“Cardio-Oncology – a new specialty combining Cardiology and Oncology”

Acting Consultant Cardiologist, Barts Heart Centre, St Bartholomew’s Hospital and Hatter Cardiovascular Institute, University College London Hospital.

Cardio-Oncology is the care of cancer patients with cardiovascular disease. While it has been established a speciality for a few years in the USA and in some parts of Europe, it is in its infancy in the UK. However the speciality is rapidly expanding in the UK with a number of hospitals developing Cardio-Oncology services. This review aims to give the reader of an overview of the exciting new specialty of Cardio-Oncology.

What is Cardio-Oncology?

Cardio-Oncology is the prevention and management of heart disease in cancer patients (Yeh & Bickford 2009). While the bulk of work is related to cardiovascular toxicity of cancer therapies it is important to remember that there are other interactions between cancer and heart disease with many common risk factors and disease pathways at cell and molecular level (Suter & Ewer 2013).

The mortality rate among patients with cancer has decreased dramatically over the last 20 to 30 years. However, the toxicity of conventional cancer treatment (both chemotherapy and radiotherapy) is greater than previously appreciated and is a leading cause of morbidity and mortality in survivors (Barac et al. 2015). New “targeted therapies” are being developed at a rapid pace many of which have recognised or unrecognised cardiovascular toxicities. The cardiac toxicities of cancer treatment include heart failure, cardiac ischaemia, arrhythmias, pericarditis, valve disease and fibrosis of the pericardium and myocardium (Lenihan & Cardinale 2012) (Figure 1).

Chemotherapeutic agents can broadly be divided into cytotoxic agents (anthracyclines e.g. Doxorubicin, taxanes e.g. Paclitaxel and others like 5 Fluorouracil, Cyclophosphamide and Cisplatin) and molecular targeted therapy [Monoclonal antibodies e.g. Trastuzumab (Herceptin), tyrosine kinase inhibitors e.g. Sunitinib and Vascular endothelial growth factor antibodies (VEGFs) e.g. Bevacizumab] (Table 1). The cardiovascular side-effects of these agents are varied (Figure 2) and have traditionally been divided into type 1 and type 2 effects although there may be some overlap (Plana et al. 2014).

Type 1 effects are commonly caused by anthracyclines and result in myofibrillar disarray causing cumulative and dose-related damage. These effects appear to be permanent and irreversible. Type 2 effects are caused by Trastuzumab and are not dose related and there are no ultra-structural abnormalities and the cardiac effects are thought to be reversible. However there is growing evidence that this demarcation into type 1 and 2 effects may be somewhat arbitrary with considerable overlap being present (Bloom et al. 2016).

Radiotherapy can cause cardiac damage through macrovascular and microvascular injury (Figure 3). The risk of radiation-induced heart disease is increased with anterior or left chest irradiation, lack of shielding, higher doses and with concomitant anthracycline chemotherapy (Lancellotti et al. 2013). Patients who received radiotherapy historically are at increased risk compared to current radiotherapy regimes due to the development of better shielding protection.

Presentation
Cardio-Oncology patients can present in a number of ways (Bellinger et al. 2015). Depending on the cardiac diagnosis (e.g. heart failure versus ischaemia) different investigations and management plans are formulated.

Investigations

Troponin and Brain Natriuretic Peptide (BNP) levels can be measured during chemotherapy and in case of decompensation. Elevated levels indicate some degree of myocardial cell damage and/or myocardial strain and are prognostic (Cardinale et al. 2004). However studies have not yet been undertaken to determine prospectively if initiating cardio-protective treatment in response to abnormal blood tests has a prognostic benefit. Additional novel markers (ST2, galectin, myeloperoxidase, high sensitive CRP) have also been measured in some studies and risk scores to determine cardio-toxic risk developed (Herrmann et al. 2014). However more work still needs to be done on this front (especially to show a prognostic benefit from using these scoring systems) before they are routinely employed in clinical practice.

Cardiac imaging is the primary investigative modality. With the known effect of chemotherapy on cardiac function, cardiac imaging has been used to monitor this. Traditionally in the USA nuclear medicine (MUGA – multi-gated acquisition) scans have been used to monitor ejection fraction (EF) in cancer patients. The predominance of this imaging technique in the USA is due to widespread availability and good reproducibility. However such an approach has considerable drawbacks – namely repeated exposure to radiation with repeated surveillance scans and an inability to offer a more nuanced assessment of cardiac function other than EF.

In most other countries echocardiography is the key initial imaging investigation. It widely available, inexpensive and does not expose the patient to radiation. In addition it can evaluate systolic and diastolic function in addition to valve disease and pericardial effusions. Echocardiography has also been used primarily for surveillance of those undergoing cardio-toxic treatment. Older guidelines focussed on repeated monitoring of EF with a decrease in EF below a certain level postponing or stopping cancer treatment (Curigliano et al. 2012). Changes in EF are late markers in the assessment of cardiac function. EF is a composite marker reflecting longitudinal, radial and circumferential myocardial contractility. A deterioration in any one of these types of contractility can be compensated for by increased contractility in the other two directions. As such the EF may remain unchanged despite deterioration in one type of contractility and is thus an insensitive marker of myocardial function in this situation (Abraham et al. 2007). In addition, the recommendations regarding the level of change in serial EF measurements that mandate alterations in chemotherapeutic approach (Curigliano et al. 2012), are close to the coefficient of variability for EF, assessed by routine departmental echocardiography. The use of 3D echocardiographic to obtain volumetric EF calculations is more reproducible, compares favourably with cardiac magnetic resonance EF calculations and is advocated as the preferred echocardiographic method of calculating EF (Plana et al. 2014).

Newer parameters of deformation and contractility hold the prospect of being able to identify cardiac involvement before EF changes, and thus alert clinicians early, before irreversible damage occurs. Candidate parameters include echocardiographic strain imaging, tissue Doppler annular velocities and chamber volumes. Current guidelines recommend strain imaging in monitoring for cardio-toxicity (Lancellotti et al. 2013).

Other imaging modalities have their role also. Cardiac magnetic resonance (CMR) imaging can complement echocardiography by demonstrating the location of focal myocardial fibrosis by late gadolinium imaging and diffuse fibrosis by the newer T1 and T2 mapping techniques (Neilan et al. 2013). CMR can also identify acute inflammatory changes associated with chemotherapy and can be invaluable in monitoring for the resolution of cardiac oedema in this context (Thavendiranathan et al. 2013). CMR is however limited by availability, cost and patient acceptance, making it unlikely to wholly supplant echocardiography.

Computed Tomography of the Coronary Arteries (CTCA) is also a useful investigation especially when assessing the effects of radiotherapy-induced fibrosis and coronary atherosclerosis and has been recommended in European Association of Cardiovascular Imaging and American Society of Echocardiography guidelines (Plana et al. 2014; Lancellotti et al. 2013).

Management and Prevention

Patients with chemotherapy or radiotherapy induced heart failure, valve disease or coronary ischaemia should be treated as per standard European and national guidelines, but some registries suggest that cancer survivors may be undertreated for conventional CV risk factors (Weaver et al. 2013; Meacham et al. 2010). The treatment of coronary disease with stents (and the associated antiplatelet agents) may be difficult if cancer surgery or treatment with chemotherapy that may seriously diminish platelet numbers, is imminent. Currently clinicians deal with these situations on an empirical individualised basis, although with national and international registries becoming available, it is to be hoped these important aspects of clinical care may become rationalised.

There is limited data on the cardio-protective effect of Angiotensin Converting Enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta blockers in patients undergoing chemotherapy (Seicean et al. 2013; Cardinale et al. 2006). Their use in this context (e.g. when the EF or strain values drop significantly with chemotherapy but still remain in the “normal” range) is unlicensed. Current trials are investigating this and whether cancer therapy-related cardiotoxity can be prevented – the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research (MANTICORE) and Prevention of Cardiac Dysfunction during an Adjuvant Breast Cancer Therapy (PRADA) Trials (Pituskin et al. 2011; Heck et al. 2012).

Desraxozane (an iron chelator) has been shown to reduce doxorubicin-induced cardio-toxicity (Cvetković & Scott 2005). It may be initiated at the first dose of anthracycline or after a cumulative doxorubicin dosage of ≥ 300 mg/m2. However its use is licensed in the treatment of only a few cancers and It’s use is not widespread and although a previously a worsening in cancer outcomes was suggested, subsequent studies have not confirmed this potential (Swain et al. 1997).

Additional work has been done on the cardioprotective effect of mineralocorticoid receptor antagonists (Akolkar et al. 2015) and on statins (Seicean et al. 2012). However randomized control trials are awaited for both of these drug classes before incorporation into guidelines.

The current UK perspective – services and training

There is an increased recognition that optimal cardiovascular care for cancer patients can be best delivered through dedicated Cardio-Oncology services. Cardio-Oncology services are now being developed at a number of hospitals in the UK (Cubbon & Lyon 2016). Both authors are currently involved in establishing Cardio-Oncology services at their respective hospitals. Given the increased success of oncological treatments the number of cancer patients with cardiovascular problems will increase with time resulting in a greater need for Cardio-Oncology services.

Training programmes in Cardio-Oncology are well established in the USA with trainees from both Cardiology and Oncology undertaking these fellowships with the ultimate aim of developing Cardio-Oncology services with Cardiologists and Oncologists working together as a team (Okwuosa & Barac 2015). Currently only a few hospitals in the UK offer Cardio-Oncology Fellowships. The aim of the British Cardio-Oncology Society (http://bc-os.org/) is to expand training in Cardio-Oncology and ultimately develop formal training programmes.

Key points

  • Cardio-Oncology is a new and exciting specialty involved with the prevention and management of heart disease in cancer patients
  • Chemotherapy, radiotherapy and cancer itself have cardiovascular effects
  • Cardiovascular complications include heart failure, valve disease, pericarditis, pericardial effusions, ischaemic heart disease and arrhythmias
  • Imaging investigations are key for detection of abnormalities and monitoring of patients with echocardiography the principal imaging modality
  • Limited evidence showing the cardio-protective effect of ACE inhibitors, ARBs and beta blockers – new trials ongoing
  • Current expansion in Cardio-Oncology services and training opportunities in the UK

Conflicts of interest

Both authors are members of the British Cardio-Oncology Society.