Heart disease (cardiotoxicity) from cancer treatment
(Adverse effects of chemotherapy and radiotherapy on the heart)
Cancer treatment can induce cardiac side effects that occur early and can be reversible or irreversible or cardiac injuries and/ or progressive cardiac remodeling that may manifest years later.
Chemotherapy is one of the possible causes of heart failure or left ventricular dysfunction, that often requires evaluation from a cardiologist. An interesting fact showing the impact of cancer treatment on the heart is the following: Survivors of pediatric cancer who have been treated with anthracyclines and/or mediastinal radiotherapy have an increased lifetime risk for heart failure (15 times higher probability than matched controls). Cardiotoxicity of the anthracyclines and mitoxantrone
The major causes of chemotherapy-induced cardiomyopathy are the anthracyclines, daunorubicin, and doxorubicin. Anthracycline chemotherapeutics and mitoxantrone (a chemically similar antineoplastic medication) can cause irreversible dilated cardiomyopathy that is related to cumulative dose. The dilated cardiomyopathy, induced by these drugs should be treated with the usual therapy for congestive heart failure. Α mechanism of anthracycline cardiotoxicity is oxidative stress from the production of reactive oxygen species, causing lipid peroxidation of cell membranes but other mechanisms have been also implicated.
Myocyte injury may occur early after anthracycline exposure (according to data from endomyocardial biopsy and troponin measurements). However,
clinical manifestation occasionally may not become apparent until months to
years after drug exposure due to cardiac reserves and the activation of compensatory mechanisms. The probability of cardiomyopathy due to anthracyclines is dependent on the cumulative dose of medication: the risk of heart failure is up to 5% at a dose
< 400 mg/m2 of body surface area, but can reach
approximately 45% at 700 mg/m2.
Although anthracycline cardiotoxicity is usually dose dependent, there
is considerable variability in the susceptibility among patients. Many patients
tolerate standard dose anthracycline treatment without long term cardiac
adverse effects, while in some other patients cardiotoxicity may occur even
after the first dose. Factors increasing the risk of cardiomyopathy include age >70,
preexisting cardiac disease, concomitant use of cyclophosphamide and previous
chest irradiation.
Early cardiac side effects, when they occur, are typically reversible and
self-limiting and include dysrhythmia, repolarization changes in the ECG,
pericarditis, and less frequently myocarditis. However, with a higher
cumulative dose, irreversible dilated cardiomyopathy can occur. All anthracyclines may cause left ventricular systolic dysfunction, but
there are differences in the frequency of this side effect between various
anthracyclines (By order of frequency doxorubicin > idarubicin or epirubicin
> mitoxantrone> liposomal anthracyclines). Liposomal anthracyclines have
the lowest rates of cardiotoxicity.
Because anthracycline chemotherapy can cause left ventricular systolic
dysfunction, before beginning such chemotherapy, all patients should have an
initial evaluation of ventricular function by echocardiography.
Chemotherapy should not be initiated if the ejection fraction (EF) is
< 30%, but it may be administered to patients with high-risk malignancies
and an EF 30%-50%.
If EF is 50% or more, the risk of cardiomyopathy is low. However, the EF should
be assessed again after dose levels of 300 mg/m2 and 400 mg/m2 and
after each subsequent dose. Discontinuation of chemotherapy is indicated
if the EF decreases from baseline by 10% or more to a level lower than normal,
or if the EF decreases to less than 50%, in patients who previously had a
normal EF.
Anthracyclines and mitoxantrone may also cause (in < 1% of the patients)
acute toxicity which is usually (but not always) reversible.
A VIDEO: Cardiotoxicity from chemotherapy (cardio-oncology). An echocardiography case and a brief overview of the topic.
The echocardiographic findings of a woman 60 years old with anthracycline cardiotoxicity are presented in the video. The cardiovascular side effects of drugs used in cancer treatment are presented. If you want to watch the video in full screen then, after starting the video, click on the symbol[] in the lower right corner.
Acute
cardiotoxicity is characterized by ECG changes (QT interval prolongation and
nonspecific ST-segment and T- wave changes), supraventricular arrhythmia or
transient left ventricular dysfunction.
Other drugs used for the treatment of malignant disease (cancer etc) that can
cause cardiotoxicity are the following:
The fluoropyrimidines
The second most common cause of cardiotoxicity (next to anthracyclines) among
chemotherapeutic drugs are the fluoropyrimidines, fluorouracil (FU) and
capecitabine. These drugs are used in the treatment of malignant solid tumors
of the head and neck, gastrointestinal system, or breast. Fluoropyrimidines can
induce angina or myocardial infarction, usually (but not always) due to
coronary vasospasm. They can also cause supraventricular or ventricular
arrhythmias. Angina may appear as effort angina or angina at rest and is often
accompanied by ECG changes (ST segment deviation). Rarely they can also cause
myocarditis leading to heart failure. This heart failure is often reversible
with the discontinuation of fluoropyrimidine administration and standard heart
failure treatment. Treatment for angina or an acute coronary syndrome due to fluoropyrimidines
requires immediate discontinuation of the chemotherapeutic agent and includes
medications that induce coronary vasodilatation such as nitrates and calcium
channel blockers. Usually, cardiotoxicity from fluoropyrimidines requires
permanent cessation of this treatment and switching to other alternative
chemotherapeutic agents.
Trastuzumab
Trastuzumab (Herceptin), is a monoclonal antibody that blocks the HER-2 receptor (human epidermal growth factor receptor-2) and is used in the treatment of breast cancer. It can cause reversible cardiomyopathy with reduced ejection fraction (EF). This more commonly manifests as asymptomatic left ventricular systolic dysfunction with a reduced EF but occasionally also symptomatic heart failure may occur. Factors associated with a higher probability of Trastuzumab cardiotoxicity include age >50 years and previous or especially concurrent anthracycline use. The risk of heart failure during treatment with trastuzumab as adjuvant therapy is approximately 5%, but may reach 25% in combination with anthracyclines. In contrast, concurrent treatment with trastuzumab and radiation therapy does not increase cardiotoxicity risk. Cardiac function should be assessed with echocardiography before the onset of trastuzumab treatment and then at 3, 6, 9, and 12 months after initiating trastuzumab. If the left ventricular EF declines 10 -15 percentage points from baseline to below the lower limit of normal, trastuzumab is withheld for four weeks. Then the EF is reassessed and if it remains below these levels, the drug should be discontinued, whereas if the EF improves, resumption of treatment with trastuzumab under frequent cardiologic assessment can be considered. Trastuzumab-related cardiotoxicity is often reversible and usually responds to standard treatment for heart failure. Many patients tolerate continued treatment or resumption of treatment with trastuzumab (after a period of discontinuation of the drug and resolution of cardiac abnormalities).Cyclophosphamide
Cyclophosphamide cardiotoxicity is relatively rare. In high doses, such as those administered for bone marrow transplantation (140 mg/kg) it can induce acute cardiomyopathy ( a dilated cardiomyopathy similar to that induced by anthracyclines, with similar treatment) or hemorrhagic myopericarditis. This toxic effect is not related to the cumulative dose. In such cases the manifestation of heart failure is rapid, occurring within days of drug administration.
Paclitaxel-the taxanes
Paclitaxel belongs to the category of the taxanes. It may cause bradycardia, usually asymptomatic, but it is important to know that rarely it may cause atrioventricular block. It may cause hypotension during infusion. It can increase the risk of cardiomyopathy (left ventricular systolic dysfunction) when
combined with an anthracycline, with the risk of the occurrence of left ventricular dysfunction at a lower cumulative dose of anthracycline.
VEGF inhibitors (monoclonal antibodies and tyrosine kinase inhibitors)
VEGF inhibitors (monoclonal antibodies and tyrosine kinase inhibitors) constitute another class of medications for the treatment of malignancies that can exert adverse effects on the heart.VEGF (vascular endothelial growth factor) inhibitors exert their action by inhibiting VEGF-mediated angiogenesis. VEGF is a factor that plays an important role in the formation of new vessels (angiogenesis) which will supply the tumor and thus its inhibition is a strategy to prevent tumor growth. These drugs produce that effect (VEGF inhibition) through various mechanisms. Small molecule tyrosine kinase inhibitors (sunitinib and sorafenib) are nonselective inhibitors of VEGF receptors. They also inhibit up to 50 different kinases in addition to their intended target, thus producing adverse effects. They can cause hypertension, ischemia, left ventricular dysfunction and heart failure. Bevacizumab, a monoclonal antibody that targets VEGF is associated with a fivefold increase in the risk of heart failure.An overview and classification of the types of cardiotoxicity
In summary, chemotherapy can predispose to left ventricular.
systolic dysfunction or clinical heart failure, hypertension, myocardial ischemia, arrhythmia, valvular heart disease and pericardial disease, with different chemotherapeutic drug classes predisposing to different cardiac adverse effects.
Malignancy and chemotherapy have been found to correlate to the development of atrial fibrillation, which is the most common arrhythmia associated with cancer treatment. QT interval prolongation ( a predisposing factor for torsades de pointes) is also an adverse effect that can be caused by several chemotherapeutic agents, such as cyclophosphamide, the taxanes, thalidomide and tyrosine kinase inhibitors.
Hypertension can be caused by VEGF inhibitors (bevacizumab, sorafenib, and sunitinib). ACE-inhibitors and nondihydropyridine calcium channel blockers have shown satisfactory effects in the treatment of hypertension induced by VEGF-inhibitors.
Left ventricular systolic dysfunction or heart failure can be caused by the anthracyclines (doxorubicin, daunorubicin, epirubicin), monoclonal antibodies (trastuzumab), alkylating agents (cyclophosphamide) and tyrosine kinase inhibitors. Anthracyclines cause cardiotoxicity type I (which means permanent myocardial damage due to the destruction of cardiomyocytes), whereas trastuzumab usually causes cardiotoxicity type II (reversible myocardial dysfunction due to systolic dysfunction of cardiomyocytes).
Global longitudinal strain (GLS) is a parameter related to the systolic myocardial deformation in the longitudinal direction derived by speckle tracking echocardiography. It can show myocardial systolic dysfunction earlier than the EF. A reduction in the absolute value of GLS by 15% of its initial (baseline-before chemotherapy) value is an indication of cardiotoxicity and can predict the subsequent reduction of EF and the development of heart failure. However, GLS has some limitations: It is dependent on image quality and also on the technology and software of the echocardiographic device used. Thus, patients should be followed up with the same device, since different devices may have differences in the calculated GLS value.
Left ventricular systolic dysfunction or heart failure can be caused by the anthracyclines (doxorubicin, daunorubicin, epirubicin), monoclonal antibodies (trastuzumab), alkylating agents (cyclophosphamide) and tyrosine kinase inhibitors. Anthracyclines cause cardiotoxicity type I (which means permanent myocardial damage due to the destruction of cardiomyocytes), whereas trastuzumab usually causes cardiotoxicity type II (reversible myocardial dysfunction due to systolic dysfunction of cardiomyocytes).
Echocardiographic indices of left ventricular systolic function used in cardio-oncology
A clear indication of cardiotoxicity due to chemotherapy is a reduction of the left ventricular ejection fraction, EF by 10% from its baseline value (its value before the initiation of chemotherapy) to a level below normal. (In cardio-oncology 50% is considered as the lower limit of normal EF). Another indication is the reduction of EF to a value <50% in patients who had a normal baseline EF.Global longitudinal strain (GLS) is a parameter related to the systolic myocardial deformation in the longitudinal direction derived by speckle tracking echocardiography. It can show myocardial systolic dysfunction earlier than the EF. A reduction in the absolute value of GLS by 15% of its initial (baseline-before chemotherapy) value is an indication of cardiotoxicity and can predict the subsequent reduction of EF and the development of heart failure. However, GLS has some limitations: It is dependent on image quality and also on the technology and software of the echocardiographic device used. Thus, patients should be followed up with the same device, since different devices may have differences in the calculated GLS value.
The role of echocardiographic evidence of cardiotoxicity in treatment decisions
In cases with echocardiographic evidence of cardiotoxicity (either a reduction in the left ventricular EF or in GLS-see above) treatment with an ACE-inhibitor and beta-blocker should be initiated. Also, more frequent echocardiographic monitoring of the patient will be needed and serious consideration of the cardiotoxicity issue by the oncologist in order to make a decision on possible alteration of the chemotherapeutic regimen. Cooperation between the oncologist or hematologist and the cardiologist is necessary. The oncologist is responsible for deciding if it is possible to change chemotherapy by discontinuing the cardiotoxic drug, possibly by replacing it with another drug with lower cardiotoxicity or no cardiotoxicity or if the dose will be reduced. The decision is not simple, cooperation with the cardiologist is essential, and it is necessary to take into account both the necessity of specific chemotherapy based on the type and severity of malignant disease and the severity of cardiotoxicity (cost-benefit assessment between side effects and therapeutic action of the chemotherapeutic agent).Preventive strategies for cardiotoxicity
The best strategy for treatment and prevention of further deterioration
of cardiomyopathy induced by chemotherapy is the withdrawal of cardiotoxic
drugs or use of fewer cardiotoxic agents. This should always be balanced
against the need to treat the malignant disease. A few studies suggest that
treatment with ACE- inhibitors, angiotensin II receptor blockers, or
beta-blockers as a single-drug therapy may protect against chemotherapy-induced
cardiomyopathy. The beta-blocker carvedilol may exert its protective effect in
part through a potent antioxidant effect, thus targeting one of the mechanisms
of anthracycline-induced cardiomyopathy. A combined preventive treatment of
patients receiving intensive chemotherapy for hematologic malignancies with.an
ACE- inhibitor (enalapril), plus a beta-blocker (carvedilol) can reduce the
detrimental effects of this treatment in LV ejection fraction,(as shown in a
small study, the OVERCOME trial). Furthermore, the extensive documentation that
the combination an ACE- inhibitor and a beta-blocker can markedly reduce
mortality in the general heart failure population suggests that this strategy
should be used, but also further tested, during cancer therapy.
Current guidelines state that treatment of chemotherapy-induced heart failure
should follow the same principles as in treating heart failure due to other
cardiomyopathies. The current main strategy is to stop ongoing chemotherapy
with cardiotoxic drugs, to avoid further use of anthracyclines and administer
to the patient traditional heart failure therapy. There are still unresolved
issues, such as the question: "what degree of heart dysfunction, or heart
failure, is acceptable as a prize for the cure of a malignant disease?"
Adverse effects of chest radiotherapy on the heart
Radiotherapy used for the treatment of tumors can also produce heart disease when it involves the thoracic area. Localized and carefully planned irradiation can reduce cardiac damage.Radiotherapy can cause heart failure due to the destruction of cardiomyocytes, macrovascular and microvascular damage which may lead to progressive atherosclerosis and coronary artery disease with a subsequent myocardial infarction or the development of myocardial fibrosis. This can lead to varying degrees of diastolic or systolic dysfunction. In addition, radiotherapy may cause pericardial inflammation with subsequent pericardial thickening leading to the development of constrictive pericarditis, or significant endothelial damage of the heart valves leading to the development of valve disease (regurgitation or stenosis).
GO BACK TO THE HOME PAGE AND TABLE OF CONTENTS LINK :
2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines
Bloom MW, Hamo CE, Cardinale D, et al. Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging. Circ Heart Fail. 2016;9(1):e002661. doi:10.1161/CIRCHEARTFAILURE.115.002661
LINK https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709035/
Bloom MW, Hamo CE, Cardinale D, et al. Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging. Circ Heart Fail. 2016;9(1):e002661. doi:10.1161/CIRCHEARTFAILURE.115.002661
LINK https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709035/
Smiseth O, et al. Cardioprotection During Chemotherapy Need for Faster Transfer of Knowledge From Cardiology to Oncology and Role for a Cardio-Oncologist. Journal of the American College of Cardiology 2013;61: 2363-2364.
LINK http://www.onlinejacc.org/content/61/23/2363
Koutsoukis A, Ntalianis A, Repasos E, Kastritis E, Dimopoulos MA, Paraskevaidis I. Cardio-oncology: A Focus on Cardiotoxicity. Eur Cardiol. 2018;13(1):64-69. doi:10.15420/ecr.2017:17:2
Ewer SM. Guest Editorial: Is Cardio-Oncology Ready For Algorithms? European Cardiology Review 2018;13(1):62-63.
LINK https://www.ecrjournal.com/articles/cardio-oncology-ready-algorithms
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