Cardio-Oncology Toxicities and Management · 4/21/2017 · III. Cancer therapies can increase CV...

Cardio-OncologyToxicities and Management

Duke Debates: Controversies in the Management of Patients with Hematologic Malignancies

April 21, 2017

Michel G. Khouri, MD

Assistant Professor of Medicine

Division of Cardiology

Duke University Medical Center

Disclosures

• I do not intend to discuss an off-label use of a product during this activity.

• I have not had any relevant financial relations during the past 12 months to disclose

• Financial: Chimerix, Inc. (spouse)

Outline

I. Cardiovascular disease & Cancer Therapya) The basis for Cardio-Oncology

b) Treatment-related cardiovascular disease (‘cardiotoxicity’)i. Traditional and novel anticancer agents

c) Treatment-independent metabolic adverse effects

d) Integrated concept of CVD and cancer / cancer therapy

II. What can we do about cardiotoxicity?a) Early detection

b) Prevention & Treatment

THE BASIS FOR CARDIO-ONCOLOGYCardiovascular Disease & Cancer Therapy

I. Survival gains in cancer and CV disease in recent decades

II. Cancer and CV disease pose competing risks:

i. Cancer survivors remain at risk for CV disease

ii. CV disease survivors remain at risk for malignancy

III. Cancer therapies can increase CV riskI. Toxicities of conventional cancer

treatments remainII. New ‘targeted’ therapies are being

developed rapidly, many of which have recognized or unrecognized cardiovascular toxicities

The Basis for Cardio-OncologyWhy Cardio-Oncology?

Driver, et al. BMJ, 2008


Armenian, et al. JCO, 2016

Incidence of CV Disease by Cancer TypeKaiser Permanente (SC)

>36K adult cancer survivors (≥2 years); >73K controls


Armenian, et al. JCO, 2016

All Cancer Survivors

Overall Survival in Cancer among Survivors with and without CV diseaseKaiser Permanente (SC)

>36K adult cancer survivors (≥2 years); >73K controls

The Basis for Cardio-OncologyWhat is Cardio-Oncology?

Cancer

Biology

&

Disease

Cancer Therapy

Past &

Present

Cardiovascular Risk Factors &

Disease

Cancer

Biology

&

Disease

Cancer Therapy

Past &

Present


Disease

Treatment-related‘Cardiotoxicity’

• Acute toxicity can affect access to life saving drugs• Chronic toxicity can affect survival, morbidity and QOL


Acute Toxicity

50’s yo woman receiving Carfilozimib for multiple myeloma

A few days later …

Cancer

Biology

&

Disease

Cancer Therapy

Past &

Present


DiseaseCV and Cancer links

• Cancer – CVD relationship not well characterized• Incident CVD and/or RF’s can limit access to cancer therapies


Spectrum of Cardio-Oncology

Glycemic control

↓ lean body mass

↑ fat mass

Metabolic derangements of cancer/ treatment with CV risk

Adverse lifestyle effects of cancer/treatment with CV risk

Deconditioning / sedentary lifestyle

Obesity

Depression / anxiety

Cardiotoxicity of cancer treatment

(Cytotoxic agents, Targeted agents, Radiation, Immunotherapies)

LV dysfunction (↓LVEF, ↓GLS)

Heart failure

Myocardial ischemia / infarct

Arrhythmia, long QT, SCD

Myocarditis

Pericardial constriction

Pericardial effusion

Valvular disease

Accelerated atherosclerosis

Hypertension

VTE events

ATE events

PAD

Pulmonary HTN

Vasospasm

Proteinuria (renovascular)

Management of Pre-existing CVD in Cancer

Anticoagulation / antiplatelet therapy needs

Arrhythmia (brady- or tachy-), long QT

Cardiac amyloidosis (e.g., complicating plasma cell dyscrasias)

Hypertension (essential, renovascular, or secondary)

Dyslipidemia

LV dysfunction (↓LVEF, ↓GLS)

Heart failure

Ischemic heart disease

Pulm HTN / Right heart failure / significant TR

PVD (arterial and/or venous)

Cardiac toxic effects Vascular toxic effects

Cardio-oncology Patient

CANCER TREATMENT-RELATED CVD(‘CARDIOTOXICITY’)

Cardiovascular Disease & Cancer Therapy

Spectrum of Cardiotoxicity

Adapted from Lenneman C, et al. Circ Res, 2016

Spectrum of Cardiotoxicity

AnthracyclinesCardiomyopathy

Heart Failure

FluoropyrimidinesMyocardial ischemia

VT / VF / SCD

Endocrine / Androgen Deprivation Therapy

(ADT)Metabolic syndrome

DiabetesCADVTEATE

↑ CV Events(pre-existing CVD)

RadiationCAD

Valvular disease Pericardial disease

Restrictive CMP

MT InhibitorsArrhythmias

Alkylating AgentsATE

Myocardial ischemia

Cytotoxic Therapies Hormonal Therapies

Conventional Therapies

TrastuzumabCardiomyopathy

Heart Failure

BMTCAD

HypertensionDyslipidemia

Cardiomyopathy

VEGF Signaling Pathway (VSP) Inhibitors

HypertensionCardiomyopathy

ATE

Anti-BCR-ABL TKIsPericardial effusion

ATEVTE

Pulmonary HTNPAD

Proteosome InhibitorsHypertension

CardiomyopathyArrhythmia

ATE

ImmunomodulatorsATE, VTE

HDAC InhibitorsATE, VTE

Signaling Pathways Other Targeted

Novel (Targeted) Therapies

mTOR InhibitorsHypertension

Myocardial Ischemia

ImmunotherapiesMyocarditis / Myositis

Anthracycline CardiotoxicityDose related

1979

<400 mg/m2: 0.14%550 mg/m2 : 7%>700 mg/m2 : 18%

2003

<400 mg/m2: 5%550 mg/m2 : 26%

Von Hoff, et al. Ann Intern Med 1979 Swain, et al. Cancer 2003

Anthracycline CardiotoxicityTime to onset

Mulrooney, et al. BMJ 2009

0 10 20 30 Time since diagnosis (years)

Childhood Cancer Experience Adult Cancer Experience

Cardinale, et al. Circulation 2015

BCR-ABL Kinase InhibitorsVascular complications

9 Patients with PAH- Median 34 months post-Dasatinib- 88% women, 67% pleural effusion- None with complete PAH resolution

Dasatinib – Pulmonary Hypertension

Montani, et al. Circulation 2012

Nilotinib – Peripheral arterial disease

Ponatinib – Peripheral arterial disease

• Temporarily withdrawn from market for serious ‘arterial thrombotic events’ in 19% of treated patients

• Resumed sales under narrower indication and black box warning

Valent, et al. Blood 2015

Radiation TherapyChildhood Cancer Experience

Mulrooney, et al. BMJ 2009

Mediastinal Radiation TherapyEffects on Autonomic Function?

Groarke, et al. JACC 2015

Mediastinal Radiation Therapy Autonomic Dysfunction

Groarke, et al. JACC 2015

Chemoradiation TherapyCardiovascular disease in Hodgkins Lymphoma

Van Leeuwen, et al. JAMA Int Med 2015

TREATMENT-INDEPENDENT METABOLIC ADVERSE EFFECTS

Cardiovascular Disease & Cancer Therapy

↓ Cardiovascular Reserve Capacity

↑ Risk of CVD & Mortality

Adapted from Koelwyn, et al. JACC 2014 and Jones, et al. JACC 2007Adapted from Groarke, et al. Eur Heart J 2013

Indirect Effects ‘Multiple hit’ Hypothesis

CV Effects of Cancer Treatments

• Current anticancer therapies have unique and varying degrees of direct and indirect sequential and progressive CV insults

– Direct: myocardial toxicity, ischemia, hypertension, arrhythmias

– Indirect: unfavorable lifestyle changes

• Anthracycline - well-known cardiotoxicity

– Dose-dependent, irreversible cardiomyocyte necrosis

– Early- or late-onset LV dysfunction and heart failure

• Targeted agents – emerging recognition of cardiotoxicity

– Interfere with molecular pathways crucial to CV health

– Potentially reversible CV effects

CV RISK ASSESSMENT AND CARDIOPROTECTIONCardiovascular Disease & Cancer Therapy

Integrated Concept of CVD & Cancer

CV reserve Subclinical dysfunction

Clinical disease

Multiple hit

Baseline

CV health

&

Risk factors

Cancer

Diagnosis

Cytotoxic,

Targeted,

Radiation

Therapy

(“CV insult”)

Cardiovascular

toxicity

(↓LVEF)

(ACC/AHA

Stage B)

Heart failure

(ACC/AHA

Stage C & D)

CV disease

&

Premature

death

Disease

Progression

Khouri, et al. Circulation 2012

Approach to CV Risk StratificationHematologist-Oncologist as ‘gatekeeper’

• Assessment of cancer prognosis– Age, early-stage vs. advanced disease, disease-site specific

• Assessment of CV disease potential– Existing CVD

• Coronary, valvular, cardiomyopathy, HTN, PAD, arrhythmias, etc.

– Shared risk factors / co-morbid conditions• Smoking, obesity, hyperlipidemia, DM, sedentary, aging

– Role for CVD risk score(s) (e.g., ASCVD, Framingham, Reynolds, etc.)?

• Assessment of cardiotoxicity potential of proposed treatment(s)• Cardio-oncology risk assessment

– Cancer prognosis vs. CVD / cardiotoxicity potential

• Consider acute cardio-oncologic implications– Existing CVD or treatment cardiotoxicity potential as barriers to life-saving therapies

• Consider long-term cardio-oncologic implications– Development of CVD undermining expected cancer prognosis (survival, QOL, etc.)

Approach to CV protectionThe role of the Cardio-Oncologist

Primordial PreventionTreat all high cardiac risk patients

AdvantagesMinimize screening

DisadvantagesTreatment despite:-Normal function

-Low (~5%) overall incidence of overt HF

Primary PreventionScreen for subclinical dysfunction

(Imaging, blood biomarkers)Advantages

Minimize unnecessary treatmentDisadvantages

Intensive / frequent screeningOptimal screening method uncertain

Potential delayed diagnosis / treatment

AdvantagesEarly intervention:

(1) Maintain access to life-saving therapies, and (2) Limit development of CVDDisadvantages

Duration of treatment uncertain

CV Risk Threshold MetOncologist referral to Cardio-Oncologist

EARLY DETECTIONWhat can we do about cardiotoxicity?

Diagnostic testing

Emerging Biomarkers

Biochemical markers

Strain echo (tissue Doppler/speckle tracking)

Cardiac magnetic resonance imaging

Targeted nuclear cardiology

Functional capacity testing

Surveillance

Traditional Imaging

Echocardiography

Nuclear cardiology

Diagnosis Guide treatment

Baseline

CV health

&

Risk factors

Cancer

Diagnosis

Cytotoxic,

Targeted,

Radiation

Therapy

(“CV insult”)

Cardiac toxicity

(↓LVEF)

(ACC/AHA

Stage B)

Heart failure

(ACC/AHA

Stage C & D)

CV disease

&

Premature

death

Disease

Progression

DetectionTraditional & New Approaches


LV Ejection Fraction

2D Echo 3D Echo

Early detection3D vs. 2D Echo LVEF

Walker, et al. J Clin Oncol 2010

LVEF Sensitivity for Cardiotoxicity

Ewer, et al. J Clin Oncol 1984

Myocardial StrainSpeckle-tracking Strain Echocardiography

Adapted from Kisslo; Gorcsan, et al. J Am Coll Cardiol 2011

Strain% change from

resting dimension

StrainTissue deformation

10cm

L0

8cm

L1

-20%

Early detectionLongitudinal Strain vs. 3D Echo LVEF

Post-TCPHPre-Trastuzumab

LVEF 54%GLS –17%

Trastuzumab x 3MPre-Pertuzumab

LVEF 53%GLS –11%

Trastuzumab x 5MPertuzumab x 2M

LVEF 29%GLS –7%

Early detectionBiochemical markers - Troponin


(495)

(145)

(63)

Early detectionTroponin vs. Other Blood-based Biomarkers

Ky, et al. J Am Coll Cardiol 2013

• 81 breast cancer patients; HER2+• Mean LVEF 64±5% → 59±6% (P < 0.0001) over 15 months• Cardiotoxicity (n = 26) defined by CREC criteria and heart failure (n = 5)• µs Troponin I and Echo longitudinal strain at anthracycline completion

– Predicted subsequent development of cardiotoxicity

• *Longitudinal strain only independent predictor of cardiotoxicity and LVEF <50%

Early detectionEcho Strain vs. Troponin

*

Sawaya, et al. Circ Cardiovasc Imaging 2012

Prognostic Value of EchoTraditional & Novel Parameters

Ali, et al. JASE 2016

Cardiac Events Cardiotoxicity

Negishi, et al. JASE 2013

Modalities of Cardiotoxicity DetectionEchocardiography RNA

(MUGA)cMR

Blood Biomarkers

2D 3D Strain TroponinNatriuretic peptides

Target(s) LVEF; LV Vol LVEF; LV Vol Myocardial deformation

LVEF; LV Vol LVEF; LV Vol;Myocardialdamage/

deformation

Myocardial injury

Myocardial stretch/ stress

Availability ++++ +++ +++ +++ + ++++ ++++

Cost Low Medium Medium Low

Reproducibility ++ +++ +++ ++++ ++++ ++++ ++++

Cardiac structure

Temporal resolution ++++ + +++ - -

Spatial resolution ++ + +++ - -

Myocardial function

Systolic +++ +++(+) ++++ ++++ ++++ - -

Diastolic ++++ + ++++ - ++ - -

Tissue characterization + - - - ++++ - -

Potential to detect subclinical cardiac toxicity

Low LowModerate-

HighLow Moderate High Unknown


Current State of Detection in Cardiotoxicity

• Current standard detection modalities in cardio-oncology (i.e., resting LVEF) are insensitive for cardiotoxicity and may not be prognostic

• Emerging imaging modalities that assess myocardial deformation, functional capacity testing, and blood biomarkers have potential to improve early detection

• However, evidence with these modalities remains based on small, single center studies

• Future investigation with large, prospective studies is required to validate their diagnostic and prognostic utility, determine optimal timing of assessments, and standardize cut-off points

PREVENTION & TREATMENTWhat can we do about cardiotoxicity?

Diagnostic testing

Emerging Biomarkers

Biochemical markers

Strain echo (tissue Doppler/speckle tracking)

Cardiac magnetic resonance imaging

Targeted nuclear cardiology

Functional capacity testing

Surveillance

Traditional Imaging

Echocardiography

Nuclear cardiology

Diagnosis Guide treatment

Baseline

CV health

&

Risk factors

Cancer

Diagnosis

Cytotoxic,

Targeted,

Radiation

Therapy

(“CV insult”)

Cardiac toxicity

(↓LVEF)

(ACC/AHA

Stage B)

Heart failure

(ACC/AHA

Stage C & D)

CV disease

&

Premature death

Disease

Progression

Prevention and Treatment

ACE inhibitors / Angiotensin Receptor Blockers

Beta blockers

Aldosterone Antagonists

Statins

Dexrazoxane

Exercise

Primordial

prevention

Primary

prevention

Secondary

preventionTreatment


Re

spo

nd

ers

(%

)

(n = 130) (n = 71)

Cardinale, et al. JACC 2010

For effective cardioprotection, timing is the key . . .

Current Means of Cardioprotection

• Cardio-active agents– ACE inhibitors– Angiotensin receptor blockers– Beta-blockers– Statins– Aldosterone antagonists– Dexrazoxane* (Anthracyclines)

• Exercise• Chemotherapy

– Dose reduction– Dosing administration / formulation (e.g., liposomal DOX) – Alternative, less toxic agents (e.g., lapatinib, pertuzumab)– Stop chemotherapy

Primordial PreventionBeta Blockers

J Am Coll Cardiol 2006

Kaya, et al. Int J Cardiol 2013

Primordial PreventionACE Inhibitors + Beta Blockers

Bosch, et al. J Am Coll Cardiol 2013

Primordial PreventionStatins

Seicean, et al. J Am Coll Cardiol 2013

p=0.03

Statins

Controls

Primordial Prevention

Kalam, et al. Eur J Cancer 2013

Primary PreventionTroponin + ACE Inhibitors


Primary PreventionStrain + Beta Blockers

Eur Heart J Img 2013

What is the optimal strategy?ACC/AHA Heart Failure guidelines (2013)

Stage A: Recommendations (Class I, LOE C)Conditions that may lead to or contribute to HF, such as ... cardiotoxic

agents, should be controlled or avoided. • “…it may be reasonable to evaluate those who are receiving (or who

have received) cardiotoxic chemotherapy agents for LV dysfunction.”

• “The use of advanced echocardiographic techniques or biomarkers to identify increased HF risk in those receiving may be useful ...”

ESMO guidelines (2012)• Patients receiving anthracyclines and/or trastuzumab in the adjuvant

setting should perform serial monitoring of cardiac function at baseline, 3, 6, and 9 months during treatment, and then at 12 and 18 months after the initiation of treatment.

• Monitoring should be repeated during or following treatment as clinically indicated.

Yancy, et al. Circulation 2013

Curigliano, et al. Ann Oncol 2012

Current Guidelines in Cardio-OncologyESC CPG POSITION PAPER

2016 ESC Posit ion Paper on cancer treatments

and cardiovascular toxicity developed under the

auspices of the ESC Committee for Pract ice

Guidelines

The Task Force for cancer t reatments and cardiovascular toxicity of

the European Society of Cardiology (ESC)

Authors/Task Force Members: Jose Luis Zamorano* (Chairperson) (Spain),

Patr izio Lancellot t i* (Co-Chairperson) (Belgium), Daniel Rodr iguez Munoz (Spain),

Victor Aboyans (France), Riccardo Asteggiano (Italy), Maur izio Galder isi (Italy),

Gilber t Habib (France), Daniel J. Lenihan1 (USA), Gregory Y. H. Lip (UK),

Alexander R. Lyon (UK), Teresa Lopez Fernandez (Spain), Dania Mohty (France),

Massimo F. Piepoli (Italy), Juan Tamargo (Spain), Adam Torbicki (Poland), and

Thomas M. Suter (Switzer land)

ESC Commit tee for Pract ice Guidelines(CPG): Jose LuisZamorano (Chairperson) (Spain), Victor Aboyans (France),

Stephan Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon (Spain), Gonzalo Baron-Esquivias (Spain),

Helmut Baumgartner (Germany), Jeroen J. Bax (The Nether lands), Hector Bueno (Spain), Scipione Carer j (Italy),

Veronica Dean (France), Çet in Erol (Turkey), Donna Fitzsimons (UK), Oliver Gaemper li (Switzer land),

Paulus Kirchhof (UK/Germany), Philippe Kolh (Belgium), Pat r izio Lancel lot t i (Belgium), Gregory Y. H. Lip (UK),

Pet ros Nihoyannopoulos (UK), Massimo F. Piepoli (Italy), Piot r Ponikowski (Poland), Marco Roffi (Switzer land),

Adam Torbicki (Poland), Ant onio Vaz Carneiro (Portugal), and Stephan W indecker (Switzer land)

Document Reviewers: Stephan Achenbach (CPG Review Coordinat or) (Germany), Giorgio Minot t i (CPG Review

Coordinator) (Italy), Stefan Agewall (Norway), Lina Badimon (Spain), Hector Bueno (Spain), Daniela Cardinale

(Italy), Scipione Carer j (Italy), Giuseppe Cur igliano (Italy), Evandro de Azambuja (Belgium), Susan Dent (Canada),

Cet in Erol (Turkey), Michael S. Ewer (USA), Dimit r ios Farmakis (Greece), Rainer Fietkau (Germany),

Donna Fitzsimons (UK), Oliver Gaemper li (Switzer land), Paulus Kirchhof (Germany/UK), Philippe Kohl (Belgium),

Paul McGale (UK), Piot r Ponikowski (Poland), Juergen Ringwald (Germany), Marco Roffi (Switzer land),

* Correspondingauthors:JoseLuisZamorano, Headof Cardiology, University Hospital Ramon Y.Cajal,CarreteraDeColmenar Km9.100, 28034Madrid, Spain.Tel: + 3491336 85 15,

E-mail: zamorano@secardiolo gia.es;Patrizio Lancellotti, University of Liege Hospital,GIGA Cardiovascular Sciences, Departments of Cardiology, Heart ValveClinic, CHU Sart Tilman,

Liege, Belgium and Gruppo Villa Maria Care and Research, Anthea Hospital, Bari, Italy. Tel: + 32 4 366 7194, Fax: + 32 4 366 7195, E-mail: [email protected] Represent ing the Internat ional CardiOncology Society (ICOS)

Thecontent of these European Society of Cardiology (ESC) Guidelines hasbeen published for personal and educational use only. No commercial use isauthorized.No part of the ESC

Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of awritten request to Oxford Uni-

versity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]).

Disclaimer . The ESC Guidelines represent the viewsof the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at

the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-

mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-

aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or

therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and

accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor

do the ESC Guidelines exempt health professionals from takinginto full and careful consideration the relevant official updated recommendations or guidelines issued by thecompetent

public health authorities, in order to manage each patient’s case in light of the scientifically accepted datapursuant to their respective ethical and professional obligations. It isalso the

health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

& The European Society of Cardiology 2016. All rights reserved. For permissions please email: [email protected].

European Heart Journal

doi:10.1093/eurheartj/ehw211

European Heart Journal Advance Access published August 26, 2016

by guest on September 23, 2016

http://eurheartj.oxfordjournals.org/D

ownloaded from

Zamorano, et al. Eur Heart J, 2016

Plana, et al. JASE, 2014

Prevention / Treatment• ACE inhibitors or Beta blockers are recommended after

detection of cardiotoxicity by LVEF decline– Promising data for ACEI’s, B-Bl’s (emerging for statins)

– However, large randomized / prospective trials needed• Optimal timing of intervention? What detection method is best?

• Primordial prevention? Revisit use of Dexrazoxane?

• Duration of therapy?

• Intra-class differences among beta blockers, ACE inhibitors, etc.?

• Studies needed to evaluate exercise as intervention

• Future Steps– Genetic profiling to characterize risk

• Personalized cardioprotection?

The Goal of Cardio-Oncology

CANCER OUTCOMES

CVOUTCOMES

Cancer

Biology

&

Disease

Cancer Therapy

Past &

Present


Disease

Cardio - Oncology

Thank You

Cardio-Oncology Toxicities and Management · 4/21/2017 · III. Cancer therapies can increase CV...

Documents

Transcript of Cardio-Oncology Toxicities and Management · 4/21/2017 · III. Cancer therapies can increase CV...