Cardio-Oncology



Cardio-Oncology


Courtney M. Campbell

Ajay Vallakati

Daniel Addison

Ragavendra R. Baliga



INTRODUCTION

Cardio-oncology is an emerging discipline that encompasses the cardiovascular care of the oncology patient.1,2,3,4,5 The discipline also includes cardiac amyloidosis, addressed in Chapter 30. Cardio-oncology patients can present in a variety of settings including (1) prior to initiation of cancer therapy for cardiovascular optimization, (2) acutely with complications directly related to ongoing or recent cancer therapy initiation, (3) prior to intervention or surgery for risk assessment, and (4) during survivorship, years to decades later with complications related to prior oncology therapy. If oncology patients do not already follow with cardiology, ideally they would present to cardiology at the time of initial cancer diagnosis. Patients could then be followed closely by cardiology throughout and after oncology treatment (Algorithm 26.1). This chapter’s focus is on management of a patient throughout cardiotoxic oncology therapy.


PREVENTATIVE CARDIO-ONCOLOGY

Regardless of oncology treatment modality, primary prevention is paramount. The current approach for cardiotoxicity risk assessment and optimization uses the ABCDE model (Algorithm 26.2) that encompasses Awareness, Aspirin (acetylsalicylic acid, ASA), Blood pressure, Cholesterol, Cigarettes, Diet, Diabetes, and Exercise.6,7 Prior to initiation of oncology therapy, patients should be aware of cardiovascular disease signs and symptoms to allow for prompt recognition of potential cardiovascular complications. Aspirin should be initiated in select patients, if indicated for preexisting cardiovascular disease. Blood pressure should be controlled. Patients should cease all tobacco use. Cholesterol lowering statins should be initiated if indicated. Diabetes mellitus control should be optimized and aggressively treated, if it occurs as a consequence of oncology therapy. Patients should maintain good diet and weight management. Exercise is encouraged throughout oncology treatment.8






In addition to improving cardiovascular risk factor management and initiation of guideline-directed medical therapy (GDMT), baseline cardiovascular testing often should be obtained prior to initiation of oncology therapy. This testing can include electrocardiogram (ECG), echocardiogram, biomarkers of troponin (Tn) and brain natriuretic peptide (BNP), and ankle-brachial index (ABI) measurement. If any specific cardioprotective therapies are indicated, these medications should be initiated at this time.


CARDIOTOXICITIES OF CANCER THERAPIES

Many oncologic therapies can cause acute and chronic cardiovascular events including left ventricular (LV) dysfunction leading to heart failure, diastolic dysfunction, fibrosis, cardiac conduction abnormalities and arrhythmias, vascular dysfunction, thrombosis, and metabolic changes. The most common classes of oncology therapy with cardiovascular toxicities as summarized in Table 26.1 will be discussed in this section.








Anthracyclines

Anthracyclines are topoisomerase II inhibitors commonly used to treat multiple malignancies including breast cancer, urothelial cancers, gynecologic cancer, gastroesophageal cancer, acute lymphoblastic/myeloid leukemias, lymphoma, and sarcoma. Cumulative exposure is associated with permanent myocardial damage and carries a U.S. Food and Drug Association (FDA) black box warning for cardiomyopathy. There is no safe dose of anthracycline, and cardiotoxicity occurs at doses below some suggested maximum thresholds.9 Patient-specific risk factors can increase risk of cardiomyopathy. These risk factors include the extremes of age, female sex, underlying cardiovascular disease, and history of prior irradiation of mediastinum. A heart failure risk prediction model has been developed for patients treated with anthracyclines.10

For patients at high risk, dexrazoxane, an iron chelation therapy, can be used. It is FDA indicated to reduce cardiomyopathy in those patients with breast cancer who receive greater than 300 mg/m2 doxorubicin. A meta-analysis demonstrated that dexrazoxane reduced the risk of clinical heart failure and cardiac events without affecting oncologic response, overall survival, and progression-free survival.11,12,13 In addition, small clinical trials have shown some efficacy in mitigating anthracycline-induced cardiotoxicity with the initiation of beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockade, mineralocorticoid antagonism, and combinations of the preceding agents.14,15,16,17,18,19 Larger trials of cardioprotective strategies are needed.


Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) are broad class of oncology medications. Tyrosine kinases are enzymes that catalyze protein phosphorylation and are important in cell growth, proliferation, and angiogenesis. Abnormal function of tyrosine kinases is implicated in many cancers. Specific oncologic TKI targets include human epidermal growth factor receptor 2 (HER-2), vascular endothelial growth factor (VEGF), BCR-ABL (formed by the Philadelphia chromosome t(9;22)), and Bruton tyrosine kinase inhibitor (BTK). Although TKIs are categorized by their primary specific targets, most TKIs are active against many different targets resulting in a range of cardiovascular toxicities.


Human Epidermal Growth Factor Receptor 2 Tyrosine Kinase Inhibitors

HER-2 target is used in treating primarily breast cancer patients. Medications in this class are humanized monoclonal antibodies that block the activation of HER-2/neu receptor resulting in impaired cell growth and survival.20 Not all HER-2 targeted therapies are associated with cardiotoxicity. Trastuzumab and possibly pertuzumab are associated with cardiotoxicity. Cardiotoxicity typically presents as an asymptomatic decrease in left ventricular ejection fraction (LVEF),

is not related to cumulative dose, and usually is reversible.21 Patient-specific risk factors that increase the risk of cardiomyopathy include past or concomitant use of anthracyclines, underlying cardiovascular disease, diabetes, obesity, renal failure, age older than 60 years, and black race.









Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

VEGF TKIs are used to treat a range of cancers including renal cell carcinoma, hepatocellular carcinoma, thyroid cancers, endometrial cancers, and sarcomas. Drugs in this class are small-molecule inhibitors and include axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, sunitinib, and vandetanib. TKIs impair angiogenesis, lymphangiogenesis, vascular permeability, and vascular homeostasis.3 Liver toxicity is the primary major side effect in this class. One drug, vandetanib, carries a black box warning for QT prolongation, torsades de pointes, and sudden death.

Cardiotoxicity with VEGF TKIs most often manifests as hypertension, which is directly related to its mechanism of action. VEGF inhibition decreases nitric oxide production, prostacyclin levels, and increases endothelin resulting in increased systemic vascular resistance. Depending on the specific drug, first-time VEGF TKI use can result in 21% to 80% patients experiencing significant increases in blood pressure as early as the first day of treatment.22 This response is dose dependent and reversible upon therapy discontinuation. The rise in blood pressure can occur within days of treatment and fall just as quickly. Patients should be empowered to change blood pressure medications based on predefined instructions and home blood pressure monitoring. Other cardiotoxic side effects include LV dysfunction (estimated at 1%-2.5%) and ischemia (1.4%-3%). Appropriately treating blood pressure decreases the risk of LV dysfunction and lowers the risk of vascular events.23,24 In one retrospective study, the best blood pressure control was observed in patients on calcium channel blockers.22


Bcr-Abl Tyrosine Kinase Inhibitors

BCR-ABL TKIs are used in hematologic malignancies, chronic myeloid leukemia, and acute lymphoblastic leukemia, with positive Philadelphia chromosome. Drugs in this class are small-molecule inhibitors and include bosutinib, dasatinib, imatinib, nilotinib, and ponatinib. Imatinib is also used to treat gastrointestinal (GI) stromal tumors, myelodysplastic syndrome, dermatofibrosarcoma protuberans, and hypereosinophilic syndrome. Cardiotoxicity is not class wide and primarily is vasculature related.25 Nilotinib and ponatinib are significantly associated with peripheral arterial occlusive disease, ischemic heart disease, and stroke. Ponatinib is also associated with venous thromboembolism, platelet dysfunction, and hypertension. Dasatinib is associated with pulmonary hypertension and platelet dysfunction. Baseline testing and monitoring of ABI is recommended for patients on nilotinib and ponatinib.


Bruton Tyrosine Kinase Inhibitors

BTKs are used to treat B-cell malignancies (chronic lymphocytic leukemia, lymphoma) and chronic graft-versus-host disease (GvHD). Drugs in this class include ibrutinib, acalabrutinib, and zanubrutinib. The most common cardiotoxicities are arrhythmia, hypertension, peripheral edema, and bleeding because of abnormal platelet aggregation. Ibrutinib increases the risk of acute hypertension by 10% to 14%. Development of hypertension is associated with double the incidence of cardiovascular events for 2 years after initiation of ibrutinib.26 Ibrutinib is also significantly associated with atrial fibrillation.27



Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies directed at PD-1, PD-L1, and CTLA-4 receptors. ICIs remove the brakes placed on T cell-mediated response and increase the immune system’s ability to scavenge for and identify foreign cells. Drugs in this class are monoclonal antibodies and include atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, and pembrolizumab. ICIs are used to treat a range of cancers including urothelial carcinoma, non-small cell lung cancer, small cell lung cancer, renal cell carcinoma, melanoma, hepatocellular carcinoma, gastric cancer, and endometrial cancer.

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May 8, 2022 | Posted by in CARDIOLOGY | Comments Off on Cardio-Oncology
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