Quick Guide to Managing Heart Health During and After Cancer Treatment

Professor Mike Kirby University of Hertfordshire

The Prostate Centre London

Declaration of interests • MK has received funding for research, conference

attendance, lecturing and advice from the pharmaceutical industry including Astellas, Pfizer, Takeda, Bayer, MSD, BI, Lilly, GSK, AZ and Menarini.

• Editor PCCJ • Also on several NHS advisory boards including the

Prostate cancer Risk Management Programme and the Prostate Cancer advisory Group.

http://www.macmillan.org.uk/throwinglight

Total Prevalence - now

Total Prevalence - 2030

Diagnosis & Treatment

Rehabilitation Early Monitoring

Later Monitoring

Progressive Illness

End of Life Care (Year 1 Deaths)

Progressive Illness

Later Monitoring Early Monitoring

Rehabilitation

Dx Rx

• Shared understanding – cancer

survival has changed; • a good conversation between

HCP and patient; • good communication between

HCPs; • a recovery package, planned

investigations and rapid access back to specialist care can produce better care without increasing cost.

Dealing with the consequences of cancer treatment

Cancer and the Heart With improved survivorship has come a rather remarkable fact: After surviving cancer, some patients are more likely to die of heart disease than recurrence of cancer e.g. breast cancer

Cancer and the Heart Chemotherapy, hormone therapy and radiotherapy can cause short term and long term CV complications – which may become one of the chief threats to a person’s survival & quality of life.

Cancer and the Heart Chemotherapy – Anthracyclines, Trastuzumab (Herceptin) Hormones – anti-oestrogens and anti-androgens (think metabolic syndrome!) Radiotherapy – can damage heart valves, coronary arteries, pericardium

Cardiovascular side effects of selected systemic cancer therapeutics

Cardiovascular effect Cancer Therapy Long term effect Mechanism

Cardiotoxicity Type I irreverisble

Anthracyclines Cyclophosphamide Cisplatin

Yes Rare Rare

Loss of myocardium Myocarditis Unknown

Cardiac dysfunction Anti HER-2 therapeutics Unlikely, except when combined with anthracyclines

Mitochondrial dysfunction

Myocardial ischaemia Pyrimidine analogues Anti-VEGF therapeutics

Rare Rare

Coronary vasospasm Arterial thrombosis

Arrhythmia Arsenic trioxide Selected TKIs

No HERG K+ blockage HERG K+ blockage

Thromboembolism Cisplatin Anti-VEGF therapeutics

Rare Endothelial damage Endothelial damage

Arterial hypertension Anti-VEGF therapeutics Unknown Multiple mechanisms Pulmonary hypertension Selected TKIs Unknown Unknown

Peripheral arterial occlusive disease Selected TKIs Unknown Unknown

Pleural effusion Selected TKIs Unknown Unknown HER-2 human epidermal growth factor receptor 2; TKI tyrosine kinase inhibitor; VEGF vascular endothelial growth factor; K+ human ether-a-go-go-related gene K+

Excess risks of cardiac morbidity after Hodgkin lymphoma therapy University of Florida, Hull et al. (2003)

The Netherlands. Aleman et al. (2007)

Princess Margaret Hospital. Myrehaug et al. (2008)

Harvard. Galper et al. (2011) Relative & Absolute XS risk

RR RR AER RR AER RR AER CABG 1.63 – – – – 3.2 18 PTCA – – – – – 1.6 18 Valve surgery 8.42 – – – – 9.2 14

Pacemaker – – – – – 1.9 9 MI/angina pectoris – 3.2 61.7 – – – –

CHF – 4.9 25.6 – – – – Cardiac hospitalisation

– – – 1.9 35.6 – –

Aleman et al (EJC Supplements 2014)

Gaps in knowledge concerning cardiotoxicity related to systemic

therapy

• Lack of universally accepted definitions of cardiotoxicity and cardiac dysfunction • Differentiation between irreversible (type1) and reversible (type2) cardiac dysfunction • Long term follow up (10-20 year) data needed • Early surrogate markers to predict long term CV prognosis • Early pharmacological intervention to mitigate cardiotoxicity • Individualised patient risk assessment

Chemotherapy and the Heart Value of Echocardiography

Can detect changes in global left ventricular function (LVEF and longitudinal strain) hence can be used: • Prior to instituting therapy • For surveillance • For detecting previously undiagnosed late onset cardiac problems

Cardiovascular effects of Chemotherapy – Anthracyclines

• Anthracyclines, e.g. Doxorubicin, commonly used to treat Leukaemia, Lymphoma, Cancers of breast, uterus, ovary and lung • Can damage heart muscle • Effects don't show up for years after therapy • Potential toxicity associated with cumulative dose • Patients develop drop in LV function (LVEF) • Prominent once dose reaches > 200mg/m2

• At 650mg/m2, 50% will develop CHF (Type1)

Cardiovascular effects of Trastuzumab (Herceptin)

• 5 year survival in early breast cancer is currently about 98% • Survival has improved dramatically in last 30 years • Trastuzumab (Herceptin) in HER-2+ patients associated with 50% lower rates of recurrence and 30% improvement in survival

Cardiovascular effects of Trastuzumab (Herceptin)

• Antibody beneficial in patients with HER-2 (Human Epidermal Growth Factor Receptor 2) • Prevents HER-2 from interacting with HER-4 Receptor • Can have toxic effect on the heart but effects are not dose dependent and are reversible (Type2)

Cardiovascular effects of Trastuzumab (Herceptin)

• Surveillance and early detection of myocardial damage is critical • Echocardiography is of value to

• Assess global left and right ventricular function and changes over time • Assess left ventricular longitudinal strain and changes over time • Biomarkers such as Troponin and Myeloperoxidase (MPO) are of benefit

Radiation-induced Heart Disease

• Most common in Lymphoma and Breast cancer • Less common with modern cardiac shielding and conformal techniques • Cumulative dose • More common with simultaneous chemotherapy

Mantle Field vs Involved Node radiotherapy for Hodgkin disease From Finch et al Cardiovascular Reviews 2014

Mantle field RT for (A) large mediastinal tumour (C) small mediastinal tumour

Involved node RT for (B) large mediastinal tumour (D) small mediastinal tumour

Planning CT scan prior to radiotherapy of the left breast The light blue line outlines the heart The green line outlines the left coronary artery. Radiation doses over the left breast: red is 74 Gy, blue is 0 Gy.

Radiation-induced Heart Disease

• Can affect the pericardium – causing constriction • Can affect valves – leading to valvulopathy • Can affect the coronary arteries– seen especially in left sided breast cancer • Increasing dose of radiation increases risk of coronary events in women undergoing radiotherapy for breast cancer •Risk of heart disease often forgotten in women!!

Radiotherapy and the Heart Value of Echocardiography

Can be used in patients receiving radiotherapy, to detect:

• Pericardial effects • Valvular abnormalities • Heart failure

Chemotherapy and the Heart Value of Echocardiography

Echo techniques valuable in patients undergoing chemotherapy Can detect changes in global left ventricular function (LVEF & longitudinal strain), hence can be used:

• Prior to instituting therapy • For surveillance • For detecting previously undiagnosed late onset cardiac problems

Survey of 500 English GPs in 2014:

77% believed that secondary and primary care working together should be responsible for managing CV health of people living with & beyond cancer Walter et al BJGP 2015

But...

Only 21% often considered history of cancer treatment when assessing CV health in patients 40% knew about the effects of radiotherapy on heart health 53% knew about hormone therapy 50% knew about chemotherapy Walter et al BJGP 2015

Education for GPs There was strong interest in learning more about how primary care can improve heart health in people living with an beyond cancer 86% wanted to receive further education on effects of cancer treatment on CV health

Walter et al BJGP 2015

The Guide is in 4 parts

1. Before cancer treatment 2. During hospital-based treatment or

hormonal treatments 3. After cancer treatment has finished 4. Criteria for referral to Cardiology

How should the patient be monitored in primary care?

CVD risk factors +/- CVD symptoms Annual screen for CV risk factors and co-morbidities & deal with them Advise on healthy lifestyle

This could be part of an annual Cancer Care Review

Who should have regular CV risk assessment?

People within 3 months of starting anti-androgen or anti-oestrogen therapy, then annually for 5+ years. Important in those with previous CVD, diabetes or CKD and be alert to the development of the metabolic syndrome

Who should have cardiac function testing?

High risk cardiotoxic cancer treatment - Test no later than 6 months after completion of cardiotoxic treatment; Continue thereafter at 5-yearly intervals, providing the 6 month assessment is normal and patient asymptomatic.

What advice should the patient be given?

• Benefits of healthy lifestyle • Macmillan self-help booklet • Discuss any new CV symptoms with GP.

Refer to Cardiology: •Abnormal cardiac function or CV symptoms detected during surveillance •Any new cardiac abnormality in symptomatic patients with established CVD •Women during/after cardiotoxic treatment who are pregnant/planning pregnancy •People during/after cardiotoxic treatment who wish to compete at high level of exercise