Chemotherapy Agents That Cause Cardiotoxicity

US Pharm. 2017;42(9):HS24-HS33.

ABSTRACT: Cardiotoxicity is a serious adverse effect of many conventional chemotherapy agents. There are many different types of cardiotoxicity, including reversible, irreversible, acute, chronic, and late-onset. Knowledge of the effects of cardiotoxicity, its management, and dosage adjustments for chemotherapeutic agents such as anthracyclines, fluorouracil, taxanes, monoclonal antibodies, and tyrosine kinase inhibitors is vital for the early detection of cardiotoxicity. It is important for pharmacists to be aware of these cardiotoxic effects in order to make appropriate recommendations for dosage adjustments and monitoring of long-term effects.

Cardiotoxicity, or medication-induced damage to the heart muscle—e.g., heart failure (HF), structural damage, and hypertension)— is a known adverse effect of many conventional chemotherapeutic agents. It is defined as either the presence of symptoms of HF with an ejection-fraction reduction ≥5% to <55% or the absence of symptoms with an ejection-fraction reduction ≥10% to <55%.¹ Cardiotoxicity affects quality of life and overall survival; given the increasing number of patients treated with biologics and chemotherapy, it is important for pharmacists and physicians to detect it early. Cardiotoxicity is divided into four categories: 1) directed cytotoxic effects of chemotherapy and associated cardiac dysfunction (including alkylating agents, anthracyclines, interferon alfa, monoclonal antibodies [Mabs], tyrosine kinase inhibitors [TKIs]); 2) cardiac ischemia (antitumor antibiotics, fluorouracil [5-FU], topoisomerase inhibitors); 3) cardiac arrhythmias (anthracyclines, other agents; resulting from cardiac ischemia) and 4) pericarditis (bleomycin, cyclophosphamide, cytarabine).¹ This article will review only the major chemotherapy agents that can cause cardiotoxicity.

Classification of Damage

The different types of cardiotoxicity include reversible, irreversible, acute, chronic, and late-onset. Irreversible damage is categorized as type 1 and reversible damage as type 2. Type 1 (direct damage) is usually caused by a cumulative dose; type 2 damage is not related to a cumulative dose. Chemotherapy drugs that can cause irreversible toxicity include anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin); alkylating agents (busulfan, carboplatin, carmustine, chlormethine, cisplatin, cyclophosphamide, mitomycin); taxanes (docetaxel, cabazitaxel, paclitaxel); topoisomerase inhibitors (etoposide, tretinoin, vinca alkaloids); and antimetabolites (cladribine, cytarabine, 5-FU).^1,2

The most common chemotherapy agents associated with type 1 damage are the anthracyclines. Anthracyclines, especially doxorubicin, are used to treat several types of cancer, including breast, gynecologic, sarcoma, and lymphoma. The mechanisms of doxorubicin cardiotoxicity are necrosis and apoptosis of cardiac myocytes followed by myocardial fibrosis.¹ Doxorubicin-induced cardiotoxicity involves several processes, such as the formation of iron-dependent oxygen free radicals and peroxidation of lipids in the membrane of myocardial mitochondria, that lead to suppression of DNA, RNA, and proteins; this results in altered adenylyl cyclase activity and disrupted calcium homeostasis.² Anthracyclines increase the risk of cardiotoxicity from cumulative doses.

Mabs, the main cause of type 2 damage, are widely used in the management of many types of cancer. Chemotherapy agents that can cause reversible cardiotoxicity are trastuzumab, bevacizumab, lapatinib, and sunitinib. These agents also may cause hypertension. A decrease in vascular endothelial growth factor (VEGF) results in a reduction of nitric oxide (NO) in the arteriolar wall. In breast cancer, human epidermal growth factor receptor 2 (HER2)–positive receptors have been associated with aggressive disease and a worse prognosis.³ Trastuzumab, a humanized Mab, has shown a 50% reduction in recurrence rates and a 33% improvement in survival.¹ Trastuzumab’s role in cardiotoxicity is not fully understood; however, data suggest that blockage of HER2 receptors is responsible for trastuzumab-induced cardiotoxicity. HER2 receptors are expressed on cardiac myocytes, which are important for protection of cardiotoxins and for embryonic cardiac development.⁴ Suppression of the HER2 gene results in dilated cardiomyopathy. This helps identify the difference between type 1 and type 2 cardiotoxicity; type 1 has a greater association with cardiac dysfunction and clinical HF, and type 2 leads to an increased loss of contractility and less myocyte death, showing more reversibility.³

For years, there was no universal definition of cardiotoxicity. Suter and Ewer proposed a system to identify drugs that cause the different types of damage, defining cardiotoxicity as a serial decline in left ventricular ejection fraction (LVEF).³ The American Society of Echocardiography defined cardiotoxicity as an LVEF drop from >10% to <53%. The Cardiac Review and Evaluation Committee has since proposed a definition of left ventricular dysfunction (LVD): “a decrease in cardiac LVEF that was either global or more severe in the septum; symptoms of congestive heart failure (CHF); associated signs of CHF, including but not limited to S3 gallop, tachycardia, or both; and decline in LVEF of at least 5% to less than 55% with accompanying signs or symptoms of CHF, or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms.”⁴

Management of Cardiotoxicity

Anthracyclines: The management of cardiotoxicity has primarily revolved around treating anthracycline toxicity; however, there are other approaches to reduce the risk of cardiac cell death.⁴ Recent studies have investigated prophylactic ACE inhibitor and beta-blocker use in chemotherapy-treated patients. Beta-blockers with antioxidant properties, such as carvedilol, have been shown to reduce the risk of cardiotoxicity. Prophylaxis with ACE inhibitors has not been shown effective for preventing a decrease in ejection fraction.¹

Conventional chemotherapeutic agents are often deemed gold-standard treatments for various malignancies based on familiarity and decades of reliable data supporting their use. However, certain agents in this group are well known to cause chemotherapy-induced cardiotoxicity because of their nonspecific cytotoxic effects on myocardial cells. Among these agents, anthracyclines, 5-FU, and capecitabine cause the highest incidence. The incidence of cardiotoxicity, mechanisms of toxicity, management, and potential effects vary between agents. Fundamentally, each chemotherapeutic class inhibits tumor growth via a cytotoxic mechanism; however, it is important to note that this is not the same mechanism that is responsible for cardiotoxicity.³

Generally speaking, the incidence of cardiotoxicity among anthracyclines ranges from 0.9% to 26%; however, the incidence is based on the cumulative dose and other risk factors, such as age.¹ Anthracyclines typically lead to cardiotoxicity via oxidative mechanisms that cause an increase in toxic free radicals, resulting in fibrosis and lipid peroxidation of cardiac membranes. These effects may lead to acute, chronic, or late-onset cardiotoxicity.⁵ Acute cardiotoxicity symptoms present as arrhythmias and elevated brain natriuretic peptide and troponin levels; however, the effects are reversible 1 week after discontinuation, and the chemotherapy agent may be resumed at a later date. In late-onset cardiotoxicity, which occurs months to years after treatment, patients present with a progressive decline in ejection fraction leading to decompensation, valvular damage, or worse arrhythmias.⁶

Of the conventional agents, anthracyclines have the most data concerning management and risk of cardiotoxicity. For that reason, agents are recommended to reduce the incidence and severity of cardiotoxicity in patients receiving anthracyclines. One agent, dexrazoxane, is recommended by American Society of Clinical Oncology to reduce cardiotoxicity in metastatic breast cancer patients receiving >300 mg/m² of doxorubicin.³ Otherwise, this drug is not routinely used in practice.⁵ The 2013 American College of Cardiology (ACC) and American Heart Association (AHA) Guidelines for Heart Failure place patients at risk for cardiotoxicity in the ACC/AHA Stage A classification, which means that the patient is at risk for developing HF that warrants the recommendation of an ACE inhibitor, angiotensin receptor blocker, or beta-blocker such as carvedilol. Studies show that the use of these agents has reduced the incidence of cardiotoxicity in this patient population.⁵ Lastly, to improve cardiac-safety parameters, it is appropriate to administer the liposome-encapsulated formulation of the anthracycline (doxorubicin or daunorubicin) to reduce the risk of cardiac dysfunction.³

5-FU: The incidence of cardiotoxicity with 5-FU is about 20%. This agent causes cardiotoxicity via a multifactorial mechanism related to its administration.³ If 5-FU is administered as a bolus, there is less risk of cardiotoxicity than when it is administered as a continuous infusion. Patients most commonly present with acute or severe effects ranging from chest pain and acute HF to myocardial infarction.⁵ It is important to advise patients that they may experience chest pain, sweating, and nausea while receiving 5-FU infusion; however, the effects are reversible following discontinuation. If a patient continues to experience cardiac effects upon secondary exposure, there is an increased chance of cardiac side effects, especially if there is a history of coronary artery disease. In rare cases, beta-blockers, calcium channel blockers, or nitrates may be initiated to reduce the risk of cardiac effects.⁷

Taxanes: Taxanes (paclitaxel, docetaxel, cabazitaxel) are the cause of cardiotoxicity in 2.3% to 8% of patients treated with a taxane regimen. Cardiotoxicity is typically observed when a taxane is used in combination with an anthracycline; the taxane potentiates anthracycline cardiotoxicity by increasing plasma levels of agents like doxorubicin.⁸ Patients often present with asymptomatic sinus bradycardia.⁵ Generally speaking, there is not an abundance of evidence implicating taxanes in cardiotoxicity, and for that reason routine monitoring is not recommended. Typically, the risk of cardiotoxicity with taxanes is highest when these agents are used in conjunction or sequentially with antracyclines.³ For example, when paclitaxel and doxorubicin are administered within 15 to 30 minutes of each other, the risk of CHF is 20%, but the risk is reduced when the administration time is increased to 4 to 6 hours.⁶ Cardiotoxicity is reported in 7% to 28% of patients receiving a regimen containing cyclophosphamide. Cyclophosphamide’s cardiotoxic mechanism is unknown but is believed to result in endothelial dysfunction and coronary artery vasospasms. This action typically leads to LVD, which progresses to pericarditis or hemorrhagic myocarditis.⁵

Mabs: Trastuzumab and pertuzumab are recombinant humanized Mabs that target HER2 receptors. They are commonly used in patients with HER2-positive breast, pancreatic, and other cancers. In combination with other chemotherapy agents, they have led to significant increases in overall survival and response rate. The incidence of trastuzumab-induced HF ranges from 3% to 7% when the drug is administered alone and up to 27% when it is administered in combination with other chemotherapy agents. The highest rate of cardiotoxicity occurs when trastuzumab is combined with anthracyclines. Studies have shown that the incidence of cardiotoxicity from trastuzumab does not depend on cumulative dose or treatment duration.⁸ Pertuzumab also causes cardiomyopathy, but the incidence rate is low.⁹ It should be withheld for at least 3 weeks for a decrease in LVEF <45% with a ≥10% absolute decrease from baseline. Pertuzumab may be resumed if there is a recovery of ≥45%; if an assessment done within 3 weeks shows no improvement, then the drug should be discontinued permanently.¹⁰

The cardiotoxicity caused by trastuzumab is associated with its inhibition of HER2 proteins and human ErbB2 signaling in cardiomyocytes. HER2 proteins and ErbB2 signaling are necessary for the growth and repair of cardiac muscles, and their inhibition leads to adenosine triphosphate (ATP) depletion and interference with growth and repair of cardiac muscles, resulting in cardiotoxicity. Trastuzumab-related cardiotoxicity may be reversible upon treatment cessation or appropriate management with cardiac therapy.⁸

The management of patients with trastuzumab-induced LVD is controversial. LVEF should be assessed prior to initiation of trastuzumab and at regular intervals during treatment. Trastuzumab administration should be withheld for at least 4 weeks in the case of ≥16% absolute decrease in LVEF from pretreatment values, LVEF below institutional limits of normal, and ≥10% absolute decrease in LVEF from pretreatment values. Trastuzumab may be resumed if, within 4 to 8 weeks, LVEF returns to normal limits and the absolute decrease from baseline is ≤15%. If there is a persistent decrease in LVEF (>8 weeks) or there have been more than three occasions when administration was suspended because of cardiotoxicity, trastuzumab should be permanently discontinued.^8,11 An algorithm showed that if LVEF is <40% while a patient is receiving trastuzumab, the drug should be stopped and assessment repeated in 3 weeks. If LVEF is still <40%, then the drug should be discontinued and the LVD treated with ACE inhibitors and beta-blockers.⁵

Bevacizumab is a recombinant humanized Mab that inhibits VEGF receptors. It is used in the treatment of many cancers, such as breast, ovarian, lung, and brain. Bevacizumab may be associated with HF, arterial and venous thromboembolism, and severe hypertension. The most common cardiotoxic event in clinical trials was hypertension, with an incidence rate of 4% to 35%. The cardiotoxicity of bevacizumab results from VEGF inhibition that leads to a decrease in nitric oxide production. Because nitric oxide is a potent vasodilator, blocking its production promotes vasoconstriction and increases peripheral vascular resistance and, consequently, increased blood pressure.⁸

TKIs: Sunitinib and sorafenib are TKIs that inhibit VEGF receptors and platelet-derived growth factor (PDGF) and stem-cell receptors (Kit). These two chemotherapy drugs have shown efficacy in patients with metastatic renal cell carcinoma and other cancers; however, they have cardiotoxic effects. Studies carried out with sunitinib and sorafenib showed a decline of 2.7% to 11% in systolic LVD and CHF. Hypertension was reported in approximately 47% of patients treated with sunitinib. Sorafenib led to cardiac ischemia in about 3% of patients and to hypertension in 17% to 43%. The cardiotoxicity of these agents lies in the fact that sunitinib inhibits ribosomal S6 kinase. The inhibition triggers proapoptotic factor Bcl-2 and cytochrome c, leading to ATP depletion, myocyte loss, and consequently LVD. Sorafenib inhibits RAF and BRAF kinases, which are relevant for myocyte survival. Inhibition of RAF causes dilation and hypocontractility, leading to increased cardiomyocyte apoptosis and fibrosis.⁹

Nilotinib, dasatinib, and imatinib are TKIs used in patients newly diagnosed with Philadelphia chromosome–positive chronic myeloid leukemia in the chronic phase. Dasatinib and imatinib are also used for acute lymphoblastic leukemia. All three agents are linked to HF, nilotinib and dasatinib are linked to QT prolongation, and imatinib is linked to edema and LVD. The mechanism driving their cardiotoxicity is the inhibition of Ab1/Arg, PDGF receptors, and c-kit. Dasatinib also targets the Src family of nonreceptor tyrosine kinases, leading to fluid retention and pericardial effusion.⁹

Patient Monitoring

Cardiac monitoring is recommended in all patients before initiation of chemotherapeutic agents. Patients receiving anthracyclines and trastuzumab should have cardiac-function monitoring at baseline; months 3, 6, and 9 during treatment; and 12 and 18 months after initiation of treatment. Patients undergoing cancer treatment should be counseled on the benefits of reducing cardiovascular risk through blood pressure control, smoking cessation, lipid reduction, and lifestyle changes. A blood pressure goal of 140/90 mmHg is recommended for most patients; for those with diabetes or chronic kidney disease, a goal of 130/80 mmHg is recommended.^2-4

Bevacizumab-induced hypertension should be managed with ACE inhibitors and dihydropyridine calcium channel blockers. MRI remains the gold standard for evaluating LV function, but it is expensive. Troponins are effective biomarkers for the early detection of cardiotoxicity; they can detect drug-induced cardiotoxicity in the earliest phase, before any reduction in LVEF. Periodic monitoring of LVEF to detect cardiotoxicity is recommended, but no study has discussed how often it should be performed. A combination of an ACE inhibitor and a beta-blocker is highly recommended in patients with LVD. Periodic monitoring with ECG and electrolytes is recommended in patients at risk for QT prolongation. With the exception of anthracyclines, cardiotoxicity from most targeting agents is reversible. Concomitant use of cardiotoxic drugs should be avoided, and early detection of asymptomatic cardiac dysfunction is important. Cardiac function should be screened at baseline as well as during treatment, and appropriate measures should be taken to manage these toxicities.^5,8,11

Conclusion

Many chemotherapy agents cause cardiotoxicity, and their use requires close monitoring as well as counseling. Many of these agents have dosing-adjustment parameters, and the pharmacist can play a vital role in verifying orders. The pharmacist can help detect the presence of cardiotoxicity by being aware of signs and symptoms of HF and advising the patient to see the physician and undergo appropriate testing.

REFERENCES

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10. Perjeta (pertuzumab) package insert. South San Francisco, CA: Genentech, Inc; March 2016.
11. Herceptin (trastuzumab) package insert. South San Francisco, CA: Genentech, Inc; March 2016.

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