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Imaging the Heart in the Cancer Patient

  • H. William StraussEmail author
  • Josef J. Fox
Living reference work entry

Abstract

The average age of a cancer patient is 67. Sexagenarians with cancer are likely to have comorbidities at the time of diagnosis. Cancer patients > 55 years old have an average of ∼ 2.9 comorbidities, while cancer patients older than 75 have an average of 4.2 comorbidities.

The likelihood of coronary artery disease as an etiology of this comorbidity increases with the age of the patient. Cardiovascular comorbidity is present in ∼ 20% of patients with neoplasm. These comorbidities increase the risk of a serious cardiovascular event during treatment. An additional risk factor is limited work capacity. If patients cannot perform 4 metabolic equivalents of work, their all cause mortality is increased. Patients with cancer and known cardiovascular comorbidity or risk factors such as diabetes, hypertension, smoking history, or limited work capacity should have medical clearance prior to invasive diagnostic procedures, major surgery, mediastinal radiation, and/or potentially cardiotoxic chemotherapy.

Medical clearance should include a detailed cardiovascular history and physical examination. This information will permit calculation of a clinical score to define the risk of adverse events as a result of a major surgical procedure, blood tests to determine hematologic and renal status, and if necessary, assessment of the patients work capacity. Stress testing with imaging should be done in patients with an intermediate risk of coronary heart disease and considered in patients with limited work capacity or advanced age. In selected patients, coronary CT angiography or coronary calcium score may be a suitable evaluation. In patients with cancer of the esophagus, breast, lung, melanoma, or lymphoma, chest-CT and PET/CT studies should be carefully evaluated to detect possible pericardial or myocardial involvement.

Chemotherapy may cause myocardial ischemia due to coronary spasm and decreased ventricular function due to irreversible or reversible myocardial damage, as well as repolarization abnormalities, which may result in fatal arrhythmia. Radiotherapy may accelerate the development of atherosclerosis of vessels in the radiation field and cause irreversible damage to myocardium in the radiation field. Myocardial perfusion imaging is useful to detect regions of acute ischemia or scar induced by therapy, while blood pool imaging is useful for serial monitoring of ventricular function.

Keywords

Heart imaging in the cancer patient Cardiovascular comorbidities in the cancer patient Cardiotoxic chemotherapy Stress testing in cancer patients Heart disease in cancer patients Cancer coexisting with cardiovascular disease 

Glossary

[18F]FDG

2-deoxy-2-[18F]fluoro-D-glucose

ACC

American College of cardiology

ACE

Angiotensin-converting enzyme

AHA

American Heart Association

AL

light chain amyloid

AMI

Acute myocardial infarction

ASCO

American Society of Clinical Oncology

ATTR

transthyretin amyloid

ATP

Adenosine triphosphate

BNP

B-type natriuretic peptide

CAD

coronary artery disease

CHF

Congestive heart failure

CI

confidence interval

C-MRI

Cardiac magnetic resonance imaging

COPD

chronic obstructive pulmonary disease

CRCD

Chemotherapy-related cardiac dysfunction

CRP

C-reactive protein

CT

X-ray computed tomography

CTCAE

Common terminology criteria for adverse events

DTPA

diethylenetriaminepentaacetic acid

DVT/PE

Deep venous thrombosis/pulmonary embolism

EDTA

ethylenediaminetetraacetic acid

ErbB2

a member of the tyrosine-protein kinase family (also known as CD340)

HER2

Human epidermal growth factor receptor 2

HR

hazard ratio

HTN

Hypertension

LEVF

Left ventricular ejection fraction

LGE

Late gadolinium enhancement

LHIS

Lipomatous hypertrophy of the interatrial septum

LV

left ventricle

METS

Metabolic equivalents

MI

myocardial infarction

MIP

maximum intensity projection

MPI

Myocardial perfusion imaging

MRI

Magnetic resonance imaging

MSKCC

Memorial Sloan-Kettering Cancer Center

MUGA

Multigated acquisition

NCI

National Cancer Institute, National Institutes of Health of the United States

PET

positron emission tomography

PET/CT

positron emission tomography/computed tomography

P-POSSUM

Predicted mortality-physiologic and operative severity score

RCRI

Revised cardiovascular risk index

RCRS

Revised cardiac risk score

RVG

Radionuclide ventriculography

SEER

Surveillance, Epidemiology, and End Results

SPECT

single-photon emission computed tomography

SUV

standardized uptake value

TEE

transesophageal echocardiography

VEGF

vascular endothelial growth factor

Face Page

Cardiovascular issues in patients with cancer fall into four major categories:
  1. 1.

    (a) Extension of the tumor to the pericardium or myocardium (seen in cancer of the esophagus, lung, lymphoma, thymoma, and breast) or (b) a neoplasm originating in the heart or blood vessels (aside from atrial myxoma, such tumors are extremely rare).

     
  2. 2.

    Damage to the heart or blood vessels due to treatment (e.g., doxorubicin cardiotoxicity, radiation therapy where major vessels and/or portions of the heart are in the field, or severe hypertension induced by VEGF inhibitors [e.g., bevacizumab]). Cardiotoxicity is the second leading cause of long-term morbidity and mortality among cancer survivors [1].

     
  3. 3.

    Secondary effects of the neoplasm on the heart (e.g., cardiac amyloid in patients with multiple myeloma – which may occur in ~30% of myeloma patients [2]).

     
  4. 4.

    Pre-existing cardiovascular comorbidity influencing the selection of therapy (e.g., pre-existing coronary, valvular, or myocardial disease causing symptoms of ischemia or heart failure).

     

Since the average age of a cancer patient is 67 years, it is not surprising that about 60% of patients over the age of 65 [3] have a significant comorbidity. The Eindhoven Cancer Registry identified these comorbidities in the Dutch population as hypertension (26%), heart disease (23%), previous cancers (20%), chronic obstructive pulmonary disease (COPD; 17%), and diabetes mellitus (16%). In the United States, SEER data identified a cardiovascular comorbidity in 32% of female breast cancer patients [4], 31% of prostate cancer patients, 53% of lung cancer patients, and 41% of patients with colorectal cancer. Comorbidities in the U.S. population were different than in the Dutch population; with diabetes (16%), COPD (16%), congestive heart failure (10%), and cerebrovascular disease (6%) [5], the comorbidity of a second cancer occurred in ~19% of adult cancer patients [6] in the United States.

A cancer patient with underlying coronary artery disease has an increased risk of a serious cardiovascular event, especially if therapy involves high-risk surgery, the use of cardiotoxic chemotherapy, or mediastinal radiation. The risk is evaluated by medical clearance, which includes a detailed cardiovascular history (including the patient’s work capacity. Inability to perform at least four METS (metabolic equivalents of oxygen) work (equivalent to performing light housework) is associated with increased all-cause mortality and physical examination, appropriate laboratory studies, review of a resting electrocardiogram, and cardiac imaging procedures (including echocardiogram, myocardial perfusion scan, chest film, and a chest computed tomography [CT] scan) as well as coronary calcium to calculate a clinical score (such as RCRS [revised cardiac risk score], POSSUM for severe morbidity, and Charlson [7] for comorbidity should be carried out.

Patients with a history of myocardial infarction (MI), percutaneous coronary interventions, or bypass surgery scheduled for intermediate- or high-risk procedures are candidates for stress testing with imaging. Myocardial perfusion imaging , especially using PET/CT with contemporaneous measurement of coronary calcium and coronary flow reserve, is preferred. In selected patients, stress echocardiography or coronary CT angiography may be suitable for detecting significant coronary stenosis, high-risk plaque (and vascular remodeling), as well as global and regional ventricular function at rest and stress. In patients with cancer of the esophagus, breast, lung, melanoma, or lymphoma, chest CT and/or PET/CT studies should be carefully evaluated to detect possible pericardial or myocardial metastases.

Cancer chemotherapy may cause impaired ventricular function, coronary spasm, hypertension, deep venous thrombosis, and pulmonary embolus (Table 1) [8], while radiation therapy can accelerate the development of atherosclerosis (particularly if vessels are in a radiation field) and possibly cause reversible or permanent myocyte damage with associated decrease in global ventricular function.
Table 1

Revised Cardiovascular Risk Index (RCRI)

High-risk surgery (supra-inguinal vascular, intraperitoneal, and/or intrathoracic surgery)

History of MI; history of positive exercise test; current chest pain due to myocardial ischemia; use of nitrate therapy; ECG with pathological Q waves

History of heart failure; pulmonary edema; paroxysmal nocturnal dyspnea; chest X-ray showing pulmonary vascular redistribution

History of cerebrovascular disease

Diabetes mellitus requiring insulin

Preoperative creatinine >2.0 mg/dL (177 μmol/L)

Management of Cardiac Risk in Noncardiac Surgery

Background

Worldwide there are over 200 million surgical procedures performed on patients under general anesthesia each year [9]. In the first 30 days after major noncardiac surgery, about 10 million adults (~5%) will have a major cardiac complication that may result in death. If patient demise within 30 days of surgery were to be listed as a separate cause of death in the United States, it would be the third leading cause of death [10, 11]. The likelihood of a patient with a perioperative MI dying within 6 months of the event is high. Although death occurs in only 0.01% of all patients undergoing operations, mortality increases to ~40% in cases of perioperative infarction [12].

The prevalence of coronary heart disease is 6% in men aged 40–59, ~20% in men aged 60–79, and ~32% in men older than 80 years. The prevalence in women is approximately half that of men at age 60 years and older [13]. Demographic data suggest that by the year 2055, more than 20% of the US population (and 25% of the world population) will be over the age of 65, and patients over age 65 will account for approximately 40% of all surgical procedures [ [5]]. SEER statistics suggest that the lifetime risk of developing cancer is about 42% for men and 38% for women [14]. In 2015, about 1,658,370 new cases of cancer were diagnosed, and about 13,776,251 Americans had a history of cancer [15]. Based on the prevalence of cancer and of coronary disease, it is likely that a patient with cancer will have coronary disease as a comorbidity.

Events

The likelihood of a perioperative major adverse cardiac event is related to the baseline risk. Patients with a history of coronary heart disease are at much higher risk for perioperative ischemic events. In the first week after surgery, ischemic episodes occur in 24–41% of patients with a history of CAD. Although the majority of events are clinically silent [16], acute clinical events occur in approximately 5% of cases (infarction, heart failure, or cardiac death). A perioperative MI, even if clinically silent, is associated with a hospital mortality rate of 15–25%. Of the patients who have a perioperative infarct, 75% are non-transmural [17]. A study of 283 radical cystectomy patients, average age 70, average duration of surgical procedure 7 h, found coexistent coronary disease in 64 patients (23%) [18]. There were 31 patients with perioperative cardiac complications including new-onset arrhythmia in 22 and MI in ten. Of these patients, 13 (42%) had a history of coronary disease. In the infarct group, there was history of previous coronary disease in four patients. All ten MI patients had at least one other postoperative complication, such as sepsis or a major wound issue. The added stress of the complication likely caused tachycardia and possibly increased blood pressure, thereby increasing myocardial oxygen demands. Pain or other factors associated with the complication may have contributed to coronary artery spasm, reducing coronary blood flow. The mean interval between surgery and MI was 3.5 days. Preoperatively, five of the ten MI patients had normal stress test results, and two patients with abnormal stress test results had stents placed before the cystectomy.

Interval Between Stent Placement and Surgery

The interval between placing a cardiac stent and perioperative cardiac events was explored in a retrospective analysis of 1,953 patients [19]. There were no significant differences between drug-eluting and bare metal stents (in-hospital mortality, ~0.6%; MI, ~0.9%; or postoperative ischemic cardiac events, 14%). There was a significant increase in the incidence of death or MI if the interval between stent placement and surgery was shorter than 42 days (42.4%), compared with 42 days to 1 year (24.5%) or longer than 1 year (11.7%).

Clinical Recognition of Perioperative Infarct

About 50% of perioperative infarcts are clinically unrecognized [20]. Typical clinical symptoms are difficult to assess owing to postoperative discomfort and the use of pain medication. In addition, electrocardiographic changes may be subtle. In a series of 65 patients undergoing head and neck surgery, troponin I was measured on postoperative day 3. Of the 65 patients, 16 (25%) had an elevated troponin level (>0.032 μg/L); only five patients had a clinically apparent infarction [21]. Myocardial damage was not related to the length of surgery (243 min in patients with elevated troponin vs. 205 min, p > 0.2) but it did correlate with postoperative inflammation, measured by elevated C-reactive protein (CRP) levels. The new worldwide standard definition of acute infarction includes an increase in cardiac enzymes (preferably troponin) to more than 99th percentile of normal laboratory values, new Q waves, or sudden cardiac death. This definition will help investigators identify factors associated with perioperative infarction. Cohn commented on the “diagnostic dilemma” presented by postoperative troponin surveillance [22], since 10–20% of patients have elevated troponin levels following noncardiac surgery. Patients with elevated troponin levels have an increased 30-day mortality (with higher peak troponin T levels associated with higher risk of death), often from noncardiac causes. Unfortunately, there is no proven beneficial treatment in asymptomatic patients with elevated troponin levels.

The pathophysiology of ischemia and infarction in perioperative patients is different than in patients outside this environment. Two retrospective autopsy studies evaluated the etiology of perioperative MI:
  1. 1.

    Dawood et al. compared fatal perioperative MI with fatal nonoperative MI [23]. The investigators evaluated the hearts of 42 patients who had elective or emergent noncardiac surgery and died of perioperative infarction within 30 days (MI occurred within 7 days in 40 patients). History of prior MI was present in 55%. Left main coronary artery disease was found in 19%, and triple-vessel disease in 59%. Plaque fissure, rupture, or hemorrhage was found in 55% of patients, and intraluminal thrombus was present in 28% (likely an underestimate, owing to autologous thrombolysis). Six patients had plaque disruption in more than one coronary artery, suggesting that there is a generalized vascular inflammation in these patients.

     
  2. 2.

    Cohen and Aretz [24] studied the hearts of 26 cases with fatal perioperative MI. Prior myocardial scar was present in 81% (compared with a clinical history in only 19%); left main coronary artery disease was present in 23%, and multivessel disease in 88%. Plaque rupture was present in 46%, and intracoronary thrombus was present in 35%. A retrospective study of 66 patients undergoing intermediate-risk noncardiac surgery, who had coronary angiography following a perioperative infarct, demonstrated demand ischemia as the predominant etiology [25].

     

The autopsy studies and the angiographic study confirm the importance of multivessel coronary disease as a predictor of coronary events. A clinical history of coronary disease, however, may be lacking, as demonstrated in the study by Cohen and Aretz.

An important factor in perioperative MI is an increase in myocardial oxygen requirement due to an increased heart rate, blood pressure, or both. Continuous monitoring demonstrated an average heart rate increase of ~32 bpm, often accompanied by an increase in blood pressure, resulting in multiple prolonged episodes of ST-depression ischemia. The duration of ischemic episodes was fivefold longer in patients with perioperative MI [26, 27]. These episodes likely reflect sympathetic surges. In the perioperative environment, the role of the “vulnerable patient,” for example, due to a hypercoagulable state, the presence of systemic inflammation [21], and anemia or fluid overload, is also important in the etiology of perioperative myocardial ischemia and infarction.

Perioperative and Intraoperative Management

Cancer surgical procedures frequently require hours of general anesthesia, clamping, and release of major vessels and may involve significant blood loss. These factors result in the release of inflammatory cytokines that may increase the thrombogenicity of pre-existing atheroma, leading to embolic, thrombotic, or vasospastic events. Many patients have a significant elevation of resting heart rate postoperatively, associated with the release of catecholamines due to transient hypoxia, extubation, postoperative pain, increased or decreased circulating blood volume, and transient increase in inflammatory states due to increased production/release of tumor necrosis factor, interleukin, and CRP owing to tissue injury [20]. Persistent tachycardia increases myocardial oxygen consumption, raising the likelihood that patients with moderate and severe coronary stenoses may develop ischemia. To minimize the increase in heart rate and blood pressure and reduce the likelihood of infarction, these patients should be treated perioperatively with beta-blockers [15, 19, 32] (if there is no contraindication), with the goal of maintaining a heart rate of 60 bpm or less and of minimizing surges in blood pressure.

Determination of Preoperative Risk

The following factors place the patient at risk for perioperative events:

1. A work capacity of <4 METS is associated with increased all-cause mortality [28] and increased postoperative length of stay [29]

2. Severe coronary disease

3. Recent heart failure

4. Prolonged duration of anesthesia

5. Large fluid shifts in the course of the procedure

6. Pain or other severe discomfort in the immediate postoperative and early recovery interval (up to 7 days)

7. Wound infection, sepsis, or dehiscence

A clinical scoring system focused on the cardiovascular system, the Revised Cardiac Risk Index proposed by Lee [30], considers six factors (Table 1) [31].

The rate of cardiac death, nonfatal MI, and nonfatal cardiac arrest is based on the number of risk factors [32]:

No risk factors

0.4%

One risk factor

1.0%

Two risk factors

2.4%

Three or more risk factors

5.4%

This index is useful for identifying patients at medium to high risk undergoing high-risk noncardiac surgery who could benefit from noninvasive cardiac stress testing [33].

Another clinical scoring system, P-POSSUM (Predicted mortality – Physiologic and Operative Severity Score), considers multiple factors, and online calculators are available [34]. The P-POSSUM calculator considers:
  • Patient age

  • The presence of heart failure and dyspnea

  • Atrial fibrillation or other arrhythmia

  • Blood pressure

  • Hemoglobin

  • White blood cell count

  • Blood urea nitrogen

  • Serum sodium and potassium

  • Glasgow coma score

  • Type of operation

  • Number of procedures

  • Estimated blood loss

  • Chance of peritoneal contamination

  • The presence of malignancy/metastasis

  • Urgency of surgery

The calculator produces a score estimating morbidity and mortality. A comprehensive discussion of patient evaluation is contained in the updated ACC/AHA guide on perioperative cardiovascular evaluation for noncardiac surgery [35]. The guidelines suggest that an MI occurring less than 90 days before surgery is associated with a postoperative 30-day mortality of 10.5%. Other factors increasing the risk of a major perioperative event include age over 62 years, history of cerebrovascular disease, the presence of heart failure, left ventricular ejection fraction (LVEF) less than 40%, elevated B-type natriuretic peptide (BNP) level, moderate or severe valvular disease, and a work capacity less than 4 METS.

Approach to the Evaluation of the Presurgical Patient with Intermediate Risk

A meta-analysis of six preoperative diagnostic tests demonstrated a sensitivity of exercise electrocardiography, MPI, and dobutamine echocardiography to be greater than 74% (confidence interval >60%) for the prediction of perioperative events [36]. Impaired left ventricular function had a surprisingly low sensitivity and poor positive predictive value for perioperative cardiac events. A direct comparison of multiple techniques suggests that CT coronary angiography and PET myocardial perfusion imaging have similar positive and negative predictive values [37]. Patients at intermediate risk for coronary events, primarily those with a score greater than 1 on the Revised Cardiac Risk Index (see Table 1), appear to be the group with the greatest benefit from preoperative testing.

Mangano and colleagues demonstrated that effective preoperative and intraoperative beta blockade can reduce the incidence of perioperative cardiovascular events particularly in low-risk patients. In addition, the investigators confirmed that preoperative revascularization does not reduce perioperative morbidity and mortality: “Coronary revascularization prior to non-cardiac surgery is only indicated in unstable patients and patients with left main disease” [38].

To assist in the selection of patients for preoperative assessment, Mukherjee and Eagle suggest utilizing MPI only on patients with clinical risk factors, such as a history of angina, MI, congestive heart failure, diabetes, and Q waves on ECG.

In a retrospective study of 271,082 patients older than 40 years undergoing intermediate- to high-risk noncardiac surgical procedures, 23,991 had preoperative noninvasive stress testing. Patients with intermediate and high risk of cardiovascular events (using the RCRI criteria) who had stress tests had improved 1-year survival and reduced length of hospital stay [39].

Preoperative testing for patients at risk of perioperative events should help identify patients at high risk for perioperative events. However, not all patients at risk of perioperative ischemia are identified on preoperative testing. Investigators compared a preoperative dobutamine echocardiogram with intraoperative transesophageal echocardiography (TEE) [40] in 54 patients scheduled for major vascular surgery. Dobutamine stress induced new wall motion abnormalities in 17 patients. Intraoperative echocardiography detected new wall motion abnormalities in 23 patients. A perioperative event occurred in 15 patients: Ten had a dobutamine-induced wall motion abnormality and a new wall motion abnormality on intraoperative TEE; in four patients, an abnormality was only detected on the intraoperative TEE, suggesting the surgery caused an added stress not inducible with dobutamine.

Myocardial Perfusion Imaging in Preoperative Assessment

MPI can be performed using single-photon or positron-emitting tracers. The most common procedures employ single-photon agents, which permit patients to be studied with exercise or pharmacologic stress. Exercise stress has the advantage of providing information about a patient’s work capacity (see “Determination of Preoperative Risk”), evidence of electrocardiographic ischemia, as well as information about the relative distribution of myocardial perfusion at rest and stress. Exercise stress is particularly useful in patients below the age of 70, with no evidence of neuropathy, orthopedic impairment, lung disease, or impaired mentation.

Patients who cannot exercise can be stressed with either intravenous administration of vasodilators (dipyridamole, adenosine, adenosine triphosphate [ATP], or regadenoson) or with catecholamine agonists (dobutamine). Vasodilator stress MPI has a sensitivity equal to exercise stress for the detection and localization of regions of decreased perfusion and has the safety advantage of intravenous aminophylline as a rapid reversing agent in the unlikely circumstance that the patient develops severe ischemia (likely from a “steal” syndrome). A major contraindication to the use of dipyridamole or adenosine, bronchospasm, can be overcome in patients who are not actively wheezing. The synthetic A2A adenosine agonist regadenoson has a low incidence of bronchospasm. Preparing the patient with inhalation of one or two puffs of albuterol before administering regadenoson reduces the likelihood of bronchospasm.

Dobutamine stress is typically a longer procedure than vasodilator stress, often requiring the addition of atropine to achieve the desired heart rate end point. Like vasodilator stress, dobutamine can be reversed pharmacologically with the short-acting intravenous beta-blocker esmolol. Atropine , however, has a half-life of ~2.5 h and in addition to dry mouth and blurred vision may cause urinary retention. To minimize these side effects, vasodilator stress MPI is overwhelmingly preferred for pharmacologic stress testing.

A retrospective review of MPI in 394 cancer patients studied for preoperative risk assessment revealed abnormal scans in 97 patients [41]. There were nine major perioperative cardiac events – all in subjects with abnormal scans. A review of stress MPI in 787 cancer patients [42] identified ischemia or scar in 36%. Ischemia or scar was seen in 36% of those stressed with adenosine, 36% of those stressed with dobutamine, and 38% of those stressed with exercise. During a 3-year follow-up, 84 patients (11%) had a cardiac event (cardiac death in 51 patients, 61% of those with a cardiac event). Cardiac events occurred in 6% of patients with a normal stress MPI and in 19% of those with ischemia, scar, or both. Ischemia on MPI was associated with a 24% likelihood of a cardiovascular event, while scar was associated with a 19% likelihood. However, the overall 3-year survival in these patients was only 44%, suggesting that ischemic heart disease played less of a role in survival than the patient’s cancer.

A meta-analysis of 24 studies reporting results on 14,918 patients with known or suspected coronary disease compared the cardiac outcome of pharmacologic (dipyridamole, adenosine, or dobutamine) with exercise stress MPI [43]. Patients were followed up for 12–55 months (median 22 months for pharmacologic stress and 20 months for exercise). There were 343 cardiac deaths and 216 nonfatal MIs in the pharmacologic stress group and 180 cardiac deaths and 277 nonfatal MIs in the exercise group (total event rate = 6.8%). In the pharmacologic stress group, the annualized event rate for cardiac death and MI (hard events) for patients with normal perfusion scans was 1.78% and 9.98% for patients with abnormal images. In the exercise stress group, the pooled hard event rates were 0.65% for patients with normal images and 4.3% for those with abnormal images. These data suggest that both pharmacologic and exercise stress-gated single-photon emission CT (SPECT) myocardial perfusion scans identify patients with a significant risk of cardiac events.

PET MPI has significant technical advantages over single-photon studies thanks to the superior spatial resolution of ~3 mm for nitrogen-13 ammonia and ∼5 mm for rubidium-82 versus ~11 mm for 99mTc. CT attenuation correction with PET minimizes false-positive scans due to breast or diaphragmatic attenuation, and gated CT imaging can provide information about coronary calcification. A major advantage of PET perfusion studies is the ability to measure absolute coronary blood flow and provide information about perfusion reserve. Reduced perfusion reserve occurs in patients with small vessel disease (patients with diabetes, left ventricular hypertrophy and subjects with metabolic syndrome) and may also be seen in patients with diffuse triple-vessel disease, where regional perfusion may appear normal [44]. Although oxygen-15-labeled water is the preferred tracer for determining regional myocardial perfusion, it is not widely available because of the ~2 min half-life of oxygen-15. Most PET perfusion studies are performed with generator-produced rubidium-82 or less frequently with nitrogen-13 ammonia. After testing the generator for breakthrough of the parent strontium-82, the 75-s half-life rubidium-82 daughter is eluted from the generator directly into the patient. The short half-life permits administration of 30–50 mCi at rest during a dynamic 7–10-min data acquisition. The vasodilator (typically dipyridamole, adenosine, or regadenoson) is administered followed by a second infusion of rudidium-82 with a dynamic acquisition similar to that at rest.

As with single-photon imaging, the images are checked for appropriate registration with the attenuation correction CT, reconstructed, placed in standard cardiac orientation, and evaluated for the regional distribution of perfusion at rest and stress as well as perfusion reserve (typically with a one-compartment model) (Fig. 1). The gated perfusion images are reviewed to determine regional and global ventricular function. Recent studies suggest that hybrid imaging with PET/CT of myocardial perfusion and contrast coronary CT angiography offers the most complete noninvasive evaluation of myocardial ischemia since the vessel perfusing a specific territory and the perfusion/perfusion reserve are measured concurrently.
Fig. 1

Abnormal rubidium-82 PET myocardial perfusion scan at stress and rest. Short axis (top rows) vertical long axis (middle rows) and horizontal long axis (bottom rows) slices demonstrate severe and extensive ischemia involving the anterior, apical and septal walls. The left ventricular (LV) cavity is dilated on stress imaging consistent with transient ischemic dilation, a poor prognostic factor. Furthermore, on gated images (not shown), the patient’s LV ejection fraction decreased from 68% at rest to 46% during stress, an additional indicator of poor prognosis. Finally, the calculated coronary flow reserve was 0.92, which is severely decreased. Cardiac catheterization performed 1 day later confirmed the presence of severe triple vessel coronary artery disease

Myocardial and Pericardial Tumor Involvement

Primary cardiac tumors are rare: The most common primary cardiac neoplasm, accounting for 75% of cases, is a benign myxoma [45]. Malignant tumors of the heart are much less common. A review of 480,331 autopsies found primary cardiac tumors in only 0.0017% [46, 47]. Sarcomas account for about 95% of primary malignant tumors, while lymphoma accounts for the remainder [48]. The lesions are usually detected and characterized with ultrasound, contrast-enhanced CT, or MRI, while radionuclide techniques such as [18F]FDG PET/CT, myocardial perfusion studies, or receptor-specific imaging may contribute valuable supplementary data.

Secondary tumors occur 100–1,000 times more frequently than primary tumors [49]. Autopsy studies demonstrate that at the time of demise, ~10% of patients with metastatic tumors have myocardial or pericardial involvement. Cardiac involvement occurs by direct extension or by hematogenous or retrograde lymphatic spread [50]. Cardiac involvement impairs function in ~30% of patients. Depending on the etiology, myocardial involvement may be seen on myocardial perfusion images (usually as a focal area of deceased perfusion), on [18F]FDG PET/CT (especially in patients with minimal physiologic myocardial [18F]FDG uptake), as a focal region of increased [18F]FDG localization (particularly in patients with metastatic melanoma or lymphoma), or with receptor agents such as 111In-pentetreotide (as a focal region of increased myocardial localization) (Fig. 2). Metastatic tumors that involve the pericardium include lung cancer and breast cancer (usually by direct involvement), leukemia, melanoma, and lymphoma [51]. Pericardial involvement can result in pericardial effusion, cardiac tamponade, or less frequently constrictive pericarditis. Long-term survivors of breast cancer or lymphoma (particularly those treated with radiation) may have chronic constrictive pericarditis.
Fig. 2

Abnormal myocardial uptake of [18F]FDG secondary to involvement by lymphoma. Top left panel: Maximum intensity projection (MIP) image of a patient with multiple [18F]FDG-avid lymphomatous lesions in the neck and chest. Other panels: Axial PET, axial CT and axial fused PET/CT slices showing intense focal [18F]FDG uptake at the apex of the left ventricle corresponding to a low attenuation mass in the myocardium, representing a lymphomatous deposit (red arrows)

When focal [18F]FDG uptake is seen in the atria, it is important to distinguish uptake in lipomatous hypertrophy of the interatrial septum (LHIS) , which is a benign process [52], from metastatic tumor involvement (Fig. 3). This phenomenon on [18F]FDG PET is akin to uptake within metabolically active brown fat deposits more commonly seen at other anatomic sites, such as the supraclavicular region, and the intensity of uptake may vary from scan to scan [53]. LHIS is more prevalent with obesity and advanced age and may be associated with atrial arrhythmias [54]. In patients with lung cancer, esophageal cancer, or metastatic melanoma, with lesions adjacent to the heart, additional imaging studies, such as cardiac MRI (C-MRI), may be required to distinguish between LHIS and a cardiac neoplasm.
Fig. 3

Temporal variability of benign [18F]FDG uptake associated with lipomatous hypertrophy of the interatrial septum (LHIS) in a patient with metastatic breast cancer. Axial PET (left) and axial fused PET/CT (right) slices of the chest at baseline (bottom panels), 12 month followup (middle panels) and 19 months followup (top panels) demonstrate variable levels of [18F]FDG uptake in the atrial septum corresponding to a fat density structure on CT

A more frequent nonneoplastic finding that may be confused with tumor situated in or adjacent to the heart is when intense [18F]FDG uptake is present within the wall of the right atrium. While physiologic [18F]FDG uptake in the ventricular myocardium (left more than right) is relatively ubiquitous (albeit variable in intensity, depending on the patient’s glycemic/insulinemic state), uptake is not typically seen in the myocardium of the atria in the absence of altered cardiovascular physiology. When right atrial wall uptake does occur, it is usually associated with atrial fibrillation [55, 56], paced rhythms, sinus tachycardia, or other tachyarrhythmias.

Cardiac Amyloidosis

Systemic amyloidosis is associated with significant morbidity and poor overall survival, particularly after organ-specific damage has occurred. Cardiac involvement, in particular, leads to arrhythmias and progressive cardiomyopathy. Myocardial infiltration is manifested by increased wall thickening, which is difficult to distinguish from other causes of hypertrophy (e.g., hypertension, aortic stenosis) on conventional imaging techniques. There are two main types of cardiac amyloid infiltration: monoclonal immunoglobulin light chain (AL amyloid) and transthyretin (ATTR), with the former carrying a much worse prognosis [57]. Endomyocardial biopsy is currently the gold standard for diagnosis of cardiac amyloidosis, but this invasive procedure carries inherent risks. C-MRI is an established imaging modality for detection of myocardial infiltration (extracellular matrix expansion), which is characterized by late gadolinium enhancement (LGE). However, LGE is not specific for amyloid on a molecular level, nor is it readily quantified. C-MRI currently lacks sensitivity for very early cardiac involvement and is unable to assess multi-organ involvement. A number of single-photon molecular imaging techniques suggested for the evaluation of cardiac amyloidosis have shown limited clinical promise, including 99mTc-aprotinin, a polypeptide protease inhibitor for targeting of antiproteases within cardiac amyloid deposits [58]. 99mTc-pyrophosphate, traditionally a bone tracer, has gained traction in recent years, especially for the purpose of distinguishing between AL amyloid and ATTR [59]. Nevertheless, 99mTc-pyrophosphate is inherently limited by its lack of specificity for amyloid fibrils and difficulty in quantifying the degree of uptake, owing to the single-photon nature of the radionuclide.

PET probes with proven efficacy for detection of amyloid-beta fibril deposits in the brains of patients with Alzheimer’s disease are now being evaluated for use in systemic amyloidosis. Three such tracers, 18F-florbetaben, 18F-florbetapir, and 18F-flutemetamol, are approved by the U.S. Food and Drug Administration for use in the evaluation of Alzheimer’s disease. Preliminary data suggest that these thioflavin T derivative PET tracers are not only effective for imaging amyloid fibril deposits in brains but are also capable of binding to and imaging amyloid deposits in the myocardium.

The first in-human study demonstrating the feasibility of amyloid-avid PET imaging for cardiac amyloidosis used the tracer 11C-PIB [60]. Ten patients diagnosed with systemic amyloidosis, including heart involvement of either AL or ATTR type, and five healthy volunteers were investigated. Myocardial 11C-PIB uptake was visually evident in all patients 15–25 min after injection and was not seen in any control subject. A significant difference in 11C-PIB retention in the heart was noted between patients and healthy controls. The authors concluded that 11C-PIB and PET could be a method for studying systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.

A second study using 11C-PiB PET/CT [61] demonstrated positive uptake in 13 of 15 biopsy-proven cardiac amyloidosis patients. No uptake was detected in five patients with no evidence of cardiac amyloidosis on endomyocardial biopsy or in ten normal subjects. The maximal myocardium-to-blood cavity ratio was significantly different between patients with versus patients without cardiac amyloidosis (median 3.9 [range 1.7–19.9] vs. 1.0 [range 0.8–1.2], p < 0.001). Five patients who received prior chemotherapy had less uptake than did chemo-naive patients (2.3 [range 1.7–3.8] vs. median 10.4 [range 1.7–19.9] p = 0.014). The investigators therefore suggested that 11C-PiB PET/CT may be a good surrogate marker of active light chain deposition in the myocardium warranting further investigation in a larger number of patients.

Dorbala et al. were the first to show the utility of 18F-florbetapir for imaging cardiac amyloidosis [62]. They imaged five control subjects without amyloidosis and nine subjects with documented cardiac amyloidosis, transthyretin, and light chain amyloid. Left and right ventricular myocardial uptake of 18F-florbetapir was noted in all the amyloid subjects and in none of the control subjects. Quantitative measures including a retention index and standardized uptake value (SUV) parameters were significantly higher in the amyloidosis subjects than in the control group.

Osborne and colleagues [63] confirmed the findings of Dorbala et al. by similarly demonstrating positive florbetapir uptake in eight amyloid patients and no uptake in three healthy controls. In addition, quantitative SUV analysis with regions drawn in the septal wall was found to be adequate in differentiating healthy controls from amyloid-positive patients in this small cohort.

The utility of 18F-florbetapir for imaging cardiac amyloid was corroborated by Park et al. using human autopsy myocardial specimens [64]. They examined sections from 30 subjects with autopsy-documented AL (n = 10), ATTR (n = 10), and non-amyloid controls (n = 10) using 18F-florbetapir and cold florbetapir compound and digital autoradiography. Diffuse or focally increased 18F-florbetapir uptake was noted in all AL and ATTR samples and in none of the control samples. Compared with control samples, mean 18F-florbetapir-specific uptake was significantly higher in the amyloid samples (p < 0.001) and, interestingly, in the AL compared with the ATTR samples (p < 0.001). They concluded that 18F-florbetapir binds specifically to myocardial AL and ATTR deposits in humans and offers the potential to screen for these two most common types of myocardial amyloid.

Finally, Law et al. [65] recently demonstrated the efficacy of 18F-florbetaben PET for detection of cardiac amyloid deposition. They studied five patients with AL amyloid, five with ATTR amyloid, and four control subjects with hypertensive heart disease. Target-to-background SUV ratio and percentage myocardial 18F-forbetaben retention were noted to be higher in amyloid patients compared with hypertensive control subjects. A cutoff value of 40% was able to differentiate between cardiac amyloid patients and hypertensive control subjects. Percentage myocardial 18F-forbetaben retention was an independent determinant of both global left ventricular longitudinal and right ventricular free wall longitudinal strain on echocardiogram via an inverse curve relationship.

Taken together, this small series of preliminary studies indicates that thioflavin T PET analogs are promising for detecting and quantifying amyloid deposition in the heart of patients with cardiac amyloidosis. Furthermore, these PET tracers may be able to distinguish between light chain and transthyretin deposition.

Cardiac Function

First-pass radionuclide ventriculography (RVG) and equilibrium blood pool imaging (often called MUGA for “multigated acquisition”) techniques were developed in the early 1970s [66]. Initial studies reported an excellent correlation of RVG-derived LVEF with values obtained by contrast ventriculography at cardiac catheterization [67, 68, 69]. At its inception, a major indication for RVG was the serial monitoring of cardiac function in patients with coronary artery disease. The technique was subsequently applied to the serial evaluation of patients receiving cardiotoxic therapies [70] and remains so today. Cancer patients who receive systemic chemotherapy are at risk for early and late cardiovascular complications (Table 2 [71]).
Table 2

Important cardiovascular side effects of cancer drugs

Side effect

Cancer drug

Rate/incidence

Mechanism

Reversible

Irreversible

Cardiovascular ischemia

Antimetabolites

 5-Fluorouracil

Frequent

Vasoconstriction

+++

+

 Capecitabine

Infrequent

Vasoconstriction

+++

+

Anti-VEGF drugs

 Bevacizumab

≤3.8%

Arterial thromboembolism

 

+++

 Sunitinib

≤3%

Arterial thromboembolism

 

+++

 Sorafenib

≤3%

Arterial thromboembolism

 

+++

Arrhythmias

Anthracyclines

Dose dependent

Supraventricular

++

 

Calcium overload

Anti-HER2/ErbB2

 Lapatinib

 

QTc prolongation, torsade

  

Anti-VEGF drugs

    

 Sunitinib

Dose dependent

QTc prolongation, torsade

  

Contractile dysfunction/heart failure

Anthracyclines

Dose dependent

Myocardial cell death

 

+++

Anti-HER2/ErbB2

 Trastuzumab

Dysfunction 3–18.1%

Myofibrillar disorganization

+++

+

Heart failure 0.4–3.6%

 

+

+

 Lapatinib

Dysfunction 1.4%

?

+

 

Heart failure 0.2%

 

+

 

Anti-VEGF drugs

 Bevacizumab

Heart failure 1–3%

?

+

 

 Sunitinib

Heart failure 8–15%

Mitochondrial dysfunction

+

 

Arterial hypertension

Anti-VEGF drugs

 Bevacizumab

Any grade

   

Grade 3/4

 Sunitinib

Any grade

   

Grade 3/4

 Sorafenib

Any grade

   

Grade 3/4

+ rare, ++ common, +++ frequent, grade NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3

Acute manifestations of chemotherapy-related cardiotoxicity include hypertension, QTc prolongation, pericarditis and/or myocarditis-like syndromes, supraventricular and ventricular arrhythmias, and acute coronary syndromes. Acute complications can occur anytime from the onset of therapy up to 2 weeks after termination of treatment but rarely cause clinical symptoms and usually resolve spontaneously. Many of these effects are dose related and transient and are often ameliorated by withdrawal of the drug or reduction of the dose. Chronic cardiotoxicity may occur early, within 1 year after completion of chemotherapy, or late, more than 1 year after chemotherapy. Both early- and late-onset chronic cardiotoxicity may culminate in an irreversible cardiomyopathy.

Chronic Cardiotoxicity

Two forms of chronic chemotherapy-related cardiac dysfunction (CRCD) are now recognized: type I and type II [72]. Type I CRCD is exemplified by anthracycline-associated cardiac toxicity, which is clearly dose related, generally irreversible, and associated with characteristic ultrastructural abnormalities. Type II CRCD is epitomized by the toxicity related to the monoclonal antibody trastuzumab, which does not appear to be dose related and is not associated with significant ultrastructural abnormalities. Type II CRCD also appears to be reversible, with a high likelihood of recovery.

Type I CRCD

Doxorubicin (or adriamycin [73]) and other anthracyclines are among the most effective classes of cancer therapy. Unfortunately, the benefits of anthracycline chemotherapy are tempered by potentially serious cardiotoxic effects, which were recognized shortly after the drugs were introduced in the late 1960s [74, 75, 76]. The cardiotoxic effects have a dose–response relationship, similar to the antitumor effects of the drug. Despite the medical community’s vast experience with this agent, cardiotoxicity remains highly problematic and oncologists and cardiologists continue to struggle with the Hippocratic dictum, “first, do no harm” [77].

The antitumor properties of anthracyclines stem from their ability to intercalate between DNA base pairs of replicating cells, causing DNA fragmentation, inhibition of polymerases, and decreased synthesis of DNA, RNA, and proteins [78]. DNA damage is thought to be mediated in part through targeting of topoisomerase IIα [79]. Doxorubicin is also a powerful iron chelator, with iron-mediated generation of free radicals resulting in the cleavage of DNA and cell membranes. The cardiotoxicity of anthracyclines apparently results from myocyte damage due to toxic free radicals and an increase in oxidative stress, which causes lipid peroxidation of membranes, leading to vacuolization. Myocyte damage is associated with a decrease in endogenous antioxidant enzymes, such as glutathione peroxidase, that are responsible for the scavenging of free radicals [80]. Each successive dose of anthracycline results in incremental cardiac myocyte death and replacement by fibrous tissue. Eventually the compensatory mechanisms of the heart are overwhelmed and dilated cardiomyopathy ensues.

Anthracycline-induced cardiotoxicity can be directly diagnosed by endomyocardial biopsy. This is best assessed by electron microscopy, with characteristic changes that include myofibrillary bundle depletion, myofibrillar lysis, distortion and disruption of the Z-lines, mitochondrial disruption, and intramyocyte vacuolization [81]. Billingham and coworkers [82] found that morphologic damage seen on right ventricular biopsy and quantified on a four-point scale (0 = no damage, 4 = diffuse damage) was related (r = 0.50) to the total cumulative doxorubicin dose between 100 and 600 mg/m2. Morphologic changes were more closely related to cumulative dose in patients who received prior mediastinal radiation (r = 0.65). In the same cohort, myocardial performance was preserved until a critical threshold dose of 550 mg/m2 was reached, after which function deteriorated, echoing the findings of Lefrak et al. A study of 158 patients who underwent single or serial endomyocardial biopsies suggested that the Billingham grading system had greater sensitivity and specificity for early detection of dose-related toxicity (p < 0.02) than noninvasive assessment of left ventricular function by gated blood pool studies or M-mode echocardiography [83].

A postmortem study of anthracycline-treated patients similarly found histopathologic changes by light microscopy in 23 of 44 (52%) patients with no clinical signs of cardiotoxicity [84]. Although no histopathologic evidence of toxicity was identified in seven of 20 (35%) patients who did express clinical signs of cardiotoxicity, this may be attributed to the lower sensitivity of light microscopy for detection of characteristic morphologic changes, when compared with electron microscopy techniques. These tissue-correlation studies suggest that morphologic alterations precede functional deterioration. Hence, endomyocardial biopsy with electron microscopy was given Class IIa recommendation for the assessment of suspected anthracycline-induced cardiomyopathy, based primarily on expert consensus [85].

Noninvasive Monitoring of Anthracycline Toxicity

Despite the high sensitivity and specificity of endomyocardial biopsy, it is not a practical method of patient monitoring given its invasive nature, inherent risks, and expense. Many investigators originally advocated for empiric discontinuation of anthracycline administration after reaching a threshold cumulative dose, based on population-wide data. In 1973, Lefrak et al. [86] found that clinically overt congestive heart failure (CHF) occurred only once in the 366 patients (0.27%) who were treated with less than 550 mg/m2 of adriamycin, but ten cases were seen in 33 patients (30%) who received more than 550 mg/m2. Consequently, an empiric restriction of 550 mg/m2 maximum cumulative dose was recommended for all patients. In a retrospective analysis, however, Von Hoff et al. [87] estimated that 3% of patients developed CHF at a cumulative doxorubicin dose of 400 mg/m2, 7% at 550 mg/m2, and 18% at 700 mg/m2, strongly suggesting an increasing risk of clinical toxicity over a continuum of cumulative doses, debunking the existence of a critical threshold. A more recent retrospective analysis of three prospective studies confirmed the nature of this exponential dose–toxicity relationship and indicated that the incidence of clinical toxicity was grossly underestimated in earlier studies. The percentage of patients with doxorubicin-related CHF was 5.0% at a cumulative dose of 400 mg/m2, 16% at 500 mg/m2, 26.0% at 550 mg/m2, and 48.0% at 700 mg/m2 [88]. The notorious unpredictability of clinical cardiotoxicity in individuals, and evidence for a y = x2 dose–toxicity relationship among populations [89], has rendered empiric dose limitation obsolete. High cumulative doses, nonetheless, remain an overwhelming risk factor.

In 1979, Alexander et al. [70] reported the utility of RVG as a marker for early detection of anthracycline-related cardiotoxicity by serially monitoring of the LVEF. RVG studies were performed on 51 patients treated with doxorubicin for various types of tumors. Five developed clinical signs of heart failure at doxorubicin doses ranging from 490 to 715 mg/m2. Absolute declines in the LVEF by more than 15% were noted prior to the development of CHF , which was clinically evident only when the LVEF declined to less than 30%. In six patients with an asymptomatic absolute decline in LVEF of 15% or less at doxorubicin doses of 460–900 mg/m2, doxorubicin was discontinued and none developed overt heart failure. Repeat measurement of LVEF several months after stopping doxorubicin showed a modest improvement in LVEF in all patients.

In 1987, Schwartz and coworkers published guidelines for surveillance of anthracycline-induced cardiotoxicity based on their experience with RVG over a 7-year period (see Table 3) [90]. In short, baseline LVEF, absolute change in LVEF, and final LVEF were determinants. They retrospectively analyzed 282 serially monitored high-risk patients and found that heart failure developed in only two (3%) of 70 patients monitored according to these guidelines. By comparison, CHF developed in 44 of 212 high-risk patients (21%) in whom the guidelines were incompletely followed (Fig. 4). Multivariate analysis demonstrated a nearly fourfold risk reduction in development of CHF in those managed according to guidelines. In the 46 patients who developed CHF, a mean decline in LVEF of 23 ± 14% was noted versus a decline of 12 ± 10 in those who did not subsequently develop CHF (p < 0.001). While these guidelines have never been prospectively validated, they are still widely accepted today. These guidelines, with an updated discussion and literature review, were updated in 2016 [91].
Table 3

Guidelines for monitoring patients receiving doxorubicin

 Perform baseline radionuclide angiocardiography at rest for calculation of left ventricular ejection fraction (LVEF) prior to administration of 100 mg/m2 doxorubicin. Subsequent studies are performed at least 3 weeks after the indicated total cumulative doses have been given, before consideration of the next dose

Patients with normal baseline LVEF (≥50%)

 Perform the second study after 250–300 mg/m2

 Repeat study after 400 mg/m2 in patients with known heart disease, radiation exposure, abnormal electrocardiographic results, or cyclophosphamide therapy or after 450 mg/m2 in the absence of arty of these risk factors

 Perform sequential studies thereafter prior to each dose

 Discontinue doxorubicin therapy once functional criteria for cardiotoxicity develop, i.e., absolute decrease in LVEF ≥10% (EF units) associated with a decline to a level ≤50% (EF units)

Patients with abnormal baseline LVEF (<50%)

 Doxorubicin therapy should not be initiated with baseline LVEF ≤30%

 In patients with LVEF >30% and <50%, sequential studies should be obtained prior to each dose

 Discontinue doxorubicin with cardiotoxicity: absolute decrease in LVEF ≥10% (EF units) and/or final LVEF ≤30%

Fig. 4

Example of patient diagnosed with Hodgkin lymphoma at age 24 who developed progressive late-onset cardiomyopathy >10 years after receiving a cumulative doxorubicin dose of 200 mg/m2 and concurrent XRT to the chest, followed by autologous stem cell transplant. (a) Rest RVG 13 years after doxorubicin therapy, LVEF = 32%, asymptomatic. (b) Rest RVG 20 years after therapy, LVEF = 17% (20% by echocardiography), NYHA Class III-IV HF

Risk Factors for Type 1 CRCD

There are many known risk factors for anthracycline-induced cardiotoxicity, in addition to cumulative dose. The pediatric population appears to be more prone to cardiotoxicity at lower cumulative anthracycline doses (250–300 mg/m2) [92]. At the opposite end of the spectrum, patients older than 65–70 years are also more susceptible to toxicity, probably due to comorbidity of underlying heart disease and/or decreased functional reserve. In one study, after a cumulative dose of 400 m/m2, patients older than 65 were more than three times more likely to develop CHF than patients younger than 65 (hazard ratio [HR], 3.28; 95% CI, 1.4–7.65, p = 0.002) [ [54]]. Other drugs, such as cyclophosphamide and trastuzumab (as will be discussed), can augment the cardiotoxic effects of anthracyclines. Chest radiation, either previously or concurrent with chemotherapy probably, increases the risk of cardiotoxicity, possibly due to endothelial cell damage caused by radiation. This factor is particularly relevant for women with breast cancer who often receive radiotherapy to the chest wall or for lymphoma patients who often undergo mediastinal irradiation. Studies indicate a higher risk of toxicity in patients with left-sided breast cancer, due to the proximity to the cardiac vessels and the myocardium. One long-term study of contemporary external beam radiation techniques, however, showed that left-sided targeting is not associated with a higher risk of cardiac death up to 20 years after treatment, but is nevertheless associated with an increased rate of coronary artery disease and MI compared with right breast treatment [93]. Several risk factors were recently elucidated in a SEER data analysis of 43,338 women with breast cancer [94]. After 10 years of follow-up, 38% of women who were treated with anthracyclines at age 66–70 eventually developed CHF with a statistically significant increase in absolute risk of 5.9% and 9.7% when compared with those who received non-anthracycline regimens or no chemotherapy, respectively. This difference was not seen in women at age 71–80, possibly because of higher baseline rates of CHF in this age group because of selection bias, with the healthier women qualifying for anthracycline regimens. Specific predictors of CHF also included years elapsed since therapy (HR, 1.79 per 10 years; 95% CI, 1.66– 1.93), Black race (HR, 1.40; 95% CI, 1.30– 1.50), trastuzumab treatment (HR, 1.46; 95% CI, 1.21–1.77), hypertension (HR, 1.45; 95% CI, 1.39–1.52), diabetes (HR, 1.74; 95% CI, 1.66–1.83), and coronary artery disease (HR, 1.58; 95% CI, 1.39–1.79). Left-sided radiotherapy did not confer a clearly increased risk for CHF (HR, 1.04; 95% CI, 0.98–1.11) in this cohort. Inexplicably, anthracycline-treated patients apparently had fewer cardiology visits and underwent fewer LVEF assessments with RVG or echo than other breast cancer patients (p < 0.0001).

Late-Onset Cardiomyopathy and the Pediatric Population

Symptomatic heart failure generally presents less than 1 year after anthracycline administration, but as suggested in the SEER data, heart failure develops in a subset of patients after a latency period of more than a decade. Strong evidence for “late-late” development of cardiomyopathy is primarily derived from pediatric cancer survivors, as seen in the early 1990s [95, 96]. Recent analyses of late cardiotoxicity in childhood cancer survivors confirm that survivors are at increased risk for many cardiac complications, foremost heart failure [97]. The cumulative incidence of adverse cardiac outcomes in cancer survivors appears to continue to increase up to 30 years after diagnosis, at which point more than 7.5% of patients who received a cumulative dose of more than 250 mg/m2 will have developed heart failure [98]. Guidelines were proposed by the Cardiology Committee of the Children’s Cancer Study Group for monitoring acute and late manifestations of doxorubicin cardiotoxicity [99]. For pediatric patients, echocardiography is the preferred method of surveillance to minimize exposure to radiation, with the more reproducible RVG reserved for confirmation of LVEF decline in high-risk patients.

Type II CRCD

Trastuzumab is a humanized monoclonal antibody that targets the extracellular domain of human epidermal growth factor receptor 2 (HER2 also referred to as HER2/neu or erbB-2), a transmembrane tyrosine kinase receptor. Interaction of the antibody with the target inhibits signal transduction, resulting in decreased tumor cell growth and survival. Approximately 25% of newly diagnosed patients with invasive breast cancers overexpress HER2 and are more likely to have an aggressive form of the disease with shortened relapse-free survival and reduced overall survival [100]. In HER2-overexpressing breast cancers, treatment with trastuzumab confers a clear survival benefit in the metastatic and adjuvant settings, both as monotherapy and in combination with cytotoxic agents. Trastuzumab-associated heart failure was recognized in the initial trials of patients with metastatic breast cancer, and a small but significant risk has been repeatedly documented in the adjuvant setting. Pure type II CRCD manifests as a loss of myocardial contractility and is less likely to cause myocyte death. The underlying pathophysiologic mechanism for this dysfunction is not fully understood, but it is believed to be directly related to inhibition of HER2 signaling, which apparently plays an essential role in the heart’s compensatory mechanisms following exposure to stress. Preclinical models support this notion, as erb2 knockout mice tend to develop cardiomyopathy following induction of cardiac stress pathways [101]. Interestingly, these mutant mice are also more susceptible to anthracycline-induced cell death, suggesting a synergistic toxicity. Similarly, limited scintigraphic data indicate that myocardial HER2 expression is upregulated shortly after anthracycline-based chemotherapy, as detected by myocardial uptake on 111In-DTPA-trastuzumab SPECT imaging [102]. One clinical study indicated that serum HER2 levels are increased in patients with depressed LVEF and chronic heart failure [103]. Clinically, patients who have never received anthracyclines do develop cardiac toxicity [104], but the risk is clearly higher in patients who have been treated concurrently or previously with anthracyclines and to a lesser degree with taxanes [105]. This risk of toxicity appears to decrease with longer intervals between the administration of the two drugs. Because trastuzumab has a long half-life, these synergistic effects may come to the fore even when anthracyclines are given after trastuzumab has already been discontinued.

A number of studies suggest that type II CRCD is potentially reversible, including the pivotal phase III trial of trastuzumab [106]. In one study by Ewer et al., 38 patients with HER2-positive breast cancer previously treated with doxorubicin developed cardiotoxicity after trastuzumab therapy, which generally improved after withdrawal of the drug. These patients were safely rechallenged with trastuzumab after the cardiac manifestations abated [107]. After doxorubicin but before trastuzumab, the mean LVEF was 0.61 ± 0.13, and the LVEF decreased to 0.43 ± 0.16 after trastuzumab (p < .0001). After withdrawal of trastuzumab, LVEF increased to 0.56 ± 0.11. Mean time to recovery of LVEF was 1.5 months and was temporally associated with medical treatment in 32 (84%) of the 38 patients but occurred without treatment in six patients (16%). Increases in LVEF were noted in 37 of the 38 patients. Subsequently, 25 of these patients were re-treated with trastuzumab; three patients had recurrent LV dysfunction, but 22 patients (88%) did not. Importantly, in nine patients who underwent endomyocardial biopsy, no ultrastructural changes were seen.

Guarneri et al. evaluated the safety of trastuzumab therapy (median 21.3 months of administration) in 173 patients with metastatic breast cancer [108]. After a median follow-up of 32.6 months, 49 patients (28.3%) experienced a cardiac event: three patients (1.7%) had an asymptomatic decrease in the LVEF of 20%; 46 patients (26.6%) experienced grade 2–3 cardiac toxicity; one cardiac-related death was noted (0.5%). LVEF or symptoms of CHF improved in all but three patients with trastuzumab discontinuation and appropriate therapy, suggesting that toxicity is manageable and generally reversible. Interestingly, baseline LVEF was significantly associated with cardiac events (HR, 0.94; p < 0.001).

The HERA trial was a large three-group, randomized trial that compared 1,698 patients randomly assigned to observation and 1,703 randomly assigned to 1 year of trastuzumab treatment. The majority (94.1%) of patients had previously been treated with anthracyclines. Eligible patients had normal LVEF (defined as ≥55%) after completion of neo/adjuvant chemotherapy with or without radiotherapy. Trastuzumab was discontinued in 5.1% of patients owing to a cardiac disorder. At a median follow-up of 3.6 years, the incidence of cardiac end points remained low, although it was higher in the trastuzumab group than in the observation group (severe CHF, 0.8% vs. 0.0%; confirmed significant LVEF decreases, 3.6% vs. 0.6%). Roughly 80% (59/73) of those who developed cardiac end points in the trastuzumab group recovered. This important study suggests that the incidence of cardiac end points remains low even after longer-term follow-up [109].

Monitoring and Management

The optimal approach for monitoring of trastuzumab-related cardiotoxicity, as with anthracyclines, lacks complete international consensus. Proposed guidelines from MSKCC are outlined in Table 4 [110].
Table 4

Proposed guidelines for the management of patients with metastatic disease who are treated with trastuzumab, based on physical status and left ventricular ejection fraction (LVEF)

Physical statusa

LVEF

Trastuzumab

LVEF monitoring

Management

Asymptomatic

↓but normal

Continue

Repeat in 4 weeks

 

↓ >10 points but normal

Continue

Repeat in 4 weeks

Consider beta-blockers

↓10–20 points and LVEF >40%

Continue

Repeat in 2–4 weeks Improved: monitor

Treat with medications for LV dysfunction

Not improved: stop trastuzumab

↓ >20 points to <40% or LVEF < 30%

Hold

Repeat in 2 weeks

Treat with medications for LV dysfunction

Improved to >A5%: restart trastuzumab

  

Not improved: stop trastuzumab

 

Symptomatic

↓ < 10 points

Continue

 

Search for noncardiac pathology (e.g., anemia)

↓ > 10 points and LVEF >50%

Continue

Repeat in 2–4 weeks

Treat for CHF

Stable or improved: continue trastuzumab

Worsened: stop trastuzumab

> 30 points

Stop

 

Treat for CHF

aHeart and body weight should be monitored weekly. Asymptomatic is defined as changes in heart rate and/or weight but without symptoms of dyspnea on exertion. Symptomatic is defined as a new, spontaneous (i.e., unsolicited) report of symptoms of dyspnea on exertion, pulmonary vascular congestion, or edema (From Keefe [110] with permission)

Similar guidelines were incorporated in the HERA trial [111].

Reducing Cardiotoxicity

Several approaches help reduce the incidence of therapy-associated cardiovascular complications. Patients should be screened for pre-existing cardiac disease, especially valvular disease and cardiomyopathy. A threshold for cumulative dose is controversial in the era of advanced monitoring techniques. Modifying anthracycline administration by prolonged infusions and liposomal formulations has met variable success. Dexrazoxane , an EDTA-like chelator, is thought to prevent anthracycline cardiotoxicity by its ability to bind iron thus preventing free radical formation. Despite the apparent cardiac benefit, the possibility of mitigating the antitumor effect has raised concern regarding the use of dexrazoxane as a cardioprotectant (ASCO guidelines 2008 [112]). Cardioactive medications, such as angiotensin-converting enzyme (ACE) inhibitors and the combined beta- and alpha-blocker carvedilol, are useful in anthracycline- and trastuzumab-induced cardiomyopathy, particularly when started early after cancer therapy [113, 114]. There is also evidence for beneficial effects of statins in this setting [115]. When appropriate, consideration should be given to alternative classes of chemotherapies, such as taxane-based therapies, or other tyrosine kinase inhibitors, for instance, lapatinib [116].

RVG Versus Other Imaging Modalities

Before discussing comparative performance of different modalities for measuring LVEF, it should be emphasized that all sequential measurements of LVEF are subject to inherent physiologic variability owing to hemodynamic, metabolic, hormonal, and pharmacologic factors, etc. One group sought to determine the limits of this variability by performing a double-blind placebo-controlled study in 39 patients who underwent two assessments separated by a 6-week placebo period, during which patients were deemed clinically stable [117]. While the total mean LEVF did not change significantly, LVEFs were quite variable on an individual basis. They determined that inherent variation in contractility is accounted for when the change in LVEF is greater than or equal to 7%. It was estimated that a 4% observed increase or decrease in LVEF following a medical intervention can occur by chance more than 25% of the time in individual patients.

RVG is considered more accurate and reproducible than two-dimensional (2D) echocardiography for assessment of LVEF. Advantages and limitations of RVG are listed in Table 5. The modified in vivo method for red cell labeling [118] is preferred over the in vitro and in vivo methods as it provides ease, safety, and high efficiency (92–95%) of labeling.
Table 5

Equilibrium radionuclide ventriculography

Advantages

Limitations

Measurements do not rely on geometric assumptions regarding shape of LV

Radiation exposure (6.2 mSv)

Functional information for all cardiac chambers

Limited information regarding structure, in particular of valves

Noninvasive

ECG gating unreliable in patients with significant arrhythmias and variability of RR interval

High accuracy and reproducibility

Limited assessment of ventricular wall thickness

Global and regional LV systolic function can be assessed

Poor technique can introduce errors in measurement

Phase analysis of segmental ventricular contraction conveys information for regional dyssynergy

 

Rarely limited by body habitus

Selecting appropriate background in patients with breast prosthesis/tissue expander may be challenging

Relatively easy to perform

 

Normal resting LVEF by equilibrium RVG is greater than 50% as is incorporated into most clinical guidelines and as defined by the Society of Nuclear Medicine. RVG with SPECT has been shown to correlate well with planar-derived LVEF values [119]. SPECT allows for better evaluation of regional wall motion, size, and shape of the left ventricle and does not have the limitation of overlap by other cardiac chambers. Exercise stress RVG may identify a reduced contractility reserve in asymptomatic patients with normal resting LVEF [120]. Measures of diastolic dysfunction obtained on equilibrium RVG may detect toxicity earlier than changes in systolic dysfunction [121].

Advantages of echocardiography include portability, lack of ionizing radiation, and the ability to evaluate other important parameters such as valvular function, wall motion, and hemodynamics, which are better assessed by echocardiography than by RVG. The major disadvantage of echocardiography is the lower reproducibility of LVEF measurement, because of the reliance on geometric assumptions. In addition, patients with – not uncommon – poor acoustic windows are precluded from this procedure. The American Society of Echocardiography and European Society of Echocardiography have defined normal LEVF by echocardiography as greater than 55% for both men and women, although some argue that the lower limit of normal should be redefined to greater than 50% [122]. Three-dimensional (3D) echocardiography is an increasingly available modality for assessment of systolic function that takes advantage of additional spatial data to provide more accurate estimates for LVEF than two-dimensional (2D) echocardiography. C-MRI is also increasingly available and appears to accurately assess left ventricular systolic function with its high spatial and temporal resolution; however, the high cost of repeated examinations and limited availability render MRI a less-than-ideal for routine monitoring of cardiotoxicity.

Several studies suggest that ejection fraction measurements by various techniques are not interchangeable. A review of eight different studies (n = 293) comparing 2D echocardiography with either RVG or contrast angiography exhibited coefficients of correlation ranging from 0.78 to 0.93. Agreement analysis with Bland–Altman plots ranged from 23% to 42% around the mean ejection fraction [123]. A non-oncologic study in patients with chronic stable heart failure who underwent evaluation by M-mode echocardiography, 2D echocardiography, MRI, and RVG showed wide variability in inter-modality measurements, with the narrowest limits of agreement between MRI and RVG at 31% around the mean LVEF [124]. Gopal et al. first demonstrated that 3D echocardiography provides values comparable to RVG and more accurate than 2D echocardiography measurements [125]. A more recent head-to-head study performed in the context of trastuzumab-associated cardiotoxicity confirmed these findings, showing a high correlation (r = ~ 0.9) between RVG, 3D echocardiography, and MRI and a weak correlation of these modalities with 2D echocardiography (r = ~0.3–0.4) for serial LVEF assessment [126]. This suggests that 3D echocardiography and MRI may in fact be interchangeable with RVG as technology continues to improve.

Additional radiopharmaceuticals have been evaluated for the early detection of anthracycline-induced cardiac damage, including necrosis imaging with 111In-antimyosin, apoptosis imaging with 99mTc-annexin-V, and imaging of cardiac innervation with 123I-MIBG [127]. As of yet, none of these scintigraphic techniques have proven advantageous over imaging of cardiac function with RVG. In particular, the clinical utility of 123I-MIBG is hampered by difficulty with quantifying changes on serial scans. This challenge may be overcome in the near future with the recent development of a quantifiable PET analog of benzylguanidine, 18F-MFBG [128, 129], which is now undergoing evaluation for use in patients with neuroendocrine tumors.

Recommendations

RVG continues to be a widely accepted method for monitoring therapy-related cardiotoxicity in cancer patients. Baseline LVEF assessments should be obtained in all patients receiving anthracyclines and should be strongly considered in patients receiving trastuzumab, particularly if given before, together with, or following anthracyclines. Risk–benefit ratios should be carefully weighed before initiating or withholding cardiotoxic therapies and are best assessed by dedicated onco-cardiologists or cardio-oncologists. Extreme caution is required when initiating or continuing the drug in patients with the previously specified risk factors, in symptomatic patients, or in patients who have abnormal systolic function at baseline. The lower limit of normal for LVEF by RVG is 50%; however, this value is subject to interinstitutional variability, owing to confounding factors such as the patient population tested, procedure technique and processing, software used for calculation, etc. Echocardiography may be substituted for RVG, particularly in children and those with known valvular abnormalities. The various modalities available for LVEF assessment should not be used interchangeably. Detailed algorithms for monitoring of toxicity by RVG and echocardiography have been provided; however, it should be emphasized that none of these have been prospectively validated. A rule of thumb is that a decline in LVEF of more than 10% to a level below normal (LVEF <50%) is indicative of subclinical toxicity in asymptomatic patients, at which point more intensive monitoring should follow. Investigation with endomyocardial biopsy should be reserved for selective cases where the diagnosis of cardiotoxicity is unclear. In view of the limitations of RVG and echocardiography for early detection of cardiotoxicity, more efficient markers of cardiotoxicity are needed. Well-established serum markers of myocardial damage such as troponins and BNP have demonstrated a clear role in this context [130, 131] but are unlikely to replace serial monitoring of LV systolic function as a marker of toxicity. ACE inhibitors and/or beta-blockers should be considered at the earliest indication of cardiac insult, unless otherwise contraindicated. The list of drugs with potential cardiotoxic effects is increasing (Table 6). As a result, serial measurement of cardiac function is likely to increase as new drugs are developed.
Table 6

Chemotherapeutic agents with vascular side effects

Agent

HTN

Angina

AMI

RP

DVT/PE

5-Fluorouracil

 

X

X

X

 

Capecitabine

 

X

X

X

 

Gemcitabine

 

X

X

X

 

Paclitaxel

X

X

X

 

X

Cisplatin

X

X

X

X

 

Cyclophosphamide

 

X

   

Bleomycin

 

X

X

  

Vincristine

X

X

X

X

 

Everolimus

X

X

  

X

Temsirolimus

X

X

  

X

Bortezomib

  

X

 

X

Combretastatin

X

X

X

  

Bevacizumab

X

X

X

 

X

Rituximab

X

X

X

  

Sorafenib

X

X

X

 

X

Sunitinib

X

X

X

 

X

Interferon

X

X

X

X

X

HTN hypertension, AMI acute myocardial infarction, RP Raynaud’s phenomenon, DVT/PE deep venous thrombosis/pulmonary embolus

Modified from table in Herrmann et al. [8] with permission of the author and publisher

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  1. 1.Department of RadiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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