Juan M. Aranda, Jr., MD, FACC, FHFSAProfessor of Medicine

Director of Heart Failure and Cardiac TransplantationUniversity of Florida College of Medicine

Cardio-Oncology: A New Horizon for

Cardiovascular Medicine

Cancer Patterns in Latin America

• Cancer burden is increasing in Central and South America

• Leading cancers diagnosed were prostate, lung, breast, cervix, colorectal, and stomach

• Uruguay, Cuba, Argentina, and Chile highest mortality

• Resource-dependent interventions to prevent, diagnose, and treat cancer are urgently needed.

Cancer Epidemiology 2016; vol 24(1).

Increasing Cancer Survivorship

18

11.7 14

9.5

6.6

4.63

De Moor et al. Cancer Epidemiol Biomarkers Prev. 2013;22(4):561-70.

Cancer Survivors by Year and Time from Diagnosis

CV Disease is the Leading Cause of Death inCancer Survivors

Zaorsky et al. Ann Oncol 2017;28(2):400-7.

Factors leading to ↑CV risk:• Shared risk factors• Shared biology• Cardiotoxicity

Baseline Risk Factors for Cardiotoxicity

Zamorano JL, et al. Eur Heart J 2016; 37:2769-2801.

Cardiovascular Complications of Cancer Therapy

Zamorano JL, et al. Eur Heart J 2016; 37:2769-2801.

Cancer Treatment RelatedCardiotoxicity

Cancer Therapy

Ventricular Dysfunction

(Anthracyclines, α-HER-2, proteasome inhibitors,TKIs, immunotherapy)

Hypertension(TKIs, proteasome

inhibitors)

Arrhythmia(Ibrutinib, crizotinib,

cisplatin, RT, immunotherapy)

Vascular Toxicity(RT, 5-FU, Bcr-Abl TKIs,Immunomodulators)

Chemotherapy Associated with Left Ventricular Dysfunction

Yeh ET, et al. J Am Coll Cardiol 2009; 53:2231-2247.

+1,000 doses per year dispensed

++1,000 to 5,000doses per year dispensed

+++5,000 doses per year dispensed

Anthracycline Regimens in the Most Widely Used Protocols for 4 Types of Cancer

Vejpongsa P, et al. J Am Coll Cardiol 2014; 64:938-45

Presentation of Anthracycline Cardiotoxicity

Acute: within 1st week of therapyReversible ↓ LVEF, SVTUsually improves with d/c of Rx

Early Onset: < 1 year after therapy– Dose related ↓ LVEF– Can get progressive symptomatic HF– (60% mortality)

• Late Onset: > 1-20 years after therapy

– Can be triggered by second insult– May improve w/ medical Rx– Can get progressive clinical HF

(typically dilated but may be restrictive in childhood survivors)

2625 breast CA pts w/ ACT chemotherapy

9% w/ cardiotoxicity 98% w/in 1st yr

Cardinale et al. Circulation 2015;131:1981.

Anthracycline Cardiotoxicity: Mechanisms

Sawyer DB, NEJM 2013;368:1154-

Factors Associated with Risk of Cardiotoxicity Following Treatment with Anthracyclines

Zamorano JL, et al. Eur Heart J 2016; 37:2769-2801.

Primary Prevention for Anthracycline-Induced Cardiotoxicity

Vejpongsa P, et al. J Am Coll Cardiol 2014; 64:938-45

Mechanism of Anthracycline-Induced Cardiotoxicity

Vejpongsa P, et al. J Am Coll Cardiol 2014; 64:938-45

• Lower response rate. Time to progression survival rate same

• Greater cardioprotection in females

• Potential risk secondary malignancy

Summary of ß-Blocker and/or ACE Inhibitor Studies for Primary Prevention of Anthracycline-Induced Cardiotoxicity

Vejpongsa P, et al. J Am Coll Cardiol 2014; 64:938-45

Prevention of Cardiotoxicity:

ControlEnalapril/ Carvedilol

OVERCOME (n=90)Heme/Hi Dose Chemo

Bosch X et al. JACC 2013;61:2355

Candesartan Placebo

PRADA (n=120)Breast/Anthracycline

Gulati et al. Eur Heart J 2016;37:1671

Bisoprolol Perindopril Placebo

MANTICORE (N=94)Breast/Trastuzumab

Petuskin et al. JCO 2017;35;870

-3.5

-3

-2.5

-1.5

-2

-1

-0.5

0

-3

-2.5

-2

-1

-0.5

0

-6

-5

-4

-2

-1

0

-0.17

-3.28

-0.80

-3

Prevention of AnthracyclineCardiotoxicity: Statins

• N=40 pts Rx’ed with anthracyclines for heme malignancies

• RCT: Atorvastatin 40 mg daily vs.placebo

• 1⁰ End-pt: % LVEF < 50% (p=NS)

Acar et al. JACC 2011;58:988-9.

Sequential Levels of Troponin I During Chemotherapy Treatment

Avila MS, et al. J Am CollCardiol 2018; 71:2281-2290.

*** for dose > 250 mg/m2, echo + biomarkers before each additional 50 mg/m2

Plana et al. J Am Soc Echocardiogr 2014;27:911-39.

Consensus Guidelines to Screen for Anthracycline Cardiotoxicity in Adults

Primary and Secondary Prevention Strategies

Vejpongsa P, et al. J Am Coll Cardiol 2014; 64:938-945.

Patients at High Risk for Developing Cardiac Dysfunction ( ASCO Guideline 2017)

• High-dose anthracycline (>250 mg/m2 doxorubicin, ≥600 mg/m2 epirubicin)

• High-dose (>30 Gy) radiotherapy where the heart is in the tx field

• Lower-dose anthracycline with lower-dose radiotherapy where the heart is in the tx field

• Tx lower-dose anthracycline or Trastuzumab alone with the presence of 2 or more CV risk factors

• Smoking, HBP, DM, dyslipidemia, older age, >6 G borderline low EF 50 to 55%, history of MI, moderate valvular heart disease at any time before or during treatment

Trastuzumab• Improved outcomes in Human Epidermal Growth Factor Receptor (HER 2)

positive breast cancer• Concomitant use with or previous anthracyclines increases toxicity or

Trastuzumab• Usually manifests during treatment• Trastuzumab-induced LV dysfunction and HF are usually reversible with

Trastuzumab interruption and/or tx with heart failure therapy.• Mechanism of action: structural and functional changes in contractile proteins

and mitochondria but it rarely leads to cell death.

608 Subjects with HER2+ Breast CARx with Trastuzumab LVEF in Pts w/ Cardiotoxicity

• Mean EF at interruption = 44.8 ± 9%• Median interruption = 64 days (42-144)

33/66 re-challenged w/ trastuzumab• 85% w/ stable EF after re-challenge• 15% w/ recurrent decline

Yu AF, et al. Breast Cancer Res Treat. 2015; 149: 489-95

Trastuzumab Cardiotoxicity Can Be Reversible

Reasons forTreatment Interruption

Total

Cardiotoxicity 66 (10.9%)Asymptomatic ↓ LVEF 46 (7.6%)

Symptomatic ↓ LVEF 20 (3.3%)

NYHA I-II 9 (1.5%)

NYHA III-IV 11 (1.8%)

Risk Factors for Trastuzumab Cardiotoxicity

Not Dose Dependent

25

20

15

10

5

01st

Quarter2nd

Quarter3rd

Quarter4th

Quarter

Yu et al. The Oncologist 2015;20:1105-1110

Guideline for Management ofTrastuzumab Cardiotoxicity

• Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin and at regular intervals during treatment.

• Withhold Herceptin dosing for at least 4 weeks for either of the following:– ≥ 16% absolute decrease in LVEF from pre-treatment values– LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF

from pretreatmentvalues.

• Herceptin may be resumed if, within 4−8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.

• Permanently discontinue Herceptin for a persistent (> 8 weeks) LVEF decline or forsuspension of Herceptin dosing on more than 3 occasions for cardiomyopathy.

http://www.gene.com/download/pdf/herceptin_prescribing.pdf

Anti-HER 2 Trastuzumab

• Cardiac monitoring every 3 months during and once after completion of Anti-HER 2 therapy

• LV assessment every 3 months after initial asymptomatic LVEF decrease

• Early detection with troponins and speckle tracking echocardiography every 3 months during adjuvant Trastuzumab therapy

• Troponins every cycle in high-risk individuals

• Interruption of Trastuzumab results in LV recovery

Comparison of Guidelines on Cardiac Dysfunction in Cancer SurvivorsRecommendations SIOG ESMO ASE/EACVI NCCN ASCOIdentifying risk factors pre-treatment Yes Yes Yes Yes Yes

Preventative strategies to minimize risk during therapy Yes Yes No No Yes

Monitor for cardiotoxicity using LVEF Yes Yes Yes Yes Yes

Use of cardiac biomarkers (troponin I, BNP) No Yes Yes (troponin) No yes

Cardiac imaging of choice for cardiac monitoring

Echocardiography or MUGA scan Echocardiography Echocardiography Echocardiography Echocardiography, strain

imaging

Timing of cardiac monitoring in asymptomatic patients

Every 2-3 cycles of anthracycline exposure

Adjuvant anthracycline and/or trastuzumab: every 3 months during therapy, then 12 and 18 months after initiation of therapy

Agents associated with type 1 toxicity: completion of therapy, then 6 months after for doses <240 mg/m2 or equivalent.Trastuzumab: every 3 months

Consider in high-risk patients within 1 year of the last anthracycline dose

Consider in high-risk patients 6-12 months after completion of therapy

Use of beta-blockers or ACE inhibitors Yes Yes No No No

Evaluation and management of cardiovascular risk factors Yes Yes No Yes Yes

Referral to cardiologist or cardio-oncologist Yes Yes Yes Yes Yes

Tan C, et al. Cardio-Oncology Connection, June 29, 2018.

Cancer Treatment Related Cardiotoxicity

Cancer Therapy

Ventricular Dysfunction

(Anthracyclines, α-HER-2, proteasome inhibitors,TKIs, immunotherapy)

Hypertension(TKIs, proteasome

inhibitors)

Arrhythmia(Ibrutinib, crizotinib,

cisplatin, RT, immunotherapy)

Vascular Toxicity(RT, 5-FU, Bcr-Abl TKIs,Immunomodulators)

5-Fluorouracil (5-FU) Cardiotoxicity• 5- FU and it’s pro-drug, capecitabine, are

fluoropyrimidine antimetabolites• Used to treat solid tumors including

colorectal, pancreatic, gastric and breast• Usually present w/ chest pain ±

ischemic EKG changes• Typically present w/in 72 hrs of initiation

(median 12 hrs)• Incidence is 1-19% (most studies ≥ 8%)• Mortality 2-13%

Saif et al. Expert Opin Drug Saf 2009; 8:191

Mechanisms of 5-FU Cardiotoxicity• Coronary artery vasospasm

– Smooth muscle vasospasm via activation of PKC• Direct toxic effect on the endothelium and myocardium• Endothelial dysfunction and thrombus formation

– ↑fibrinopeptide A– ↓protein C

• Accumulation of toxic metabolites– alpha-fluoro-beta-alanine→fluoracetate

• Allergic insult leading to an increase in inflammatory mediators andvasospasm

• Changes in RBC morphology leading to hypoxia and ischemiaSorrentino MF et al. Cardiol J. 2012;19:453-8.

Risk Factors of Cardiotoxicity• Prolonged 5-FU regimens• Higher 5-FU doses• Pre-existing cardiovascular

disease• Prior mediastinal radiation• Concurrent use of other

cardiotoxic chemotherapeutic agent, e.g. docetaxel

Kosmas et al. J Cancer Res Clin Oncol 2008;134:75-82EK

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Management of 5-FU Cardiotoxicity

Modified from Hermann J et al. Circulation 2016;133(13):1272-89

At the time of acute presentation• Stop administration of drug• Use nitrates or L-type calcium channel blockers• Cardiac monitoring, CCU for patients with cardiac biomarker elevation > 2 X

ULN for ≥ 72 hoursAt the time of consideration of re-challenge• Consider cardiac catheterization to rule out underlying CAD• Avoid re-challenge in patients with MI as a prior complication of therapy• 4 day course of aspirin, long-acting nitrates and L-type calcium channel

blockers, 48 hours before, during, and after re-challenge• Continuous EKG monitoring on day of drug administration• Consider bolus rather than continuous infusion of 5-FU if benefits of re-

challenge outweigh risks• Outside US, can try raltitrexed, UFT or S-1 that are less cardio-toxic

Pathophysiological Mechanisms of Coronary Artery Disease in Cancer Treatment

Zamorano JL, et al. Eur Heart J 2016; 37:2769-2801.

CV Effects of Cranial RT• ↑ Risk of TIA/stroke and CV events• ↑ Metabolic Syndrome (3/5):

– ↑ waist circumference (> 102 cm for men and>108 cm for women)

– ↑ triglycerides (> 150 mg/dL)– ↓ HDL (< 40 in men and < 50 in women)– ↑ Blood pressure (> 130/85)– ↑ Fasting glucose (> 110 mg/dL)

• ↓ LV mass• Risk Factors:

– Host age < 4– Cranial RT ≥ 18 Gy– Female sex

Mahmood et al. Curr Treat Options Cardiovasc Med. 2016 Jul;18(7):45

Radiation Induced Heart Disease• 40-50% of cancer pts get radiotherapy• ̴ 1 million people/year

Lancellotti et al. J Am Soc Echocar 2013; 26:1013-32; Ng A. BJH 2011; 154:23-31

Hodgkin lymphoma: Relative risk

Breast cancer: Relative risk

Radiation induced cardiovascular disease

>6.3 2-5.9

Ischemic Heart Disease 4.2-6.7 1-2.3

Valvular heart disease 8.4-9.2 -

Pacemaker 1.9 -

Congestive heart failure 4.9 -

Cardiac death 2.2-12.7 0.9-2.0

COG Guideline RecommendationsCranial RT TBI/Mediastinal RT*• Yearly physical w/ BP, weight, height, and

BMI• Yearly history and physical for neurologic

and CV symptoms• EKG at first evaluation and prn• Encourage heart healthy diet and

physical activity• Carotid and brain imaging as indicated• Consider checking lipids and glucose

(frequency not provided)

• Yearlyhistoryandphysical for neurologicand CV* signs and symptoms

• EKG at first evaluation and prn*• CV risk factor modification*:

– Check lipids, fasting glucose, orHbA1c every 2 yrs

• Encourage heart healthy diet andphysical activity*

• Brain, carotid, subclavian imaging asindicated

• Echo as per anthracycline and RT table

http://www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf

Lancellotti et al. Eur Heart J-CV imaging 2013;14:721-40

Screening Algorithm for RT Survivors

Clinical Factors Associated with Increased Risk of Cancer-Associated Venous Thromboembolism

Zamorano JL, et al. Eur Heart J 2016; 37:2769-2801.

Cancer Drug Agents Associated with Cardiac Arrhythmias

Zamorano JL, et al. Eur Heart J 2016; 37:2769-2801.

Risk Factors for QT Prolongation in Cancer Patients

Zamorano JL, et al. Eur Heart J 2016; 37:2769-2801.

Cardiology Consult

• Reason for Consult– Risk prior to cancer treatment– Strategies for preventive monitoring– Complications during cancer treatment– Monitoring post cancer treatment

• Type of Cancer• Chemotherapy plans / previous chemotherapy

history• Cardiovascular Risk Factors• PE, EKG, Baseline Troponins, BNP, Echo

• Assessment– Risk– What you should avoid

• Plan– Preventive monitoring strategies– Preventive management

• Neurohormonal blockade• Statin• Imaging surveillance timeline

• Follow-up Schedule

Comprehensive Cardio-Oncology Program

• Program Leadership– Cardiologist-Oncologist collaboration

on all aspects of program development

• Administration• Outpatient Cardio-Oncology Clinic

– Location near cancer center– Ability to coordinate cardio-oncology

clinic visits with other cancer center appointments

• Inpatient Cardio-Oncology Consults• Cardiovascular Testing• Cardio-Oncology Nurse Coordinators

– Patient care coordination to minimize treatment disruption

• Education