For left ventricular systolic dysfunction, we propose an approach that incorporates the ACC/AHA staging when evaluating and managing the care of cancer survivors. It is accepted that the risk of anthracycline-induced cardiac toxicity increases with cumulative dosing. The higher the dose of anthracycline the higher the risk of cardiac toxicity. There is disagreement about the cutoff in dosing to define high risk and for purposes of our classification, we have chosen a doxorubicin dose >240 mg/m² or its equivalent. A detailed discussion about acute treatment phase cardioprotective strategies (beta blockers/ACE inhibitors/ARBs, continuous infusion, anthracycline formulation choice, use of dexrazoxane, etc.) is beyond the scope of this chapter.

From a population standpoint, the direct relationship between cumulative dose exposure and cardiac risk has predictive value and helps to define a high-risk population; however, for the individual survivor, there is wide variation in risk, i.e., toxicity may occur at low doses so that there is no “safe” dose [24–26] or may not occur at high doses. The amount of excess risk, derived from a meta-analysis of eight trials, demonstrated that anthracyclines increased the risk of clinical cardiac toxicity 5.43-fold, subclinical cardiac toxicity by 6.25-fold, any cardiac toxicity by 2.27-fold, and the risk of cardiac death by 4.94-fold compared with non-anthracycline regimens [27]. “High risk” has been associated with several factors: (1) sex, such that women are at higher risk compared to men; (2) age, such that risk is higher at extremes of age (children and elderly); and (3) preexisting risk factors for or diagnosis of cardiovascular disease. Associated mediastinal radiation also increases the risk associated with chemotherapy [28].

For all forms of radiation-induced cardiac toxicity, it is generally accepted that the approximate risk is 1 % at 5 years and doubles every 5 years. Clinically significant radiation changes more commonly occur 10 or more years posttreatment completion and are unusual but possible before that time. At 20 years posttreatment completion, the risk for clinically significant cardiomyopathy, CAD, valvular disease, pericardial disease, and carotid artery stenosis is 8 %, 10 %, 7 %, 1 %–3 %, and 6 %, respectively.

In assessing and defining risk, radiation treatment that involves the chest (mediastinal, mantle, left side for breast cancer, craniospinal, or total body radiation) should be considered as an additional risk factor for premature or accelerated atherosclerotic vascular disease and may be considered as an additional potent risk factor comparable to diabetes, cigarette smoking, and hypertension, to guide risk stratification and set treatment targets for those risk factors that can be modified, e.g., aggressive lipid management to “secondary” prevention targets .

With knowledge of the impact of cardiac toxicity on long-term survivors of cancer, early detection of asymptomatic cardiac toxicity has become a primary goal. Current standards for screening patients and for cardiac monitoring rely primarily on the measurement of left ventricular ejection fraction (LVEF) by echocardiography or multigated acquisition scanning.

To date, there are no evidence-based guidelines for cardiac toxicity monitoring after treatment completion. There are “guidelines” based on consensus with weak evidence for both adults and pediatric survivors that are listed and referenced in Table 11.2. Screening guideline development has been slowed by the focus on a single test and the assumption that cardiac toxicity risk is binary . A combination of tests, e.g., imaging and biomarker(s) coupled with a comprehensive history and physical examination rather than a single test, may be the most effective population-based strategy that achieves an appropriate balance between lack of screening and over-screening. In the continuum of cardiac toxicity, every long-term survivor is at risk for the future development of cardiac disease. The main goals of screening are to identify the presence of structural heart disease and the patient’s place in the continuum. This theoretically allows early intervention to prevent progression by identifying the presence of asymptomatic cardiovascular disease before symptomatic progression and resultant cardiovascular morbidity. Many of the outstanding questions regarding type, frequency, and intensity of screening survivors are being considered by an ASCO-charged working group to compliment the current existing “guidelines” listed in Table 11.2.

The measurement of cardiac biomarkers (troponin I and T, B-type natriuretic peptide [BNP], and N-terminal pro-BNP [NTproBNP]) to predict late cardiac toxicity has been explored [29]. Biomarkers are attractive as a screening tool because of the ease of measurement, low cost compared to imaging, and ability to use in a serial or longitudinal manner. It is also conceivable that they have potential predictive value allowing early diagnosis and then early initiation of preventive strategies or altered monitoring schedules prior to the development of overt heart failure. Troponin in its various forms has been studied during the treatment phase as a predictor of early and late cardiac toxicity with inconsistent results that have prevented universal adoption of its use in existing “guidelines” [30].

Natriuretic peptides such as BNP and NTproBNP are secreted from the myocardium in response to increased hemodynamic stress and have been widely used in the management of heart failure. Elevated levels of these peptides have been found in asymptomatic patients treated with anthracyclines and the elevation precedes the development of overt heart failure. However, natriuretic peptides have not shown to be consistently effective for population-based screening, with little incremental value over standard clinical variables. Their major strength, however, may be in their negative predictive value, as it is atypical to have clinically significant structural heart disease with LV dysfunction and a normal BNP or NTproBNP level [7, 30]. Current consensus opinion concludes that the strength of the evidence is not strong enough to make this a standard recommendation in screening and follow-up of cancer survivors. Other biomarkers currently being investigated during the acute cancer treatment phase as predictors of late toxicity include topoisomerase 2B, myeloperoxidase, growth-differentiation factor 15, soluble fms-like tyrosine kinase receptor-1, and galectin-3 [31].

The single most useful diagnostic test in the evaluation of cardiac function before, during, and after cancer treatment has been the two-dimensional echocardiogram coupled with Doppler flow studies to quantitate systolic and diastolic function, cardiac chamber dimensions, wall thickness/mass, valvular disease, and the pericardium. In addition to systolic function, the echocardiogram provides a comprehensive assessment of diastolic function that also is critical, as early abnormalities that precede decreases in systolic function have long-term consequences in the anthracycline-treated population. Furthermore, echocardiograms provide insight into the degree of cardiac remodeling from hypertension, wall motion abnormalities from CAD, and valvular/pericardial disease that may result from radiation exposure.

Cardiac toxicity via echocardiography has been defined as an LVEF decline of ≥5 to <53 % with heart failure symptoms or an asymptomatic decrease of LVEF ≥10 to <53 % [32].

All current echocardiographic-derived measurements of left ventricular function (LVEF and FS) are load dependent and comorbidity dependent (fluid overload, sepsis, ischemic heart disease, or other drug therapy) and limited by multiple technical considerations. As a measure of global LV function, they are currently unable to consistently detect subtle, early changes in regional myocardial wall motion.

A normal LVEF or FS does not exclude cardiac dysfunction. There is a critical need to develop more robust and sensitive measures of LV dysfunction to improve our current methods of monitoring patients. Currently, there is an expanding interest in the measurement of tissue Doppler-derived strain. Each adult survivor of pediatric or adult cancer who was treated with at-risk therapy, e.g., anthracyclines or chest radiation, has ACC/AHA stage A heart failure and, as such, has defined goals of therapy that can be used to target modifiable cardiovascular risk factors. The goal of screening is to recognize and then prevent progression to the more advanced stages B, C, and D. Within this population, a high- and low-risk group can be identified to help guide frequency of assessment and surveillance.

Newer methods to assess cardiac function have been extensively reported and include cardiac MRI, three-dimensional echocardiography, and various tissue Doppler-derived measurements of regional myocardial strain. Strain imaging in the adult cancer survivor population demonstrates abnormalities that occur and persist in survivors despite preserved LVEF. To date, no modality has emerged as the “winner.” A recent extensive review of the current state of imaging in cancer patients endorsed by the American Society of Echocardiography and the European Association of Cardiovascular Imaging has been published [32].

Tests available to screen for CAD include the electrocardiogram (ECG), exercise treadmill test, exercise myocardial perfusion imaging, exercise (stress) echocardiography, electron-beam computed tomography (CT) scanning for coronary calcium, coronary CT angiography, cardiac magnetic resonance imaging, and carotid intima-media thickness measurement. The sensitivity, specificity, and predictive accuracy of these tests for the noncancer population have been reviewed in detail [33].

The US Preventive Services Task Force guidelines for CAD detection in asymptomatic patients in the noncancer population do not recommend routine ECG, exercise treadmill test, exercise myocardial perfusion imaging, exercise (stress) echocardiography, and other nontraditional testings (scanning for coronary calcium, coronary CT angiography, magnetic resonance imaging, measurement of carotid intima-media thickness) for either the presence of severe coronary artery stenosis or the prediction of coronary heart disease (CHD) events in adults at low risk for CHD events. For higher-risk patients, they found inadequate evidence that testing (beyond that obtained by a detailed cardiac history and assessment of conventional CHD risk factors) would result in interventions that lead to improved CHD-related health outcomes [34, 35].

However, these recommendations did not specifically address the survivor population at risk for radiation-induced premature CAD , which differs from atherosclerotic CAD in pathophysiology, onset (beginning at 8–10 years posttreatment completion), and lesion location (ostial or proximal left main, left anterior descending, or right coronary artery). Therefore, application of their recommendations to the survivor population may not be generalizable, but may be used to help in decision making and should guide the needed future research in this area. We are sensitized to the increased risk of CAD in the post-radiation-treated cancer survivor and have a low threshold to pursue screening (stress testing, coronary CT angiography) for any symptoms that may even remotely suggest coronary ischemia.

It can be assumed that every survivor exposed to anthracyclines and/or chest radiation is at stage A and “at risk.” Subsequent sub-characterization as low- or high-risk should be matched and drive the frequency and intensity of screening. Patient and treatment high-risk variables are listed in Table 11.3. The presence of any one variable defines a high-risk patient who should be considered at stage A.

Long-term survivors of cancer have a myriad of health issues that are increased in prevalence compared to age-matched siblings or controls; among these, cardiac toxicity is the most prevalent noncancer condition. This recognition that there are long-term health concerns after chemotherapy prompted the Institute of Medicine to publish two reports providing general recommendations for ongoing care and research for survivors of childhood and adult cancers [36, 37]. Specific recommendations about the nature and frequency of cardiac testing were not addressed.

The Children’s Oncology Group also has published revised guidelines [38] for long-term care for pediatric cancer survivors. The guidelines are expert panel, consensus-derived, based on a recognized risk, with monitoring frequency matched to risk. After baseline screening, specific testing is recommended from yearly to every 5 years based on age at treatment, dose of anthracycline, and associated exposure to radiotherapy. In addition, the panel recognized that the risk of CAD associated with radiotherapy is manifested between 5 and 10 or more years after treatment completion, and they recommend testing strategies. For survivors of adult cancer, the landscape is less clear. Current existing guidelines include the ASCO , European Society of Medical Oncology, Heart Failure Society of the European Society of Cardiology, American Society of Echocardiography/European Association of Cardiovascular Imaging, and the National Cooperative Cancer Network (NCCN) and are referenced in Table 11.2. All include a baseline CV assessment at the start of potentially cardiac toxic therapy, assessment of the treatment of associated comorbidity prior to, during, and after treatment. They suffer from varied definitions of cardiac toxicity, the role of cardioprotective strategies during and after cancer treatment, and the frequency and modality of posttreatment completion follow-up. All recommend monitoring of cardiovascular risk factors and reinforce the value of a healthy lifestyle. The “concordances” of the “harmonization” group for pediatric survivors described above could easily be extended to the adult survivors of adult cancer [39].

This section describes a general approach to the screening and care of adult cancer survivors and does not represent an absolute standard of care but provides a clinically relevant approach to guide the care of these patients based on existing data defining cardiac risk and the value of therapeutic intervention. These recommendations can be used as a roadmap allowing for individual practitioner discretion and are subject to change as knowledge and technological advances are made. The goal is the early detection of preclinical lesions/disease that are actionable, in other words, discovery when interventions should have the greatest beneficial impact. Although there are no universal guidelines, we reinforce the concept that the echocardiogram is the modality of choice for the long-term monitoring of cardiac structure and function in cancer survivors exposed to potentially cardiac toxic treatments.

For all patients, the approach can be simplified into five questions that guide subsequent testing:

With the development of hypertension, preferred treatment should be with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and β-blockers to take advantage of their potential beneficial effects on cardiac remodeling.

For cancer survivors who have been exposed to potentially cardiac toxic chemotherapy or chest radiation, cardiac decompensation is a concern during pregnancy. The hemodynamic stress is due to an increase in blood volume approaching 50 % that begins soon after gestation and peaks at 26–30 weeks. However, limited analysis shows that risk is low [42]. Because cardiac dysfunction may first become apparent during pregnancy, we encourage management input from a cardiologist before, during, and after pregnancy. Increases in cardiac output and heart rate begin early, and evaluation in the first trimester is helpful in predicting the subsequent course. Because the increase in maternal blood volume peaks at 26–30 weeks of pregnancy, we routinely reassess these patients early in the third trimester and communicate directly with their obstetrician for labor, delivery, and postpartum management.

Any low-risk stage A survivor who has a cancer recurrence and/or further malignancy requiring additional chemotherapy or radiotherapy should subsequently be considered and managed as high-risk stage A, with consideration for a cardiology consultation to help guide treatment decisions prior to, during, and after treatment.

Survivors of allogeneic stem cell transplantation are at risk for the late development of accelerated atherosclerosis and the metabolic syndrome [43], and they should be followed up according to the high-risk stage A pathway.

Carotid artery stenosis also is a recognized radiation treatment complication with an increased late incidence of transient ischemia and stroke [44, 45]. Carotid bruits may be audible on physical examination. A baseline carotid duplex study can be obtained 5 years after treatment completion.

All patients should also be given a treatment summary and survivorship care plan that outlines their future cardiac follow-up in addition to the remainder of their survivorship care. Ideally this care plan is updated at appropriate intervals should a change in status occur. This care plan should include information on healthy lifestyle and signs/symptoms that should be brought to a practitioner’s attention.

We have reviewed some of the common cardiac conditions and cardiac risk in cancer survivors and provided a practical framework for addressing these issues clinically. The following clinical vignettes explore common patient presentations and the “big” issues that may occur in the longitudinal outpatient care of adult cancer survivors. This information will be helpful to cardiologists, cardio-oncologists, oncologists, as well as primary care specialists in nursing and medicine who care for this population. Each case will address presentation, evaluation, treatment, and anticipatory guidance for survivors and incorporate known clinical guidelines when available.