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

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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?

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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

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64%

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(n=75) (n=35) (n=20) (n=12) (n=8) (n=7) (n=44)

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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

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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!