹

HFmrEF (LVEF 41-49%)

Patients with HFmrEF in the general population are felt to have a more similar course and prognosis to HFpEF than to HFrEF, though this principle does not likely apply to patients undergoing cancer treatment. Within cardio-oncology, these patients are more typically treated as patients with HFrEF due to the concern for continuing decline in LVEF due to ongoing and latent cardiotoxic effects of their cancer regimen. Certainly, medications such as anthracyclines and radiation therapy have been shown to have an increased risk of CV effects long after the end of cancer treatment, and so ongoing decline in LVEF is certainly a reasonable concern. Unfortunately, there are no good trials, and thus no guideline recommendations, for this patient population. In the absence of specific trials, it is reasonable to extrapolate the evidence from prevention and other HF trials and treat these patients with ACEI (or ARB) and evidence-based beta-blockers with consideration for use of aldosterone antagonists. As noted, nonrandomized data suggest that a strategy of ACEI and beta-blockers in patients with LVEF <45% (mean LVEF 41%) is associated with improvement of LVEF,²³ though this population included patients with HFrEF as well.

Path Forward

Areas for Continued Research

1. Optimal cardioprotective regimens, including specific medications and patient selection, to prevent HF in patients undergoing cancer therapy.
2. Optimal screening interval for patients undergoing cancer treatment.
3. Identifying patients with LV dysfunction who can continue their cancer therapy.
4. Treatment of patients with HFmrEF.

Although the guidelines do provide a useful framework for the prevention and management of LV dysfunction in patients with cancer, there are certainly areas that need continued study, and there will continue to be areas of development as new targeted cancer therapies become available clinically with undetermined short- and long-term cardiac effects. The available data do help guide the recognition of patients at increased risk of cardiotoxicity, but additional research is needed to continue to identify patient groups that will benefit from cardioprotective regimens during their cancer treatment. There are also no guidelines to direct which patients should or should not continue their cancer treatment, although the nature of the disease and treatment limit the ability to construct robust trials in this space. Until further trials can be done on patients with HFmrEF (41-49%), clinicians will have to extrapolate treatment from other patient groups such as those with HFrEF.

References

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13. 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.
14. Pituskin E, Mackey JR, Koshman S, et al. Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity. J Clin Oncol 2017;35:870-7.
15. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, et al. Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: The CECCY Trial. J Am Coll Cardiol 2018;71:2281-90.
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18. Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA 2013;310:66-74.
19. Huelsmann M, Neuhold S, Resl M, et al. PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial. J Am Coll Cardiol 2013;62:1365-72.
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Keywords: Adrenergic beta-Antagonists, Albuminuria, American Heart Association, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Anthracyclines, Antihypertensive Agents, Benzimidazoles, Bisoprolol, Breast Neoplasms, Carbazoles, Cardiotoxicity, Cardiotoxins, Dexrazoxane, Diabetes Mellitus, Diuretics, Dyslipidemias, Early Diagnosis, Echocardiography, Enalapril, Epirubicin, Factor VII, Follow-Up Studies, Heart Failure, Hypertension, Lipids, Medical Oncology, Metoprolol, Obesity, Perindopril, Physical Examination, Propanolamines, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Quality of Life, Renal Insufficiency, Chronic, Renin-Angiotensin System, Risk Assessment, Risk Factors, Smoking, Stroke Volume, Tetrazoles, Troponin, Vascular Endothelial Growth Factor A, Ventricular Dysfunction, Left

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