B P6 C56 Cardio-Oncology: Managing Cardiotoxic Effects of Cancer Therapies Flashcards
Cardio-oncology is a multidisciplinary field that encompasses the following broad clinical areas:
(1) the care of patients with pre-existing CV risk factors or disease who develop cancer
(2) Cancer patients and survivors who are at greater propensity for the development of CV risk factors or disease secondary to cancer or cancer therapy**
(3) Patients with active or a prior history of cancer who subsequently develop overt CV risk factors or disease
The American College of Cardiology and American Heart Association HF Guidelines classify exposure to cardiotoxic therapies, such as anthracyclines, as stage ______ HF.
Stage A
A study of 2625 patients treated with anthracyclines, primarily for breast cancer and hematologic disease, followed over a median of 5.2 years (interquartile range [IQR] 2.6 to 8.0) with serial echocardiography monitoring noted an overall incidence of cardiotoxicity of _____%
9%
Cardiotoxicity was defined as:
Decrease in the LV ejection fraction (LVEF) of >10% from baseline to less than an absolute value of 50%
Clinical risk factors for anthracycline-induced cardiotoxicity include:
Age of exposure
Traditional, modifiable CV risk factors (HTN, diabetes, obesity, and hyperlipidemia)
Prior chest RT
Anthracycline dose
Genetic factors
Pre-existing CV disease
More recent studies also suggest that the association between anthracycline dose and HF is modified by age of treatment, with a greater relative risk (RR) of CV disease among those who received high-dose anthracycline chemotherapy (>/= ___ mg/m2) at less than13 years of age, as compared to children older than 13 years.
250 mg/m2
In addition to modifiable CV risk factors and age at anthracycline exposure, concomitant treatment exposures such as RT (>____ Gy) are associated with an increased risk of CV disease
RT > 15 Gy
Older retrospective analyses suggest an incidence of HF, as defined by clinical signs and symptoms, of _____% at a cumulative dose of 300 mg/ m2, 4.7% at 400 mg/m2, 15.7% at 500 mg/m2, and 48% at 650 mg/m2 of anthracyclines
1.7% at 300 mg/m2
4.7% at 400 mg/m2
15.7% at 500 mg/m2
48% at 650 mg/m2
Several basic mechanisms have been proposed to explain anthracycline-induced cardiotoxicity. The first is formation of _____.
ROS and increased oxidative stress via redox cycling of the quinone moiety of doxorubicin
Formation of anthracycline-iron complexes
Topoisomerase-2B (Top2B) inhibition
Proteasome inhibitors, including _____, are used in the treatment of relapsed or refractory and newly diagnosed cases of multiple myeloma
Bortezomib and Carfilzomib
The reported incidence of all-grade and grade 3 and higher adverse CV events with these proteasome inhibitors (Bortezomib, Carfilzomib) from a meta-analysis of Phase 1 to 3 clinical trials was 18.1% and 8.2%,respectively.
_____ were the most common adverse CV events, followed by _____.
Most common:
HF (4.1%)
HTN (12.2%)
Followed by:
Arrhythmias (2.4%)
Ischemia (1.8%)
Predictors of adverse CV events with carfilzomib include:
History of HF
Baseline diastolic dysfunction
Higher doses of carfilzomib
Abnormal NT-proBNP levels at baseline or during therapy
The data related to immunotherapy cardiotoxicity are still emerging. Many published studies are derived from retrospective cohort studies or case series.These suggest that myocarditis typically occurs early, at a median time of _____ days, but over a broad range as there are also published reports of late myocarditis
34 to 65 days
The taxanes, _____, disrupt microtubular networks as their mechanism of antitumor activity. Used alone, these drugs have relatively little cardiotoxicity; there may be predominantly asymptomatic bradycardia and atrioventricular block.
Paclitaxel (Taxol)
Semisynthetic analogue Docetaxel (Taxotere)
Cyclophosphamide, used in the treatment of breast cancer and hematologic malignancies, is typically well tolerated.
At higher dosages, greater than _____ mg/kg, there have been case reports of hemorrhagic myocarditis, tachyarrhythmia, HF, and pericardial disease.
Emerging data on the use of cyclophosphamide in the post-transplant setting may suggest increased CV risk.
> 100 mg/kg
Cases of acute arterial occlusive events, including myocardial infarction and stroke, have been reported in patients receiving _____.
Cisplatin
_____ results in direct endothelial damage and increased platelet reactivity, which may potentially explain these clinical observations
Platinum
_____, are used in the treatment of many solid tumors, including gastrointestinal, breast, head and neck, and pancreatic cancers.
5-Fluorouracil (5FU) and its oral analog, capecitabine (Xeloda)
CV effects of 5FU include:
Myocardial ischemia potentially related to vasospasm
Cardiac arrhythmias
HTN
Hypotension
HF
CM
Cardiac arrest
In vitro and in vivo studies suggest that 5FU is associated with _____.
Endothelial injury
Vasospasm and vasoconstriction
Interstitial fibrosis
_____ is associated with a 6.5% incidence of cardiac events, defined by angina in 4.6%, myocardial infarction, ventricular tachycardia, and sudden death.
Capecitabine (Xeloda)
In a prospective study of 106 patients treated with 5FU, 9% (8.5%) had symptoms of cardiotoxicity, presenting primarily as _____.
5FU treatment was associated with a greater risk of ____ and _____ compared to capecitabine.
Angina
Electrocardiographic changes
Elevations in N-terminal pro hormone natriuretic peptide (NT-proBNP)
Stroke or myocardial infarction
_____ is a humanized monoclonal antibody that binds sub- domain IV of human epidermal growth factor receptor 2 (HER2)/neu, also known as ErbB2.
Trastuzumab
Trastuzumab exerts its antitumor effects by blocking HER2 cleavage, resulting in antibody-dependent, cell-mediated cytotoxicity and inhibition of ligand-independent, HER2-mediated signaling affecting the following downstream pathways: PI3K, serine/threonine-specific protein kinase Akt, mitogen-activated protein kinase (MAPK), extracellular-signal– regulated kinase 1/2 (ERK1/2), and the mechanistic target of rapamycin (mTOR)
In the Cancer Research Network, there was a 20.1% incidence of HF and/or CM with combination therapy. Ontario Cancer Registry data suggested an estimated cumulative 5-year incidence of HF of 5.2% with trastuzumab regimens, with a HF risk that was greatest in the first _____ years of cancer therapy
1.5 years
Importantly, LVEF declines with trastuzumab are largely _____ and typically occur during therapy
Reversible
As a consequence, trastuzumab- associated cardiotoxicity was initially termed type ___ dysfunction, to distinguish it from anthracycline-associated cardiotoxicity, termed type ___ dysfunction.
Trastuzumab: Type II dysfunction
Anthracyclines: Type I dysfunction
_____ is a humanized monoclonal antibody that binds HER2 at subdomain II of the HER2 extracellular domain; it is administered in conjunction with trastuzumab for high-risk and metastatic HER2+ breast cancer.
Pertuzumab
_____ signaling pathway inhibitors are used in the treatment of metastatic renal cell cancers; gastrointestinal stromal tumors; and thyroid, hepatocellular, and colon cancers
Vascular endothelial growth factor receptor (VEGFR)
Summary
