Cardio-Oncology for the

OncologistVijay U. Rao, MD, PhD, FACC, FASE, FHFSA

Director, CardioOncology

Franciscan Health, Indianapolis

Presenter Disclosure Information

Cardio-Oncology for the OncologistVijay Rao, MD, PhD, FACC, FASE, FHFSA

Objective: During this presentation,

participants will recognize the impact that

cancer treatment has on the cardiovascular

system and review best practices in managing

short and long-term cardio-toxicity

No relevant disclosures related to this talk

I will not discuss off label or investigational use in

my presentation.

Outline

Radiation therapy

Anti-Metabolite Coronary Vasospasm

Molecular Targeted Therapies (Precision Medicine)

Trastuzumab (Herceptin®)

Tyrosine Kinase Inhibitors (TKIs)

Immune Checkpoint Inhibitors (ICIs)

Franciscan CardioOncology Clinic

Franciscan CORE (CardioOncology REhabilitation

Services)

Radiation Therapy and CV disease

XRT: curative vs palliative intent

Mantle Cell Lymphoma, Adjuvant therapy in

breast cancer, Hodgkin’s lymphoma, lung cancer

Cardiac complications when dose is greater than

30 Gy

Shrinking problem: breath holding technique,

shielding, smaller fractions, PET scans

Incidental exposure of the heart to radiotherapy for breast cancer

increased the rate of major coronary events by 7.4% per gray,

with no apparent threshold. The percentage increase per unit

increase in the mean dose of radiation to the heart was similar

for women with and women without preexisting cardiac risk

factors

Radiation Induced Cardiotoxicity

Case

HPI:

47 yo female who was referred by PCP for DOE and bradycardia

Patient reported worsening DOE for the past few months, inability to get HR up with exercise, and intermittent palpitations

Denied any associated chest pain, orthopnea, PND, or lower extremity edema

Husband has noticed that she has been snoring a lot and possibly apneic at night.

Past Medical History

Obesity

Oncology History: Chondrosarcoma of the spine and ribs initially diagnosed in 2009. She had resection/reconstruction and spinal fusion at the time.

Recurrent disease in 2013 involving left chest wall and diaphragm. She again had resection/reconstruction, in addition to adjunctive RT and proton beam therapy

Remission for 5 years

Sinus bradycardia (1st Degree AV Block)

24h Holter

24 hour Holter

Results: sinus rhythm 2:1 AV block throughout with rates from 34 to 75 bpm, ventricular ectopy

consisted of 261 multifocal PVCs, 105 supraventricular ectopic beats, no pauses. No significant ST-T

abnormalities.

Differential Diagnosis for

Bradycardia/Complete Heart Block

Familial conduction disease

Cardiac Sarcoidosis

Infiltrative Cardiomyopathy

Ischemia

Medications

Radiation Therapy to the Chest

Infectious Causes: Toxo, Syphilis, Lyme, Chagas

Cardiac Tumors

Updates on Case (cMRI)

Anti-Metabolite: Coronary Vasospasm 5-FU (Fluorouracil®), Capecitabine (Xeloda®), Gemcitabine (Gemzar®): prevent DNA

replication by inhibiting thymidylate synthetase (FOLFOX, FOLFIRI)

3rd most common agent used to treat solid malignancies worldwide (breast, colorectal,

pancreatic, skin cancers)

Up to 2-5% of patients develop chest pain and ST elevation with coronary vasospasm

(most common with initiation, median time 12h and can occur up to 2 days after

infusion) and can be lethal

Occurs less often with bolus dosing (1/2 life 5FU 15-20min)

Occurs more often if patient with pre-existing CV disease (Franciscan research study

looking at calcium scoring prior to initiation of therapy, can we predict which population

is at highest risk and pre-emptively start nitrates/ccb for high risk patients?)

Can consider re-challenge with nitrate/ccb

Reversal agent (Vista-guard®) is available but very expensive

DO NOT IGNORE “chest pain” in any patient receiving anti-metabolite chemotherapy,

check ECG for all patients with these symptoms

SD Jaskanwal et al Ther Adv Med Oncol. 2018; 10: 1758835918780140.

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCM_czs235ccCFYFWHgodEJcJYA&url=http://america.aljazeera.com/articles/2015/1/30/obama-asks-for-215-million-for-precision-medicine.html&psig=AFQjCNEYwcgMADIwsWlwPiJxVisVOc8Zwg&ust=1441732824797617

Murphy CG and Morris PG. Anti-Cancer Drugs 2012, 23:765–76

Echocardiography

Myocardial strain analysis

• 10-15% drop in GLS by STE predicts future drop

in EF for both anthracycline and trastuzumab

chemotherapy [Thavendiranathan et al JACC

2014 volume (63):2751]

• GLS provided incremental prognostic information

in cancer patients when combined with clinic

variables [Rhea et al JASE 2015 28 (6) 667]

• SUCCOUR study: international trial GLS vs echo

guided strategy to prevent cardiotoxicity (mostly

anthracyclines and Herceptin)

Ewer MS et al. J Clin Oncol 2005;23:7820-6

Angiogenesis Inhibitors: HTN

Drugs: Sorafenib (VEGFR, PDGFR and Raf family kinases), Bevacizumab (VEGFR), Sunitinib (VEGFR, PDGFR)

Metastatic renal cell cancer, ovarian cancer, metastatic colorectal cancer

Prevalence: 15-60% develop HTN (link between HTN and improved progression free survival)

Risk Factors: Hx of HTN, >1 combo therapy, >65 yo, smoking, HL

Treatment: Ace-Inhibitors and/or dihydropyridine calcium channel blockers; avoid inhibitors of CYP3A4 (diltiazem, verapamil) as TKIs are substrates, could consider nevibolol(Bystolic) (beta-blocker which increases NO bioavailability); Franciscan grant written to test this

May need to decrease dose or halt therapy until HTN controlled; HTN resolves once agent stopped

VEGF Inhibition links to CV disease

Toyez et al. JASH, June 2018: Volume 12, Issue 6, Pages 409–425

Ibrutinib

Mechanism of Action FDA Approved Indications

Mantle Cell Lymphoma (MCL) (2nd line)

Chronic Lymphocytic Leukemia (CLL)

CLL subtype with 17p deletion (all lines)

Waldenstrom’s macroglobulinemia (all lines)

Marginal zone lymphoma (2nd line)

Chronic graft versus host disease

Ibrutinib and atrial fibrillation

Up to a 16% incidence of atrial fibrillation (AF) has been observed upon initiation of IB. The mechanism for IB-induced AF is not fully worked out, but it is hypothesized that the PI3K-Akt signaling pathway and the 20% incidence of IB-induced HTN may play a role.

Management of AF is particularly challenging in this setting as commonly used treatments for AF (rate/rhythm control agents and anticoagulants) have significant drug-drug interactions with IB through liver cytochrome-p450 (CYP3A4) and p-glycoprotein which can lead to adverse events.

Event Monitor

Paroxysms of rapid

Atrial fib

Sinus bradycardia, rate 52bpm

Qtc: 418msec

Treatment Considerations

Rate vs Rhythm Control: paroxysms of a.fib

Stop Ibrutinib? Dose reduce?

Symptomatic despite Lopressor: up-titrate bb or add diltiazem?

Which anti-arrhythmic would you use?

Stroke Considerations:

What to do with aspirin with hx of TIA?

Warfarin or DOACs?

IB and AF Drug-Drug Interactions

Rate Control Agents: Commonly used AF rate controlling agents such as verapamil and diltiazem have the potential to increase IB levels by as much as 4.9 fold and should not be used. Digoxin is a substrate of CYP3A4 and P-gp and thus its levels can fluctuate leading to toxicity. Beta-blockers do not interact with IB and thus should be the rate controlling agent of choice.

Rhythm Control Agents: If an AF rhythm control strategy is chosen, amiodarone and dronedarone should be avoided. Propafenone and Dofetilide are substrates of P-gp and thus could be used with caution. The class IC anti-arrhythmic, flecainide, as well as the class III anti-arrhythmic sotalol do not have drug-drug interactions with IB and thus could be considering the drugs of choice in this setting.

IB and AF Drug-Drug Interactions

Stroke prevention: Considerations are complex as IB has demonstrated excess bleeding due to its effects on platelet-mediated signaling pathways. Anti-platelet strategies should be minimized.

Warfarin: Excess bleeding was observed in an IB early study in patients taking warfarin leading to a recommendation not to co-administer these two drugs (6). As a result, there is scarce experience with warfarin and IB despite the fact that the excess bleeding was likely felt due to IB anti-platelet effects.

Direct oral anticoagulants (DOACs): Based upon their short half-life and favorable bleeding profiles, DOACs have been the favored anticoagulants thus far reported with IB (7). Dabigatran and edoxaban have the least potential for drug-drug interactions with IB, however, apixaban has been most widely used based upon expert opinion due to high rates of elderly population with renal failure and excellent GI safety profile. Dose-reduced direct oral anticoagulants (apixaban, rivaroxaban, dabigatran, and edoxaban) can be considered, but limited data exist regarding efficacy in this setting.

Ag

en

ts

CY

P 3

A4

P-g

lyco

pro

tein

Po

ten

tia

l Im

pa

ct o

n

Ibru

tin

ib C

on

c.

Po

ten

tia

l Im

pa

ct o

n

Card

iac M

ed

ica

tio

n

Con

c.

Ph

arm

aco

dyn

am

ic*

Inte

ractio

n

Co

-Ad

min

iste

r

Com

me

nt

Ibrutinib S INH

Rate Control Agents

Metoprolol Y

Verapamil S, INH INH ↑ N

Diltiazem S, INH ↑Ŧ N

Digoxin S S ±/↑ N

Rhythm Control Agents

Flecainide Y

Propafenone S INH ?

Sotalol Y

Dofetilide S ?

Dronedarone S, INH INH ↑ N

Amiodarone S, INH S, INH ↑ ↑ N

Stroke Prevention Agents

Dabigatran S ↑ X ? Consider dose

reductionRivaroxaban S S ±/↑ X ?

Apixaban S S ±/↑ X ?

Edoxaban S ↑ X ?

Betrixaban S ↑ X ?

Warfarin S ± X ?

Antiplatelet Agents

Clopidogrel X N Discontinue unless

critical due to ibrutinib

inherent bleeding risk

Prasugrel X N

Ticagrelor S INH X N

Aspirin N

Footnotes: Conc: Concentrations; INH: Inhibitor; S: substrate; ↑: Increase; ↓: Decrease;

±: Effect unknown of potential impact of competition for metabolism by CYP 3A4 among drugs

with a narrow therapeutic index.

*Additive bleeding riskŦCombination of diltiazem and ibrutinib contraindicated

Ibrutinib/atrial fib summary

IB-induced AF presents a unique and challenging clinical entity best addressed by a multidisciplinary team approach including cardiac, oncology, and pharmacy team members. Further studies evaluating stroke and bleeding rates with IB-induced AF are warranted.

Immune Checkpoint Inhibitors (ICI)

2017: 940 agents being tested in 3042 clinical

trials

CHECK-MATE study (Lancet Oncology 2016):

unresectable stage III/IV melanoma

Checkpoint Inhibitors [Ipilimumab (Yervoy)/Nivolumab (Opdivo)]

1:400 patients estimated to develop myocarditis

Moslehi et al. N Engl J Med. 2017 Jan 19;376(3):292

ICI Myocarditis Occurs early (median time to reporting 17-65 days)

Combination therapy at highest risk

Up to 1% incidence reported in retrospective case control

study

Mild sx’s (fatigue) to syncope/sudden death

Dx: ECG, troponin, ECHO, cMRI, RV biopsy

Screening/surveillance: troponins every two months while

on therapy

Tx: stop ICI therapy, high dose methylprednisolone

1000mg/day x 3 days followed by oral prednisone 1mg/kg

daily

If refractory sx’s and unstable patients: IVIG, anti-

thymocyte globulin, plasma exchange; stable patients

consider infliximabGanatra and Nieland 2018 The Oncologist 23: 518-523.

Berkman et al. Breast Cancer Research and Treatment 2014

DOI:10.1007/s10549-014-3168-3

Fig. 1 Percentage of total cardiovascular deaths versus breast cancer deaths by age of ductal carcinoma in situ (DCIS) diagnosis

Personalized Exercise Therapy in Cancer

What we know: Exercise therapy improves a patient’s CVD risk profile

favorable alterations in insulin sensitivity, lipid profile, and blood pressure with concomitant improvements in the reserve capacity of the skeletal muscle/vasculature/cardiovascular axis

Across 26 studies of breast, colorectal, and prostate cancer patients, a 37% reduction was seen in risk of cancer-specific mortality, comparing the most versus the least active patients (pooled relative risk = 0.63; 95% confidence interval: 0.54-0.73) (Friedenriech CM et al. Clin Cancer Res. 2016 Oct 1;22(19):4766-4775. Epub 2016 Jul 12)

Individualization

Exercise exposure (≥ 9 metabolic equivalents of task hours of physical activity

per week) was associated with a substantial 50% reduction in breast cancer

death in estrogen receptor (ER)–positive tumors compared with a

nonsignificant 9% reduction in ER-negative tumors. JAMA. 2005;293:2479-

2486.

The exercise prescription must be specific and targeted to the primary

endpoint or system(s) or pathway(s) known or postulated to underpin the

effects of exercise on the primary therapeutic target.

In the context of breast cancer that are ER positive, exercise

prescriptions should be designed to optimally inhibit ER activity, its

ligands, or coactivating pathways.

Increasing exercise is associated with linear reductions in the risk of

recurrence and cancer mortality but only up to a specific threshold; exercise

exposure beyond this threshold is associated with an attenuated effect on

cancer outcomes, suggesting that an upper threshold or optimal dose of

exercise exists to impact cancer outcomes

Current and next generation practice in exercise oncology.

Current practice (left column) stratifies patients based on tumor type, provides a generic exercise

prescription (typically based on predicted maximum heart rate), resulting in a heterogeneous

response. Next generation practice (right column) stratifies patients based on multiple factors,

provides a targeted exercise prescription based on phenogroup, resulting in optimized efficacy,

safety, and tolerability of exercise therapy. CPET, cardiorespiratory exercise test, CRF,

cardiorespiratory fitness, Rx, prescription.

Therapy and Cardiovascular Toxicity in Cancer

Scott JM et al. Circulation. 2018 Mar 13;137(11):1176-1191.

Cardio-Oncology Rehabilitation to Manage Cardiovascular

Outcomes in Cancer Patients and Survivors: A Scientific Statement

From the American Heart Association.

Gilchrist SC et al. Circulation. 2019 Apr 8:CIR0000000000000679

CardioOncology Rehabilitation (CORE)

Referral is not driven by a specific point in the cancer

continuum but rather by a patient’s underlying risk of

cardiac dysfunction; referral can be during therapy or in the

survivorship period

CORE: patient assessment, nutrition counseling, weight

management, bp/lipid/DM2 management, tobacco

cessation, psychosocial and physical activity management

Highly individualized (type and duration)

CORE can be center or home based

Need research in field so can pave wave for reimbursement

Track all outcomes including economic (downstream

healthcare use, ability to return to work, etc).

CardioOncology Grand Rounds

Jessica Scott, PhD from Memorial Sloan Kettering

November, 2019

Site-Visit from Franciscan CardioOncology

Program

Utilization of CPET

Establishment of CORE

Franciscan Health: CardioOncology Clinic

8 Oncologists, 4 Cardiologists, 2 nurse navigators (oral agents/iv agents), one dedicated MA, dedicated ½ day every two weeks

Prevention/screening for cardiotoxicity and CV complications of cancer therapy

Increase awareness about topic and clinical considerations among PCPs and cardiologists

Increase access to subspecialty expertise (telemedicine initiative with Franciscan outreach)

Contribute to research in the field

Incorporating CRS (cardiotoxicity risk score) in cardio-oncsetting (chemotherapy risk + patient CV risk factors), embedded in EMR for cancer patient intake; guide for referrals to clinic

TKI-HTN grant; nebivolol (Dr. Chugh)

Calcium scoring to predict 5-FU vasospasm

SURVIVE registry (Dan Lenihan at Wash U; 10 sites globally)

Banking serum samples and 6 min walk test

Indianapolis CardioOncology Network

(ICON) Case Conference

Quarterly

November, 2019

Site to be determined

Attend in person or via online/Web-X

Franciscan Health Cardio-oncology Team

Vijay U. Rao

Vijay.rao@franciscanalliance.org

Screening/exercise prescription approaches in oncology.

Three example screening/exercise prescription approaches that could be

applied to research investigations designed to assess the efficacy of

exercise on cardiovascular toxicity in the oncology setting:

(1) guideline based approach (bottom row) applies ASCO cardiotoxicity

guidelines and standard exercise guidelines;

(2) ASCO guidelines and VO2peak-based approach (middle row) applies the addition

CPET for risk stratification and exercise prescription design;

(3) multidimensional data approach (top row) applies advanced analytics for both risk

stratification and targeted exercise prescription design. ASCO,

American Society of Clinical Oncology; CPET, cardiorespiratory exercise test.