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)
______ is a humanized recombinant anti-VEGF antibody.
Bevacizumab
The CV risks associated with bevacizumab include _____.
- HTN
- Low incidence of HF (1.6%, but with a RR of 4.7 compared with placebo)
- Arterial thromboembolic events (7.1% with bevacizumab versus 2.5% with chemotherapy alone)
Sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, cabozantinib, and vandetanib are other small-molecule tyrosine kinase inhibitors (TKIs) that inhibit multiple TKs, in addition to the VEGFR signaling pathway. These antiangiogenic TKIs have been associated with _____.
HTN
CM and HF
Cardiac ischemia
Arterial thrombotic events
Sunitinib results in _____, as well as declines in _____.
HTN
Declines in LVEF
HTN secondary to sunitinib tends to occur early, with the median time to HTN (defined as a systolic blood pressure of 140 mm Hg or diastolic blood pressure of 90 mm Hg) occurring within _____ days of the first two cycles of sunitinib therapy.
1-20 days
Additional single center retrospective data suggest that average systolic blood pressure increases of 8.5 mm Hg and diastolic blood pressure increases of 6.7 mm Hg occur with any TKI therapy, greatest with _____.
Axitinib
8.5/6.7 increase in BP
The mechanisms of sunitinib cardiotoxicity are believed to be secondary to the _____.
- Inhibition of signaling pathways critical to CV homeostasis
- Energy compromise
- Increased afterload
_____, the first targeted small-molecule TK inhibitor of the fusion protein Bcr-Abl, which arises from the chromosomal translocation that creates the Philadelphia chromosome, revolutionized the treatment of chronic myeloid leukemia
Imatinib
_____, with more potent activity than imatinib against Bcr-Abl, has been associated with significant pulmonary HTN that is observed to be largely reversible with cessation of the drug.
Dasatinib
This finding prompted the FDA to recommend that patients be evaluated for cardiopulmonary disease prior to and during dasatinib treatment
_____ have both been associated with PVD and ischemic heart disease
Nilotinib and ponatinib
Moreover, nilotinib has been associated with _____.
.The incidence of PVD has been reported to be 1.3% to 6.2%, and the incidence of combined CV events, including ischemic heart disease, cerebrovascular disease, and PVD, is on the order of 10% to 15.9%
Cardiometabolic effects:
Hyperglycemia
Hyperlipidemia
QT prolongation
Ponatinib has been associated with _____, potentially related to VEGFR1-3 inhibition.
HTN
Ischemic events
HF
In the Ponatinib Ph-Positive Acute Lymphoblastic Leukemia and CML Evaluation (PACE) trial, 6% of patients experienced CV events, 3% experienced cerebro- vascular events, and 4% experienced PAD at 12 months
_____ is a small molecule Bruton’s TKI that is used in the treatment of chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, and chronic graft versus host disease.
CV toxicities:
Ibrutinib
CV toxicities: HTN, atrial fibrillation and supraventricular arrhythmias, ventricular arrhythmias, HF, and bleeding.
ADT includes gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide, goserelin, and triptorelin; GnRH antagonists (Degarelix); and antiandrogens, such as flutamide and bicalutamide.
These therapies have adverse cardiometabolic effects, and low testosterone is also implicated in metabolic syndrome.
Studies suggest that they result in _____.
- Increased body weight (particularly visceral adiposity)
- Decreased insulin sensitivity
- Dyslipidemia (increased LDL and triglycerides)
Moreover, treatment with ADT has also been associated with adverse CV events, including _____.
Doronary disease
Myocardial infarction
HF
Sudden cardiac death
Death due to CV disease
_____ is a selective estrogen receptor modulator widely used in adjuvant therapy for estrogen receptor–positive breast cancer.
Tamoxifen
Data regarding the cardioprotective effect of tamoxifen have been conflicting.
Tamoxifen does exert a favorable effect on lipids, with a reduction in total cholesterol and LDL levels
_____ (e.g.,anastrozole,letrozole,exemestane) block the conversion of androgens to estrogen.
Aromatase inhibitors
Some studies demonstrate a potential effect of Tamoxifen on decreasing the ischemic heart disease incidence, with a RR of 0.76 (95% CI, 0.60 to 0.95; P = 0.02), although other studies demonstrate no significant effect.
An increased risk of thromboembolic events, however, is well established; they occur largely during the first _____ years of exposure and in older women.
A meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group confirmed a significant, but small, increased risk in venous thromboembolism with tamoxifen.
2 years
Aromatase inhibitors are associated with worse ______, and a longer duration of exposure is reportedly associated with an increased risk of CV disease.
Hypercholesterolemia and HTN
Pooled data analyses from multiple large cohort studies suggest that there is a modestly increased risk of CV disease, as defined by myocardial infarction, angina, or HF with aromatase inhibitors compared with tamoxifen (odds ratio [OR], 1.26; 95% CI, 1.10 to 1.43; p < 0.001)
The clinical manifestations of RT cardiotoxicity include _____.
Coronary disease
CM and HF
Valvular disease
Arrhythmia
Pericardial disease
Increasing data suggest that early subclinical changes, including cardiac perfusion defects and longitudinal strain abnormalities, can occur earlier, within ___ months of RT, even with the use of current techniques.
6 months
Moreover, a study of women treated for breast cancer between 1958 and 2001 suggested that major CV events increased by ____% for each Gy increase in mean heart dose
7.4%/ Gy increase in mean dose
In _____, a randomized trial of standard versus high-dose RT in locally advanced lung cancer, high-dose RT was associated with a 38% increased risk of all-cause mortality, and RT dose to the heart specifically was associated with worse overall survival.
RTOG 0617
In addition to the RT ____ (total and mean heart dose), which is a critical determinant of the development of cardiac disease, additional risk factors include the radiation field, younger age, higher number of fractions, concomitant chemotherapy (anthracyclines), CV risk factors (diabetes, tobacco use, obesity, HTN, hypercholesterolemia),and CV disease.
RT dose delivered
Irradiation also results in valvular disease with _____.
Leaflet thickening
Fibrosis
Calcification
Irradiation also results in valvular disease with leaflet thickening, fibrosis, and calcification. _____-sided valves are more commonly affected, particularly the aortic valve, followed by the mitral and triuspid valves.
Left-sided valves (AV)
Followed by:
MV
TV
Fibrosis and calcification of the _____ typically occur in irradiation.
Aortic root
Aortic valve annulus
Aortic valve leaflets
Aortic-mitral intervalvular fibrosa
Mitral valve annulus
Base and mid portions of the mitral valve leaflets
______ has been noted as a distinguishing feature with radiation exposure valve affectation.
Sparing of the mitral valve tips and commissures
_____ is more common than stenosis, with the exception of the aortic valve in irradiation
Regurgitation
The reported incidence of significant valve disease in radiation induced heart disease is ___% at 10 years, ___% at 15 years, and ___% at 20 years,with the incidence increasing significantly after 20 years and related to dose
Incidence of valve disease in radiation:
1% at 10 yrs
5% at 15 yrs
6% at 20 yrs
The pathophysiology of radiation-induced heart disease may be related to an increase in _____ and osteogenic factors, including _____.
TGF-B
Osteogenic factors:
Bone morphogenetic protein 2, osteopontin, and alkaline phosphatase
RT has also been associated with an increased risk of HF with preserved ejection fraction.
On a microvascular level, irradiation results in _____.
On a macrovascular level, there is _____.
Microvascular level:
* Endothelial cell loss and dysfunction,
* Increased inflammation
* Decreased capillary density
Macrovascular level:
* Proximal (ostial) involvement of coronary arteries
* Lesions can be fibrous, fibrocalcific, fibrofatty, and laden with cholesterol and lipid.
Irradiation also results in autonomic dysfunction, defined by an _____.
Elevated resting heart rate
Abnormal heart rate recovery
Causes myopericarditis, arrhythmias
Cyclophosphamide
Causes vasculotoxicity, including endothelial dysfunction, arterial vasospasm, HTN
Cisplatin, carboplatin, oxaliplatin
Causes coronary vasospasm, myocardial ischemia, infarction, arrhythmias, ECG changes, sudden death
5-Fluorouracil, capecitabine
Causes pulmonary HTN, pericardial effusion.
Cardiopulmonary status should be evaluated prior to and during therapy
Dasatinib
Causes peripheral vascular disease, ischemic heart disease, QT prolongation, cardiometabolic effects
Nilotinib
Causes cytokine release syndrome
CAR T Cell therapies
Causes metabolic syndrome, ischemia, coronary artery disease, HTN
Leuprolide, goserelin, triptorelin, degarelix, flutamide, bicalutamide
Causes hypercholesterolemia, HTN, HF, combined endpoint of dysrhythmia, valvular disease, and pericarditis
Aromatase inhibitors (anastrozole, letrozole, exemestane)
Causes thrombosis but has favorable effects on lipids
Tamoxifen
Causes valvular disease, pericardial disease, vascular disease, ischemia, coronary artery disease, CM, HF
Radiation therapy
Summary
