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Cardio-Oncology
June 12, 2014
Daniel J Lenihan, MDProfessor, Division of Cardiovascular MedicineDirector, Clinical ResearchCardio-Oncology ProgramVanderbilt University
Presenter Disclosure InformationDr Enrique Lopez Innovation and Humanitarian Award
PresentationTampa, FL 6.12.14
•I will not discuss off label use or investigational use in my presentation.
•I have financial relationships to disclose:
–Research support from: Acorda, Inc; Millenium, Inc
–Consultant (modest): AstraZeneca, Roche, Onyx, Oncomed
Why discuss cardiac disease and cancer? Let’s consider…
• These are by far the two most common disease conditions in the developed world
• Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it
• Cancer therapy is more effective than ever before at treating cancer, but has a price..
• Therapeutic choices for both cardiology and oncology have significant overlap
In any patient, heart disease and cancer are likely to overlap
Driver BMJ 2008:337:p. 2467
Why discuss cardiac disease and cancer? Let’s consider…
• These are by far the two most common disease conditions in the developing world
• Cardiac disease may pre-exist cancer therapy or may be caused or exacerbated by it
• Cancer therapy is more effective than ever before at treating cancer, but has a price..
• Therapeutic choices for both cardiology and oncology have significant overlap
In breast cancer patients, heart disease has
a great impact….
JAMA. 2001;285:885-892
Even in early stage breast cancer, cardiac disease does matter…
• Patients with early stage breast cancer are 4x more likely to die of non-cancer conditions (up to 45 % are cardiac in nature)
Hanrahan, et al. JCO 25: 4952-4960, 2007
Why discuss cardiac disease and cancer? Let’s consider…
• These are by far the two most common disease conditions in the world
• Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it
• Cancer therapy is more effective than ever before at treating cancer, but has a price..
• Therapeutic choices for both cardiology and oncology have significant overlap
Increased Risk Of Fatal Side Effects From 3 'Targeted' Cancer DrugsMedical News TodayTreatment with three relatively new "targeted" cancer drugs has been linked to a slightly elevated chance of fatal side effects, according to a new analysis led by scientists at Dana-Farber Cancer Institute.http://www.medicalnewstoday.com/releases/241256.php
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Chart TitleNumber of PUBMED articles on Cardio-Oncology
19712014
Why discuss cardiac disease and cancer? Let’s consider…
• These are by far the two most common disease conditions in the world
• Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it
• Cancer therapy is more effective than ever before at treating cancer, but has a price..
• Therapeutic choices for both cardiology and oncology have significant overlap
Anti-VEGF Therapy can decrease blood flow resulting in cancer control
Willitt, JCO 2006
Therapy for both Oncology and Cardiology are intimately intertwined at the vascular level
Kirchmair R. Circulation. 2005 May 24;111(20):2662-70.
Systemic Effects of Anti-VEGF Therapy
Normal Tissues
(VEGF constitutively expressed)
Tumor Tissues
(VEGF upregulated)
Lung cancer (bevacizumab)Inhibition of tumor growth, tumor cavitation
Hepatocellular carcinoma (sorafenib)Tumor necrosis
Renal cell carcinoma (sunitinib)Tumor shrinkage, tumor cell necrosis
Colorectal cancer (bevacizumab)Deceleration of tumor growth
efficient chemotherapy delivery
1 2 3
Hypertensive remodelingMicrovascular rarefactionCardiomyopathy (sunitinib and sorafenib)
Microcirculation: 1. normal arteriole, 2. functional rarefaction(endothelial dysfunction,vasoconstriction), 3. anatomic rarefaction
Thrombotic microangiopathyGlomerulopathy / glomerulonephritisProteinuriaHypertensive nephropathy
Vaklavos, et al Oncologist 2010, p 130.
Sunitinib, a novel oral chemotherapeutic agent with anti-VEGF properties, is associated with
hypertension and heart failure
Khakoo, et al, 2008; 112:2500-8
Definition of a “Kinase Inhibitor”:
• A drug that interferes with cell communication and growth and is sometimes used to treat cancer
Date of download: 5/31/2014
Copyright © The American College of Cardiology. All rights reserved.
From: The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients
JCHF. 2013;1(1):72-78. doi:10.1016/j.jchf.2012.09.001
Incidence of Cardiovascular Toxicity by TypeThe incidence of cardiovascular toxicity varied by type of toxicity and by chemotherapy agent received. Many patients received multiple therapies in succession and are included only once in “All Patients.” CV = cardiovascular; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal B-type natriuretic peptide.
Figure Legend:
Date of download: 5/31/2014
Copyright © The American College of Cardiology. All rights reserved.
From: The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients
JCHF. 2013;1(1):72-78. doi:10.1016/j.jchf.2012.09.001
The Stanford Monitoring Algorithm for Targeted TherapiesCardiovascular monitoring algorithm for patients with renal cell carcinoma receiving targeted chemotherapy. BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; other abbreviations as in Figure 1.
Figure Legend:
Newer Chemotherapy with Anti-VEGF
properties
What about the detection of cardiac damage during cancer treatment?
7
10
5.4
1
1.5
12
4
15
20
0 5 10 15 20 25
Doxo 500 mg/m2
Doxo 1000 mg/m2
Doxo bolus > 550 mg/m2
Doxo low dose weekly > 600 mg/m2
Doxo (400-499 mg/m2) + Dexrazoxane
Dauno 500 mg/m2
Dauno 1000 mg/m2
Epirubicin < 900 mg/m2
Epirubicin 1000 mg/m2
Anthracycline Cardiotoxicity : Effects of Different Drugs, Scheduling, and Cardiac
Protection with Dexrazoxane
CHF (%)
Hensley ML et al J Clin Oncol 1999; 17(10):3333-3355
How often is cardiac toxicity detected by Echo and MUGA After Four Cycles of AC Chemotherapy?
(NCI-CTC Version 2)
Perez EA et al. J Clin Onco. 2004:22, 3700-3704
Abbreviations: LVEF, left ventricular ejection fraction; NCI-CTC, National Cancer Institute Common Toxicity Criteria; AC, doxorubicin and cyclophosphamide; MUGA, multiple-gated aquisition; ECHO, echocardiogram.
Bowles, Erin et alJNCI 2012 p1293
Heart Failure definitely occurs over time
The real world incidence of HF with chemotherapy is higher than expected
23% increased rate of developing HF compared to age matched controls
Chen J, et alJACC 2012
Slamon D et al; NEJM 2011:365:1273-83
In the case of HER2+ breast cancer, treatment clearly benefitted the disease but came at a cost
Principles for the Management of Cardiac Disease that provides benefit for Cancer Patients
• Biomarkers used in Cardiology are also used in Oncology
• Cardiac specific therapy allows for more effective cancer treatment
Cardinale et al. Circ. 2004;109:2749-2754
Troponin I is valuable in detecting Cardiotoxicity
BNP guided therapy for cardiac disease (eg. HF) is very useful and appears to change the
outcome….
Kaplan-Meier curves examining time to first event of the primary clinical endpoint showed a clear divergence between the groups by 6 months (p=0·034) and remained significant when reanalysed to include only heart-failure events or death (p=0·049).
Troughton et al. Lancet. 2000: 355, 1126-30
In a pilot study of 109 patients undergoing anthracycline based therapy…
Comparison of LV Ejection Fraction at Baseline and Completion*
Shaded box: Patients with Cardiac Events
* Only 3/10 had LVEF criteria for toxicity
Test n Sensitivity Specificity Positive Predictive Value Negative Predictive Value
1 BNP >100 109 100 (72,100) 59 (49, 69) 22 (11, 35) 100 (94, 100)
1 BNP > 150 109 100 (72,100) 81 (71, 88) 37 (20, 56) 100 (95, 100)
1 BNP > 200 109 91 (59, 100) 90 (82, 95) 50 (27, 73) 99 (94, 100)
LVEF<50% or
change >15%102 30 (7,65) 84 (75, 91) 17 (4, 41) 92 (84, 97)
The test characteristics of BNP in detecting cardiotoxicity
All data is % with 95 % CI6 of 9 patients with elevated BNP greater than 200 who did not develop an event were on cardioprotective medications throughout chemotherapy
Elevated pre-chemo BNP predicted toxicity in patients receiving anthracyclines
Lenihan, et al: JCO 08, abstract 18S
Factors associated with having a cardiac event during the study period
Normal BNP < 100 pg/ml
PREDICT Study: A multicenter study in Patients undergoing
anthRacycline-based chemotherapy to assess the Effectiveness of using biomarkers to Detect and Identify Cardiotoxicity and describe Treatment
Daniel J Lenihan, MDProfessor, Division of Cardiovascular MedicineVanderbilt UniversityCCOP Annual Meeting 2010
PREDICT Study
TotalAccrual:597 patients
PREDICT: Demographics
and risk of cardiotoxicityAbstract 9624
PREDICT study:
Utility of Biomarkers
Abstract 9644
Reduced Multivariate Analysis (Table 3)
Univariate Analysis of Cardiac Biomarkers (Table 2)
Diagnostic Performance of Biomarkers (Table 4)
Out of 51 patients at Vandy, 7 have confirmed cardiac events.
Cardiac Biomarker Elevation from Baseline and Cardiac Events
0%0%0%
1-2
7%
28%
64%
0
20
40
60
80
100
2-4 4-6 6-8 8-10 10-12 >12
0%
(n=75) (n=35) (n=20) (n=12) (n=8) (n=7) (n=44)
months
Res
pon
der
s (%
)
D Cardinale, et al. JACC 2010, jan 26.
The effect of time for initiation of HF therapy and the percent of patients who
improve
In regards to Ischemic insults, we have a paradigm
Kloner et al, Circ 2001; p2981
Classic Triad of Heart Failure
• Dyspnea
• Lower extremity edema
• Fatigue
Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3485-3490
How Accurate is Clinician Reporting of Chemotherapy Adverse Effects?
How Accurate is Clinician Reporting of Chemotherapy Adverse Effects?
• Comparative study of patient reporting of eight symptoms with physician reporting of same symptoms
• Physician Sensitivity=47%
• Physician Specificity=68%
JCO 2004 22:3485-3490
Principles for the Management of Cardiac Disease provide Benefit to Cancer Patients
• Biomarkers used in Cardiology are also used in Oncology
• Cardiac specific therapy allows for more effective cancer treatment
There is significant reversibility of LV dysfunction with trastuzumab-related cardiac
toxicity
Ewer, et al Journ of Clinical Oncology 2005,23;p 7820-6.
• What about Prevention? Ben Franklin thought it was a good idea…
ACE Inhibition appears quite important in preventing heart failure
Cardinale D et al. Circulation. 2006;114:2474-2481
Carvedilol appears protective during adriamycin based chemotherapy
Kalay et al. JACC. Dec 2006. 48:2258-62Data expressed as mean values.
Statin therapy prior to and during chemotherapy was protective
JACC 2012, p 2384
Prevention of Cardiotoxicity is possible
Bosch, X et al, JACC 2013, p 2355
Are there things on the cancer therapy horizon that could be concerning for
cardiomyopathy?
There is a balance between protein synthesis and degradation
Monte S. Willis, M.D., Ph.D., and Cam Patterson, M.D., M.B.A. NEJM 2013;368:455-64.
Dick,LR and Flemming,PE Drug Discovery Today ;15 (5/6) March 2010
A report of 6 cases describing carfilzomib related cardiac dysfunction and the patterns of cardiotoxicity
Parameter Case 1 Case 2 Case 3 Case 4 Case 5 Case 6Carfilzomib Exposure Dosing (mg/m2) 20x1 then 27 27 20 20 27 20x1 then 27
Duration of Therapy (mos)
3 5 6 1 3 3
Total Cumulative Dose (mg/m2)
405 903
972 141
540
444
Baseline NYHA Class I I I I I I
LVEF 50 – 55 60 – 65 55 55-60 58 68
BNP (pg/mL) N/A 79† 594*† N/A N/A N/A
Troponin N/A N/A < 0.05 N/A N/A N/AWith Carfilzomib Worst NYHA Class III II III III III III
Nadir of LVEF (%) 25 – 30 47 50 < 20 25 – 30 44
Highest BNP or NT-proBNP† (pg/mL)
1837† 170† 2988† 2026 640 744
Highest Troponin < 0.05 < 0.05 < 0.05 2.5 0.01 < 0.05
Recovery Carfilzomib Discontinuation
Permanent Temporary Permanent Permanent Permanent Temporary
Heart Failure Therapy Initiated
Beta-blocker; ACE-I; loop diuretic
None Beta-blocker; ARB
Beta-blocker; ACE-I
Beta-blocker; aldosterone antagonist
Beta-blocker; aldosterone antagonist; loop diuretic
Best NYHA Class I II III I II II
Highest LVEF 40 50 55 50 48 68
Lowest BNP (pg/ml) 65 104 2032 39 470 110
Summary of Cardiac Events HF, LV dysfunction
Mild LV and RV dysfunction
HF ACS, HF, QTc, LV dysfunction
HF, LV dysfunction
HF, LV dysfunction
A
B
Cardio-Oncology
• The demographic profile for cancer patients being treated with chemotherapy is identical to typical cardiac patients
• Optimal management of cardiac disease includes prevention, early detection and careful medication choices
• Close collaboration between cardiology and oncology is feasible and essential
• Ongoing research will further define the best collaborative practice
Monitoring Cardiac Disease in Survivors
Lenihan, D JCO 2012
www.icosna.org
ICOS is:
• A collection of interested providers focused on improving cardiac health in cancer patients
• A mix of academic, practice, governmental, regulatory, and industry professionals
• Committed to our patients wherever they are
The International CardiOncology SocietyAn Update
• Exactly what does this society mean?• How do we do things?• What are our goals?• How do we achieve them?• Is there really a future for this?
We do things in many ways:• Day to day improvement in our practices• Monthly webinars available to all• Periodic presentations at major meetings• Annual ICOS congresses• Development of current “Best Practice”• Data review for ongoing early phase and late phase
clinical trials• Ongoing participation in major professional society
efforts• Ongoing individual and multicenter research• Consistent involvement with regulatory agencies in many
countries
ICOS goals• Research
– Engage large databases– Cardiac safety endpoint
adjudication– Hypothesis testing
research
• Advocacy• Patients/families• Providers
• Education– Provider case review– Patient directed – Professional meetings– Industry/regulatory webinars– Trainee organization
• Be a Resource• Up to Date information• Identify Goals for the future• Provide innovation• Be an example of
collaboration
Kouri M et al. Circulation 2012
A Paradigm for Cardiology Oncology Cooperation
ICOS=
A public, private, patient, provider, regulatory, governmental PARTNERSHIP
Come to Nashville (Music City USA) sometime!