Cardiovascular Disease in Cancer Survivors

Cardiotoxicity of Radiation Therapy to the Thorax

Radiation therapy improves survival in patients with Hodgkin lymphoma, early-stage breast cancer, and other thoracic malignancies. With higher survival rates, cardiovascular disease has emerged as the most common nonmalignant cause of death in patients treated with chest radiation therapy, accounting for 25% of deaths in survivors of Hodgkin lymphoma.

Radiation therapy causes a wide spectrum of cardiac diseases (Table 40). Thoracic irradiation damages all cells, including those of the pericardium, myocardium, valves, coronary vasculature, and conduction system, with clinical disease usually presenting two to three decades after treatment. The risk for radiation-induced cardiac injury is further increased in patients who are concomitantly taking anthracyclines or trastuzumab. Recognition of the cardiovascular complications associated with radiation therapy has led to techniques that limit total dosage and field size.

Acute pericarditis is the most common early manifestation of radiotoxicity; however, it is now less common (incidence of 2.5%) because of changes in shielding, divided dosing, and lower cumulative doses. The presentation, diagnosis, and treatment are similar to those of idiopathic acute pericarditis. Chronic or constrictive pericarditis develops in up to 10% to 20% of patients at 5 to 10 years after radiation therapy. Pericardial calcification is not always present radiographically (Figure 45). Late constriction can occur in those who have not experienced acute pericarditis.

Radiation therapy also damages the microvasculature, causing endothelial dysfunction and ischemia that result in myocardial fibrosis, diastolic dysfunction, and restrictive physiology. Radiation-induced cardiomyopathy presents similarly to primary restrictive cardiomyopathy. Differentiating cardiomyopathy due to myocardial fibrosis from pericardial constriction is essential because the conditions have different treatments and outcomes.

Although all cardiac valves may be affected by radiation therapy, left-sided involvement predominates. Valvular insufficiency due to tissue retraction is the most common valvular lesion in the first two decades after therapy, with later fibrosis and calcification leading to mixed regurgitation and stenosis.

Radiation therapy results in fibrosis of the conduction system and may lead to sinus node dysfunction, fascicular and bundle branch blocks, and complete heart block. The need for a permanent pacemaker is more common after valve replacement surgery in patients who have received radiation therapy.

Coronary artery disease (CAD) occurs earlier and with increased incidence in patients treated with radiation therapy. Coronary artery lesions are typically ostial, long, smooth, and concentric and have a higher fibrotic content than typical atherosclerotic lesions. The incidence of CAD is increased by traditional risk factors (such as smoking, dyslipidemia, and hypertension), and therapy to address these risk factors is indicated. In-stent restenosis rates with bare metal stents are significantly higher in patients with radiation-induced CAD. There are no data on the outcomes with drug-eluting stents. In patients with radiation-induced CAD, native vessels, including the left internal mammary artery, may be rendered unusable for bypass. The postoperative course may be complicated by radiation-induced lung injury (pleural effusion, prolonged ventilation) and a higher incidence of atrial fibrillation. Limited data are available on outcomes in patients undergoing cardiac surgery for radiation-related valvular or coronary disease.

There is no consensus on cardiac testing in asymptomatic patients after chest radiation. Baseline cardiac evaluation that includes echocardiography is reasonable, and several organizations have recommended starting stress echocardiography at 5 to 10 years after completion of therapy or at age 30 years, whichever comes first. The role of serum biomarkers in surveillance is unclear, and their use is not recommended. Routine screening with nuclear medicine testing or coronary CT should be avoided.

Although effective for risk factor reduction, statins, ACE inhibitors, and aldosterone inhibitors have not been proved to prevent radiation-induced cardiovascular disease.

Key Points

  • Thoracic irradiation damages all cells, including those of the pericardium, myocardium, valves, coronary vasculature, and conduction system, with clinical disease usually presenting two to three decades after treatment.
  • Traditional cardiovascular risk factors, such as smoking, dyslipidemia, and hypertension, should be aggressively managed because of the increased risk for coronary artery disease in patients with a history of chest radiation therapy.

Cardiotoxicity of Chemotherapy

  • Question 4

Chemotherapy may result in many types of cardiovascular toxicity (Table 41). Two broad categories of chemotherapeutic cardiac injury have been defined based on severity: type I, which is marked by dose-dependent cardiac dysfunction with irreversible ultrastructural necrosis, and type II, which is not dose dependent and is often reversible.

Type I injury is associated with the use of anthracyclines, such as doxorubicin, daunorubicin, and epirubicin. Acute anthracycline toxicity, which can present as heart block, arrhythmias, heart failure, myocarditis, and pericarditis, occurs in less than 1% of patients and may be reversible. Chronic progressive anthracycline toxicity usually presents as dilated cardiomyopathy and is most closely linked with the use of doxorubicin. Chronic progressive toxicity has an early onset (within 1 year of treatment) in 1.6% to 2% of patients and a late onset (after 1 year) in up to 5% of patients. Late-onset chronic progressive toxicity is related to total cumulative dose. In patients with a cumulative anthracycline dose of 550 mg/m2, the incidence of heart failure is up to 26%, and toxicity may not become clinically evident until 10 to 20 years after treatment. Factors associated with increased risk for anthracycline toxicity include concomitant use of cyclophosphamide, trastuzumab, or paclitaxel; previous chest irradiation; and female sex. Lower risk for cardiotoxicity is associated with epirubicin and idarubicin compared with doxorubicin. Concomitant dexrazoxane reduces the risk for doxorubicin toxicity. Limited data from small studies have shown the angiotensin receptor blocker valsartan may protect against some of the cardiotoxicity of anthracyclines.

Type II injury is more commonly associated with molecularly targeted therapy, such as trastuzumab. Trastuzumab toxicity results in left ventricular systolic dysfunction, with symptoms of heart failure in 3% to 7% of patients. It is more common in patients older than 50 years or with concomitant anthracycline use. Patients who demonstrate normalization of left ventricular function after discontinuation of trastuzumab may receive additional therapy.

Multitargeted tyrosine kinase inhibitors and anti–vascular endothelial growth factor antibodies are increasingly being used as targeted molecular therapy. Of the tyrosine kinase inhibitors, sunitinib has been most frequently associated with cardiotoxicity, with up to a 50% incidence of new or worsened hypertension and up to a 15% incidence of decreased left ventricular ejection fraction (LVEF). These effects may be reversible with early recognition. Surveillance with baseline N-terminal proB-type natriuretic peptide measurement and LVEF assessment at baseline, 1 month, and every 3 months thereafter has been advocated for patients taking sunitinib. Not all tyrosine kinase inhibitors carry the same risk for cardiotoxicity. The anti–vascular endothelial growth factor antibody bevacizumab is associated with significant but reversible hypertension.

In patients preparing to receive chemotherapy associated with known cardiotoxicity, an electrocardiogram should be obtained at baseline. Baseline evaluation of LVEF (with echocardiography or multigated acquisition scanning) is important if the associated cardiotoxicity includes left ventricular dysfunction and heart failure. It is reasonable to repeat echocardiography at a total cumulative anthracycline dose of 300 mg/m2 and before each dose in patients with pre-existent left ventricular dysfunction or those receiving higher cumulative doses. European guidelines suggest that patients receiving trastuzumab should undergo repeat echocardiography every 3 months. In general, cardiovascular consultation should be obtained in asymptomatic patients who demonstrate a decline in LVEF of 10% or more or in patients with symptoms of heart failure associated with a decline in LVEF of 5% or more to a level below 55%. Three-dimensional echocardiographic evaluation of left ventricular volumes may be more accurate in detecting small changes.

In patients with clinical signs or symptoms of cardiac dysfunction, cardiac biomarkers (such as troponin and N-terminal proB-type natriuretic peptide) along with imaging techniques (such as echocardiographically derived global longitudinal strain) may be helpful in identifying early toxicity and guiding individual therapy. At present, treatment of patients with chemotherapy-induced heart failure follows standard paradigms.

Key Points

  • Chronic anthracycline toxicity usually presents as irreversible dilated cardiomyopathy.
  • Cardiotoxicity from trastuzumab manifests as reversible left ventricular systolic dysfunction.