Role of Echocardiography in Patients Treated with Cardiotoxic Drugs

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8 Role of Echocardiography in Patients Treated with Cardiotoxic Drugs

Basic Principles

• Several anti-neoplastic agents are associated with significant cardiotoxicity.

• Agents most commonly associated with cardiotoxic risk include anthracyclines (doxorubicin), as well as the tyrosine kinase inhibitors trastuzumab, sunitinib, and sorafenib (Table 8-1).

• Cardiotoxicity associated with anti-cancer therapy is typically associated with a global decline in left ventricular ejection fraction (LVEF), although early manifestations may include diastolic dysfunction.

• Radiation therapy is also associated with significant cardiotoxic effects.

• Echocardiography is important to assess both systolic and diastolic cardiac function, extent of valvular disease, and evidence for any pericardial disease.

TABLE 8-1 COMMON CHEMOTHERAPY AND ANTI-CANCER AGENTS ASSOCIATED WITH SIGNIFICANT CARDIOTOXICITY

Type of Agent	Potential Cardiac Complication
Anthracyclines
Doxorubicin	Early postinfusion, transient, often reversible decline in LVEF; arrhythmias, myopericarditis; more commonly, a decline in LVEF > 1 year after therapy
Tyrosine Kinase Inhibitors
Trastuzumab	Potentially reversible, significant decline in LVEF
Bevacizumab	Hypertension, arterial thrombosis
Sunitinib	Decline in LVEF, hypertension
Sorafenib	Myocardial infarction, hypertension
Imatinib	Diastolic dysfunction, pericardial effusion
Alkylating Agents
Cisplatin	Hypertension, vascular dysfunction
Cyclophosphamide	Pericarditis/myocarditis, decline in LVEF with high doses
Antimetabolites
5-Fluorouracil	Coronary vasospasm, myocardial ischemia
Antimicrotubules
Paclitaxel	Arrhythmia, heart failure

Anthracycline Cardiotoxicity

• Anthracyclines (e.g., doxorubicin) are widely known to be associated with cardiotoxic effects.

• Doxorubicin cardiotoxicity can occur early or late during therapy. Early changes occur acutely or within the first year of therapy. Late dysfunction occurs months or many years after the initial exposure.

• Overall, doxorubicin cardiotoxicity is indistinguishable from other forms of heart failure with LV dilatation, wall thinning, and decreased contractility (Figure 8-1).

• An increased risk of cardiotoxicity is associated with higher cumulative dosages of doxorubicin (particularly > 550 mg/m²) and with pre-existing cardiac disease, including hypertension, valvular disease, and ischemic heart disease.

Figure 8-1 A, An example of a dilated cardiomyopathy secondary to doxorubicin exposure. B, This same patient also suffered from severe functional mitral regurgitation secondary to annular dilatation.

Trastuzumab Cardiotoxicity

• Trastuzumab is a humanized monoclonal antibody targeting the ErbB2 receptor.

• Cardiotoxicity risk is increased in the setting of prior exposure to anthracyclines as well as concomitant cardiovascular disease such as hypertension or coronary disease.

• Cardiotoxicity is often observed during the treatment phase and can be reversible with cessation of therapy or institution of cardioprotective medications.

• Trastuzumab cardiotoxicity is also echocardiographically indistinguishable from other forms of systolic heart failure (Figure 8-2).

Figure 8-2 This patient sustained trastuzumab cardiotoxicity and had a mild decline in LVEF during trastuzumab therapy.

Radiation Therapy

• Radiation can induce myocardial fibrosis and vascular changes, pericardial disease, valvular stenoses, and coronary atherosclerosis. The conduction system is also sensitive to fibrosis.

• Restrictive cardiomyopathy with fibrosis and diastolic dysfunction can be seen in radiotherapy-treated patients.

• Pericardial involvement includes acute or chronic effusions, pericarditis, and pericardial constriction. Constriction is a late manifestation often occurring at greater than 18 months (Figure 8-3).

• In terms of valvular disease, the left-sided valves (mitral and aortic) are most frequently involved, with manifestations of regurgitation or stenosis occurring late. The mean time from radiation to symptom onset has been noted as greater than 8 years (Figure 8-4).

• Fibrosis of the conduction system can also occur, manifesting as right bundle branch block and rarely more advanced heart block.

• Premature coronary disease with accelerated atherosclerosis is also observed (Figure 8-5).

Figure 8-3 An example of a small pericardial effusion and pericardial thickening (arrow) related to radiation exposure.

Figure 8-4 A, Evidence of severe mitral annular calcification and leaflet thickening secondary to radiation exposure in the distant past. This patient also had severe aortic stenosis from thickened and calcified leaflets. B, This apical 4-chamber view from the same patient emphasizes the degree of calcification as well as subvalvular thickening. This patient also developed RV dysfunction secondary to mitral valvular disease. C, Color Doppler in this same patient shows moderate mitral regurgitation secondary to leaflet calcification and thickening and failure of adequate coaptation.

Figure 8-5 Coronary angiogram demonstrating a left anterior descending coronary artery lesion (arrow) in a patient who received radiation as a child for lymphoma.

Additional Agents and Cardiotoxic Effects

• Additional tyrosine kinase inhibitors are also known to have off-target effects.

• Sunitinib and sorafenib are associated with an increased incidence of hypertension and LVEF decline. Bevacizumab also results in contractile dysfunction.

• Myocardial ischemia has been seen with 5-fluorouracil (5-FU) alone and in combination with cisplatin.

• Hypertension and vascular dysfunction are common side effects of many of the agents, including bevacizumab, sorafenib, sunitinib, and cisplatin.

• Pericarditis is rarely observed with cyclophosphamide and cytarabine, and effusions can be seen with all-trans retinoic acid and imatinib therapy.

Step-by-Step Approach

Step 1: Determine Left Ventricular Size and Systolic Function; Evaluate for Segmental Wall Motion Abnormalities

Key Points

• Anthracyclines, trastuzumab, sorafenib and sunitinib cause a global decrease in LVEF that is indistinguishable echocardiographically from other forms of systolic heart failure.

• Myocardial ischemia and focal wall motion abnormalities may be observed with other agents, including 5-FU.

• Accurate, reproducible estimation of cardiac function is essential, and quantitative assessment should also be performed if image quality is adequate.

• Additional cardiac stress, such as hypertension or ischemic heart disease, may increase cardiotoxic risk.

Step 2: Determine Diastolic Function

Key Points

• Diastolic dysfunction may be an early marker of chemotherapy or anti-cancer therapy–associated cardiotoxicity.

• Restrictive cardiomyopathy can be seen with radiation-induced disease.

Step 3: Determine Degree of Valvular Disease

Key Points

• The valvular disease that occurs in the setting of chemotherapy cardiotoxicity is typically functional.

• However, radiation therapy is associated with an increased risk of aortic and mitral valvular disease most typically secondary to leaflet abnormalities.

Step 4: Determine Extent of Pericardial Disease

Key Points

• Radiation therapy can be associated with acute or chronic pericarditis, and pericardial effusions.

New, Sensitive Echocardiographic Indices to Detect Cardiotoxicity

• Once a global reduction in cardiac function is observed, there may be irreversible dysfunction and it may be necessary to interrupt anticancer therapy.

• LVEF is also not a robust predictor of incident cardiotoxicity.

• There is a need to develop sensitive, predictive markers of incident cardiac dysfunction.

• Strain imaging quantifies myocardial deformation and is a tool under active investigation to determine subclinical ventricular dysfunction before changes in ejection fraction are evident (Figure 8-6).

• Exercise or dobutamine stress testing has also been proposed as a means of assessing contractile reserve and subclinical dysfunction.

Figure 8-6 Typical output that one might derive from speckle tracking strain image analysis from an apical 4-chamber view.

Suggested Readings

1 Altena R, Perik PJ, van Veldhuisen DJ, de Vries EG, Gietema JA. Cardiovascular toxicity caused by cancer treatment: Strategies for early detection. Lancet Oncol. 2009;10:391-399.

This is an excellent summary regarding the current imaging and biomarker strategies used in the detection of cardiotoxicity.

2 Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: Review of potential cardiac problems. Clin Cancer Res. 2008;14:14-24.

This is a comprehensive review of the potential cardiotoxicities associated with breast cancer therapies.

3 Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011-2019.

This is a very interesting cohort study, which finely details the changes in cardiac function observed with sunitinib.

4 Suter TM, Procter M, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac adverse effects in the Herceptin Adjuvant trial. J Clin Oncol. 2007;25:3859-3865.

This study describes the early cardiac effects observed with trastuzumab in a large adjuvant randomized clinical trial. The late effects were also published and noted below (see Suggested Reading 9).

5 Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: Incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53:2231-2247.

This is an excellent summary of the potential cardiotoxicities observed with a diverse panel of cancer therapies.

6 Berry GJ, Jorden M. Pathology of radiation and anthracycline cardiotoxicity. Pediatr Blood Cancer. 2005;44:630-637.

This is a comprehensive review of the effects of radiation on the cardiac system.

7 Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005;23:7685-7696.

This is an interesting review of the cardiotoxic effects and proposed mechanisms of cardiotoxic chemotherapies.

8 Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: Course, pathophysiology, prevention and management. Expert Opin Pharmacother. 2007;8:1039-1058.

This is a well-written review of anthracycline-associated cardiotoxicity.

9 Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol. 2010;28:3422-3428.

This article details the cardiac substudy from a large adjuvant clinical trial of trastuzumab and describes the natural history of trastuzumab on cardiac function.

10 Chen MH, Kerkela R, Force T. Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118:84-95.

This is a state-of-the-art review of the potential mechanisms and cardiotoxicities observed with the tyrosine kinase inhibitors.

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