Cardio-oncology

Editor-In-Chief of Cardiology: Anuradha Kolluru M.D.

Dr. Anuradha Kolluru is a leading board certified general cardiology physician with over 10 years of practice experience in treating patients for a variety of cardiovascular diseases. Dr Kolluru is board certified by the American Board of Internal Medicine (ABIM) in many specialties including internal medicine, cardiovascular disease, nuclear cardiology, echocardiography, cardiovascular CT and vascular interpretation (RPVI).

Areas of interest for Dr. Kolluru include women and heart disease, cardio-oncology, cardio-metabolic, cardiac imaging, heart failure and preventive cardiology. Learn more about Dr. Kolluru.

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• Cardio-oncology is an evolving field in cardiology that provides cardiac care for cancer patients and its survivors. It deals with early detection , reducing the adverse cardiovascular side effects , treating and preventing the cardiovascular effects of cancer therapies , such as radiation , chemotherapy , targeted molecular therapy and newly emerged Immunotherapy.

Leading causes of mortality

Heart disease and cancer are the two main causes of mortality globally, accounting for 46.1% of deaths worldwide.
Due to current advancement in cancer treatment, there has been decrease in mortality in cancer patients. However, the cancer therapy-related cardiovascular complications are a major cause of morbidity and mortality in people living with or surviving cancer. Cancer related cardiovascular complications are in particular chemotherapy and radiation therapy-induced cardiac toxicities

Cardio-oncology

Cardiovascular effects of cancer treatments

All chemotherapeutic agents and radiation therapy primarily target tumor cells but also result in collateral damage to normal tissues including the cardiovascular system.

The most recent European Society of Cardiology guidelines listed these cancer related cardiovascular complications broadly into nine major categories. The cardiac complications include myocardial dysfunction and congestive heart failure( CHF) , coronary artery disease, valvular heart disease, arrhythmia, and pericardial diseases. The vascular complications classified into arterial hypertension, thromboembolic event, peripheral vascular disease and stroke, and pulmonary hypertension

Cardiovascular complications of Radiation Therapy

Radiation therapy to the chest has improved survival in patients with Hodgkin lymphoma, early-stage breast cancer, and other thoracic malignancies . With higher survival rates with radiation therapy, cardiovascular disease has emerged as the most common noncancer related cause of death in patients treated with chest radiation therapy, accounting for 25% of deaths in survivors of Hodgkin lymphoma. Thoracic irradiation, especially to the left side damages all cells, including those of the pericardium, myocardium, valves, coronary vasculature and conduction system, with clinical disease usually presenting two to three decades after treatment.

They can present as chronic or constrictive pericarditis, radiation-induced cardiomyopathy, valvular heart disease , sinus node dysfunction, atrioventricular conduction blocks involving the fascicles, bundles or complete heart block. Coronary artery disease (CAD) occurs earlier with increased incidence and more aggressive disease in patients treated with radiation therapy. Coronary artery lesions are typically ostial, long, smooth, and concentric and have a higher fibrotic content than typical atherosclerotic lesions. In patients with radiation-induced CAD, treated with percutaneous coronary intervention ( PCI) , in-stent restenosis rates with bare metal stents are significantly higher . Coronary artery bypass and valve surgery in them is also challenging as left internal mammary artery may be rendered unusable for bypass graft. The postoperative course may be complicated by radiation-induced lung injury (pleural effusion, prolonged ventilation) and a higher incidence of atrial fibrillation.

Radiation therapy

Acute pericarditis is the most common early manifestation of radio toxicity; however, it is now less common (incidence of 2.5%) because of changes in shielding, divided dosing, and lower cumulative doses

Traditional cardiovascular risk factors, such as smoking, dyslipidemia, diabetes and hypertension, should be aggressively managed because of the increased risk for coronary artery disease .

There are no guidelines or consensus on cardiovascular testing in asymptomatic patients with chest radiation. Baseline echocardiography is reasonable, and several organizations have recommended to start with at least stress echocardiography at 5 to 10 years after completion of therapy or at age 30 years, whichever comes first .

Cardiovascular complications of chemotherapy

Types of cardiac injury

Chemotherapy may affect cardiovascular system in many different ways, resulting in toxicity. Broadly , these were categorized into two types of cardiac injury in the past .

Type I injury is marked by dose-dependent cardiac dysfunction with irreversible ultrastructural necrosis leading to cardiomyocyte death.

Type II injury is dose independent, cardiomyocyte dysfunction and is often reversible with discontinuation of the culprit chemotherapeutic agent.

Due to rapidly evolving newer oncological medications and therapies ,this classification falls short to include additional cardiovascular toxicities (endothelial , vascular and immunological toxicities ) and few chemotherapeutic agents have overlapping injury patterns ( both type 1 and type 2).

Type I injury is associated with the use of anthracyclines, such as doxorubicin, daunorubicin, and epirubicin. Daunorubicin was the first anthracyclines with cardiotoxicity being reported half a century ago, in the original study of the 19 children (of solid tumors or acute leukemia )who received daunorubicin . The discovery and the demonstration of dose-dependent probability of CHF associated with anthracycline chemotherapeutic agents in the 1970s were perhaps the first collaboration between oncologists and cardiologists.

Heart block, arrhythmias, heart failure, myocarditis, and pericarditis, occur in less than 1% of patients manifesting as acute anthracycline toxicity and may be reversible. Dilated cardiomyopathy can be a manifestation of chronic progressive anthracycline toxicity and is most closely linked with the use of doxorubicin. Chronic progressive toxicity has an early onset (within 1 year of treatment) in 1.6% to 2% of patients and a late onset (after 1 year) in up to 5% of patients. Late-onset chronic progressive toxicity is related to total cumulative dose. In patients with a cumulative anthracycline dose of 550 mg/m2, the incidence of heart failure is up to 26%, and toxicity may not become clinically evident until 10 to 20 years after treatment. Concomitant use of cyclophosphamide, trastuzumab, or paclitaxel; previous chest irradiation; and female sex increase the risk of anthracycline toxicity . Dexrazoxane can reduce the risk for doxorubicin toxicity.

Anthracyclines are Topoisomerase II inhibitor that introduces therapeutic effect by causing apoptosis due to DNA intercalation, Enzyme interaction, Reactive Oxygen Species (ROS) generation and DNA adduct formulation. They are used in many malignancies at varying dosages and has Cardiotoxicity. Cardiotoxicity risk is related to cumulative dose exposure and Is often not reversible. It Manifests as LV Dysfunction and Heart Failure, hence monitoring risk via serial echocardiogram recommended.Role for Dexrazoxane, renin angiotensin system inhibitors and Beta Blockers for LVEF preservation has been studied

Type II injury is more commonly associated with molecularly targeted therapy, such as trastuzumab. Overexpression of human epidermal growth factor receptor 2 (HER2/ErbB2) in breast cancer is a poor prognostic indicator. Trastuzumab (Herceptin), a humanized anti-HER2 monoclonal antibody targeting the extracellular domain of this receptor, dramatically changes the survival in HER2 positive breast cancer.These receptor (ErbB2/ ErbB4) are also expressed in cardiomyocytes and play a protective role against myocardial stress.The binding of anticancer drugs to HER2 receptor may disrupt this cardioprotective pathway and result in cardiotoxicity leading to left ventricular systolic dysfunction, with symptoms of heart failure in 3% to 7% of patients. Risk increases with age older than 50 years and concomitant anthracycline use. If needed additional therapy can be administered after normalization of left ventricular function.

Chemotherapeutic agents

List of Antineoplastic Agents

Most chemotherapeutic agents have directly or indirectly have some degree of cardiotoxicity.

Traditional chemotherapeutic agents with cardiovascular toxic effects

Alkyl-like agents (platinum compounds)	cisplatin, carboplatin, oxaliplatin
Antimetabolites	Fluorouracil, capecitabine
Alkylating agents	cyclophosphamide
Antimicrotubule agents	Taxanes (paclitaxel vinka alkaloids
Antitumor antibiotics	Anthracyclines and Bleomycin

Alkylating agents ( nitrogen mustards ) and Alkyl -like agents (platinum compounds )

Nitrogen mustards (i.e., cyclophosphamide and ifosfamide) and the platinum-containing molecule, cisplatin, are one of the oldest classes of anticancer agents. Alkylating agents (Cyclophosphamide, ifosphamide, melphalan) inhibit DNA transcription, thereby affecting protein synthesis. Cyclophosphamide have been associated with development of left ventricular dysfunction ( LVD) in 7–28% of patients and may be dose related (≥150 mg/kg and 1.5g/m2d), occurring shortly after initial administration. LVD has also been observed with ifosfamide at doses that exceed 12.5 g/m2. Cyclophosphamide-induced cardiotoxicity include pericardial effusions, myocarditis, pericarditis, and heart failure which is irreversible in 25% of cases at a doses of  ≥ 1.55 g/m2/day.

Cisplatin treatment is associated with both acute and late-onset cardiotoxicity and in addition has vascular events such as deep vein thrombosis and pulmonary embolism. Other relatively uncommon , occurring in ~2% of patients include acute myocardial infarction, angina pectoris, and cerebrovascular ischemia . Likely pathophysiology of adverse vascular events, is multifactorial including procoagulant and direct endothelial toxic effects, as well as hypersensitivity reactions occurring during treatment.

Antimicrotubule agents ( Taxanes and vinca alkaloids)

Taxanes (ex. paclitaxel and docetaxel) bind to and inhibit disassembly of microtubules, interrupting cell division.Taxanes cause mitotic arrest and activate caspase-dependent apoptosis through microtubule destabilization. They also interfere with the metabolism and excretion of anthracyclines and may potentiate LVD risk. Microtubule agent like paclitaxel causes arrythmias, conduction blocks, ventricular tachycardia and thrombosis . Vinca alkaloids ( vincristine, vinblastine) cause myocardial ischemia and coronary spasm.

Chemotherapy

Antimetabolites ( Fluoropyrimidines)

The fluoropyrimidines are important antimetabolites and include 5-fluorouracil (5-FU) and its oral prodrug, capecitabine. These agents are used in the treatment of gastrointestinal, breast, and head and neck tumors. Fluoropyrimidines may cause myocardial ischemia by inducing coronary artery spasm. In cancer patients treated using 5-fluorouracil (5-FU) containing regimen, cardiac symptoms generally occur early during the drug infusion. The pathogenic mechanism of cardiovascular toxicity associated with 5-FU is not completely understood; however, coronary thrombosis, arteritis, and vasospasm have been proposed as possible explanations. The incidence of coronary vasospasm varies by agent and schedule of administration. When high-dose 5-FU–based chemotherapy was given as a continuous intravenous infusion, events consistent with coronary vasospasm (angina, arrhythmia, or sudden death) were reported in up to 5.4% of patients. Symptoms are generally reversible after cessation of the fluoropyrimidine and with the administration of vasodilators. There is a high risk of relapse with fluoropyrimidine rechallenge and relapse is associated with higher mortality.Therefore, rechallenge should be reserved for those without reasonable alternative cancer therapies and should occur only in the context of informed consent, aspirin therapy, vasodilator therapy with L-type calcium channel blockers ((nifedipine and diltiazem)) or nitrates ( long-acting isosorbide mononitrate ) or both, continuous electrocardiographic monitoring (ideally in a coronary care unit), and bolus, rather than continuous, 5-FU infusion.

Newer Targeted cancer therapies

• HER2 inhibitors- Trastuzumab, newer are ( pertuzumab, trastuzumab emtansine, lapatinib)
• Vascular endothelial growth factor (VEGF) signaling pathway inhibitors
• VEGFA monoclonal antibody ( bevacizumab), VEGF trap ( aflibercept) , VEGFR2 monoclonal antibody (ramucirumab)
• Tyrosine kinase inhibitor with antiVEGF action - sunitinib, sorafenib, pazopanib, axitinib, vandetanib, regorafenib, cabozantinib, lenvatinib
• BCR-ABL tyrosine kinase inhibitors- dasatinib, nilotinib, ponatinib, imatinib
• Other multitargeted tyrosine kinase inhibitors
• Anaplastic lymphoma kinase inhibitors( crizotinib, ceritinib)
• mTOR inhibitors( everolimus, temsirolimus)
• Bruton's tyrosine kinase inhibitor( ibrutinib)
• MEK inhibitor ( trametinib)

Multitargeted tyrosine kinase inhibitors and anti–vascular endothelial growth factor inhibitors/antibodies

These are increasingly being used as targeted molecular therapy. Unfortunately, despite their “selective” action they can still cause cardiovascular complications such as arterial hypertension (HTN), QT interval prolongation, CHF, cardiomyopathy, stroke, acute myocardial infarction, thromboembolic events and cardiovascular deaths. Sunitinib, pazopanib, and especially vandetanib prolong the QT and therefore increase the risk of Torsades de pointes (TdP), a form of lethal arrhythmia. These drugs should be used extra-cautiously if no other alternative , in the presence of a history of QT prolongation or concomitant antiarrhythmic treatments, bradycardia, or electrolyte abnormalities, while in such conditions vandetanib should be completely avoided. . Of the tyrosine kinase inhibitors, sunitinib has been most frequently associated with cardiotoxicity, with up to a 50% incidence of new or worsened hypertension and up to a 15% incidence of decreased left ventricular ejection fraction (LVEF). These effects may be reversible with early recognition. . The anti–vascular endothelial growth factor antibody bevacizumab is associated with significant but reversible hypertension.

Immunotherapy

Immune checkpoints prevent the immune system from attacking normal tissues (self), but immunotherapy can take advantage of this by inhibiting the checkpoints and allowing the immune system to be more aggressive and so attack cancer cells.

• cytokines ( IL-2, Interferon, BCG)
• immunomodulatory drugs ( lenalidomide, pomalidomide )

• Immune Checkpoint Inhibitors (ICI):
  • –  Anti PD-1 and PD-L1/2: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab
  • –  Anti CTLA-4: ipilimumab
• Chimeric Antigen Receptor T cells (CAR-T): Kymriah, Yescarta
• Monoclonal antibodies (mAb): -mab
• B-specific T-cell engager antibodies (BiTEs): blinatumomab
• Natural Killer (NK) cells
• Proteasome inhibitors: bortezomib, carfilzomib, ixazomib
• Vaccines

Immune checkpoint inhibitors

Antibodies that block these checkpoints , release the brakes on the immune system and allow it to aggressively attack the tumor. To date, development of these agents has focused on two major targets: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein-1 (PD-1) pathway. Immune checkpoint inhibition has demonstrated superb efficacy in a variety of malignancies that have historically conferred a poor prognosis. Side effects are related to resultant autoimmunity from the less-regulated immune system. Though rare, immune-mediated cardiac toxicity has been observed in patients enrolled in large clinical trials and in individual case reports. In accordance with preclinical data, autoimmune myocarditis has been reported with both anti-CTLA4 and anti-PD-1 therapies.

Chimeric Antigen Receptor T cells (CAR-T): Kymriah, Yescarta

This is the most recent development for the treatment of hematological malignancies especially B cell lymphomas and and in relapses. The T cells from the patients are taken out genetically altered in the laboratory and infused back into them after lymph depleting chemotherapy with fludarabine and cyclophosphamide. Cytokine release syndrome ( CRS) and neurotoxicity are the two most common side effects . Cardiovascular effects from cytokine release syndrome include , hypotension, tachycardia, arrhythmias, LV dysfunction , heart failure and shock. Monitoring of these patients both short term and long term survillance mitigates the cardiovascular adverse outcomes. Toclizumab ( antibody against interleukin -6) infusion has shown to decrease the CRS.

Malignant pericardial effusion

Malignancy accounts for 13% to 23% of pericardial effusions and may be the first presentation of the disease. Lung, breast, and esophageal cancers; melanoma; lymphoma; and leukemia are the most common malignancies that cause pericardial effusions.Cardiac tamponade results when the pericardial fluid pressure impairs filling of one or both ventricles, leading to decreased cardiac output.

Immunotherapy

Monitoring

A baseline electrocardiogram should be obtained in patients who are planned to receive chemotherapy associated with known cardiotoxicity. Serial electrocardiograms during the course of therapy needed to monitor QT interval prolongation with few specific agents. Baseline evaluation of left ventricular ejection fraction (LVEF), either with echocardiography or multi-gated acquisition scanning is important, if the associated cardiotoxicity includes left ventricular dysfunction and heart failure. It is reasonable to repeat echocardiography at a total cumulative anthracycline dose of 300 mg/m2 and before each dose in patients with pre-existent left ventricular dysfunction or those receiving higher cumulative doses. European guidelines suggest that patients receiving trastuzumab should undergo repeat echocardiography every 3 months. In general, cardiovascular consultation should be obtained in asymptomatic patients who demonstrate a decline in LVEF of 10% or more to LVEF of less than 53% or in patients with symptoms of heart failure associated with a decline in LVEF . Three-dimensional echocardiographic evaluation of left ventricular volumes may be more accurate in detecting small changes. Strain imaging ( newer technique in echocardiography) helps detect early signs before the LV EF declines

In patients with clinical signs or symptoms of cardiac dysfunction, cardiac biomarkers (such as troponin and N-terminal proB-type natriuretic peptide) along with imaging techniques (such as echocardiographically derived global longitudinal strain) may be helpful in identifying early toxicity and guiding individual therapy. At present, treatment of patients with chemotherapy-induced heart failure follows standard paradigms and is unique for each class of medications.

Traditional cardiovascular risk factors, such as smoking, dyslipidemia, diabetes and hypertension, should be aggressively managed. Exercise and heart healthy diet recommended

Despite significant understanding of the molecular and pathophysiologic mechanisms behind the cardiovascular toxicity of cancer therapy, there is not enough data for the monitoring and management of patients.

Wireless ECG Monitor

Multi-disciplinary approaches toward individualized cardio-oncology care

Cardio-oncology is an integrative and translational medicine between cardiologists and oncologists mainly focusing on the diagnosis, prevention, and management of cardiovascular complications associated with the development and treatment of malignancy. It helps oncologist deliver the care with minimizing the cardiovascular side effects and improve morbidity and mortality of these cancer survivors.

Clear communication is the key and involves multidisciplinary team including cardiologists, oncologists, imaging specialists, clinical pharmacologists and primary care physician. The patient, and their family members are essential for many shared decisions and life-modifying decisions. These shared decisions require periodic reconsideration during the course of therapy. The fact that many decisions must be based on limited evidence, and in the context of rapidly evolving cancer therapeutics, experience and expert opinion increases the complexity of the care.

Cardio-oncology care should include primary prevention of cardiovascular complications in “high risk” patients with aggressive risk factor modifications and ongoing monitoring early toxicities, effective treatment of complications that have already developed and active prevention of worsening complications, pre-operative assessment of cardiovascular risks for cancer surgeries, and investigation of possible cardiac invasion from malignancy.

Topics in cardio oncology

• Radiation-related heart and vascular disease
• Myocardial dysfunction and heart failure (HF)
• Coronary artery disease (CAD)
• Valvular heart disease (VHD)
• Arrhythmias – acquired LQT syndrome, atrial fibrillation and atrioventricular (AV) blocks.
• Arterial hypertension.
• Thromboembolic disease.
• Peripheral vascular disease and stroke.
• Acute chemotherapy treatment side effects
• Imaging and cardio toxicity

Cardio-oncology journals

• ACC journal of Cardio-oncology
• BMC journal of Cardio-oncology

Cardio-oncology on Medpage

• MedPage Today Cardio-Oncology Connection.

Resources in cardio-oncology

• ACC cardio-oncology resources list

External links

• Cardio-oncology principles and organisational-issues
• American College of Cardiology - Cardio-oncology section
• Overview of Cardio-oncology
• Modern day cardio-oncology a report from the 'Heart Failure and World Congress on Acute Heart Failure 2018
• JACC:The Novel Coronavirus Disease (COVID-19) Threat for Patients with Cardiovascular Disease and Cancer

Position statements

GUIDELINE AND POSITION STATEMENTS

References

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