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Cardiovascular Toxicities of Targeted Therapy
Introduction
Cardiotoxicity is one of the worrisome side effects of cancer-directed therapy. Cardiac adverse events can range from mild to severe and vary between classes of targeted agents. Some relevant cardiac adverse events include electrocardiogram (ECG) changes, QT prolongation, hypertension, arrhythmias, pericardial disease, and heart failure. Cardiac toxicities can limit the use of these drugs and warrant their discontinuation. Preexisting comorbidities and cardiac conditions can add to or worsen cardiac toxicity. The Common Terminology Criteria for Adverse Events (CTCAE) provides descriptions and grading for cardiovascular side effects. In this chapter, we will first review the various targeted therapies that are known to cause cardiotoxicities, and then discuss in detail each of the cardiotoxicities and their respective management. Table 16.1 shows the grading of each cardiac toxicity based on the National Cancer Institute (NCI) CTCAE version 5.0.
TABLE 16.1
Common Cardiac Adverse Effects as Graded by NCI CTCAE Version 5.0
| CTCAE Term | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
|---|---|---|---|---|---|
| Heart failure | Asymptomatic with laboratory (e.g., BNP) or cardiac imaging abnormalities | Symptoms with moderate activity or exertion | Symptoms at rest or with minimal activity or exertion; hospitalization; new onset of symptoms | Life-threatening consequences; urgent intervention indicated (e.g., continuous IV therapy or mechanical hemodynamic support) | Death |
| Left ventricular systolic dysfunction | - | - | Symptomatic due to drop in ejection fraction responsive to intervention | Refractory or poorly controlled heart failure due to drop in ejection fraction; intervention, such as ventricular assist device, intravenous vasopressor support, or heart transplant indicated | Death |
| Corrected QT interval prolongation on the ECG | Average QTc 450–480 ms | Average QTc 481–500 ms | Average QTc ≥501 ms; >60 ms change from baseline | Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia | Death |
| Hypertension | Systolic BP 120–139 mmHg or diastolic BP 80–89 mmHg | Systolic BP 140–159 mmHg or diastolic BP 90–99 mmHg if previously WNL; change in baseline medical intervention indicated; recurrent or persistent (≥24 h); symptomatic increase by >20 mmHg (diastolic) or to >140/90 mmHg; monotherapy indicated or initiated | Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg; medical intervention indicated; more than one drug or more intensive therapy than previously used indicated | Life-threatening consequences (malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated | Death |
BNP, B-Natriuretic peptide; BP, blood pressure; CTCAE, Common Terminology Criteria for Adverse Events; ECG, electrocardiogram; ms, milliseconds; NCI, National Cancer Institute; WNL , within normal limits.
Adapted from National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, 2017. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf .
Targeted Therapies Associated With Cardiotoxicity
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HER2 targeting antibodies (trastuzumab, pertuzumab, T-DM1): Trastuzumab and pertuzumab are monoclonal antibodies directed toward the HER2 receptor. They specifically target the erbB2 receptor tyrosine kinase. Trastuzumab is used mainly in HER2-neu-positive breast cancer and in metastatic HER2-neu-positive gastric cancers. These drugs carry a black box warning for cardiomyopathy and heart failure, with an increased risk of heart failure in patients with concomitant use of anthracyclines. T-DM1 (ado-trastuzumab emtansine) is an antibody drug conjugate, which is composed of trastuzumab, a thio linker, and a microtubule inhibitor. This drug had been approved for use in first- or second-line HER2 neu-positive metastatic breast cancer.
Mechanism of action
ErbB2/neu is a member of the epidermal growth factor family. Its gene is amplified in many cancer types, and its overexpression is associated with poor prognosis in breast and ovarian cancer. It is overexpressed in 25% to 30% of breast cancer patients.
Mechanism of cardiotoxicity
Neuregulins (neu-differentiation factors) and heregulin (ligand with acetyl choline receptor–inducing activity and glial growth factor) along with erbB2 are associated with cardiac myocyte development and have been shown to inhibit the growth of cardiac stem cells and lack capacity for cardiogenic differentiation and vascular formation. Thus interruption of this pathway can lead to cardiac toxicity. Manifestations range from asymptomatic decline in heart function to symptomatic congestive heart failure. Reported symptoms include tachycardia, palpitations, lower extremity edema, dyspnea on exertion, and clinical heart failure.
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HER2–targeting tyrosine kinase inhibitors (TKIs) (lapatinib): Lapatinib is a TKI against EGFR1 and HER2 that results in the inhibition of signaling pathways downstream of HER2. Lapatinib is metabolized in the liver and thus dose adjustments are required in patients with hepatic impairment. Lapatinib has been used in combination with chemotherapy, mostly capecitabine. The most common side effects are diarrhea, rash, and anorexia. Based on a clinical trial comparing lapatinib and capecitabine with capecitabine alone, there were no significant symptomatic cardiac adverse events in the combination treatment arm. Furthermore, no treatment withdrawal or dose reductions due to decreases in left ventricular ejection fraction (LVEF) were reported. There were, however, reports of asymptomatic cardiac events in 4 out of 163 women in the combination treatment arm. One of the four women in the combination arm developed Prinzmetal angina; however, with treatment cessation, her symptoms improved. Due to the decrease in LVEF, the dose was reduced to 1000 mg daily and there was no recurrence of cardiac event noted thereafter.
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Multi-TKIs (sorafenib, sunitinib, pazopanib, axitinib, vandetanib, regorafenib, lenvatinib, cabozantinib)
Mechanism of action
An overview of the vascular endothelial growth factor (VEGF) pathway and the mechanism of action of VEGF inhibitors is discussed elsewhere in this book. The specific effects of VEGF inhibition on cardiac tissue are discussed here.
TKIs have antitumor activity in a variety of malignancies
These TKIs have anti-VEGF activity, but also have activity against growth factor receptors such as EGFR, FGFR, and RET. Their broad coverage is attributed to the similarity of structures at the ATP-binding site region. Because their effects are not limited to VEGF receptors, but also to other growth factor receptors, these drugs are referred to as multitargeted TKIs, or antiangiogenic TKIs. Examples of antiangiogenic TKIs that are in clinical use are sorafenib (inhibits VEGFR2, fms-like tyrosine kinase 3 [FLT3], PDGFR, and fibroblast growth factor receptor [FGFR]-1); sunitinib (inhibits c-kit, VEGFR1-3, PDGFR-alpha, PDGFR-beta, FLT3, CSF-1R, RET); pazopanib (inhibits VEGFR1-3, PDGFR-alpha and -beta, FGFR1 and 3, c-KIT); axitinib (selective VEGFR inhibitor that targets VEGFR1-3); vandetanib (inhibits VEGFR, RET, and EGFR); regorafenib (targets VEGFR1-3 in addition to RET, c-KIT, PDGFR-alpha and -beta, FGFR1 and 2, and other membrane-bound and intracellular kinases); and lenvatinib (targets VEGFRs, RET, and FGFR).
Mechanism of cardiotoxicity
VEGF is a protein that upregulates endothelial cell nitric oxides synthase (ecNOS), which upregulates nitric oxide (NO) production, thereby modulating vasodilation, microvascular hyperpermeability, and angiogenesis. VEGF inhibitor-induced hypertension is mediated by suppression of NO production.
Types of cardiotoxicity
In general, the cardiotoxicities associated with anti-VEGF agents are hypertension, thromboembolic disease, left ventricular dysfunction, myocardial ischemia, QT prolongation, and thrombotic angiopathy.
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BCR/ABL and c-KIT inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib): The mechanism of cardiotoxicity with BCR/ABL and c-KIT targeting drugs is similar to that of multitargeted TKIs.
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