Cardio-Oncology
June 12, 2014
Daniel J Lenihan, MD
Professor, Division of Cardiovascular Medicine
Director, Clinical Research
Cardio-Oncology Program
Vanderbilt University
Presenter Disclosure Information
Dr Enrique Lopez Innovation and Humanitarian Award
Presentation
Tampa, 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 noncancer
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 Drugs
Medical News Today
Treatment 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
Number of PUBMED articles on Cardio-Oncology
400
350
300
250
200
150
100
50
0
1971
2014
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
Tumor Tissues
Normal Tissues
(VEGF upregulated)
(VEGF constitutively expressed)
Hypertensive remodeling
Microvascular rarefaction
Cardiomyopathy (sunitinib and sorafenib)
Lung cancer (bevacizumab)
Inhibition of tumor growth, tumor cavitation
Hepatocellular carcinoma (sorafenib)
Tumor necrosis
1
2
3
Microcirculation: 1. normal arteriole, 2. functional rarefaction
(endothelial dysfunction,vasoconstriction), 3. anatomic rarefaction
Renal cell carcinoma (sunitinib)
Tumor shrinkage, tumor cell necrosis
Thrombotic microangiopathy
Glomerulopathy / glomerulonephritis
Proteinuria
Hypertensive nephropathy
Colorectal cancer (bevacizumab)
Deceleration of tumor growth
efficient chemotherapy delivery
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
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
Figure Legend:
Incidence of Cardiovascular Toxicity by Type
The 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.
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
Figure Legend:
The Stanford Monitoring Algorithm for Targeted Therapies
Cardiovascular 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.
Date of download:
5/31/2014
Copyright © The American College of Cardiology.
All rights reserved.
Newer
Chemotherapy
with Anti-VEGF
properties
What about the detection of cardiac
damage during cancer treatment?
Anthracycline Cardiotoxicity : Effects of Different Drugs,
Scheduling, and Cardiac Protection with Dexrazoxane
15
Epirubicin 1000 mg/m2
4
Epirubicin < 900 mg/m2
12
Dauno 1000 mg/m2
1.5
Dauno 500 mg/m2
Doxo (400-499 mg/m2) + Dexrazoxane
1
Doxo low dose weekly > 600 mg/m2
5.4
Doxo bolus > 550 mg/m2
10
Doxo 1000 mg/m2
20
Doxo 500 mg/m2
7
0
5
10
15
CHF (%)
Hensley ML et al J Clin Oncol 1999; 17(10):3333-3355
20
25
How often is cardiac toxicity detected by Echo and MUGA
After Four Cycles of AC Chemotherapy?
(NCI-CTC Version 2)
Abbreviations: LVEF, left ventricular ejection fraction; NCI-CTC, National Cancer Institute Common Toxicity
Criteria; AC, doxorubicin and cyclophosphamide; MUGA, multiple-gated aquisition; ECHO,
echocardiogram.
Perez EA et al. J Clin Onco. 2004:22, 3700-3704
Heart Failure definitely occurs
over time
Bowles,
Erin et al
JNCI 2012
p1293
The real world incidence of HF with chemotherapy
is higher than expected
Chen J, et al
JACC 2012
23% increased rate of developing HF compared to age matched controls
In the case of
HER2+ breast
cancer, treatment
clearly benefitted
the disease but
came at a cost
Slamon D et al; NEJM
2011:365:1273-83
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
Troponin I is valuable in detecting Cardiotoxicity
Cardinale et al. Circ. 2004;109:2749-2754
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
The test characteristics of BNP in detecting cardiotoxicity
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)
102
30 (7,65)
84 (75, 91)
17 (4, 41)
92 (84, 97)
LVEF<50% or
change >15%
All data is % with 95 % CI
6 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, MD
Professor, Division of Cardiovascular Medicine
Vanderbilt University
CCOP Annual Meeting 2010
PREDICT Study
Total
Accrual:
597
patients
PREDICT:
Demographics
and risk of
cardiotoxicity
Abstract 9624
Univariate Analysis of Cardiac Biomarkers (Table 2)
PREDICT
study:
Utility of
Biomarkers
Abstract 9644
Reduced Multivariate Analysis (Table 3)
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
The effect of time for initiation of HF
therapy and the percent of patients who
improve
Responders (%)
100
80
64%
60
28%
40
7%
20
0%
0%
0%
0%
0
1-2
2-4
4-6
6-8
8-10
10-12
(n=75)
(n=35)
(n=20)
(n=12)
(n=8)
(n=7)
>12 months
(n=44)
D Cardinale, et al. JACC 2010, jan 26.
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
How Accurate is Clinician Reporting
of Chemotherapy Adverse Effects?
Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3485-3490
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
Data expressed as mean values.
Kalay et al. JACC. Dec 2006. 48:2258-62
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
Carfilzomib Exposure
Baseline
With Carfilzomib
Recovery
Parameter
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
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
NYHA Class
LVEF
BNP (pg/mL)
Troponin
Worst NYHA Class
I
50 – 55
N/A
N/A
III
I
60 – 65
79†
N/A
II
I
55
594*†
< 0.05
III
I
55-60
N/A
N/A
III
I
58
N/A
N/A
III
I
68
N/A
N/A
III
Nadir of LVEF (%)
25 – 30
47
50
< 20
25 – 30
44
Highest BNP or NTproBNP† (pg/mL)
1837†
170†
2988†
2026
640
744
Highest Troponin
< 0.05
< 0.05
< 0.05
2.5
0.01
< 0.05
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
Lowest BNP (pg/ml)
40
65
50
104
55
2032
50
39
48
470
68
110
HF, LV
dysfunction
Mild LV and RV
dysfunction
HF
ACS, HF, QTc,
LV dysfunction
HF, LV
dysfunction
HF, LV
dysfunction
Summary of Cardiac Events
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 Society
An 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
A Paradigm for Cardiology Oncology Cooperation
Kouri M et al. Circulation 2012
ICOS=
A public, private, patient, provider,
regulatory, governmental PARTNERSHIP
Come to Nashville (Music City
USA) sometime!