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Cardio-Oncology
Duke Heart Failure Symposium
October 15, 2016
Michel G. Khouri, MD
Assistant Professor of Medicine
Divisio...
Disclosures
• I do not intend to discuss an off-label use of a product during this activity.
• I have not had any relevant...
Outline
I. Cardiovascular disease & Cancer Therapy
a) The basis for Cardio-Oncology
b) Treatment-related cardiovascular di...
THE BASIS FOR CARDIO-ONCOLOGY
Cardiovascular Disease & Cancer Therapy
The Basis for Cardio-Oncology
What is Cardio-Oncology?
Cancer
Biology
&
Disease
Cancer Therapy
Past &
Present
Cardiovascul...
Cancer
Biology
&
Disease
Cancer Therapy
Past &
Present
Cardiovascular Risk Factors &
Disease
Treatment-related
‘Cardiotoxi...
Cancer
Biology
&
Disease
Cancer Therapy
Past &
Present
Cardiovascular Risk Factors &
Disease
CV and Cancer links
• Cancer ...
I. Survival gains in cancer and CV disease
in recent decades
II. Cancer and CV disease pose competing
risks:
i. Cancer sur...
CANCER TREATMENT-RELATED CVD
(‘CARDIOTOXICITY’)
Cardiovascular Disease & Cancer Therapy
Cancer Therapies
Adapted from Huang, et al. Trends in Pharmacological Sciences, 2014
Cytotoxic Therapies Targeted Therapies
Spectrum of Cardiotoxicity
Adapted from Lenneman C, et al. Circ Res, 2016
Spectrum of Cardiotoxicity
Anthracyclines
Cardiomyopathy
Heart Failure
Fluoropyrimidines
Myocardial ischemia
VT / VF / SCD...
Mechanisms of Cardiotoxicity
On-target toxicity
Cytotoxic Therapies Targeted Therapies
Force, et al. Circulation, 2013 Bel...
Mechanisms of Cardiotoxicity
Off-target toxicity
Promiscuous
Selectivity for intended target
Broad Target Selectivity for ...
Radiation Therapy
Coronary Events in Breast Cancer
Darby, et al. NEJM 2013
1958 - 2001
50 year old
300 cGy mean dose
No ri...
Chemoradiation Therapy
Cardiovascular disease in Hodgkins Lymphoma
Van Leeuwen, et al. JAMA Int Med 2015
Mediastinal Radiation Therapy
Effects on Autonomic Function?
Groarke, et al. JACC 2015
Mediastinal Radiation Therapy
Autonomic Dysfunction
Groarke, et al. JACC 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 ...
INTEGRATED CONCEPT OF CVD & CANCER
Cardiovascular Disease & Cancer Therapy
Diagnostic testing
Emerging Biomarkers
 Biochemical markers
 Strain echo (tissue Doppler/speckle tracking)
 Cardiac mag...
The Goal of Cardio-Oncology
CANCER
OUTCOMES
CV
OUTCOMES
Cancer
Biology
&
Disease
Cancer Therapy
Past &
Present
Cardiovascu...
THE FUTURE OF CARDIO-ONCOLOGY
Cardiovascular Disease & Cancer Therapy
Current Guidelines in Cardio-OncologyESC CPG PO SIT ION PAPER
2016 ESC Position Paper on cancer treatments
and cardiovascu...
Challenges in Cardio-Oncology
Future Investigational Needs
• Most current data regarding toxicities derive from cancer cli...
Potential of Cardio-Oncology
Integrated in Cardiology Novel Investigational Platform
Bellinger, et al. Circulation, 2015
Cardio-oncology clinic
• Middle aged woman with multiple myeloma s/p
Immunmodulator/Steroids/Proteosome inhibitor (Carfilo...
Thank You
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Cardio-Oncology

Michel Khouri, MD
Duke University Medical Center

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Cardio-Oncology

  1. 1. Cardio-Oncology Duke Heart Failure Symposium October 15, 2016 Michel G. Khouri, MD Assistant Professor of Medicine Division of Cardiology Duke University Medical Center
  2. 2. 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)
  3. 3. Outline I. Cardiovascular disease & Cancer Therapy a) 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. The future of Cardio-Oncology a) Aiming to optimize outcomes in our patients i. Future investigations ii. Role in cardiology clinical practice and as a research platform
  4. 4. THE BASIS FOR CARDIO-ONCOLOGY Cardiovascular Disease & Cancer Therapy
  5. 5. The Basis for Cardio-Oncology What is Cardio-Oncology? Cancer Biology & Disease Cancer Therapy Past & Present Cardiovascular Risk Factors & Disease
  6. 6. 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-Oncology What is Cardio-Oncology?
  7. 7. Cancer Biology & Disease Cancer Therapy Past & Present Cardiovascular Risk Factors & Disease CV 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-Oncology What is Cardio-Oncology?
  8. 8. 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 risk I. Toxicities of conventional cancer treatments remain II. New ‘targeted’ therapies are being developed rapidly, many of which have recognized or unrecognized cardiovascular toxicities The Basis for Cardio-Oncology Why Cardio-Oncology? Driver, et al. BMJ, 2008
  9. 9. CANCER TREATMENT-RELATED CVD (‘CARDIOTOXICITY’) Cardiovascular Disease & Cancer Therapy
  10. 10. Cancer Therapies Adapted from Huang, et al. Trends in Pharmacological Sciences, 2014 Cytotoxic Therapies Targeted Therapies
  11. 11. Spectrum of Cardiotoxicity Adapted from Lenneman C, et al. Circ Res, 2016
  12. 12. Spectrum of Cardiotoxicity Anthracyclines Cardiomyopathy Heart Failure Fluoropyrimidines Myocardial ischemia VT / VF / SCD Androgen Deprivation Therapy (ADT) Metabolic syndrome Diabetes CAD VTE ATE ↑ CV Events (pre-existing CVD) Radiation CAD Valvular disease Pericardial disease Restrictive CMP MT Inhibitors Arrhythmias Alkylating Agents ATE Myocardial ischemia Cytotoxic Therapies Hormonal Therapies Conventional Therapies Trastuzumab Cardiomyopathy Heart Failure BMT CAD Hypertension Dyslipidemia Cardiomyopathy VEGF Signaling Pathway (VSP) Inhibitors Hypertension Cardiomyopathy ATE Anti-BCR-ABL TKIs Pericardial effusion ATE VTE Pulmonary HTN PAD Proteosome Inhibitors Hypertension Cardiomyopathy Arrhythmia ATE Immunomodulators ATE VTE HDAC Inhibitors ATE VTE Signaling Pathways Other Targeted Novel (Targeted) Therapies mTOR Inhibitors Hypertension Myocardial Ischemia
  13. 13. Mechanisms of Cardiotoxicity On-target toxicity Cytotoxic Therapies Targeted Therapies Force, et al. Circulation, 2013 Bellinger, et al. Circulation, 2015
  14. 14. Mechanisms of Cardiotoxicity Off-target toxicity Promiscuous Selectivity for intended target Broad Target Selectivity for M Approved Kinase Inhibi Unsupervised against 300 kinases Low High % inhibition Selectivity for intended target Promiscuous Adapted from Uitdehaag J, et al. PLoS One, 2014 Adapted from Li, et al. JACC, 2015 Opening"the"Box:"Rela) ve"Potency"and" Specificity"of"TKIs"
  15. 15. Radiation Therapy Coronary Events in Breast Cancer Darby, et al. NEJM 2013 1958 - 2001 50 year old 300 cGy mean dose No risk factors Death from IHD by age 80 AR: 1.9% increased to 2.4% 1 or more risk factors Death from IHD by age 80 AR: 3.4% increased to 4.1%
  16. 16. Chemoradiation Therapy Cardiovascular disease in Hodgkins Lymphoma Van Leeuwen, et al. JAMA Int Med 2015
  17. 17. Mediastinal Radiation Therapy Effects on Autonomic Function? Groarke, et al. JACC 2015
  18. 18. Mediastinal Radiation Therapy Autonomic Dysfunction Groarke, et al. JACC 2015
  19. 19. TREATMENT-INDEPENDENT METABOLIC ADVERSE EFFECTS Cardiovascular Disease & Cancer Therapy
  20. 20. ↓ 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
  21. 21. INTEGRATED CONCEPT OF CVD & CANCER Cardiovascular Disease & Cancer Therapy
  22. 22. 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 prevention Treatment Khouri, et al. Circulation 2012
  23. 23. The Goal of Cardio-Oncology CANCER OUTCOMES CV OUTCOMES Cancer Biology & Disease Cancer Therapy Past & Present Cardiovascular Risk Factors & Disease Cardio - Oncology
  24. 24. THE FUTURE OF CARDIO-ONCOLOGY Cardiovascular Disease & Cancer Therapy
  25. 25. Current Guidelines in Cardio-OncologyESC CPG PO SIT ION PAPER 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Authors/Task Force Members: Jose Luis Zamorano* (Chairperson) (Spain), Patrizio Lancellotti* (Co-Chairperson) (Belgium), Daniel Rodriguez Mun˜oz (Spain), Victor Aboyans (France), Riccardo Asteggiano (Italy), Maurizio Galderisi (Italy), Gilbert 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 (Switzerland) ESC Committee for Practice Guidelines (CPG): Jose Luis Zamorano (Chairperson) (Spain), Victor Aboyans (France), Stephan Achenbach (Germany), Stefan Agewall (Nor way), Lina Badimon (Spain), Gonzalo Baro´ n-Esquivias (Spain), Helmut Baumgartner (Germany), Jeroen J. Bax (The Netherlands), He´ctor Bueno (Spain), Scipione Carerj (Italy), Veronica Dean (France), Çetin Erol (Turkey), Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Paulus Kirchhof (UK/Germany), Philippe Kolh (Belgium), Patrizio Lancellotti (Belgium), Gregory Y. H. Lip (UK), Petros Nihoyannopoulos (UK), Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Marco Roffi (Switzerland), Adam Torbicki (Poland), Anto´ nio Vaz Carneiro (Portugal), and Stephan W indecker (Switzerland) Document Reviewers: Stephan Achenbach (CPG Review Coordinat or) (Germany), Giorgio Minotti (CPG Review Coordinator) (Italy), Stefan Agewall (Norway), Lina Badimon (Spain), He´ctor Bueno (Spain), Daniela Cardinale (Italy), Scipione Carerj (Italy), Giuseppe Curigliano (Italy), Evandro de Azambuja (Belgium), Susan Dent (Canada), European Heart Journal doi:10.1093/eurheartj/ehw211 European Heart Journal Advance Access published August 26, 2016 byguestonSeptember23,2http://eurheartj.oxfordjournals.org/Downloadedfrom Zamorano, et al. Eur Heart J, 2016 Plana, et al. JASE, 2014
  26. 26. Challenges in Cardio-Oncology Future Investigational Needs • Most current data regarding toxicities derive from cancer clinical trials that excluded patients with history of CVD and metabolic disorders – What is ‘real world’ cardiotoxicity? • Essential to distinguish between treatment-related CVD and treatment-independent metabolic adverse effects – Standard definitions and CV endpoints – Robust, consistent monitoring – Centralized adjudication of endpoints – Core labs for precise surrogate biomarker analyses – Appropriate control groups
  27. 27. Potential of Cardio-Oncology Integrated in Cardiology Novel Investigational Platform Bellinger, et al. Circulation, 2015
  28. 28. Cardio-oncology clinic • Middle aged woman with multiple myeloma s/p Immunmodulator/Steroids/Proteosome inhibitor (Carfilozimib most recently) with episodic DOE, orthopnea, EF 40%, GLS -12%. Presents for cardiac evaluation prior to SCT next week. – Is she okay to get SCT? • Middle aged man with myelodysplastic syndrome s/p multiple rounds of chemotherapy, s/p multiple pRBC transfusions for symptomatic anemia. TTE prior to SCT shows moderate-severe AS/AR. – Can AoV disease be treated and he still get SCT?
  29. 29. Thank You

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