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….
Women Men
Heart
Disease
No Heart Heart
Disease 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 1975-1977 1984-1986 1996-2002
• All sites 50 53 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
Lung cancer (bevacizumab) Microvascular rarefaction
Inhibition of tumor growth, tumor cavitation Cardiomyopathy (sunitinib and sorafenib)
Hepatocellular carcinoma (sorafenib)
1 2 3
Tumor necrosis
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
100
75
Percent of Patients
55
50
25
14
0
LVEF HF with EF Improved
Decrease Normal EF After Optimal
After Chemo 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 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 20 25
CHF (%)
Hensley ML et al J Clin Oncol 1999; 17(10):3333-
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 x x x x x
ECG x x x+
MDASI x x x x
Baseline End
+if clinically indicated
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
Cardiac No Cardiac
Event Event
Label Value Total P
n (%) n (%)
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 30 100 109 100 (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)
EF15% 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 15-
20% incidence of cardiotoxicity from high-
dose 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