Introduction

Cardiac dysfunction is a known consequence of multiple cancer therapies and can have a significant impact on patient quality of life, morbidity, and mortality. As has been shown with studies on anthracyclines and radiation therapy, cancer survivors can remain at increased risk for heart disease years after treatment,^1-4 and subsequent cardiovascular (CV) events are the leading cause of morbidity and mortality behind recurrent cancer in these patients.⁵ With an increasing number of cancer survivors, 15.5 million as of January 2016,⁶ there is naturally an increased focus on reducing their heart disease burden and improving their long-term outcomes.

To this end, the American Society of Oncology (ASCO) convened a systematic review of the literature and multidisciplinary expert panel to synthesize the available data and create a set of guidelines for the "Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers."⁷ Endorsed by the American College of Cardiology and American Heart Association, the guidelines include recommendations beginning with identifying those patients with cancer who are at increased risk and extending through surveillance after completion of cancer therapy. The evidentiary basis for the guidelines drew from a total of 8 systematic reviews, 12 randomized controlled trials, 49 cohort studies, 32 before-and-after studies, and 3 cross-sectional studies, all published between 1999 and 2016. When appropriate, expert recommendations supplemented the available evidence if there was consensus with >80% of the panelists.

The ASCO guidelines provide practical, evidence-based recommendations for the active clinician with the overarching goal of reducing the burden of cardiac dysfunction in cancer survivors. Relative to the earlier guidelines by the European Society for Medical Oncology in 2012,⁸ the treating clinician may recognize a more limited scope of recommendations by the ASCO panel. In general, the ASCO panel was more likely to adhere to the current state of the literature and withhold recommendations if specific supporting evidence was lacking. The ASCO guidelines are also focused on cancer survivors primarily, with recommendations focused on prevention and screening only in as much as they are known to affect outcomes in survivors. Management of acute cardiac toxicity during cancer treatment was considered outside the scope of the guidelines.

We review the ASCO guidelines and concurrently use actual patient encounters to highlight the practical integration of these recommendations. Figure 1, taken from the guideline document, gives an overview of how the recommendations align with the timeline for optimal treatment of a patient with cancer.

Figure 1: Overarching Clinical Questions Addressed in the 2016 ASCO Clinical Practice Guideline⁷

Recommendations Prior to Initiation of Cancer Treatment

• Which patients with cancer are at increased risk for developing cardiac dysfunction? (Recommendation 1). This recommendation should be reassessed throughout the patient's care.
• Which preventative strategies minimize risk before initiation of therapy? (Recommendation 2)

Key Points

• All patients with cancer should receive a baseline risk assessment, including a comprehensive history and physical examination, with optimization of identified CV risk factors.
• An assessment of left ventricular (LV) function, most commonly done by transthoracic echocardiography (TTE), should be done prior to potentially cardiotoxic therapy.
• 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
• Avoid or minimize the use of potentially cardiotoxic therapies if established alternatives exist with comparable cancer-specific outcomes.

Case 1

A 62-year-old male smoker is diagnosed with adenocarcinoma of the lung with metastasis to the brain. He has a history of head and neck cancer diagnosed 5 years ago (squamous cell cancer of the tonsils) that was surgically resected and irradiated. He undergoes a frontal lobe resection of his brain metastasis and radiation with a gamma knife procedure and is then started on pembrolizumab. Two months after starting checkpoint-inhibitor therapy, he is noted to have an LV apical aneurysm and large LV thrombus on computed tomography (CT) surveillance of his cancer. On subsequent TTE, his LV ejection fraction (LVEF) is noted to be 35%. He endorses no symptoms other than an episode of chest pain approximately 2 months prior, 5 days after his first dose of pembrolizumab. On cardiac catheterization, he has severe 3-vessel coronary artery disease and undergoes percutaneous coronary intervention of his right coronary artery, first obtuse marginal artery, and left circumflex artery with multiple drug-eluting stents. His left anterior descending artery was also completely occluded in his mid-segment. Review of his positron emission tomography/CT scan that was performed before initiation of cancer treatment revealed extensive aortic, carotid, and coronary atherosclerosis. He had not seen cardiology at any point and was on no cardiac medications until he was admitted for evaluation of his LV aneurysm and LV thrombus, 2 months after initiation of his cancer therapy.

Case 1 represents a missed opportunity to identify and treat important baseline risk factors at time of cancer diagnosis. The patient's age, hyperlipidemia, and smoking status placed the patient at high CV risk, and the PET/CT further confirmed that he already had extensive atherosclerotic disease at time of diagnosis. At a minimum, he would have certainly met guideline indications for being placed on a statin and aspirin to help reduce his risk of myocardial infarction.

In accordance with multiple other cardio-oncology guideline and position statements, the ASCO expert panel recommends identifying 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.⁷ In survivors of childhood cancer and anthracycline-based chemotherapy or radiation, traditional CV risk factors have been shown to significantly increase a patient's risk for coronary artery disease, valvular disease, and heart failure (HF).⁹ In patients on anthracycline therapy, hypertension, for example, conferred a relative risk of 12.4 (95% confidence interval, 7.6-20.1; p < 0.001) for development of HF on top of the risk already associated with the cancer therapy itself. Optimization of these risk factors, therefore, offers a potential therapeutic target to reducing late CV outcomes in survivors.

In addition to a complete history and physical exam, it is also recommended to perform a baseline assessment of LV function, with TTE or equivalent, in patients before potentially cardiotoxic cancer therapy.

The guidelines highlight specific cancer-therapy regimens that place patients at notable long-term risk for cardiac dysfunction, listed above under "Key Points." These regimens include anthracycline, radiation, and trastuzumab. Although these are the regimens with the most data and highest level of evidence linking them to cardiac dysfunction, research into newer regimens is ongoing, and the treating clinician should stay abreast of the current state of the literature given the rapid expansion of available cancer therapies. To that end, it is worth noting that anti-angiogenic kinase inhibitors are currently associated with a 10-15% risk of LV dysfunction, and the rate of HF associated with carfilzomib-based therapy (an irreversible proteasome inhibitor) for multiple myeloma exceeds 10% in several studies.

Recommendations During Cancer Treatment

• What strategies minimize risk during potentially cardiotoxic therapy? (Recommendation 3)
• What are the preferred surveillance/monitoring approaches during treatment in patients at risk for cardiac dysfunction? (Recommendation 4)

Key Points

Minimize Risk

• CV risk factors should continue to be managed and optimized during treatment with potentially cardiotoxic therapy.
• Methods to reduce radiation field to the heart are recommended.
• For patients at high risk for cardiotoxicity, the treating team should also consider these modifications to reduce the risk of treatment-related cardiac dysfunction:
  • Continuous anthracycline infusion (versus bolus dosing)
  • Liposomal formulation of doxorubicin
• Dexrazoxane is the only recommended medication for the prevention of LV dysfunction in the ASCO guidelines.

Surveillance/Monitoring

• Patients should be assessed during treatment with careful history and physical.
• For patients with signs and symptoms of cardiac dysfunction, TTE (or magnetic resonance imaging [MRI]), biomarkers or TTE-derived global longitudinal strain (GLS) imaging, and referral to cardiology based on findings are recommended.
• Routine surveillance with serial cardiac biomarkers and/or imaging in asymptomatic patients at increased risk may be offered, though there is no recommended surveillance interval.
• No absolute recommendations exist on the continuation or discontinuation of cancer therapy in patients with evidence of cardiac dysfunction.

Case 2

A 41-year-old woman with history of coronary vasospasm now asymptomatic on diltiazem is diagnosed with stage IIB, T2N1 invasive ductal carcinoma (ER+, PR+, HER-2+). She is started on paclitaxel, carboplatin, trastuzumab, and pertuzumab, though pertuzumab is stopped after cycle 1 for nausea and vomiting. She undergoes screening TTE after cycle 5 of treatment and is noted to have an LVEF of 50% (normal is ≥54%; her baseline LVEF was 67%) as well as a GLS of -17.1% (normal is ≤-19%; her TTE-derived baseline GLS was -21.6%). Trastuzumab is initially held for 4 weeks, and the patient is referred to cardiology coinciding with a repeat TTE 1 month later (LVEF = 54%, GLS = -18.5%). During the initial visit with cardio-oncology, the negative inotropic drug diltiazem is stopped, and carvedilol is started in the setting of sinus tachycardia on her evaluation. She is subsequently restarted on her trastuzumab therapy. A TTE 2 months later demonstrates an improved LVEF of 60% and a normalized GLS of -20.1%.

Case 2 highlights important clinical considerations during treatment for cancer. The woman in the case is diagnosed with LV dysfunction per the 2014 expert imaging consensus¹⁰ as well as the packaging guidelines for trastuzumab.¹¹ Close monitoring for LV dysfunction and subsequent treatment if it occurs have been associated with improved CV outcomes in anthracycline-based chemotherapy.¹² A separate study found that patients with elevated troponin during anthracycline exposure also benefited from treatment with enalapril and carvedilol.¹³ These studies lend support to the idea that screening with biomarkers and/or imaging and early identification of cardiotoxicity can potentially lead to improved outcomes. However, the optimal screening interval and protocol (biomarkers, imaging, etc.) and any recommendations for titration of medical therapy remain unknown.

The ASCO guidelines also highlight that no recommendation can be made regarding alterations on cancer treatment based on screening results. Any decision that is made should certainly be a multidisciplinary one that weighs both the benefits and risks of a cancer treatment regimen. The dual goal should be to first minimize interruptions in cancer therapy while also reducing the potential for long-term cardiac morbidity and mortality.

Trastuzumab provides a good case study to evaluate the impact that screening may have on cancer treatment, whether appropriate or inappropriate. After FDA approval, the prescribing guidelines in the package insert adopted the screening protocol from the original trials along with dosing considerations to holding trastuzumab for a drop in LVEF greater than 16% from baseline or greater than 10% to below the institutional limit of normal. Importantly, though, more recent retrospective analyses have shown that patients who meet the definition of trastuzumab-mediated LV dysfunction but whose LVEF remains greater than or equal to 50% can be continued on trastuzumab without significant, long-term cardiac effects.¹⁴ Patients with overt clinical HF likely do require at least temporary cessation of cancer treatment, but, again, this decision should be made in a multidisciplinary fashion.

Continuation of trastuzumab therapy may also be aided by the addition of "cardio-protective" medications, as in Case 2. The ASCO guidelines did not highlight any particular regimen for these patients, though the treating clinician can also use the 2013 HF guidelines as a reference. They advocate the use of renin-angiotensin system (RAS) inhibitors and selected beta-blockers in patients with asymptomatic LV dysfunction (stage B).¹⁵

Recommendations After Cancer Treatment

• What are the preferred surveillance and monitoring approaches after treatment in patients at risk for cardiac dysfunction? (Recommendation 5)

Key Points

• Survivors of cancers treated with potentially cardiotoxic therapy should receive a careful history and physical examination.
• CV risk factors should be regularly evaluated and managed in cancer survivors treated with cardiotoxic therapies.
• TTE may be performed between 6 and 12 months after cancer therapy in patients at increased risk. MRI can be used if TTE is not available or feasible.
• Patients with asymptomatic LV dysfunction on screening should be referred to a cardiologist/cardio-oncologist.
• There is no recommended further screening interval for asymptomatic patients without evidence of LV dysfunction on their 6-12 month post-cancer therapy evaluation.
• Individuals with signs and symptoms of cardiac dysfunction should be offered a TTE (MRI if not available or feasible) and serum cardiac biomarker evaluation.

Case 3

A 32-year-old woman with hypertension and previous acute myelogenous leukemia is status post-anthracycline-based chemotherapy (unknown total dose) and a matched unrelated donor transplant 8 years prior complicated by evidence of graft versus host disease in her skin and eyes. She presents to cardiology for evaluation and management of her hypertension. She does not endorse any chest pain, orthopnea, paroxysmal nocturnal dyspnea, or edema. She does report that she fatigues more easily than she used to with a little dyspnea on exertion. Recent blood pressures have been over 150/90 mmHg on 2 occasions, although her blood pressure is 117/82 mmHg on 25 mg of metoprolol at the time of cardiology evaluation. Her exam is significant only for a soft S4. Her N-terminal pro-B-type natriuretic peptide (NT-proBNP) is 934, low-density lipoprotein is 153, and high-density lipoprotein is 58. She is started on a statin as well as RAS inhibition with lisinopril. Cardiac MRI done 2 months later shows an LVEF of 57%. Repeat NT-proBNP at that time is 68.

Cancer survivors are at significantly increased risk of CV morbidity over their lifetimes, which has been best studied in childhood survivors of cancer therapy with radiation and/or anthracyclines.⁹ Although the ASCO guidelines recommend screening at 6-12 months, the most appropriate screening protocol after that remains unknown. The use of both TTE and biomarkers has been suggested by experts.

In Case 3, this patient had new onset fatigue with some dyspnea on exertion and was found to have a significantly elevated NT-proBNP. Treatment with RAS inhibition was associated with a decrease in NT-proBNP, and the patient improved clinically. Cardiac MRI done 2 months later did show a normal LVEF. One can postulate whether an LVEF assessment or GLS measurement done at the time of the elevated NT-proBNP would have shown a reduction that subsequently recovered with treatment, but that is conjecture. It is fairly well-accepted that earlier detection improves outcomes, but how and when to screen remains unclear. The treating clinician should, at a minimum, remain vigilant and understand that cancer survivors, certainly patients with exposure to anthracyclines and/or radiation, will remain at significantly elevated CV risk over their lifetimes.

Beyond the Guidelines: Prevention of LV Dysfunction

An important, ongoing area of research is the appropriate selection of high-risk patients who might benefit from cardio-protective medications to prevent subsequent LV dysfunction. Other than dexrazoxane, which is the only FDA-approved medication for this indication, the ASCO guidelines do not advocate any particular pharmaceutical regimen due to insufficient evidence.

Trials of potential cardio-protectant medications have been conducted before and after the ASCO guidelines that strongly suggest overall that certain patient groups may benefit from medications, including RAS inhibition and specific, clinically-proven beta-blockers, to help prevent the onset of LV dysfunction during treatment with high-risk cancer therapies. Given small study sizes as well as varying inclusion and exclusion criteria, however, it is not currently possible to make data-driven recommendations for specific patients. However, the astute clinician should consider using these medications in patients at high risk or patients who already need to be treated for high blood pressure or hyperlipidemia. These patients should be considered as stage A HF (at risk).¹⁵

Summary

The ASCO guidelines provide reasonable, evidence-based guidelines to aid in the management of patients undergoing cancer therapy as well as survivors of cancer therapy. The expert panel appropriately refrained from making recommendations where more evidence was needed. Further studies are anticipated to help fill in the gaps in clinical evidence.

References

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13. 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.
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Keywords: Adenocarcinoma, Adrenergic beta-Antagonists, Anthracyclines, Aneurysm, Antibodies, Monoclonal, Humanized, Aspirin, Biomarkers, Pharmacological, Blood Pressure, Brain, Carbazoles, Carboplatin, Carcinoma, Ductal, Cardiac Catheterization, Cardiotoxicity, Chest Pain, Cohort Studies, Confidence Intervals, Coronary Artery Disease, Coronary Vasospasm, Cross-Sectional Studies, Dexrazoxane, Diabetes Mellitus, Diltiazem, Doxorubicin, Drug-Eluting Stents, Dyslipidemias, Echocardiography, Dyspnea, Edema, Enalapril, Epirubicin, Epithelial Cells, Frontal Lobe, Graft vs Host Disease, Heart Failure, Hypertension, Hyperlipidemias, Leukemia, Myeloid, Acute, Lipoproteins, HDL, Lipoproteins, LDL, Lisinopril, Magnetic Resonance Imaging, Medical Oncology, Metoprolol, Multiple Myeloma, Myocardial Infarction, Natriuretic Peptide, Brain, Nausea, Obesity, Oligopeptides, Paclitaxel, Peptide Fragments, Percutaneous Coronary Intervention, Physical Examination, Physical Exertion, Positron-Emission Tomography, Product Labeling, Propanolamines, Proteasome Inhibitors, Quality of Life, Referral and Consultation, Renin-Angiotensin System, Retrospective Studies, Risk Assessment, Risk Factors, Smoking, Smoking Cessation, Stroke Volume, Tachycardia, Sinus, Thrombosis, Tonsillar Neoplasms, Troponin, Unrelated Donors, Vomiting

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