Cardiac Care for the Cancer Survivor

Suma H. Konety, MD, MSCardiovascular Division

University of Minnesota

Overview

• Cancer treatment related cardiotoxicity – what, when, how, who?

• Strategies to prevent cardiac toxicity.• Role of cardiac imaging in screening.• Future directions to mitigate risk.

Current State

• Long term cancer survivors are increasing.• Cancer treatment can lead to unintended and lasting

damage to the cardiovascular system. • Many antineoplastic agents cause cardiotoxicity.• Broad clinical spectrum of cardiac problems. • The pathophysiology is not completely understood.• There is no clear consensus on how to treat cardiac

dysfunction in cancer patients.

Cancer Therapies Implicated in Cardiovascular Complications

• Chemotherapy agents– Anthracyclines

• Daunorubicin• Doxorubicin• Epirubicin• Idarubicin• Mitoxantrone

– Tyrosine kinase inhibitors• Trastuzumab• Avastin• Sunitinib• Dasatinib

– Alkylating Agents• Cyclophosphamides

• Radiation therapy– Mantle – Mediastinal– Cervical – Supraclavicular – Left breast radiation

Cardiovascular Complications From Cancer Therapy

Chemotherapy • Cardiomyopathy

– Asymptomatic– Symptomatic

• Arrhythmias• Hypertension• Coronary heart disease• Dyslipidemia

Radiation therapy• Coronary heart disease• Valvular heart disease• Pericardial disease• Vascular disease• Congestive heart failure• Arrhythmias

Signs and Symptoms Cancer Therapy Induced Cardiomyopathy

Symptoms• Shortness of breath• Chest pain• Palpitations• Swelling of the feet• Abdominal fullness

Signs• Jugular venous distension• Cardiac murmur• S3, S4• Pericardial rub• Rales, wheezes• Peripheral edema

Chemotherapy Induced Cardiomyopathy

• LVEF <50% or a 10% drop in LVEF is widely accepted as LV dysfunction in the oncology community.

• LV dysfunction could be symptomatic or asymptomatic.

• LV dysfunction could manifest acutely or have a late onset and can also be chronic and progressive.

Yeh ETH, et al. JACC 2009:53.

Pathophysiology of Anthracycline Cardiac Toxicities

• Anthracyclines has been a mainstay of therapy for breast cancer, leukemia, lymphoma, sarcoma, etc..

• Damages nuclear DNA, changes calcium handling and cellular contractility, suppresses factors that regulate cell survival and protein synthesis.

• Serial imaging is the current screening strategy • Early detection and treatment could be lifesaving

Anthracycline-induced cardiomyopathy

CHF in Breast Cancer Survivors

Using the Surveillance, Epidemiology and End Results (SEER) Medicare database women aged 66 to 70 treated with anthracycline compared with other chemotherapy had a 26% higher risk of CHF.

Pinder MC, et al. JCO 2007;25(25):3808-3815.

Strategies For Prevention of Anthracycline- induced CHF

Statins Protect Breast Cancer Patients From Heart Failure

Using the Cleveland Clinic database women with breast cancer after treatment with anthracycline who received statin therapy compared to cancer controls not on statin had a 70% lower risk of incident CHF.

Seicean S, et al. JACC 2012;60:2384-90.

SECONDARY PREVENTION

Diagnostic OptionsCancer Therapy Induced Cardiomyopathy

• HOW– Imaging

• Nuclear ventriculography• Echocardiography – 2D, 3D, strain, stress• Cardiac magnetic resonance• Vascular function

– Biomarkers• NT pro-BNP• Troponin

• WHO• WHEN

• Observational study of 42 patients with anthracyclines compared to 15 healthy controls

• On cardiac MR - no myocardial edema or focal scar• Diffuse myocardial fibrosis was found in the

anthracycline treated patients compared to controls• Implication -

• Is DF a transition step from normal to irreversible damage?• Role of RAS modulators to reverse the remodeling process?

ACC/AHA Guidelines for Evaluation and Management of HF

Secondary PreventionCancer Therapy Induced Cardiomyopathy

• There is paucity of well-conducted RCTs that would provide the evidence to support pharmacological intervention.

• Studies have failed to demonstrate clinically significant improvement in cardiac function in childhood cancer survivors.*

• However, survivors treated with high dose (≥300 mg/m2) of anthracyclines benefited most from the intervention.*

• In muscular dystrophy patients, there was survival benefit with afterload reduction.+

* Silber JH et al. J Clin Oncol: 22; 2004.+ Connuck DM et al. Am Heart J: 155;2008.

Risk Factors For Chemotherapy Related Cardiac Toxicity

COG LTFU Guidelines: 2008

Chemotherapy: Screening

COG LTFU Guidelines: 2008

Radiation therapy

• 294 patients w/ Hodgkin's• >35 Gy radiation• Exercise stress test• Conventional risk factors were not

consistently present in patients w/ CHD• 14% (n=40) had CHD, >50% coronary

stenosis• More common >10 yr after radiation• Screening recommended 5-10 years

after radiation

Radiation Therapy and Heart Disease

Increasing risk of death and coronary events in women treated with higher doses of RT and increased cardiac risk factors.

Darby SC et al. NEJM: 368; 2013.

Risk Factors For Radiation Therapy Related Cardiac Toxicity

COG LTFU Guidelines: 2008

Radiation Therapy: Screening

COG LTFU Guidelines: 2008

Referral to the Cardiology

• Subclinical abnormalities on screening evaluations– Left ventricular dysfunction LVEF <55%– Arrhythmias– QT interval prolongation

• 5-10 years after chest radiation– > 40 Gy of chest radiation– > 30 Gy of chest radiation + anthracyclines

• Isometric exercise program in any high risk patient– Patients involved in varsity team sports

Health Counseling• Heart health

– Blood pressure (<140/90 mmHg), weight (BMI <25), cholesterol, glucose • Heart Healthy diet

– Fresh fruits, vegetables, whole grains– Calories from fat <35% of total calories eaten each day– Limit saturated fat

• Daily exercise– Aerobic exercise generally safe– Avoid intensive isometric exercises (heavy weight lifting, wrestling)– High repetition weight lifting using lighter weights safer

• Dental Health• Tobacco cessation

Conclusions

• It is clear that both the disease (cancer) and the treatment itself carry life threatening risk.

• Variability on susceptibility to cardiac damage is not completely explained by clinical and demographic factors, suggesting genetic predisposition.

• Pharmacogenomics is a promising strategy to minimize harm and maximize benefits.