|Year : 2017 | Volume
| Issue : 2 | Page : 60-67
Managing cancer patients: The heart really matters
RR Kasliwal, Madhu Mary Minz
Department of Cardiology, Medanta - The Medicity, Gurgaon, Haryana, India
|Date of Web Publication||31-Mar-2017|
Madhu Mary Minz
Department of Cardiology, Medanta - The Medicity, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
Early diagnosis of cancer and advances in the methods of cancer treatment over the past 25–30 years has led to increased number of cancer survivors. However, the conventional cancer treatments, radiotherapy, and the newer targeted therapy while successful at treating cancers are known to cause ill effects on the heart. Cardiotoxicity can develop during cancer treatment or can occur within days or months or even years after cessation of cancer treatment. The side effects of cancer treatment on the heart can be transient or can sometimes cause permanent damage to the heart, requiring life-long cardiac medications. The cardiovascular complications include myocardial dysfunction and heart failure, coronary artery disease, valvular heart disease, arterial hypertension, arrhythmia, QT prolongation, peripheral vascular disease, thromboembolic disease, and pericardial diseases. Chemotherapy-induced cardiotoxicity can sometimes affect the ongoing cancer treatment, reduce quality of life, and increase the risk of death from cardiac-related causes. Early diagnosis of cardiac side effects using biomarkers such and imaging followed by initiation of cardioprotective drug is of utmost importance, so that the cancer patient can get overall benefit of life-saving cancer therapy. A long-term follow-up to identify late cardiac complications is also encouraged.
Keywords: Cancer chemotherapy, cardiotoxicity, targeted therapy
|How to cite this article:|
Kasliwal R R, Minz MM. Managing cancer patients: The heart really matters. J Clin Prev Cardiol 2017;6:60-7
| Introduction|| |
Cancer is among the leading causes of death worldwide, and according to the International Agency for Research on Cancer – GLOBOCAN – approximately 14 million new cases and 8.2 million cancer-related deaths occurred in 2012. As per Indian Council of Medical Research, the estimated number of cancer patients in India is around 2.5 million with over 7 lakhs new patients getting registered every year. Cancer-related deaths amount to 556,400 annually.
The numbers of cancer survivors continue to increase because of both advances in early detection and newer chemotherapy agents. However, mortality and morbidity among cancer survivors has increased due to side effect of cancer treatment. Cardiovascular disease (CVD) is one of the most common reasons for premature mortality in cancer survivors. Heart disease following cancer treatment may be the result of direct cardiovascular damage caused by treatment itself or because of accelerated atherosclerotic process due to cancer treatment, especially in the presence of baseline cardiovascular risk factors. Conventional chemotherapeutics and some of the newer anticancer signaling inhibitors carry a substantial risk of cardiovascular complications that include:
- Myocardial dysfunction and heart failure
- Coronary artery disease (CAD)
- Valvular disease
- Arterial hypertension
- Arrhythmia and QT prolongation
- Peripheral vascular disease (PVD)
- Thromboembolic disease
- Pericardial disease.
While some of these side effects manifest early during cancer treatment and hence affect the ongoing cancer therapy, some side effects manifest years later. Some complications are irreversible and cause progressive CVD while others induce only transient dysfunction with no apparent long-term sequelae. The complications are more frequent when two or more chemotherapy agents are combined and/or radiotherapy (RT) is also included in the treatment protocol as these modalities have a complimentary or synergistic cardiotoxic effect. The challenge for the treating oncologist and cardiologist is to balance the need for life-saving cancer treatment with the assessment of risk from cancer drug-associated cardiovascular side effects to prevent long-term damage to the heart. Furthermore, sometimes, the full spectrum of cardiotoxicity frequently does not become apparent until months or even years after the cancer treatment; hence, long-term follow-up of patients exposed to potentially cardiotoxic cancer drug is needed.
[Table 1] summarizes common predisposing factors for cancer chemotherapy-related cardiotoxicity, whereas [Table 2] summarizes the cardiovascular complications of commonly used chemotherapeutic agents.
|Table 2: Cardiovascular complications of commonly used chemotherapy agents|
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| Cardiovascular Complications of Commonly Used Chemotherapy Agents|| |
Myocardial dysfunction and heart failure
Cardiac dysfunction is the most serious complication of cancer treatment. Cardiotoxicity can manifest early after chemotherapy or as a late presentation. Conventional chemotherapies such as anthracyclines (doxorubicin, idarubicin, epirubicin), antimetabolites (clofarabine), and alkylating agents (cyclophosphamide) can cause permanent myocardial cell injury resulting in cell loss (apoptosis/necrosis) and hence an irreversible damage (Type I). This can later on lead to progressive remodeling resulting in late cardiomyopathy. Whereas novel agents such as immune-therapies and targeted therapies cause transient reversible dysfunction (Type II) due to disarray of contractile elements and mitochondrial dysfunction. However, preexisting heart disease and combination of therapies can lead to unpredictable long-term complications.
Anthracyclines and nonanthracycline analog mitoxantrone
These are very effective antineoplastic agents for solid tumors and hematological malignancies; however, their cardiotoxic effects are well established. The complications are mostly dose dependent and can depend on susceptibility of the patient. Incidences of heart failure were 3%, 7%, and 18% with a cumulative dose of 400, 500, and 700 mg/m 2. The most accepted pathophysiological mechanism is generation of reactive oxygen species which eventually damages cardiomyocytes, and hence, the dysfunction is irreversible. Topoisomerase (Top 2b) was recently revealed as mediator of toxicity; inhibition of which causes double-stranded breaks in DNA which leads to myocyte death. Acute side effects are generally reversible and self-limiting and can manifest as electrocardiography (ECG) changes, arrhythmias, or pericarditis. It is not certain if early dysfunction can be progressive or can evolve into late dysfunction. Elevation of biomarkers may identify the people at risk for progressive disease. Early changes can appear within 1st year of treatment and late dysfunction can appear after several years. Due to good cardiac reserve and compensatory mechanisms, clinical manifestation can appear late.
Risk factors for developing cardio-toxicity with anthracyclines
Age (pediatrics age >65 years), female sex, renal failure, preexisting heart disease/hypertension, cumulative dose, combined chemotherapy (with alkylating or microtubule agents and immune and targeted agents), previous RT to heart with genetic predisposition.
Using drugs such as epirubicin with an altered anthracycline structure;using altered drug delivery, and schedule system (infusion instead of bolus); use of cardioprotective agents such as dexrazoxane; using cardio- protective medications
Cyclophosphamide-related toxicity appears at high doses (>140 mg/kg) within days and primarily in patients with older age, bolus dose, and combination with other therapies or postmediastinal radiation.
Cisplatin and taxanes
Cisplatin requires high intravenous fluid infusion to avoid toxicity and this volume overload can lead to heart failure. Taxanes (docetaxel) when combined with other agents have been shown to lead to heart failure.
Immunotherapies and targeted therapies
These novel, selective mechanism-based agents target at molecular pathways as in kinase inhibition by monoclonal antibodies or soluble decoy receptors. Kinases play a crucial role in cardiovascular homeostasis and myocardial regulation as well; hence, by virtue of this inhibition, these agents actually result in off-target effects on heart. Trastuzumab inhibits a humanized monoclonal antibody and targets human epidermal growth factor receptor 2 (HER2) which is overexpressed in a subgroup of breast cancer patients. Earlier 27% of the patients who were treated with trastuzumab and conventional chemotherapy like cyclophosphamide and doxorubicin developed symptomatic or asymptomatic heart failure. Mechanism of toxicity is structural and functional changes in contractile protein and mitochondria. Administering trastzumab after anthracycline or other agents and regular cardiac monitoring has reduced incidence of heart failure and has improved outcome of HER2 positive breast cancer patients. Long-term follow-up in these patients is also reassuring. Trastusumab-associated cardiotoxicity appears early during treatment and is reversible with interruption of therapy and initiation of cardioprotective medicines.
Previous/concomitant anthracycline treatment or RT, age (65 years), previous left ventricular (LV) dysfunction, hypertension, and advanced age.
Reducing anthracycline burden and increasing time duration between anthracycline and trastuzumab.
Inhibition of vascular endothelial growth factor signaling pathway (bevacizumab, sunitinib)
These agents, when used with other conventional agents, can cause hypertension, vascular toxic effects, and reversible or irreversible LV dysfunction with heart failure. Risk factors for developing cardiotoxicity are preexisting heart failure, CAD, valvular heart disease, or ischemic cardiomyopathy.
There seems to be a synergistic effect of cardiotoxicity if RT and cardiotoxic chemotherapy are administered together. Mediastinal fibrosis is common post-RT along with diastolic dysfunction and reduced exercise capacity. Systolic dysfunction can occur if anthracyclines are combined with RT and previous CAD or valvular heart disease exists.
| Diagnostic Tools for Cardiotoxicity|| |
Screening and risk stratification can be done by proper history and clinical examination of the patient scheduled to receive chemotherapy. Following investigations are helpful in monitoring the effects of chemotherapy and for diagnosing ensuing cardiotoxicity.
To be done before and during the chemotherapy to identify ST-T changes, arrhythmias, QT prolongation, and conduction disturbances. These changes can be transient and not very specific.
For assessment of left ventricular ejection fraction (LVEF) before, during, and after the treatment. LVEF assessment by two-dimensional Simpson's or by three-dimensional (3D) method is done. Diagnostic criteria for cardiotoxicity is decrease of LVEF >10% value below lower limit of normal. Global longitudinal strain (GLS) of LV indicates early detection of LV dysfunction; and a relative reduction of GLS >15% from baseline indicates cardiac dysfunction. Advantage of echocardiography is its wide availability, lack of radiation, and evaluation of other hemodynamic parameters such as diastolic function, pulmonary hypertension, and valvular disease and pericardial involvement. Stress echocardiography is indicated for patients with high pretest probability for CAD.
Nuclear cardiac imaging (multiple-gated acquisition)
Less than ten percent decrease in LVEF or a value < 50% suggests cardiotoxicity. The advantage is that it is reproducible. Radiation exposure and limited structural and hemodynamic parameters limit the use.
Cardiac magnetic resonance imaging
Cardiac magnetic resonance imaging is useful for cardiac structure and function. It is used to confirm the cause of LV dysfunction in challenging cases. It is of use to evaluate cardiac masses, pericardial involvement myocardial fibrosis, and infiltrative conditions. It is much more accurate and reproducible.
Elevated troponin I, high-sensitivity troponin I, brain natriuretic peptide (BNP), and N-terminal pro BNP (NT-pro BNP) are suggestive of cardiac myocyte injury and denote a bad prognosis. High values may suggest benefit with cardioprotective medications.
High-sensitivity troponin with GLS provides the greatest sensitivity (93%) and negative predictive value (91%) to predict cardiotoxicity.
| Management of Patients With Cardiotoxicity|| |
Patients who develop asymptomatic or clinical LV dysfunction benefit from angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and beta blockers. Starting early treatment and a combination therapy has proved to be more beneficial.
Coronary artery disease
The chemotherapeutic agents known to cause CAD are fluoropyrimidines, platinum compounds, and vascular endothelial growth factor (VEGF) inhibitors with or without RT.
Fluoropyrimidines used in gastrointestinal cancers are known to cause myocardial ischemia in 18% of patients, whereas 6%–7% can have silent ischemia seen during stress test. Chest pain with ECG changes can appear within days of drug administration and can persist even after drug cessation. The pathophysiological mechanism is endothelial injury or vasospasm.
Cisplatin can cause ischemia in 2% of patients by creating a procoagulant state and arterial thrombosis.
Immunotherapies and targeted agents can cause a procoagulant state, arterial thrombosis, and endothelial injury. Bevacizumab is reported to cause arterial thrombosis in 3.8% of patients  treated for metastatic diseases, especially in age >65 years with vascular disease.
Radiation, especially supradiaphragmal, can lead to accelerated atherosclerosis, plaque rupture and thrombosis. Incidence and onset of complication are dose dependent. Thoracic doses >30 Gy can cause valvular disease, left anterior descending artery gets exposed in left breast irradiation and left main, circumflex, and right coronary artery for Hodgkin's lymphoma. Ostial lesions are common. Presentation can be as acute coronary syndrome or it can manifest even 15–20 years after irradiation. Other than ischemia, radiation can also cause pericardial disease, arrhythmias myocardial fibrosis, and valvular heart diseases.
Risk factors for developing CAD postradiation include younger age at exposure, overall dose (>30–35 Gy), division into fractions (>2 Gy), use of cytotoxic chemotherapy, irradiation technique (tele-RT is more toxic than brachytherapy), longer time since exposure.
Diagnostic tools and management
The presence of traditional risk factors for atherosclerosis can accelerate the incidence and onset of CAD; hence, clinical evaluation is of paramount importance in patients planned for RT. Because of high incidence of silent ischemia stress test, abnormalities are very common in patients with a history of RT, especially in Hodgkin's lymphoma and left breast cancer. Screening for CAD is by serial ECGs, cardiac enzyme stress tests, and echocardiogram should be done in patients receiving the culprit agents. Cardiac radionuclide and angiography can be diagnostic. Evaluation for subclinical ischemia even after 20 years is necessary in patients with a history of irradiation. The incidence of heart disease can, however, be reduced by proper risk stratification depending on age and preexisting CAD, avoiding combination with anthracyclines, thoracic shielding, and dose adjustments of radiation.
The management of CAD is by nitroglycerine and calcium channel blockers.
Valvular heart disease
Radiation-induced valvular heart disease is a well-established slow and progressive complication. Mechanism of damage is by ionizing radiation or fibrosis of the cardiac muscle, which is adjacent to valve rings resulting in distortion and loss of function and due to calcification. These changes include mostly by the mitral, aortic, and tricuspid valve. The progression to fibrotic thickening and calcification of the valves occurs much later, with stenosis often appearing 20 years after RT. Mitral and aortic valve regurgitation and aortic stenosis are the most common defects.
Chemotherapy agents do not affect valves directly, but valvular function is seen secondary to LV dysfunction or infective endocarditis.
Baseline and serial echocardiography and 3D echo are recommended in patients treated with RT. Cardiac magnetic resonance imaging (MRI) and computed tomography (CT) are useful to see the severity and involvement of ascending aorta postradiation.
Novel agents, VEGF (such as bevacizumab and sunitinib), are known to contribute or worsen preexisting hypertension. The incidence depends on age, history of hypertension, type of cancer (renal cell), therapeutic schedule, and combination cancer therapies. The complication seems to be associated with reduced function of nitric oxide synthase, endothelial dysfunction, disruption of normal capillary function in normal tissue, oxidative stress, and glomerular injury. VEGF inhibition also causes renal thrombotic microangiopathy. Acute complication can result into heart failure, proteinuria, or intracerebral hemorrhage.
Risk factor includes preexisting hypertension and advanced age.
Treatment of chemotherapy-induced hypertension is aimed at reducing the risk of morbidity yet maintaining effective dosing of therapy for optimal cancer treatment. The goal of treatment in these patients is usually limited to assess the risk factors and to maintain a blood pressure (BP) <140/90 mmHg. Ambulatory BP monitoring, renal functions, lipid profile, and renal sonography may be required. Information about drug interaction (with steroids, nonsteroidal anti-inflammatory drugs [NSAIDs], and erythropoietin) and pain and stress management are necessary for achieving the goal. Specific guidelines are not yet available. ACE inhibitors, ARB, and calcium channel blockers are the first-line of treatment; beta-1 blockers such as nevibulol are important because of its action on nitric oxide signaling. Severe hypertension may require reduction of VEGF inhibitor dosing or, in some cases, interruption of treatment. Diuretics can lead to electrolyte imbalance and QT prolongation hence should not be used as first-line drugs. Close monitoring and evaluation of treatment with lifestyle management remain the main stay of treatment.
Common chemotherapy drugs causing arrhythmias are summarized in [Table 3].
Rhythm disturbances associated with anti-cancer therapy are generally transient. They are thought to be due to metabolic changes and resolve after electrolyte imbalance is corrected. However, some complications due to chemotherapy on heart rhythm is proposed to be due to direct electrophysiological effect on cardiac structure and function including myocardial ischemia and heart failure which creates a pro-arrhythmogenic substrate. Metabolic changes and electrolyte balance concomitant medications such as anti-psychotics and anti-emetics are contributory factors. The arrhythmias can vary from transient sinus tachycardia, bradycardia, or conduction defects to QT prolongation and life-threatening ventricular tachycardia.
QT prolongation is associated with many cancer drug and occurs most commonly in patients with comorbidities such as diarrhea, vomiting causing electrolyte imbalance, and medications such as anti-emetics and anti-psychotics which too prolong QT interval. QT prolongation can lead to life-threatening torsade de pontes and hence needs close monitoring. QTc prolongation >450 ms in males and >460 ms in females are taken as upper limit of normal. Prolongation >500 ms or a change from baseline >60 ms is considered risky and warrants temporarily interruption of cancer treatment. Arsenic trioxide used in certain leukemia and myeloma is the most common culprit which prolongs the QT in 26%–93% of patients resulting in serious ventricular tachycardias, followed by anthracyclines and tyrosine kinase (TK) inibitors (vandetanib) which is used in thyroid cancer.
Risk factors for QT prolongation includes electrolyte imbalance (hypokalemia <3.5 mEq/L, hypomagnesemia <1.6 mg/dl, hypocalcemia, 8.5 mg/dl) caused by vomiting diarrhea or loop diuretics; hypothyroidism; concurrent use of other QT prolonging medicines such as (antiarrhtyhmics, antibiotics, antipsychotics, antidepressants, antiemetics). Other nonmodifiable factors can be baseline QT prolongation, family history of sudden death, advanced age, female sex, h/o CAD, impaired renal, or hepatic function.
Supraventricular tachycardias are common, with atrial fibrillation being the most common, which can occur during therapy or after treatment. It can occur due to direct tumor effects, LV dysfunction, comorbidities, electrolyte imbalance of postoperative lung resection.
Ventricular arrhythmias are secondary to QT prolongation, chemotherapy, or RT toxic effects in the presence of predisposing risk factors.
Conduction defects commonly seen after RT and are generally permanent. Paclitaxel and thalidomide are mostly implicated.
Serial ECG to monitor QTc interval at baseline and every week thereafter and monthly during first 3 months depending on the drug schedule and risk factors. Echocardiography is done to assess LV systolic function, diastolic function, and valvular disease. Treatment aims at correcting electrolyte imbalance, removing other predisposing factors, and individualizing the antiarrhythmic drugs and device implantation (such as overdrive pacing or permanent pacemakers).
Treatment in atrial fibrillation includes rhythm management, anticoagulation, and stroke prevention using CHA2DS2-VASc and HAS-BLED score though it needs to be individualized depending on risk–benefit criteria. If CHA2DS2VASc score is >2 and platelet count is >50,000/mm 3, anticoagulation can be considered. Beta blocker or dihydropyridine calcium channel blocker can be used to control heart rate.
This is a rare but dreaded complication of cancer chemotherapies and bone marrow transplantation. Dasatinib, a TK inhibitor used in chronic myelogenous leukemia (CML), can cause severe precapillary pulmonary hypertension. It can occur 8–40 months after exposure to this agent  and generally reversible after therapy is interrupted. Cyclophosphamide and other alkylating agents can also cause pulmonary hypertension.
Baseline assessment warrants risk factor assessment, assessment of New York Heart Association functional class, 6-min walk test, NT-pro BNP, echocardiography to assess pulmonary arterial hypertension (PAH) at least every 3–6 months.
Multidisciplinary team decision is necessary for risk–benefit ratio of continuing treatment with PAH versus stopping culprit drug.
Cancer patients are in hypercoaguable state due to procagulant, antifibrinolytic, and proaggregating actions of tumor cells. Certain chemotherapeutic agents such as cisplatin, bevaciizumab, sinitinib, sorafenib, and hormonal therapy such as tamoxifen can increase chances of venous and arterial thromboembolic events by direct endothelial effects or change in coagulation profile.
Arterial thrombosis is rare and occurs in 1% of patients with metastatic, breast, colorectal, and lung cancers with anthracyclins, taxanes, platinum-based drugs, and tamoxifen.
Venous thrombosis is, however, more frequent with high rate of morbidity and mortality and is sometimes the first manifestation of an occult cancer. It is common in hospitalized patients undergoing chemotherapy, especially through indwelling catheter. Venous thromboembolism (VTE) is the most common cause of death in postoperative patients of cancer.
Risk factors for venous thromboembolism
Primary site of cancer (pancreas, brain, stomach); histology (adenocarcinoma); metastatic stage; patient related factors such as old age and female sex; comorbidities such as infection, renal disease, lung disease; history of VTE; major surgery, hospitalization, hormonal therapies, central catheters, concomitant chemotherapy agents.
Prophylactic anticoagulation is recommended in only high-risk patients who are hospitalized and have to undergo major surgery. Acute VTE is treated by low molecular weight heparin (LMWH) for 3–6 months and thereafter long-term anticoagulation is necessary. Recurrent VTE justifies vena cava filter and dose adjustment of LMWH replacement with other anticoagulants.
Peripheral vascular disease
PVD is seen commonly in patients treated with nilotinib, ponatinib, or BCR-ABL TK inhibitors used in CML. Raynaud's phenomenon and ischemic stroke are also seen with cisplatin, 5-fluorouracil, paclitaxel, and methotrexate.
Risk of stroke is doubled after mediastinal, cervical, or cranial RT. Mechanism of small vessel injury is by endothelial damage and thrombus formation, whereas medium to large vessel involvement is due to vasa vasorum occlusion with medial necrosis, adventitial fibrosis, accelerated atherosclerosis leading to arterial stiffness and advanced atherosclerosis.
Baseline risk assessment with clinical examination, ankle-brachial index, and peripheral Doppler study is necessary. Antiplatelet therapy is indicated only in symptomatic PVD. Need for revascularization/stenting should be individualized.
Acute pericarditis is seen with anthracyclins, cylophosphamide, cytarabine, bleomycin, and RT and presents with chest pain, fever, ST-T changes, and large effusions. The pathology is due to accumulation of collagen fibers in mesothelium of epicardium, visceral pericardium, and interstitium  which increases the fibrous layer thickness. Echocardiography or CT scan is diagnostic treatment is with NSAIDs and colchicines. Pericardiocentesis and pericardial window may be required for large effusions.
Pericardial effusion is very common in cancer patients and is due to cancer itself, infections, heart failure, or fluid retention.
RT can lead to cardiac sympathetic imbalance leading to rhythm disturbance, silent ischemia, and high pain threshold.
| Recommended Methods to Monitor Patients on Cancer Treatment to Monitor the Heart|| |
Following are the recommended methods for monitoring patients on cancer treatment for potential cardiotoxicity:
LV dysfunction: ECG, MRI, multiple-gated acquisition scan, sampling of serial troponin, and/or NT-pro BNP levels.
- CAD: lipid profile, exercise stress test, radionuclide, angiography, echocardiogram, ECG
- Pericarditis: ECG, chest X-ray, and echocardiogram
- Cardiomyopathy: ECG, echocardiogram, and radioisotopic angiography
- Valvular heart disease: echocardiogram, ECG, cardiac catheterization
- Arrhythmias: ECG and 24-h ECG.
| Strategies to Reduce Chemotherapy-induced Cardiotoxicity|| |
Early assessment of risk factors known to cause cardiotoxicity by detailed history and clinical evaluation can never be over emphasized. History of previous anthracycline, RT, h/o CAD, hypertension, arrhythmia, valvular disease, or presence of traditional risk factors should be considered before choosing the drug regimen, dose, and duration of therapy. Baseline ECG, LVEF assessment, biomarkers, and BNP monitoring are recommended. It is advisable to reassess LV function after four cycles of chemotherapy if LVEF has reduced by 15% points or 10% to a value below 50 and repeat assessment after 3 weeks confirms the drop in LVEF or if troponin I or BNP are elevated, interruption of chemotherapy should be considered. Keeping in mind, the late presentation of cardiac damage in anthracite-based regimen, it is pertinent to assess systolic function after 6 months of cessation of chemotherapy, annually for 2–3 years, and then at 3–5 years' interval for life[Table 4].
|Table 4: Strategies to reduce cancer chemotherapy-induced cardiotoxicity|
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Strict optimization of risk factors and initiation of cardioprotective drugs are recommended before chemotherapy. Beta blocker, ACE inhibitors, ARBs, and dexrazoxane (for anthracycline) have showed beneficial effects.
Long-term follow-up is of utmost importance in cancer patients who have undergone RT or chemotherapy with drugs known to cause cardiotoxicity. It is known that LV dysfunction and heart failure can present even 10 years after cancer treatment; hence, it is important to create awareness of possible cardiac disease in cancer survivors to report early signs of cardiac disease and encourage regular follow-up with cardiac imaging and biomarkers evaluation.
There are no conflicts of interest.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]