Prevention, Assessment, and Management of Treatment-Induced Cardiac Disease in Cancer Patients
David A. Slosky
INTRODUCTION
During the last 30 years, the development of effective detection and treatment strategies for many malignancies has led to a significant population of cancer survivors (1,2). It is estimated that approximately 60% of adults newly diagnosed with cancer will survive for 5 or more years beyond the time of diagnosis. The National Cancer Institute and the Centers for Disease Control and Prevention estimate that there are more than 12 million cancer survivors in the United States (1). The impact of cancer and cancer treatment on the health of a survivor is substantial. Effects include organ damage and functional disabilities that occur as a consequence of the disease and/or the treatments. In addition, there are numerous psychosocial issues that confront adult cancer survivors. The recognition of these effects is increasing and there is accumulating evidence available to guide the physician caring for these people. The effects have become more common with the increased use of complex, intensive multi-agent and multi-modality cancer interventions. As a consequence of improved survival in cancer patients, they are reaching an age where cardiovascular disease is manifest. There is an increase in cardiovascular events including myocardial ischemia, myocardial infarction, hypertension, pericardial effusion, congestive heart failure, stroke, and depression. Long-term cancer survivors are at risk for a variety of cardiac effects.
The care of a patient with cardiovascular disease is a challenging and complex process. Caring for a patient with a malignancy multiplies these complexities and requires strong collaboration and evidence-based decisions. As the complexity of cancer therapeutics continues to rise and specialized molecular targets of cancer growth are targeted, collaborative management of multiple comorbidities will be required. These treatments may have important adverse effects on the cardiovascular system. It then becomes imperative for cardiovascular specialists to have an understanding of the prevention, identification, and treatment of cardiac disease in cancer patients in order to provide optimal care and outcomes. Today’s oncologists must be fully aware of cardiovascular risks to avoid or prevent adverse cardiovascular effects.
Management of hypertension, coronary artery disease (CAD), the surgical patient with cancer, metastatic pericardial effusion, and valvular or structural heart disease; recognition of behavioral effects of a cancer with an emphasis on depression; and end of life decisions all require an organized, multidisciplinary approach to provide the best care and optimize outcomes while maintaining a high quality of life. This chapter will attempt to elucidate these challenges and provide a framework to approach these issues.
Chemotherapy-induced cardiovascular toxicity traditionally has included cardiomyopathy with or without overt congestive heart failure, endothelial dysfunction, and arrhythmias. Doxorubicin-induced cardiomyopathy is the most studied form of chemotherapy-induced cardiotoxicity.
Radiotherapy-induced cardiotoxicity is a significant issue that is under-recognized and may lead to CAD, valvular heart disease, chronic pericardial disease, arrhythmias, conduction system disease, and carotid artery stenosis. Cancer patients represent a rapidly expanding patient population at risk for premature cardiovascular disease. This growth leads to an increase in cardiovascular-related mortality and potentially may offset the advancements in cancer survival.
Chemotherapeutic Agents Associated with Cardiovascular Toxicity
Anthracyclines: The original anthracycline was isolated from the bacteria Streptomyces peucetius and was subsequently named daunorubicin. Adriamycin was developed as a derivative and later designated as doxorubicin. This agent serves as one of the gold standards of oncologic treatment, particularly because of its broad spectrum of activity.
The mechanism of oncologic action for anthracyclines has not been fully defined. There appear to be multiple mechanisms that play a role in tumor destruction. These include inhibition of DNA and RNA synthesis (3). There may also be an interaction with topoisomerase II and direct reaction with the cellular membrane, which leads to alteration of function (4). Anthracyclines have been shown to induce breaks in double-stranded DNA and free radical formation. This can lead to intracellular accumulation of mutated or oxidatively modified proteins, which can lead to endoplasmic reticulum stress. This reaction may induce activation of the cascade of caspases, which leads to apoptosis (cell death). It has been established that anthracyclines can induce myocyte injury via the induction of autophagy. This is an evolutionary mechanism in which damaged proteins and organelles are removed and recycled. This process supports cell survival during stress; however, within the
context of disease and treatment, autophagy promotes cell death (5).
context of disease and treatment, autophagy promotes cell death (5).
Doxorubicin and other anthracyclines generally lead to irreversible cardiotoxicity. This toxicity is related to cumulative lifetime total dose; however, using cardiac biomarkers and sophisticated imaging techniques, left ventricular (LV) dysfunction may be detected before clinical manifestations are apparent. Early animal studies with anthracyclines demonstrated cardiotoxicity, which was later confirmed in clinical trials. Von Hoff and colleagues defined a curve plotting the probability of developing congestive heart failure as a function of the cumulative dose in approximately 4,000 patients who had received the drug on a 3-week administration schedule (6,7). Dosing guidelines emerged from these studies, which demonstrated that a cumulative dose of approximately 550 mg/m2 correlated with a likelihood of congestive heart failure in approximately 5% of patients. Subsequent information suggests the dose at which one sees toxicity is lower and likely cumulative. The toxicity associated with anthracyclines is variable in individual patients. There have been a number of investigations into this phenomenon; however, there are no current screening or predictive tools to determine which patients will develop cardiac dysfunction. There are studies to identify cardiac biomarkers such as brain natriuretic peptide (BNP) and troponin in the early detection of cardiac toxicity; however, the data require further validation (8,9). The only test that has been shown to be sufficiently sensitive to detect early cardiotoxicity is a cardiac biopsy.
Unfortunately, the examination is expensive and confers risk to the patient such as cardiac perforation and tamponade. Therefore, there is a need for noninvasive techniques to identify cardiotoxicity. The focus of identification of cardiotoxicity from anthracyclines has shifted to prevention and protection. The first goal of cardioprotection is to allow the cancer therapy to be administered with maximum effectiveness with a minimum of cardiotoxicity. A second goal is to preserve the structural and functional integrity of the heart so that there is sufficient reserve when exposed to additional stressors later in life. These include additional chemotherapy exposure, radiation, hypertension, valvular heart disease, and ischemic heart disease. The assumption should be made that anthracycline toxicity begins with the first exposure and that each subsequent dose is additive. There are multiple modalities that have evolved for cardioprotection. These include dose limitation, schedule modification, innovative delivery systems, analogues, and chemical cardioprotection.
A number of pharmacologic agents for cardioprotection have been explored, which include Coenzyme Q10, N-acetylcysteine, calcium channel blockers, and alpha tocopherol.
Dexrazoxane is the singular compound that has shown efficacy in reducing doxorubicin cardiotoxicity. This compound belongs to a class of agents called bisdioxopiperazines which, when hydrolyzed, yield a compound that is similar to ethylenediaminetetra acetic acid, a metal ion chelating agent. It is postulated that dexrazoxane may enter the cell by diffusion and chelate free iron or iron bound to iron-anthracycline complexes, thereby reducing oxygen radical production (10,11). Preclinical studies of dexrazoxane suggested reduced cardiotoxicity in a number of different models and set the stage for human studies to protect patients from anthracycline toxicity. Two large multicenter trials were conducted by Swain et al. (12). These studies were performed to evaluate the ability of dexrazoxane to confer cardioprotection in patients with metastatic breast cancer who were anthracycline naïve. From these trials, one can conclude that dexrazoxane is cardioprotective for patients who receive it from the initiation of chemotherapy onward. A concern that dexrazoxane may interfere with tumor response has been raised and remains a source of controversy. Though the trial data by Swain may inform how anthracyclines are used, these findings are not conclusive. Additional studies are needed to define the role of this drug in cancer patients receiving anthracyclines. Currently, the drug is not approved for early use by the FDA in adults (13).
Doxorubicin affects the heart in a number of different ways (14,15). Cardiotoxicity has been categorized as early and late forms. Early toxicity occurs with or follows infusion within hours or days. Late toxicity is seen weeks, months, or years following the administration of the drug and primarily manifests as cardiac dysfunction (16,17). Early toxicity is more common in the elderly and may manifest as transient electrocardiographic (ECG) changes in the ST segment with T-wave changes (18). The patient may also experience atrial or ventricular ectopy (19,20). There is an association between early cardiotoxicity and the use of large single doses of doxorubicin.
Clinical Recognition of Doxorubicin-Associated Cardiotoxicity
Congestive heart failure is generally a progressive process with a preclinical course. Patients with doxorubicininduced cardiomyopathy may not experience symptoms until the cardiac damage is established. Manifestations may include tachycardia or a slow return of the heart rate to baseline after minimal activity, which indicates limited cardiac reserve. Another symptom that is common is dyspnea while performing activities that did not previously elicit this symptom. This is another indicator of diminished cardiac reserve. The patient may also complain of difficulty with climbing stairs or fatigue that is out of proportion to the activity level. As cardiac dysfunction progresses, the patient may experience resting dyspnea, nocturnal dyspnea, weight gain, fluid retention, and a diastolic gallop (S3). Modalities such as transthoracic echocardiography (TTE) and radionuclide assessment of LV function (multigated acquisition [MUGA]) have traditionally been used to evaluate LV function. Small changes in noninvasive measurements may indicate early toxicity. Cardiac ultrasound has an advantage in that there is no radiation exposure and is less costly. Valve integrity and wall thickness may also be evaluated. There is evidence that a difference of 2% in the mean LV ejection fraction is significant. It is important to emphasize
that measurement of the ejection fraction is a snapshot in time. Factors that may have an influence on cardiac function include changes in sympathetic and parasympathetic tone, heart rate variability, metabolic changes, anemia, hormonal variation, nutritional state, pharmacologic interventions, and analgesic medications.
that measurement of the ejection fraction is a snapshot in time. Factors that may have an influence on cardiac function include changes in sympathetic and parasympathetic tone, heart rate variability, metabolic changes, anemia, hormonal variation, nutritional state, pharmacologic interventions, and analgesic medications.
Risk Factors for Doxorubicin Cardiotoxicity
Factors that are associated with increased risk include nonanthracycline anticancer therapies such as radiation to the heart, extremes of age, and preexisting heart disease (Table 31.1). Significant data related to susceptibility to cardiovascular injury have evolved from the study of children with cancer enrolled in protocols in which they received anthracycline-based therapy for hematologic malignancies such as leukemia, lymphoma, and sarcomas. In a study of pediatric cancer survivors compared with their siblings, 14,358 patients followed for up to 30 years after their cancer diagnosis were three times more likely to experience a chronic cardiovascular event (1).
Management of Patients Receiving Anthracyclines
Noninvasive testing using echocardiography or nuclear imaging should be used to assess LV function at baseline. Subsequent evaluation may vary according to the dose of anthracycline used and the clinical symptoms of the patient. If patients receive 300 to 450 mg/m2 and are asymptomatic with no clinical signs of cardiac dysfunction, then one might consider the assessment of LV function, troponin, and BNP every one to two cycles. An echocardiogram approximately 3 to 4 months after completion of therapy is reasonable, as is a follow-up study annually for 5 years and then every 2 to 3 years. There is no ideal algorithm to avoid anthracycline-induced cardiac dysfunction. However, the goal is to maximize survival and minimize mortality from cancer and the cardiotoxicity of cancer therapy. Therefore, the oncologic benefit is weighed against the cardiotoxic risks. Clinical judgment is critical and is as important as algorithms in the decision-making process.
TABLE 31.1 Anthracycline Cardiotoxicity (Risk Factors) | ||||||||||||||||||||
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Treatment of Established Doxorubicin-Associated Cardiac Dysfunction
The principles of intervention for patients who have experienced anthracycline cardiotoxicity include amelioration of additional cardiac damage, optimization of cardiac reserve, symptom reduction, reduction of workload, improvement of cardiac output, facilitation of cellular regeneration, and possible organ transplantation. It is critical to consider avoidance of additional exposure to anthracycline if cardiotoxicity exists. There is no evidence that a change to a different form of anthracycline is of benefit. This could result in additional damage to the myocardium. It is important to be sure that the patient’s symptoms are due to LV dysfunction and not due to other causes. Symptoms of cardiac dysfunction are many times nonspecific and may be related to other conditions such as pulmonary infiltrates, metastatic disease progression, endocrine abnormalities, infections, deconditioning, neurologic conditions, and anemia.
Modalities available for patients who have experienced anthracycline-associated heart failure include mitigation of additional injury, optimization of cardiac reserve, pharmacologic intervention to reduce workload and increase cardiac output, and possible organ transplantation. After withdrawal of the agent and the patient’s symptoms have been treated, the physician should follow standard guidelines for the treatment of heart failure that have been well publicized by the American Heart Association (AHA) and the American College of Cardiology (ACC). Angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking drugs have been shown to improve symptoms and prolong survival in patients with congestive heart failure. There is limited information and there are no large clinical trials to suggest that the cancer patient should receive different therapy.
Commonly used agents include enalapril, carvedilol, and metoprolol. The drugs should be administered at low dosage levels and titrated according to the patient’s clinical response including blood pressure since these agents may lead to hypotension. This is particularly important in the cancer patient who is receiving therapy and may be volume depleted. Patients with advanced heart failure should be managed by an experienced team of cardiologists. These patients may require intravenous inotropic agents, LV assist devices, biventricular pacing, and implantable cardioverter defibrillators. The need for heart transplantation in the cancer patient with advanced heart failure is rare; however, the indications are expanding (21).
The potential cardiotoxicity of selected nonanthracycline chemotherapy drugs is summarized in Table 31.2.
TABLE 31.2 Cardiotoxicity of selected nonanthracycline cancer chemotherapy agents | ||||||||||||||||||||||
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