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 Lenihan, MD
MDAnderson Cancer Center
CCOP Annual Meeting 2009
Daniel J. Lenihan, MD
MD Anderson Cancer Center
Houston, TX
I will discuss off label use and/or investigational use of certain
medication.
Research Support: Biosite, Inc.
Consultant: Genentech, Bayer/Onyx
Speakers bureau: None
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
These are by far the two most common disease
conditions in the developed world….
Men
Women
Heart
Disease
No Heart
Disease
Heart
Disease
No Heart
Disease
•Lifetime risk of developing coronary heart disease at age 40 years (U.S.)
Women
Men
Cancer
Cancer
No Cancer
No Cancer
•Lifetime risk of developing cancer (U.S.)
American Cancer Society. Cancer facts & figures 2007,
Lancet 1999;353:89-92.
Five-year Relative Survival (%)* during Three Time
Periods By Cancer Site
•
Site
All sites
1975-1977
50
1984-1986
53
1996-2002
66
•
Breast (female)
75
79
89
•
Colon
51
59
65
•
Leukemia
35
42
49
•
Lung and bronchus
13
13
16
•
Melanoma
82
86
92
•
Non-Hodgkin lymphoma
48
53
63
•
Ovary
37
40
45
•
Pancreas
2
3
5
•
Prostate
69
76
100
•
Rectum
49
57
66
•
Urinary bladder
73
78
82
*5-year relative survival rates based on follow up of patients through 2003. †Recent changes in classification of ovarian cancer
have affected 1996-2002 survival rates.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of
Cancer Control and Population Sciences, National Cancer Institute, 2006.
†
In any patient, heart disease and cancer are likely to overlap
Driver BMJ 2008:337:a2467
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
Baseline Characteristics of Breast Cancer Cohort
and Chemotherapy Subgroups
Doyle JJ et al. J Clin Oncol. 2005 Dec 1;23(34):8597-605.
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
www.msnbc.msn.com. Aug 2005.
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
Anti-VEGF Therapy can decrease blood
flow resulting in cancer control
Willitt, JCO 2006
You are only as good as your endothelium (or your
small vessels…)
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
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
Classic Triad of Heart Failure
• Dyspnea
• Lower extremity edema
• Fatigue
Difficulties in diagnosing “heart
failure”
• Can be a wide range of presentations
• Many of the symptoms of heart failure
overlap with other disease states such as
COPD, Obesity, Nephrotic Syndrome, Drug
induced Edema, Cirrhosis, Sleep Apnea,
and Cancer
• How to effectively and efficiently
differentiate between these entities?
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
Principles for the Management of Cardiac
Disease Benefit 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.
Recovery of LV dysfunction with standard
HF therapy
Jensen, et al. Annals of Oncology. 2002. 13:499-709.
Significant Improvement in EF After Optimal HF Therapy
100
Percent of Patients
100
75
55
50
25
14
0
LVEF
Decrease
After Chemo
HF with
Normal EF
EF Improved
After Optimal
Treatment
Lenihan et al, HFSA 2008
Carvedilol appears protective during adriamycin based
chemotherapy
Data expressed as mean values.
Kalay et al. JACC. Dec 2006. 48:2258-62
ACE Inhibition appears quite important
for prevention of toxicity
Cardinale D et al. Circulation. 2006;114:2474-2481
Troponin I is valuable in detecting Cardiotoxicity
Cardinale et al. Circ. 2004;109:2749-2754
BNP, a marker of volume overload, may also be an
effective marker of subsequent myocardial
damage
No HF
Developed HF
Okumura et. al. Acta Haematologica. 2000. 104:158-163.
How do we best detect cardiotoxicity by Echo?
Sa = longitudinal (annular) systolic contraction, E = transmitral E wave velocity, A = transmitral A wave velocity,
Ea = longitudinal (annular) early diastolic relaxation velocity. *P < 0.05 compared to baseline. **P < 0.01 compared to baseline.
***P < 0.001 compared to baseline. ****P < 0.0001 compared to baseline. #P < 0.05 compared to low dose.
Belham et al. Eur J Heart Failure. 2006: Oct 23 epub.
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
Detecting Cardiotoxicity
Summary of current methods
• The guidelines* at present suggest a
baseline EF measurement and a repeat study
at some time interval (keep in mind that more than 1/3 of
patients with heart failure have a normal EF and their prognosis is similar to
those with systolic dysfunction)
• Symptoms are the mainstay of the diagnosis
of heart failure (and the utility of that is in question)
• No recommendation for biomarker testing
or preventive therapy
*AHA,ACC,HFSA, and ASCO websites
Rationale
• Anthracycline-induced cardiotoxicity is well
known and frequently limits treatment.
• The severity of myocardial damage is
dependent on several factors.
• Current monitoring techniques, such as MUGA
or Echo, have substantial limitations and only
detect LV dysfunction after it occurs
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
Study Timeline
Cycle
1
2
3
4
5
6
Weeks (approximate)
0
3
6
9
12
15
18
24
BNP
x
x
x
x
x
x
x
x
TROPONIN
x
x
x
x
x
x
x
x
EF (by Echo)
x
x
x+
Physical Exam
x
x
x
ECG
x
x
x+
MDASI
x
x
x
Baseline
+if
clinically indicated
x
x
x
x
x
x
End
TABLE 1. BASELINE DEMOGRAPHICS
Number of patients=109
%
Gender (Male/Female)
48 / 52
Age (years ± std dev)
56 ± 14
Cancer Diagnosis
Breast
10
Sarcoma
55
Lymphoma
32
Other
3
Cardiac Diagnosis
Coronary Artery Disease
10
Prior Myocardial Infarction
4
Risk Factors
Diabetes
14
Family History of Early Heart Disease
20
Hypertension
50
Hyperlipidemia
32
Obesity
35
Smoking
11
Cardiac Medications
Beta Blocker
22
Ace Inhibitor
17
ARB
13
Statins
23
Aspirin
10
Antiplatelets
6
Summary of Cardiac Events (Pilot Data)
Results:
• The only factors significantly associated
with cardiac toxicity included older age,
history of MI and elevated BNP
Factors associated with having a cardiac
event during the study period
Label
Cardiac
Event
Value
n
No Cardiac
Event
(%)
n
Total
P
(%)
Previous Myocardial Infarction
Yes
2
50
2
50
4
0.0500
1 BNP over 100 before event
Yes
11
22
40
78
51
0.0001
1 BNP over 150 before event
Yes
11
37
19
63
30
<.0001
1 BNP over 200 before event
Yes
10
50
10
50
20
<.0001
No
7
8
77
92
84
EF suggests cardiotoxicity
0.3758
Yes
3
17
Normal BNP < 100 pg/ml
15
83
18
Univariate logistic regression modeling the
probability of having a cardiac event
(Pilot data)
Accuracy of each test for
predicting cardiac events
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)
EF<50 or change>15%
102
30 (7, 65)
84 (75, 91)
17 (4, 41)
92 (84, 97)
All data expressed as percent (95% Confidence Interval)
Rationale
• Troponin and BNP markers are reliable,
noninvasive and simple to measure.
• Early identification of LV dysfunction
would stratify patients needing adjustments
in their chemotherapy or who may benefit
from concurrent use of cardioprotective
agents (e.g. beta blockers or ACE
inhibitors).
Statistical Considerations
• The study by Cardinale et. al. notes a 1520% incidence of cardiotoxicity from highdose chemotherapy.
• Our Pilot data shows an incidence of at least
10% for cardiotoxicity from all
anthracycline regimens.
Inclusion Criteria
•
•
•
Patient age 18-85 years
Starting a new course of chemotherapy
that includes an anthracycline (does not
have to be first-line therapy and previous
anthracycline use is allowed)
Has a life expectancy greater than 12
months
Exclusion Criteria
•
•
•
•
•
Unstable angina within the last 3 months
Myocardial infarction within the last 3
months
LVEF less than 40%
Patients receiving concurrent dexrazoxane
Decompensated HF in the last 3 months
Cardiac Event
•
•
•
•
•
Any new symptomatic cardiac arrhythmia
Acute coronary syndrome
Symptomatic HF
Development of asymptomatic left ventricular
dysfunction (defined as LVEF less than 50 %
with a normal baseline or a decrease of greater
than 15% from baseline)
Sudden cardiac death (defined as rapid and
unexpected death from cardiac causes with or
without known underlying heart disease)
Univariate logistic regression modeling the
probability of having a cardiac event
(Pilot data)
Summary of Cardiac Events (Pilot Data)
PREDICT Study
Equipment Features for Biomarker
Testing
•
•
•
•
•
Built in quality control features
Simple one-step testing
Accurate
Results in 15 minutes
Low maintenance
Conclusion
• The ability to predict and identify patients
who develop cardiotoxicity with
chemotherapy needs improvement
• Biomarkers may actually identify those
patients long before heart failure is present
• Establishing a method to easily and reliably
detect cardiotoxicity can have a profound
impact on outcomes
Supported in part by the Lance Armstrong Foundation