Cardiovascular Toxicities of Chemotherapy

ANTHRACYCLINES

Anthracyclines are a class of antibiotics isolated from pigment-producing bacillus Streptomyces and include daunorubicin, doxorubicin, epirubicin, and idarubicin. Anthracyclines are key components of many curative and palliative regimens in combination with other agents for the treatment of various malignancies, including breast cancer, sarcoma, acute leukemia, and lymphoma. They are the class of antineoplastic agents most closely associated with cardiotoxicity. A meta-analysis of published studies has concluded that patients treated with anthracycline-based chemotherapy were five times more likely to develop reduced left ventricular ejection fraction (LVEF) and CHF in comparison with patients treated with nonanthracycline regimens.

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  Mechanism: There are several hypotheses regarding the mechanism of anthracycline-induced cardiotoxicity, but free-radical formation after binding to iron, which leads to DNA damage, is generally the most accepted hypothesis. It is believed that the myocardium is more susceptible to free-radical damage than other tissues because it has less free-radical scavenging enzymes. Other possible mechanisms that have been postulated include mitochondrial dysfunction leading to reduced adenosine triphosphate (ATP) production in cardiac myocytes and a decrease in glutathione peroxidase concentration.

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  Presentation: Anthracycline-induced cardiotoxicity has been categorized into three forms: acute, early-onset chronic, and late-onset chronic. ^, Each form may be classified further as subclinical (without CHF) or clinical (with CHF). Acute cardiotoxicity is rare, occurring in less than 1% of patients and is observed immediately after infusion. It typically manifests as an acute but transient decrease in LVEF due to decline in myocardial contractibility. This is frequently reversible within weeks after discontinuation of therapy. Arrhythmias can also be an acute presentation, including tachyarrhythmias (supraventricular or ventricular) and bradyarrhythmias (heart block). Other findings including myocardial ischemia, dilation of the left ventricle, and in rare cases, myocarditis and pericarditis may be observed. Myocarditis typically presents as chest discomfort and shortness of breath shortly after intravenous infusion of chemotherapy. The electrophysiological abnormalities may present as an increased QT interval, ST-T changes, and decreased QRS voltage, and are generally observed in 20% to 30% of patients. Abnormalities in cardiac biomarkers, such as increased serum B-type natriuretic peptide (BNP) and cardiac troponin levels, may also occur. Usually, the manifestations of acute toxicity resolve after discontinuation of the causative agent.

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  Incidence: Early-onset chronic cardiotoxicity occurs in 1.6% to 2.1% of patients during treatment or within 1 year after completion of treatment, with a peak incidence at about 3 months post-treatment. The late-onset chronic form occurs in 1.6% to 5% of patients, at least 1 year after completion of treatment. In a few cases, it may not be clinically evident even 10 to 20 years after the first dose of chemotherapy. Middle-age adults make up a large proportion of cancer-survivors with clinical signs of chronic onset cardiotoxicity who have received anthracycline-based chemotherapeutics as children or young adults. Early-onset and late-onset chronic cardiotoxicity typically present as a progressive decline in the LVEF leading to a dilated cardiomyopathy or, less commonly, a restrictive cardiomyopathy. In the most severe form, they can progress to severe left ventricular (LV) systolic dysfunction and clinical heart failure which may be progressive, and is associated with a poor prognosis.

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  Risk factors: Many risk factors have been identified for the development of anthracycline-induced cardiotoxicity, but the most important risk factor is the lifetime cumulative dose of anthracycline. Studies that have evaluated the cumulative probability of doxorubicin-induced HF have determined that it occurs in 3% to 5% with 400 mg/m ² , 7% to 26% at 550 mg/m ² , and 18% to 48% at 700 mg/m ² . Other risk factors for anthracycline toxicity include intravenous bolus administration, higher single doses, female gender, preexisting cardiac disease, and history of prior mediastinal irradiation. Also, children and older adults (age > 70 years) appear to be more susceptible to anthracycline-induced cytotoxicity. ^, Finally, concomitant use of other agents with known cardiotoxic effects, such as cyclophosphamide, actinomycin D, mitomycin, etoposide, trastuzumab, and paclitaxel, may have an additive effect on anthracycline-induced cardiomyopathy.

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  Pretreatment evaluation: Given the multitude of cardiovascular toxicities, it is generally warranted that all adult patients scheduled to receive an anthracycline-based therapy should have a comprehensive assessment of their baseline cardiac function before initiation of therapy ( Fig. 10.1 ). For patients with baseline LVEF less than 40% or patients with current CHF or history of CHF with reduced ejection fraction less than 50%, anthracycline-based chemotherapy is generally not recommended. Even for patients with no history of CHF and baseline LVEF greater than 50%, it is recommended to optimize controllable risk factors, especially hypertension, before the initiation of therapy. Routine surveillance imaging using periodic echocardiography should be offered during treatment based on the patient’s risk factors for developing cardiac dysfunction. Cardiac magnetic resonance imaging (MRI) or a multigated acquisition (MUGA) scan can be used alternatively if echocardiography is not technically feasible or available. A study by Cardinale and colleagues demonstrated the importance of monitoring cardiac function using echocardiography to detect anthracycline-related cardiotoxicity. It was observed that with repeated cardiac imaging, most cases of cardiotoxicity were detected within 1 year of chemotherapy completion. Some clinicians advocate quantification of LVEF before and after therapy and sometimes after every one to two cycles in select high-risk patient populations. A post-anthracycline LVEF measurement is critically important in breast cancer patients who are scheduled to receive trastuzumab, a monoclonal antibody associated with cardiac dysfunction and clinical CHF. It is recommended that a decrease in LVEF of more than 15% to a level less than 50% of baseline or decline to an LVEF less than 40% should result in considering cessation of anthracycline administration or switching to non–anthracycline-containing regimens. It is also recommended that in patients who require chest radiation therapy, radiation be administered at lower doses and with the use of more precise radiation fields, excluding the heart as much as possible.

  

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  Biomarkers: Blood cardiac biomarkers can also be used to identify cardiotoxicity while receiving therapy, especially plasma troponin increase. Increases in cardiac troponins T and I reflect myocardial cell death or injury, while chronic increases in BNP indicate ventricular wall stress. Troponin elevations represent an effective method for monitoring cardiac status as numerous studies have demonstrated correlations between troponin elevations and subsequent LVEF decline. Unfortunately, early rises in biomarker levels are difficult to link with final clinical endpoints because clinically apparent signs of heart failure can often arise years after initial therapy. More conclusive studies are needed to establish the utility of these biomarkers for anthracycline-induced cardiotoxicity diagnosis in clinical practice.

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  Treatment of heart failure: Patients developing CHF due to anthracycline-induced cardiomyopathy should cease anthracycline therapy and should be aggressively managed with current standard of care regimens for CHF using combinations of various medications including angiotensin converting enzyme (ACE) inhibitors, diuretics, β-blockers, and spironolactone. ^, Other procedural interventions can be considered on an individual basis and may depend on cancer status.

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  Treatment of asymptomatic LV dysfunction: Patients who develop asymptomatic decline in LVEF (<50%) due to cardiotoxicity can be managed with guideline-based CHF treatment using ACE inhibitors/angiotensin receptor blockers (ARB) alone or in combination with β-blockers. Studies have shown that early initiation of ACE inhibitors in isolation or in combination with β-blockers is associated with greater LVEF improvement or recovery. Also, clinicians should regularly follow up these patients and evaluate and manage cardiovascular risk factors, including hypertension, diabetes, and dyslipidemia.

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  Prevention: Multiple approaches have been proposed for the prevention of anthracycline-induced cardiomyopathy. Reducing the cumulative anthracycline dose limits cardiotoxicity, hence various contemporary treatment protocols that use high doses of anthracyclines (>400 mg/m ² ) are now less frequently prescribed. It has been observed that slow continuous infusion rather than bolus administration is associated with a lower occurrence of clinical heart failure and subclinical cardiac damage. However, replacing bolus administration with a slow infusion may exacerbate exposure effects including myelotoxicity, mucositis, and alopecia, and may also lead to patient discomfort due to prolonged hospitalization. This strategy did not find merit in children with acute lymphoblastic leukemia. Liposomal encapsulation of anthracycline alters the pharmacokinetics and tissue distribution without affecting antitumor efficacy and has also been shown to reduce cardiotoxicity. ^, It has been proposed that due to their large size, liposomes are unable to cross the gap junctions of normal endothelium in the heart and other normal tissues, but diffuse more readily through the leaky vasculature of tumors. Liposomal infusions are generally recommended for patients who are likely to receive a lifetime cumulative dose of doxorubicin greater than 450 mg/m ² .

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  Dexrazoxane: Dexrazoxane is the only US Food and Drug Administration (FDA)–approved cardioprotective agent for anthracycline-induced cardiotoxicity. In various trials, it has been shown to reduce cardiotoxicity by minimizing LVEF decline and reducing cardiac marker release. ^, Unfortunately, concerns about the possible compromise of antineoplastic efficacy and increase in secondary tumors, especially in childhood lymphoma and leukemia following dexrazoxane, have led to its restricted use. ^, Dexrazoxane has largely been evaluated in women with advanced breast cancer and adults with sarcoma, and it is currently approved for breast cancer patients undergoing treatment with extended anthracycline dosing in excess of 300 mg/m ² .

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  Cardiac drugs: β-blockers, ACE inhibitors, ARBs, and statins have been evaluated in randomized controlled trials for the primary prevention of anthracycline-induced cardiotoxicity. Early trials using carvedilol and nebivolol suggested a cardioprotective role of β-blockers to prevent anthracycline-induced LV dysfunction. However, a trial including 192 women with HER2-negative breast cancer, did not demonstrate any benefit of carvedilol monotherapy over placebo with regard to LVEF decline and diastolic function. A combined role of β-blocker and ACE inhibitor in the primary prevention of anthracycline-induced cardiotoxicity was evaluated in the OVERCOME trial. The combination of carvedilol with enalapril was beneficial in preventing anthracycline-induced cardiotoxicity with treated patients demonstrating a lower incidence of CHF or death compared with placebo. A randomized trial comparing the cardioprotective effects of candesartan and metoprolol in patients with early breast cancer undergoing adjuvant chemotherapy found that candesartan, and not metoprolol, was effective in preventing anthracycline-induced decline in LVEF. Additionally, a few studies have shown that statins seem to have protective effects during chemotherapy with anthracycline. In a retrospective analysis of anthracycline-treated patients with breast cancer, incidental statin prescription was linked with less deterioration of LVEF and lower incident CHF. However, there is not enough evidence to support statin administration to the general population scheduled for anthracycline therapy and large multicenter studies are needed.