DURING THE PAST DECADE THERE HAVE BEEN considerable advances in the use of chemotherapy for the treatment of the various cancers such as Hodgkin’s and non-Hodgkin’s lymphoma, acute leukemias, colorectal and lung cancer, and local tumor control particularly with breast cancer. Metastases to various organs causes untold suffering and pain. Chemotherapy is effective in many patients, but its toxic effects on the heart, particularly on the myocardium, often limit their use in patients who may need these agents the most. Most important, cardiomyopathy caused by chemotherapeutic agents causes death in a significant number of patients. Further research is required to provide new effective agents with less toxicity.

CHEMOTHERAPEUTIC AGENTS

It is common for chemotherapeutic agents to be associated with myocardial damage reduction in ejection fraction and heart failure. The toxic effects of anthracyclines on the heart are well known. Doxorubicin, in a total toxic dose range of greater than 550 mg/m2, causes heart failure and arrhythmias. Daunorubicin in a total toxic dose range of greater than 550 mg/m2, has the same toxicity as doxorubicin. The anthracenedione mitoxantrone causes significant decrease in left ventricular ejection fraction and heart failure. Amsacrine at conventional doses causes ventricular arrhythmias. Cyclophosphamide at a dose of greater than 100–120 mg/kg over 2 days may cause heart failure, hemorrhagic myocarditis, pericarditis, and necrosis of the myocardium. Ifosfamide has similar cardiotoxic effects and can cause heart failure. 5-Fluorouracil at conventional doses may cause chest pain and coronary artery spasm that causes anginal pain and rarely, myocardial infarction. Busulfan at conventional doses may cause fibrosis of the endocardium. Cisplatin at conventional doses may cause chest pain and myocardial ischemia. Vincristine and vinblastine at conventional doses may cause myocardial infarction. Mitomycin C in conventional doses causes myocardial damage that is similar to radiation-induced injury. Interferons in conventional doses may exacerbate underlying cardiac disease. Interleukin-2 in conventional doses causes abnormal heart rhythms, hypotension, and myocardial damage.

CARDIAC DAMAGE FROM ANTHRACYCLINES

Anthracyclines contain an aromatic ring structure that intercalates in between DNA base pairs. The mechanism of cardiotoxicity appears to be inhibition of the function of topoisomerase II. This enzyme is critical in allowing DNA to undergo efficient repair. Most important, these agents generate free radicals that can damage cell membranes partly by lipid peroxidation. Amsacrine and mitoxantrone produce lower quantities of free radicals and cause less cardiotoxicity and cardiomyopathy compared with the doxorubicin, daunorubicin, idarubicin, and epirubicin. Cardiac tissues possess a low ability to detoxify these free radicals because of the presence of only small amounts of catalase that converts hydrogen peroxide to water. In addition, anthracyclines chelate iron. These anthracycline–ironcomplexes produce cardiac-damaging hydroxyl radicals. Research is required in this area to find molecules that may modify these toxic effects. One agent, dexrazoxane, undergoes hydrolysis to a carboxylamine that is capable of removing iron from the anthracycline–iron complex. It is partly effective in protecting the myocardium from damage.

Listed below are electrocardiographic manifestations of anthracycline cardiac damage.

1. Prolongation of the QT interval may occur in some cases following the first or subsequent doses. Thus, other drugs that may increase the QT interval should not be administered concurrently because arrhythmias may be precipitated.

2. Increased heart rate, sinus tachycardia, and abnormal heart rhythms may arise from the atrium such as supraventricular tachycardia.

3. Electrical conduction disturbances such as atrioventricular block and bundle branch block may occur.

4. ST segment elevation and T-wave changes that reflect pericarditis or myopericarditis may occur. The damage to the heart may culminate in heart failure and death during the first 2 weeks of therapy, albeit rarely.

Most of the cardiac toxic effects of anthracyclines are caused by prolonged therapy and the cumulative dose of the drug. There is loss of cardiac myocytes with increasing doses of these agents. Vacuolation of cells and myofibrillar dropout cause weakness of muscle elements that lead to dilatation of the ventricular muscle, which constitutes a chronic dilated cardiomyopathy that may appear and progress many years after cessation of anthracycline therapy.

Signs and Symptoms
Main symptoms of cardiotoxicity are shortness of breath and fatigue caused by cardiomyopathy that causes poor ejection of blood from the heart (ejection fraction) into the arteries. These are symptoms of heart failure. Physical signs include edema, enlargement of the liver, and accumulation of fluid in and around the lungs, and pleural effusions. The veins in the neck may be distended with blood that the heart is unable to pump forward (indicating jugular venous pressure). The chest x-ray may show signs of heart failure. Abnormal heart rhythms are common.

There are several diagnostic tests to reveal anthracycline cardiotoxicity. Patients are usually followed with radionuclide ventriculography, which gives a good assessment of the left ventricular ejection fraction. A decrease in the ejection fraction to less than 40% is a signal for the development of heart failure. An ejection fraction below 45% indicates that myocardial damage has already taken place. Echocardiographic assessment is not as accurate as radionuclide ventriculography for determination of the ejection fraction, but it gives the best assessment over myocardial wall abnormalities and regional cardiac relaxation. These subtle abnormalities as well as the echocardiographic findings described above may be the first signals of cardiac damage.

Management of Cardiotoxicity
Arrhythmias are one symptom of cardiotoxicity. They are managed with administration of beta-blockers. Supraventricular tachycardia and bothersome sinus tachycardia can be controlled with atenolol, 25–50 mg once daily or metoprolol, extended-release 50 mg once daily. A major contraindication to beta-blockers is the precipitation of wheezing and severe asthmatic attacks in susceptible individuals. They are, however, safe in patients with mild chronic bronchitis (see Beta-Blockers). Patients with ejection fractions less than 45% should be commenced on an afterload reducing agent such as an ACE inhibitor: enalapril 5 to 10 mg once daily or similar dosage of another ACE inhibitor
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Patients with heart failure should be managed with optimal therapy with diuretics such as furosemide 20–60 mg once daily, an ACE inhibitor, digoxin, and a small dose of a beta-blocker. If heart failure persists, spironolactone should be added to the regimen. Changes in dose schedules to weekly intravenous infusions rather than a larger dose every 3 weeks appears to afford some cardioprotection.

Research Implications
In the prevention of cardiotoxicity, the use of liposomeencapsulated anthracyclines appears to be controversial. Dexrazoxane is capable of accepting the iron from the anthracycline–iron complex that generates tissue-damaging hydroxyl radicals and provides some cardioprotection. However, this agent may increase the incidence of myelosuppression and has not been shown to increase disease-free survival. Its use is limited to oncologists. Agents that require further clinical testing include coenzyme Q10, melatonin, probucol, beta-blockers, calcium antagonists, and glutathione. A transgenic mouse overexpressing the human complementary DNA for multiple drug resistance, driven by an alpha-cardiac myosin gene, has been developed. These transgenic mice appear to be resistant to anthracycline-mediated cardiac-myocyte dropout. Newer agents that can be of value to many patients who suffer from cancer worldwide are being researched and developed.

CYCLOPHOSPHAMIDE

Cyclophosphamide and ifosfamide high-dose therapy may cause severe cardiomyopathy and heart failure in patients undergoing stem cell transplantation. Acute myocyte necrosis, with damage to the endothelial lining of the heart, and hemorrhagic myopericarditis may occur with a 30% mortality rate. The ECG shows abnormal patterns and the chest x-ray is a good test for detecting heart failure. An echocardiogram is not a test used for the detection of heart failure, but it is useful in revealing weakness of the heart muscle, pericarditis, or pericardial effusions. Serious complications are more common in patients with preexisting heart disease, particularly in those with left ventricular dysfunction and an ejection fraction of less than 45%.

Interferon alfa is a drug used in the management of chronic myelogenous leukemia, hairy cell leukemia, and Kaposi’s sarcoma. It may cause severe dilated cardiomyopathy with symptoms and signs of heart failure that are reversible when the drug is discontinued. Interleukin-2 is a drug that has been noted to cause hypotension, rarely myocardial infarction, noncardiogenic pulmonary edema, and kidney failure.

5-FLUOROURACIL

This is a frequently used agent and its associated cardiotoxicity may be more common than previously thought. Cardiotoxic effects occur when the drug is administered as a continuous infusion and within 5 h of infusion. Symptoms and signs are usually reversible within a few days. 5-Fluorouracil should be discontinued when cardiotoxicity arises and reinstitution is not advisable due to high incidence of recurrence. The overall incidence of cardiotoxicity ranges from 2 to 18% with a mortality of 2–15%. Unfortunately, there is no method to predict which patients are risk, because it has been noted that pre-existing heart disease, dose and route of administration, age, and chest radiation do not consistently correlate with associated toxicity. In a study of 1083 patients, however, those with a prior history of heart disease had a significantly increased risk (4.5 vs. 1.1%) of developing chest pain compared with patients without known heart disease (<0.01).

Acute Cardiovascular Effects
Chest pain often may not have a cardiac origin, but true anginal pain has been noted with the use of 5-fluorouracil, albeit rarely. Onset of pain usually occurs within hours of receiving a second or third dose but may be associated with the first dose. Anginal attacks may occur upon rechallenge with fluorouracil and, unfortunately, may not be prevented with the usual antianginal medications that include nitrates or calcium antagonists. In some patients typical crushing chest pain may occur with electrocardiographic changes that improve after discontinuation of the drug. Patients who have experienced chest discomfort with ECG changes should be administered further doses of 5-fluorouracil only if absolutely necessary, and this should be done in a cardiac unit with appropriate monitoring.

The ECG may reveal no abnormalities during chest pain, yet several hours later ST segment elevation or nonspecific ST-T wave changes may be observed. Myocardial infarction, cardiogenic shock, and death have been reported, albeit rarely.

Typical episodes of variant angina may occur within hours of administration (from 2 to 5 days following dosing). Several hypotheses regarding the mechanism of this variant angina have been proposed: coronary artery spasm, endothelial cell damage with thrombus formation, increased myocardial oxygen demand, and interference of myocardial cell metabolism. Results are inconclusive. Prophylactic nitroglycerin orally or skin preparations have failed to prevent chest pain with electrocardiographic evidence of ischemia. Unfortunately, prophylaxis using verapamil, nifedipine, or diltiazem with added intravenous nitroglycerin has also failed. When adequate protective treatment is unavailable as in this scenario, recommencing
therapy with this agent may be fraught with danger. Observable ECG changes include ST segment elevation, ST depression, nonspecific ST-T wave changes, and new Q waves. These are all suggestive for myocardial infarction, T-wave inversions, and sinus tachycardia. Occasionally arrhythmias that include atrial fibrillation, ventricular premature beats, nonsustained ventricular tachycardia, and rarely, ventricular fibrillation have been reported. Echocardiography may reveal left ventricular wall motion abnormalities, hypokinesia, and reduced ejection fraction.