Cardio-oncology: Principles and organisational issues by Dr Han Naung Tun(Henry Han )

1. Cardio-oncology: Principles and
organisational issues
Dr. Han Naung Tun
MBBS, MD
Working Member in Council of Cardio-oncology
European Society of Cardiology and American College of
Cardiology

2. Introduction to cardio-oncology
• 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

3. Why Heart Disease and Cancer are important to Discuss?
• The progressively ageing population with an increasing incidence of cancer patients and
patients with CV diseases (CVD)
• 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..

4. • The probability of every physician facing cancer and CVD patients is high.
• Everyone should be aware of
The toxicity of a CT agent
or of RT
The risk factors and pre-
existing CVD
predisposing to
cardiotoxicity
The use of preventive and
curative measures during
possible cardiotoxic
therapy

5. • 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.
Oncologist and cardiologists should undertake the therapeutic
option for a cancer patient by:

6. Cancer therapy and 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.

7. Possible CV complications of CT and/or RT
• 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
Zamorano JL . et al ,Eur Heart J. 2016;37:2768-801.

8. 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.

9. Cardiotoxicity

10. • 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.

14. Coronary Artery Disease
• 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.

16. Significant fibrosis of the left anterior descending (LAD) artery
after chest radiation
Proposed mechanism of involvement of NF-κB in radiation-
induced vascular disease
Radiother Oncol (2010) 97(1):149–61

18. 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.

20. 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

21. • 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.

22. Mechanisms of arrhythmias in cancer patients 9th ed. Glenview, IL: Pearson Education, Inc; 2013.

23. 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.

24. 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.

26. 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.

27. • 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.

28. • 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.

30. Clinical Trials Assessing DOACs in CA Patient with VTE
Chest. 2015;147:475-483

31. 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.

32. 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.

33. 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.

34. 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.

35. 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.

36. • 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.

38. Objectives of cardio-oncology teams
• The objectives of a C-OT are
the optimisation of preventive
strategies
the screening for early or late-
onset complications
the re-assessment of risk of
cardiovascular complications in
patients

40. Cancer survivorship programme

41. ACC Onco -cardioloogy , Indiana Chapter, Franciscan Health

44. Take Home Messages
• 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