Cardio-Oncology for the Primary Care Physician

• Atul R. Chugh, MD, FACC, RPVI

• Medical Director, Cardiovascular Research

• Team Member, Franciscan Cardio-Oncology Team

Disclosures

• Consultant: Recor, Inc.

• Speaker Bureaus: Amarin, Inc; Boston Scientific,

Objectives

• To highlight the burden of additive cardiovascular risk in patients with cancer both in the U.S. and world

• To present the more common cardiovascular associations noted in patients with cancer in relation to the cancer therapies

• To give primary care providers a detailed view of the workings and foci of a cardio-oncology clinic at Franciscan Health

Part I: Burden of Cardiovascular Risk and Events in Patients with

Cancer

Cardiovascular Disease and

Breast Cancer: Where These

Entities Intersect

A Scientific Statement From the American Heart Association, Volume: 137, Issue: 8, Pages: e30-e66

A Scientific Statement From the American Heart Association, Volume: 137, Issue: 8, Pages: e30-e66

Key Facts and Figures

Pudil R. The Future Role of Cardio-oncologists. Card Fail Rev. 2017;3(2):140–142. doi:10.15420/cfr.2017:16:1

The number one cause of mortality in US women is cardiovascular disease (CVD), yet the general public awareness of this remains suboptimal despite large-scale public education campaigns.

Cardiovascular (CV) disease and cancer remain the two most common causes of mortality in developed countries. According to recent data from the American Cancer Society, the lifetime probability of being diagnosed with an invasive cancer is 43% for men and 38% for women.

The number of cancer survivors has never been greater and is expected to reach more than 20 million in the U.S. by 2026.

Key Facts and Figures

• Rates of CV problems from cancer-related therapeutics have been reported to be in excess of 30 %, and cardiotoxicity is the second most common cause of morbidity and mortality in cancer survivors.

• Compared with the general population, adult survivors of multiple myeloma, lung cancer, non-Hodgkin lymphoma, and breast cancer have a higher risk of cardiovascular disease (CVD)

• Almost 10% of ALL drugs in the last four decades have been recalled from the clinical market worldwide due to cardiovascular safety concerns, (e.g., rofecoxib, tegaserod, and sibutramine) despite great efforts to reveal cardiotoxicity in the preclinical phase of development

Fradley MG, Brown AC, Shields B et al. Developing a comprehensive cardio-oncology program at a cancer institute: the Moffitt Cancer Center Experience. Oncol Rev.

Radiation Increases Risk of Major Coronary Events in Women after Radiotherapy for Breast Cancer

7.4% increases in major coronary events perGray of mean heart dose

1460 participants > 66 yoFrom 5 SWOG breast Cancer

Trials 1999-2011Increase prevalence of• Hypertension 73%

• Hyperlipidemia 57%

Impact of CV risk factors on cardiac events and survivaloutcomes among survivors of Breast cancer

Baseline CV Risk Factors associated with:

• Increase risk of death• Worse progression free

survival• Worse cancer survival• Increase risk of CV events

with • Each additional risk factor

Hershman D et al J Clin Oncol 2018

Part II: Cancer Therapies Associated with Cardiovascular

Risks

Cancer Treatment and Cardiovascular Adverse Effects

Cancer Treatment Cardiovascular Adverse Effects

Anthracyclines (eg, doxorubicin, epirubicin)Left ventricular dysfunction, heart failure, myocarditis, pericarditis, atrial fibrillation, ventricular tachycardia, ventricular fibrillation

Alkylating agents (eg, cisplatin, cyclophosphamide)Left ventricular dysfunction, heart failure, myocarditis, pericarditis, arterial thrombosis, bradycardia, atrial fibrillation, supraventricular tachycardia

Taxanes (eg, paclitaxel) Bradycardia, heart block, ventricular ectopy

Antimetabolites (eg, 5-fluorouracil, capecitabine)Coronary thrombosis, coronary artery spasm, atrial fibrillation, ventricular tachycardia, ventricular fibrillation

Endocrine therapy (eg, tamoxifen, anastrozole, letrozole)Venous thrombosis, thromboembolism, peripheral atherosclerosis, dysrhythmia, valvular dysfunction, pericarditis, heart failure

HER-2–directed therapies (eg, trastuzumab, pertuzumab) Left ventricular dysfunction, heart failure

Cyclin-dependent kinase 4/6 inhibitors* (eg, ribociclib) QTc prolongation

Radiation therapyCoronary artery disease, cardiomyopathy, valvular disease, pericardial disease, arrhythmias

Source: Lenneman CG, Sawyer DB. Cardio-Oncology: An update on Cardiotoxicity of Cancer-Related Treatment. Circ Res

2006;118: 1008-1020.

Anthracycline-Induced Cardiotoxicity

• Anthracyclines are a keystone in the treatment of many cancers, such as lymphomas, leukemias and sarcomas, but also for early or advanced breast cancer.

• Their side-effects are usually dose-dependent and more frequently detected in the first year after completing treatment, however can manifest acutely in up to 30% of patients soon after infusion

Cardiac Failure Review 2019;5(2):112–8.

Mechanisms of Anthracycline-Derived Cardiotoxicity

Cardiac Failure Review 2019;5(2):112–8.

During Treatment MRI EF

Cardiac MRI, Anthracycline Treated ( 200-250 mg/m2) Jones DN et all, JACC: Heart Failure 2018

Anti-HER 2 Drugs

HER-2 is overexpressed in 25–30% of breast cancers and this has led to research specifically targeting drugs such as trastuzumab (Herceptin) pertuzumab (Perjeta) and lapatinib (Tykerb).

Trastuzumab is the prototypical biological drug. It is a humanized monoclonal antibody that targets ErbB2 and had been a mainstain in breast cancer therapy since its introduction in 1998.

It can also cause cardiotoxicity that spans from asymptomatic decreases in LV ejection fraction (LVEF) to congestive HF.

Cardiac Failure Review 2019;5(2):112–8.

VEGF inhibitors and Hypertension/Cardiomyocyte Toxicity

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway (VSP) have been important additions in the therapy of various cancers, especially renal cell carcinoma and colorectal cancer.

Bevazicumab (Avastin), the first VSP to receive FDA approval in 2004 targeting all circulating isoforms of VEGF-A, has become one of the best-selling drugs of all time.

The second wave of tyrosine kinase inhibitors (TKIs), which target the intracellular site of VEGF receptor kinases, began with the approval of sorafenib in 2005 and sunitinib in 2006.

Heart failure was subsequently noted, in 2–4% of patients on bevacizumab and in 3–8% of patients on VSP-TKIs.

Common VEGF Inhibitors and Treatment IndicationsTouyz RM, Herrmann J. Cardiotoxicity with

vascular endothelial growth factor inhibitor

therapy. npj Precision Oncology. 2018;2(1):13.

Categories of BP in Adults

*Individuals with SBP and DBP in 2 categories should be

designated to the higher BP category.

BP indicates blood pressure (based on an average of ≥2

careful readings obtained on ≥2 occasions, as detailed in

DBP, diastolic blood pressure; and SBP systolic blood

pressure.

BP Category SBP DBP

Normal <120 mm Hg and <80 mm Hg

Elevated 120–129 mm Hg and <80 mm Hg

Hypertension

Stage 1 130–139 mm Hg or 80–89 mm Hg

Stage 2 ≥140 mm Hg or ≥90 mm Hg

Blood Pressure (BP) Thresholds and Recommendations for Treatment and Follow-Up

Normal BP(BP <120/80

mm Hg)

Promote optimal lifestyle habits

Elevated BP(BP 120–129/<80

mm Hg)

Stage 1 hypertension(BP 130–139/80-89

mm Hg)

Nonpharmacologic therapy(Class I)

Reassess in 3–6 mo(Class I)

BP goal met

No Yes

Reassess in 3–6 mo(Class I)

Assess and optimize

adherence to therapy

Consider intensification of

therapy

Reassess in 1 mo

(Class I)

Nonpharmacologic therapy and

BP-lowering medication(Class I)

Reassess in 1 y

(Class IIa)

Clinical ASCVD or estimated 10-y CVD risk

≥10%*

YesNo

Nonpharmacologic therapy (Class I)

BP thresholds and recommendations for treatment and follow-up

Nonpharmacologic therapy and

BP-lowering medication†(Class I)

Reassess in 3–6 mo(Class I)

Stage 2 hypertension(BP ≥ 140/90 mm Hg)

VEGF and Mechanisms

Peter Kružliak, Jan Novák, Miroslav Novák; Vascular Endothelial Growth Factor Inhibitor–Induced Hypertension: From Pathophysiology to Prevention and Treatment Based on Long-Acting Nitric Oxide Donors, American Journal of Hypertension, Volume 27, Issue 1, 1 January 2014, Pages 3–13, https://doi.org/10.1093/ajh/hpt201

VEGFi Induced Hypertension:Parallel Mechanisms

Peter Kružliak, Jan Novák, Miroslav Novák; Vascular Endothelial Growth Factor Inhibitor–Induced Hypertension: From Pathophysiology to Prevention and Treatment Based on Long-Acting Nitric Oxide Donors, American Journal of Hypertension, Volume 27, Issue 1, 1 January 2014, Pages 3–13,

Frequency of VEGFi Hypertension

• Wu et al. showed a 22.5%–57.7% incidence of VEGFi therapy–induced hypertension, with 7.5, 6.1, and 3.9 relative risks for developing hypertension when bevacizumab, sorafenib, and sunitinib, respectively, were used.

• Hypertension was reported in up to 36% of patients treated with bevacizumab, 16%–47% of patients treated with sunitinib and in 17% of patients treated wtih sorafenib (3% of these with grade 3 or 4)

• In the combined treatment with bevacizumab and sorafenib, the incidence of hypertension was 67%, and it was 92% for the combination of bevacizumab and sunitinib in patients with advanced solid tumors or RCC.

• In the phase I study of cediranib, one-third of the patients developed grade 3 or 4 hypertension54 occurring at cediranib doses ≥20mg.

• Patients with past medical history of hypertension appear to be at higher risk of VEGFi-induced hypertension.

Peter Kružliak, Jan Novák, Miroslav Novák; Vascular Endothelial Growth Factor Inhibitor–Induced Hypertension: From Pathophysiology to Prevention and Treatment Based on Long-Acting Nitric Oxide Donors, American Journal of Hypertension, Volume 27, Issue 1, 1 January 2014, Pages 3–13, https://doi.org/10.1093/ajh/hpt201

5-FU and Cardiotoxicity

• Fluoropyrimidines such as 5-fluorouracil (5-FU) form the foundation of a wide variety of chemotherapy regimens.

• It is the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world.

• 5-FU is the second most common chemotherapeutic drug associated with cardiotoxicity after anthracyclines, which can manifest as chest pain, acute coronary syndrome/myocardial infarction or death.

Ther Adv Med Oncol. 2018; 10: 1758835918780140.

• The reported incidence of cardiotoxicity related to 5-FU ranges from 1.2% to 18%

• With shorter bolus regimens, the incidence of cardiotoxicity typically lies between 1.6% to 3% of cases.

• With more prolonged regimens, these percentages increase to 7.6% to 18%

• A review of 377 cases of 5-FU associated cardiotoxicity confirmed that the majority of cases of cardiotoxicity occur in the setting of continuous infusion

Ther Adv Med Oncol. 2018; 10: 1758835918780140.

• Coronary artery spasm

• Autoimmune-mediated injury of the myocardium

• Endothelial damage

• Thrombogenic effects or thrombus formation

• Direct myocardial toxicity causing necrosis

• Global dysfunction

• Accumulation of metabolites

Ther Adv Med Oncol. 2018; 10: 1758835918780140.

Immune Checkpoint Inhibitors

The advent of immunotherapy is represented by immune checkpoint inhibitors (ICIs), whose purpose is to inhibit molecules such as cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) and of programmed cell death 1 (PD-1) and its ligand PD-L1.

These include: Pembrolizumab (Keytruda), Nivolumab (Opdivo), Cemiplimab (Libtayo), Atezolizumab (Tecentriq), Avelumab (Bavencio), Durvalumab (Imfinzi)

These drugs have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer (Merkel cell carcinoma).

Cases of fulminant and other cardiovascular disorders (pericarditis, vasculitis and AV blocks) have been reported by several independent groups.

Cardiac Failure Review 2019;5(2):112–8.

Common Associations-Summary

• Anthracyclines: Heart failure

• Anti-HER-2: Heart failure

• Anti-VEGF: Hypertension and heart failure

• 5-FU: Coronary spasm/MI

• Immune-Checkpoint Inhibitors: Myocarditis

Part III-A Cardio-Oncology Clinic

Cardio-Oncology Clinic and Responsibilities

• Identify patients at risk for cardiotoxicity (in concert with other physicians)

• Cardiovascular screening

• Cardiovascular surveillance: before, during and after therapies

• Partnership with oncologist to guide therapies

• Research

Cardiotoxicity Risk Score

Herrmann J, Lerman A, Sandhu NP, Villarraga HR, Mulvagh SL, Kohli M. Evaluation and management of patients with heart disease and cancer: cardio-oncology. Mayo Clin Proc. 2014;89(9):1287–306.

Multidisciplinary Approach to

CardioOncology

Herrmann J, Lerman A, Sandhu NP, Villarraga HR, Mulvagh SL, Kohli M. Evaluation and management of patients with heart disease and cancer: cardio-oncology. Mayo Clin Proc. 2014;89(9):1287–306.

Herrmann J, Lerman A, Sandhu NP, Villarraga HR, Mulvagh SL, Kohli M. Evaluation and management of patients with heart disease and cancer: cardio-oncology. Mayo Clin Proc. 2014;89(9):1287–306.

Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice

Guidelines, Annals of Oncology, 2012, Volume 23 (supplement 7), pages vii155–vii166

Non-Contrast Echocardiography

Contrast Echocardiography

• Reported normal values of GLS varied from −15.9% to −22.1% (mean, −19.7%; 95% CI, −20.4% to −18.9%).

• The threshold for change in GLS to predict cardiotoxicity is not clear, although between 10% and 15% appears to have the best specificity.

Thavendiranathan P, Poulin F, Lim K-D, Plana JC, Woo A, Marwick TH. Use of Myocardial Strain Imaging by Echocardiography for the Early Detection of Cardiotoxicity in Patients During and After Cancer Chemotherapy. Journal of the American College of Cardiology. 2014;63(25):2751-68.

https://my.clevelandclinic.org/florida/ccf/media/Files/nursing/2014-dicc-handouts/Session33_CurrentTrendsinCardiacOncology.pdf

During treatment - Echo Strain

N = 43, 21% CTOX, AC followed by TZM N = 81, 30% CTOX, all, trastuzumab, 40% A

Sawaya H et al, Am J Cardiol 2011; 107; 1375 Negishi K et all, JASE 2013, 26: 493-8

Protective Agents

• ACE/ARBs

• Carvedilol

• Dexrazoxane (Zinecard): indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use with the initiation of doxorubicin therapy

• Uridine triacetate (Vistogard): • following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, or• who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central

nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration

Summary

The incidence of cardiotoxicity/cardiovascular disease in patients with cancer continues to be on the rise

Agents causing these cardiotoxicities should be well-known to the clinical community

The use of a cardio-oncology clinic for these patients may be of great benefit