Cardio-oncology: principles and organisational issues

Keywords

cancer, cardio-oncology, chemotherapy, radiotherapy, toxicity

Introduction to cardio-oncology

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 [1]:

• The progressively ageing population with an increasing incidence of cancer patients and patients with CV diseases (CVD) and the consequent increase of the prevalence of patients suffering from both conditions.
• The increasing survival from cancer and CVD with an increase in the prevalence of these two conditions combined.
• Most survivors from cancer therapy develop or die from CVD, more than from cancer recurrence.
• Patients cured for cancer should not die of a CV complication.
• Patients suffering from cancer may have CVD risk factors and/or a pre-existing CVD, often concealed, enhancing the toxic effects of CT and RT. An adequate and aggressive risk factor control and CV diagnostic work-up strongly enhance survival.
• CT and RT toxicity may develop many years after treatment. Tight follow-up protocols to avoid long-term cardiac side effects are essential for adequate treatment.
• Cancer-cardiac patients may undergo different treatment if managed by a separate approach of care by oncologists or cardiologists, due to a more or less aggressive treatment of the two conditions separately. The best treatment may be achieved if cardiologists and oncologists are interacting properly, building a C-O expert team.

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:                  

• Planning the optimal treatment regimens to minimise cardiotoxicity without compromising anticancer efficacy.
• Detecting CV effects when potential cardiotoxic agents are used, with particular attention to subclinical signs and symptoms.
• Preventing CV side effects with a careful CV work-up before using therapies with significant cardiotoxicity, paying attention to the patient’s comorbidities that should be controlled.

Cancer therapy cv toxicities

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 [1]:

• 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
• Pulmonary hypertension
• Pericarditis

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 and heart failure (HF)

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.

Coronary artery disease (CAD)

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.

Valvular heart disease (VHD)

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.

Tachyarrhythmias and bradyarrhythmias

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.

Arterial hypertension

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.

Thromboembolic disease

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.

Peripheral vascular disease and stroke

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.

Pericardial disease

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.

Pleural effusion

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.

Autonomic dysfunction

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.

Pulmonary hypertension

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.

Special populations

Paediatric cancer population

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.

Elderly cancer population

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.

Pregnant women

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 [2].

Cardio-oncology services

Our group has recently published the rationale, organisation, and implementation of C-O services [3].

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 [6] (Table 1).

Table 1. Recommended requirements of a cardio-oncology clinic. With permission from [3].

Objectives of cardio-oncology teams

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 [7].

1) Prior to the cancer therapy

• The prevention of CV complications in patients who are going to be submitted to cancer treatments requires the evaluation of the CV risk profile and physical examination, looking for CV diseases, blood pressure and cardiac function [1]. This screening may help in selecting the appropriate therapy and is mandatory in the adjuvant setting or for cancers with good prognosis when patients are cured or may survive for a long time and long-term toxicity is not acceptable. Accordingly, the optimal frequency of monitoring should be defined, and the interactions of cancer drugs with pre-existing cardiac drugs (e.g., CYA3A4 inhibitors/inducers…) and the appropriate use of CV medications such as antiplatelet and anticoagulant therapy should be evaluated [1].
• The optimisation of CV health for cardiac patients and the facilitation of anti-cancer treatment in patients with CV complications are both consequences of this approach. When it may not be achieved, interdisciplinary discussion to ensure the most efficacious cancer treatment without CV harm is recommended.

 2) During cancer treatment

• Early identification and treatment of CV complications are missions of a C-OT with a careful monitoring of symptoms/signs to differentiate those related to cancer from others due to cardiac involvement. The dilemma is the balance of continuing versus interrupting anti-cancer therapy, and whether the cancer or CV disease is the major threat for the patients [1]. Applying the best cardiology care may allow continuing or minimising interruptions of essential cancer treatments.

3) After cancer treatment

• The surveillance for late CV complications in cancer survivors is probably the most difficult to translate into practice because the detrimental effects exerted by both systemic CT and RT can appear years to decades later.

Cancer survivorship programme

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 [3].

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 [3].

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 [1].

The basics for long-term surveillance programmes for cancer survivors

• Raise awareness of possible cardiac disease among cancer survivors and provide appropriate follow-up in clinical practice.
• Inform patients of their increased risk of CVD after CT/RT, advise and support them to make appropriate lifestyle changes.
• Instruct patients to report early signs and symptoms of CVD promptly.
• Due to LV dysfunction and HF potential occurrence even in asymptomatic patients, always programme a periodic screening with cardiac imaging and biomarkers, such as BNP, particularly in those treated with high cumulative doses or those who demonstrated reversible LV dysfunction during cancer treatment.
• Investigate any symptom suggestive of HF promptly.
• Do not discontinue cardioprotective HF therapy but continue it indefinitely even with stable normal systolic LV function as long as no further cancer therapy is planned.
• Actively look for CAD, ischaemia and vascular disease in patients with a history of mediastinal radiation, even if asymptomatic, starting five years post treatment and then at least every five years thereafter.
• Perform ultrasound scanning of the carotid arteries in patients with previous neck irradiation, for the risk of stroke in order to rule out the presence of subclinical carotid stenosis.
• In asymptomatic patients, the EACVI/ASE recommend a screening echocardiogram at 10 years post radiation and serial examinations every five years thereafter.

Conclusions

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 [3].