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
The Basis for Cardio-OncologyWhy Cardio-Oncology?
Armenian, et al. JCO, 2016
Incidence of CV Disease by Cancer TypeKaiser Permanente (SC)
>36K adult cancer survivors (≥2 years); >73K controls
The Basis for Cardio-OncologyWhy Cardio-Oncology?
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
Cardiovascular Risk Factors &
Disease
Treatment-related‘Cardiotoxicity’
• Acute toxicity can affect access to life saving drugs• Chronic toxicity can affect survival, morbidity and QOL
The Basis for Cardio-OncologyWhat is Cardio-Oncology?
Acute Toxicity
50’s yo woman receiving Carfilozimib for multiple myeloma
A few days later …
Cancer
Biology
&
Disease
Cancer Therapy
Past &
Present
Cardiovascular Risk Factors &
DiseaseCV and Cancer links
• Cancer – CVD relationship not well characterized• Incident CVD and/or RF’s can limit access to cancer therapies
The Basis for Cardio-OncologyWhat is Cardio-Oncology?
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
Khouri, et al. Circulation 2012
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
Cardinale, et al. Circulation 2004
(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
Khouri, et al. Circulation 2012
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
Khouri, et al. Circulation 2012
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
Cardinale, et al. Circulation 2006
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
Cardiovascular Risk Factors &
Disease
Cardio - Oncology
Thank You