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Dr. Riccardo Asteggiano ,
Prof. Thomas M. Suter
Prof. Jeroen J Bax ,
Cardio-oncology (C-O) has become a cardiology subspecialty oriented to the prevention, diagnosis, treatment and follow-up of cardiovascular (CV) diseases due to cancer treatment. Every field of cardiology could be interested in these complications and in this article we summarise the discipline and its field of action. We also explain the organisation, the roles, and the function of a C-O service, particularly important for the correct delivery of care for C-O patients.
cancer, cardio-oncology, chemotherapy, radiotherapy, toxicity
The first example of cardiac cancer treatment toxicity was described in relation to anthracyclines more than fifty years ago. The concept that chemotherapy (CT) and radiotherapy (RT) may induce potentially deadly cardiovascular (CV) side effects developed progressively and cardiologists were charged with the management of patients with these complications. The complexity and the peculiarity of the CV toxicities of cancer therapy evolved quickly, requiring specific formation and skills: C-O was born. In a few short years, C-O has shown huge growth and development. The reasons are :
So, the probability of every physician facing cancer and CVD patients is high. Everyone should be aware of: 1) the toxicity of a CT agent or of RT, 2) the risk factors and pre-existing CVD predisposing to cardiotoxicity, and 3) the use of preventive and curative measures during possible cardiotoxic therapy.
Oncologist and cardiologists should undertake the therapeutic option for a cancer patient by:
CT toxicity is related to the mechanism of action of the drugs, the doses, the manner of administration, and the underlying predisposing factors such as cardiac conditions, genetic pattern and age, and it can manifest itself immediately or many years after the treatment.
Concomitant CT and RT treatments may interfere in toxicity, with mutual potentiation.
Irreversible cytotoxicity or interaction with functional aspects of the function of cardiac cells not primarily cytotoxic may lead to ventricular dysfunction. Furthermore, different mechanisms may lead to arterial hypertension, venous and arterial thromboembolism, myocardial ischaemia and infarction and arrhythmias with several CT agents.
Acute toxicity may appear very rarely or quite frequently with different drugs.
Also, the incidence of chronic toxicity is variable and may develop over a long period of time.
Clinical signs and symptoms, electrocardiographic modifications, cardiac imaging tools (mainly left ventricular ejection fraction [LVEF] and strain assessment), troponin and natriuretic peptide elevation may identify early CT toxicity.
Several strategies are available for the prevention and treatment of toxicity of the different CT drugs, based on accurate patient selection, short- and long-term monitoring, and on therapies which may prevent and delay cardiac dysfunction in this setting.
Possible CV complications of CT and/or RT are :
Many conditions may develop together and complicate the evolution. Every single side effect should be evaluated and fully treated to avoid progression of the entire picture and maintain the best outcome.
Myocardial dysfunction due to CT toxicity may be due to cell necrosis (Type I toxicity) leading to permanent cardiac damage, or due to a cell dysfunction, mainly by biologic drugs (Type II toxicity) with generally reversible conditions.
Risk factors for cardiotoxicity during anthracycline therapy are: 1) cumulative dose, 2) female sex, 3) age >65 years or <18 years, 4) renal failure, 5) pre-existing cardiac diseases leading to increased wall stress, 6) arterial hypertension, 7) genetic factors, and 8) concomitant or previous RT involving the heart and/or a concomitant or incorrect timing of administration of alkylating, anti-microtubule agents and particularly immunotherapy and targeted therapies.
Early ventricular dysfunction detection should be carried out by assessing LVEF before and periodically during CT. Two-dimensional (2D) and three-dimensional (3D) echocardiography and strain testing as well as other imaging tests and biomarkers may be used. It is recommended to use the same method with good quality, possibly by the same operator, during all of the follow-up to avoid inter-test variability.
If normal LVEF is found at the beginning, re-evaluation should occur every four CT cycles. An LVEF <50% and a reduction of LVEF >10% but not under the lower limits is an expression of toxicity and requires repeated short-term assessment during and shortly after CT. A reduction of LVEF of >10% under the lower limit indicates the beginning of ACE-Is (or ARBs) + beta-blocker therapy to prevent further LV dysfunction. The same drugs are recommended in asymptomatic LV dysfunction or symptomatic HF.
The screening of a pre-existing CAD to guide the choice of CT drugs requires a careful clinical evaluation based on age, gender, history and diagnostic tests for ischaemia. Pyrimidine analogues may have a high risk and need close monitoring with regular electrocardiograms (ECGs) during the entire duration of administration. Should ischaemia be detected, temporary suspension is mandatory and eventually a drug challenge again, if no alternative therapies are present.
RT may lead to a CAD with specific clinical characteristics related to its physiopathology. Sudden death instead of a progressive symptom appearance may be the first and unique event. These patients have to undergo a long-term follow-up (FU) by ischaemia induction tests even many years after the end of cancer treatment.
The most common cause of VHD in patients with cancer is RT (up to 10% of treated patients), with fibrosis and calcification of the aortic root, aortic valve cusps, mitral valve annulus and base and mid portions of the mitral valve leaflets.
2D and 3D echocardiography are the methods of choice for diagnosis and follow-up.
Many conditions due to radiation (mediastinal fibrosis, impaired wound healing and associated CAD, myocardial and pericardial disease) make cardiac surgery challenging. Transcatheter valve implantation may be the option to choose in this situation for aortic stenosis, while bypass using the mammalian artery may be impossible.
A basal 12-lead ECG with QTc determination is required in all patients before CT and RT as a mandatory rule at baseline.
Repeat ECGs should be performed mainly in patients with LQT history, organic heart disease, and other QT-prolonging factors. A QTc >500 msec is the threshold for discontinuing the treatment. Also, an increase of >60 msec or the appearance of arrhythmias requires therapy interruption. Avoidance of conditions potentially inducing torsade de pointes (hypokalaemia, extreme bradycardia and other QTc-prolonging drugs) is recommended.
An important emerging issue is atrial fibrillation, mainly after ibrutinib therapy, which has peculiar behaviour with difficult management. Also, there are the related problems of thromboembolic prevention, eventually with novel oral anticoagulants (NOACs).
Some CT drugs and RT may damage conduction systems leading to bradyarrhythmias, requiring temporary or permanent interruption or modification of the therapy and/or pacemaker implantation.
Careful monitoring of blood pressure before beginning CT is a rule. Periodic control of blood pressure (BP) must be carried out in every patient submitted to CT, mainly with vascular endothelial growth factor (VEGF) inhibitors.
The management of hypertension should be carried out according to current guidelines. To avoid CV complications an early and aggressive antihypertensive treatment is mandatory. The preferred agents are ACE-Is /ARBs, and dihydropyridine calcium channel blockers, while non-dihydropyridine channel blockers should be avoided due to possible drug interactions.
If BP is not controlled, then the therapy should be reinforced and VEGF inhibitors should be reduced or discontinued. Once BP is controlled, VEGF use may be re-assessed.
Cancer-related risk factors for venous thromboembolism are: 1) primary site of cancer (pancreas, brain, stomach, kidney, lung, lymphoma, myeloma), 2) histology (especially adenocarcinoma), 3) advanced stage (metastatic), and 4) the initial period after cancer diagnosis.
Patient-related factors are: 1) demographics - older age, female sex, African ethnicity, 2) comorbidities - infection, chronic kidney disease, pulmonary disease, thrombotic disease, obesity, 3) history of venous thromboembolism or inherited thrombophilia, and 4) low performance status.
Treatment-related factors are: 1) major surgery, 2) hospitalisation, 3) type of CT, mainly with anti-angiogenic agents, 4) hormonal therapy, 5) transfusions, and 6) central venous catheters.
The use of thromboprophylaxis is considered in patients hospitalised for cancer, although a recent meta-analysis failed to find evidence of the prevention efficacy or risk. Low molecular weight heparin (LMWH) could induce thrombocytopaenia that does not occur with vitamin K inhibitors (VKI).
In recent times the use of NOACs seems to be safe and effective for thromboembolism prevention in cancer patients.
Even in the absence of CVD risk factors, severe peripheral artery disease (PAD) can occur in up to 30% of patients treated with many CT drugs (nilotinib, ponatinib or BCR-ABL tyrosine-kinase inhibitors [TKIs] used for chronic myeloid leukaemia). Its occurrence may be in the first months of therapy or after several years.
Also, Raynaud’s phenomenon and ischaemic stroke may occur. The risk of stroke is at least doubled after mediastinal, cervical or cranial RT. Also, intracranial aneurysms due to RT have been demonstrated.
Similar consequences are reported for the aorta.
Several CT drugs (predominantly anthracyclines) may lead to acute pericarditis; however, this has become uncommon during RT and is usually associated with pericardial or mediastinal tumours.
Acute pericarditis with typical chest pain, fever, ST-T changes and large effusions, even leading to tamponade, may develop 2 to 145 months after thoracic RT, with an absolute cumulative incidence of 2-5%. Echocardiography and CT scanning are useful tools for evaluation.
Pericardial effusion treatment consists of non-steroidal anti-inflammatory drugs and colchicine. Pericardiocentesis may be required for large effusions.
In cancer patients, pleural effusion is commonly due to the cancer itself, HF, infections or other causes.
Some cancer drugs (e.g., dasatinib and imatinib) may induce fluid retention or a reversible pleural effusion through additional unknown mechanisms.
Damage to the cardiac nervous system may be seen after chest RT with sympathovagal imbalance and inappropriate sinus tachycardia, altered heart rate variability and decreased sensibility. A higher pain threshold or silent ischaemia may develop in cancer survivors with manifest CAD after RT.
Precapillary pulmonary hypertension is a rare complication of some cancer agents (mainly in patients submitted to stem cell bone marrow transplantation treated with dasatinib). This condition is often reversible after drug discontinuation or replacement with another TKI, such as nilotinib. Recently, cyclophosphamide and other alkylating agents have been considered as contributors to the development of severe pulmonary veno-occlusive hypertension, which lacks effective pharmacological treatment.
Baseline echocardiographic evaluation, including the search for signs of right ventricular overload, should be performed in every patient with programmed CT that can cause pulmonary hypertension (dasatinib). Patients with baseline increased pulmonary arterial pressure require cardiology assessment for its aetiology, particularly in case of LV dysfunction or chronic thromboembolic pulmonary hypertension, as it may affect the strategy of cancer treatment.
The lifelong risk of childhood cancer survivors having CV toxicity from cancer therapies is eightfold higher than normal. This population is continuously increasing due to the greatly enhanced survival rates.
Anthracyclines and/or RT are the most used cardiotoxic agents for cancer in paediatric patients; therefore, lifelong follow-up of these patients is recommended.
The elderly population is the other group most affected by the cardiotoxicity of cancer therapy, due largely to the prevalence of classic CVD risk factors and CV comorbidities or diabetes. Also, general illnesses such as kidney or liver dysfunction lead to pharmacokinetic or pharmacodynamic impairment with altered drug elimination. All of these conditions make the elderly CV system more vulnerable to the additional burden of CT or RT.
Very little is known about the maternal risk of CT cardiotoxicity. Pharmacokinetic and pharmacodynamic changes and the circulatory overload occurring during pregnancy may lead to toxic effects.
Close monitoring, including clinical cardiac assessment and echocardiographic evaluation before CT and re-evaluation before every dose, should be considered in the pregnant condition.
A long-term observational case report seemed to demonstrate no significant long-term cardiotoxic effects in children born from mothers treated with CT during pregnancy .
Our group has recently published the rationale, organisation, and implementation of C-O services .
Dedicated professionals for multidisciplinary specialised evaluation and consistent, continuous, co-ordinated, cost-effective care during the cancer therapy process should be included in C-O services [4,5]. A knowledge of the cardiac side effects of anti-cancer treatments, the natural history of the malignancy and the benefits of oncologic treatments is essential for long-term CV and cancer disease-free survival.
C-O services should consist of multidisciplinary C-O teams (C-OT), that may differ according to the size of the hospital where they are located, from a single part-time specialist to a large C-O clinic with many specialists in a university or oncology hospital. In large centres, the C-OT should include core members (medical and radiation oncologists, haematologists, cardiologists and specialised nurses) and support members (patients' GPs, cardiac surgeons, cardiologists specialised in other domains, palliative care team, clinical laboratory specialists, hospital pharmacists, psychologists, radiologists, social workers, a data manager). The effective functioning of the C-OT is based on agreeing on local protocols and quality standards for the efficient use of resources  (Table 1).
Table 1. Recommended requirements of a cardio-oncology clinic. With permission from .
Cardiology service/departmentOncology service/departmentGeneral intensive care unit
Cardiology service (haemodynamic section)Radiation and medical oncology and haematology services
Intensive cardiac care unitCardiac transplant programme
- Dedicated outpatient clinic
- 24/7 hrs
- Structured clinical protocols
- Cancer survivorship programmes
- Structured training programmes
Specialist oncology centres: “in house” basic cardiology services
General/district hospitals: consultant cardiologist for inpatients and outpatients
Connected with primary care physicians
Recommended Available for acute inpatient problems
Multidisciplinary team: cardiologist, radiation and medical oncologist, haematologist, hospital pharmacist, oncology and heart failure nurses, psychologist
Available for acute inpatient problems
Clinical laboratory specialist, geneticist, data manager
Cardiac rehabilitation centre
Heart failure centre
Valvular heart centre
24/7 hr cardio-oncology available for acute inpatient/outpatient
Educational patient programmes
- Standard echocardiography
- Advanced echocardiography (3D, strain)
- CMR, cardiac CT, PET-CT
BIOMARKERS (troponin, BNP, NT-proBNP)
- Cardiac catheterisation; electrophysiology, cardiac surgery
Smaller services should be connected to larger regional cardio-oncology services for interventional procedures and complex cases
CABG, valvular heart surgery, percutaneous revascularisation procedures, non-coronary interventional procedures, electrophysiological studies, cardiac device implantation
- Internal audit processes
- Participation in national/European databases and research programmes
Lead cardio-oncology research programmes
The objectives of a C-OT are the optimisation of preventive strategies and the screening for early or late-onset complications, as well as the re-assessment of risk of cardiovascular complications in patients in need of treatment for secondary cancers .
1) Prior to the cancer therapy
2) During cancer treatment
3) After cancer treatment
The correct long-term strategy for cardiotoxicity monitoring requires the existence of a C-OT and the organisation of a long-term surveillance programme, focused on patients’ education and treatment adherence .
Furthermore, those involved with care should be aware that after cancer therapy patients frequently experience atypical CV symptoms – for example, silent ischaemia after mediastinal RT .
Every patient at risk should enter a C-O follow-up programme. Good compliance with this programme may be achieved by explaining to patients the potential risks and consequences of cardiotoxicity, and the possibility of its significant reduction with lifestyle measures, adherence to planned controls, and therapy compliance. General practitioners and nurses should be actively involved in the programme. Specific recommendations about diagnostic tests and the timing for long-term follow-up have been stated in the recent ESC position paper on cancer treatments and CV toxicity .
The basics for long-term surveillance programmes for cancer survivors
Cardio-oncology is a relatively new subspecialty involving many fields of cardiology. Its relevance is quickly evolving for the increasing population with C-O conditions. The organisation of effective C-O services is mandatory to be able to deal with the very difficult clinical problems of these patients; however, there are still many obstacles to implementing CO services which require a solution (Table 2).
Table 2. Obstacles in implementing cardio-oncology clinics (COCs). With permission from .
Riccardo Asteggiano1, MD, FESC; Thomas M. Suter2, MD, PhD; Jeroen J. Bax3, MD, PhD, Past-President ESC
Address for correspondence:
Dr Riccardo Asteggiano, Via San Marino 11 - 10134 Turin, Italy
The authors have no conflicts of interest to declare.
On behalf of the Council of Cardio-Oncology of the European Society of Cardiology
Our mission: To reduce the burden of cardiovascular disease.
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