CASE 1

A 51-year-old woman presents to the emergency department with dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea. She has a history of newly diagnosed breast cancer having recently completed treatment with anthracycline followed by trastuzumab. An echocardiogram was ordered, which revealed moderately dilated left ventricle (LV) and severely depressed LV systolic function (left ventricular ejection fraction; LVEF 25%) with global hypokinesis (Figure 16-1).

CASE 2

An 82-year-old man with a history of advanced renal cell cancer presents with asymmetric left leg swelling and pain. He has been receiving cancer treatment with a vascular endothelial growth factor (VEGF) signaling pathway inhibitor (pazopanib). A venous duplex ultrasound of the lower extremities was ordered, which confirmed a deep vein thrombosis (DVT) in the left leg from the proximal femoral vein to the calf veins (Figure 16-2). He was placed on lifelong anticoagulation with Warfarin.

CASE 3

A 70-year-old man with a history of metastatic prostate cancer on chronic androgen-deprivation therapy presents complaining of shortness of breath with exertion and fatigue. Workup was notable for an electrocardiogram (ECG) with ischemic ST-T wave changes in the anterior leads and blood testing revealing an elevated cardiac troponin I. He underwent coronary angiography that demonstrated a significant stenosis in the proximal left anterior descending artery (Figure 16-3). He underwent a stenting procedure and was placed on aspirin, clopidogrel, and atorvastatin.

There are approximately 15.5 million cancer survivors in the United States and that number is expected to increase to more than 20 million by 2026.¹ As a result, cardiovascular disease (CVD) has become the second leading cause of long-term morbidity and mortality among cancer survivors.^2,3 Understanding the cardiac toxic effects of contemporary cancer therapies and the cancer itself has become of paramount importance and has been the impetus for the discipline of cardio-oncology.

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  Current anticancer therapies are associated with unique and various degrees of direct as well as indirect cardiovascular (CV) insults.

  
  
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  The true incidence of cancer treatment-induced CV injury is likely underreported and varies widely, depending on the type and duration of therapy, and underlying patient comorbidities.

  
  
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  Among older cancer survivors, CVD is a more common contributor than cancer to mortality.^1,4

  
  
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  Survivors of childhood cancers are at a 15-fold increased risk of developing congestive heart failure (CHF) and at a 7-fold increased risk of premature death due to cardiac causes when compared to the general population.⁵

  
  
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  The U.S. National Health and Nutrition Examination Survey reported adult cancer survivors, compared to noncancer controls, were more likely to report ischemic heart disease (13.7% vs 5.2%) and CHF (7.9% vs 2.1%).⁶

  
  
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  Anthracyclines and mediastinal radiation therapy reveal a dose-dependent increased risk of cardiotoxicity (LV systolic dysfunction).

  
  
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  A contemporary large population-based cohort study with a median follow-up of 20 years revealed a 4.5-fold increased risk of CHF in Hodgkin lymphoma survivors treated with ≥250 mg/m² of doxorubicin compared to those not treated with doxorubicin or mediastinal radiation therapy.⁷

  
  
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  Mediastinal radiation therapy ≥30 Gy was associated with a 2.8- to 4.7-fold increase in CHF.⁷

  
  
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  A combination of lower dose anthracyclines (≤250 mg/m² doxorubicin) plus mediastinal radiation therapy resulted in a 5.4-fold increased risk of CHF.⁷

  
  
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  In contemporary randomized controlled breast cancer trials for trastuzumab, there appears to be an increase in symptomatic heart failure (HF; 0.6%-4.1%) and a significant increase in asymptomatic LV systolic dysfunction (3%-19%), with about one-third having persistent LV systolic dysfunction.^8,9

  
  
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  Of note, roughly 80% of those enrolled in clinical trials for trastuzumab, similar to most cancer trials, did not have a history of CVD or HF, and as such real-world registry data suggest a higher rate of trastuzumab-associated cardiotoxicity.^10,11

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  CVD and cancer are intricately linked due to shared common risk factors, coexistence of both diseases in an aging population, and direct adverse effects of cancer treatments on CV health.

  
  
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  There are several purported mechanisms of anthracycline toxicity including: DNA damage caused by disruption of the normal catalytic cycle of topoisomerase 2β causing DNA double-strand breaks and activation of apoptosis, as well as changes in the transcriptome causing mitochondrial dysfunction and generation of reactive oxygen species.^12,13

  
  
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  Trastuzumab blocks the ErB2 (aka Her2) pathway, which normally acts as a response/repair mechanism to myocardial injury.¹⁴

  
  
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  Radiation therapy increases the risk of early and complex atherosclerosis in any vascular bed within the radiation field.¹⁵

  
  
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  Inhibitors of VEGF affect angiogenesis, endothelial cell survival, vasodilatation, and cardiac contractile function with resulting hypertension (HTN), the most common on-target CV effect.¹⁶

  
  
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  Table 16-1 provides a more comprehensive list of treatment-related cardiac effects by class of therapy.

Non-treatment-related modifiers of CV risk include: