PREDICT Study:

A multicenter study in

P

atients undergoing anth

R

acycline-based chemotherapy to assess the

E

ffectiveness of using biomarkers to

D

etect and

I

dentify

C

ardiotoxicity and describe

T

reatment 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….

Heart Disease No Heart Disease Heart Disease No Heart Disease

•Lifetime risk of developing coronary heart disease at age 40 years (U.S.)

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 • • • • • • • • • • • • All sites Breast (female) Colon

Site

Leukemia Lung and bronchus Melanoma Non-Hodgkin lymphoma Ovary Pancreas Prostate Rectum Urinary bladder

1975-1977

50 75 51 35 13 82 48 37 2 69 49 73

1984-1986

53 79 59 42 13 86 53 40 3 76 57 78

1996-2002

66 89 65 49 16 92 63 45 5 100 66 82

*5-year relative survival rates based on follow up of patients through 2003. Cancer Control and Population Sciences, National Cancer Institute, 2006.

†Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of

†

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 nature) in 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

(VEGF upregulated)

Normal Tissues

(VEGF constitutively expressed) Lung cancer (bevacizumab) Inhibition of tumor growth, tumor cavitation Hypertensive remodeling Microvascular rarefaction Cardiomyopathy (sunitinib and sorafenib) Hepatocellular carcinoma (sorafenib) Tumor necrosis Renal cell carcinoma (sunitinib) Tumor shrinkage, tumor cell necrosis 1 2 3 Microcirculation: 1. normal arteriole, 2. functional rarefaction (endothelial dysfunction,vasoconstriction), 3. anatomic rarefaction 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 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 Epirubicin 1000 mg/m2 Epirubicin < 900 mg/m2 Dauno 1000 mg/m2 Dauno 500 mg/m2 Doxo (400-499 mg/m2) + Dexrazoxane 1 1.5

4 12 Doxo low dose weekly > 600 mg/m2 Doxo bolus > 550 mg/m2 Doxo 1000 mg/m2 5.4

10 Doxo 500 mg/m2 7 0 5 Hensley ML et al J Clin Oncol 1999; 17(10):3333-3355 10 15 CHF (%) 15 20 20 25

Study Timeline

Cycle Weeks (approximate) BNP TROPONIN EF (by Echo) Physical Exam ECG MDASI 0 x x x x x x Baseline x 1 3 x x + if clinically indicated 2 6 x x x 3 9 x x x x 4 12 x x x 5 15 x x x 6 18 x x x 24 x x x + x x x x x + x End

TABLE 1. BASELINE DEMOGRAPHICS

Number of patients=109 Gender (Male/Female) Age (years ± std dev) Cancer Diagnosis Breast Sarcoma Lymphoma Other Cardiac Diagnosis Coronary Artery Disease Prior Myocardial Infarction Risk Factors Diabetes Family History of Early Heart Disease Hypertension Hyperlipidemia Obesity Smoking Cardiac Medications Beta Blocker Ace Inhibitor ARB Statins Aspirin Antiplatelets % 48 / 52 56 ± 14 10 55 32 3 10 4 14 20 50 32 35 11 22 17 13 23 10 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 Previous Myocardial Infarction 1 BNP over 100 before event 1 BNP over 150 before event 1 BNP over 200 before event EF suggests cardiotoxicity Value n Yes 2 Cardiac Event (%) n 50 2 No Cardiac Event (%) Yes Yes 11 Yes No Yes 11 10 7 3 Normal BNP < 100 pg/ml 22 37 50 8 77 17 40 19 10 15 50 78 63 50 92 83 Total 4 51 30 20 84 18 P 0.0500

0.0001

<.0001

<.0001

0.3758

Univariate logistic regression modeling the probability of having a cardiac event (Pilot data)

1 BNP > 100

test

Accuracy of each test for predicting cardiac events

n

109

Sensitivity

100 (72, 100)

Specificity

59 (49, 69)

Positive predictive Value

22 (11,35)

Negative predictive value

100 (94,100) 1 BNP > 150 109 100 (72, 100) 81 (71, 88) 37 (20, 56) 100 (95, 100) 1 BNP > 200 EF<50 or change>15% 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) 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