Therapy-Related Cardiac Toxicity in Cancer Patients

Therapy-Related Cardiac Toxicity in Cancer Patients

JEAN-BERNARD DURAND, M.D., FCCP, FACCASSOCIATE PROFESSOR OF MEDICINE

MEDICAL DIRECTOR CARDIOMYOPATHY SERVICESUNIVERSITY OF TEXAS

MD ANDERSON CANCER CENTERHOUSTON, TEXAS

I will not discuss off label use and/or investigational use in my presentation.

I have the following financial relationships to disclose:– Astellas– Employee of: University of Texas MD Anderson

Cancer Center

Jean-Bernard Durand, M.D.Presenter Disclosure Information

Overview• Cardiovascular disease is the number two killer

of cancer survivors• 108 million baby boomers will enter healthcare

industry by 2015• By 2015 over 15 Million U.S. cancer survivors

– Many definitions of a cancer survivor– Cardiologist viewpoint: survivorship starts at time of

diagnosis (Dr.Fitzhugh)

Overview

• Cancer treatment has shifted to targeted therapies, with more than 30 new agents in the past five years – Life-saving drugs and cardiology approach should

support use; not interrupt use– Limited randomized controlled trials on prevention of

cardiotoxicity – Treatment is based on prevention, early detection,

prevention of progression heart failure

Armstrong GT et al. JCO.2009;27:2328-2338

Late Mortality Among 5 Year Survivors of Childhood Cancer CCSS

N=20,483

• CAD or history of MI• Hypertension• Diabetes• Alcoholism• Cardiotoxic drugs• Inherited

cardiomyopathies• Sleep apnea

• Valvular heart disease • Congenital heart defects• Other:

– Obesity– Age– Reduced or falling vital

capacity– Smoking– High of low hematocrit

level

Risk Factors for Heart Failure

Dexrazoxane

Dexrazoxane

New Hypothesis

Doxorubicin-induced cardiotoxicity is mediated by Top2b

Two different Top2: a and b

Doxorubicin poisons both Top2a and Top2b.

Proliferating cells express Top2a.

However, the adult heart only expresses Top2b.

Top2bTop2b

15 mg/kg Doxorubicin IP Control

+/+ ∆/∆+/+∆/∆

Acute Model

Reactive Oxygen Species

Topoisomerase IIb

Top2b is required for doxorubicin-induced ROS production

?

Doxorubicin

Top2b deletion prevents doxorubicin-cardiotoxicity

Yeh et al Nature 2012

                                                                     American Cancer Society

Cancer 2005; 104:2492-8

RPCT-Valsartan for Prevention of Cardiotoxicity

o Placebo

Valsartan

RPCT- Lipitor 40mg daily/Total dose doxo=251mg,one cycle per month X 6 monthsJACC Vol 58:2011

Therapies for Prevention of Cardiotoxicity with Anthracyclines

Comparison of LVEF at Baseline and After Chemotherapy

Kalay et al. JACC. Dec 2006. 48:2258-62Data expressed as mean values.

JACC Apr 9 2013

Overcome Trial

N=90

JACC Apr 9 2013

Overcome Trial

N=90

Journal of American College of Cardiology January 2010

Limited Time to Start Therapy

Journal of American College of Cardiology January 2010

Responders Have Less Cardiac Event Rates

703 patients (216 males) Age 47±12 years Treated with HDC Poor prognosis malignancies

TnI serum determination: Baseline = Before HDC Early = soon after HDC (0,12,24,36,72 hours) Late = 1 month after HDC Circulation 2004

♫ Follow-up = 48 months♫ MACE incidence

Cardiac Events3.5 Year Follow-up

Sudden deathCardiac deathAcute pulmonary edemaHeart failureAsymptomatic LVEF >25%Life-threatening arrhythmiasConduction disturbances requiring PM implantation

PersistentTnI +

NegativeTnI

TransientTnI +

Circulation 2004

1%

*= p<0.001 vs. TnI -

37% *

#= p<0.001 vs. TnI +-

84% * #

Positive predictive value = 84% Negative predictive value = 99%

=

=

=

High risk

Intermediate risk

Low risk

Persistent TnI+

Transient TnI+

Negative TnI

Cardiac Risk Stratification

Troponin I Early Positivity

Enalapril n = 56 pts

Controls n = 58 pts

physical examination, ECG, ECHO: b,1,3,6,12 months

started 1 month after HDC continued for 1 year

443 pts High-dose CT

TnI + = 114 pts (24%)

Secondary End-pointsFollow-up 12 months

Sudden death 0 (0%) 0 (0%) 0 (0%) NSCardiac death 2 (2%) 0 (0%) 2 (3%) NSAcute pulmonary edema 4 (2%) 0 (0%) 4 (3%) NSHeart failure 14 (12%) 0 (0%) 14 (22%) <0.001Life-threatening arrhythmias 11 (10%) 1 (2%) 10 (16%) 0.01

CUMULATIVE EVENTS 31 (28%) 1 (2%) 30 (52%) 0.001

Totaln=112 P

ACEI n=54

Controlsn=58

Cardinale et al. Circulation 2006

Cycle 1Baseline ECGEcho/Strain

TroponinBNP

Cycle 2BNP/Troponin

(-) proceed,(+) Echo(Strain),

Consider Ace/BB?

Continue Chemo

Cycle 3BNP/Troponin

(-) proceed,

(+) Echo(Strain), Consider Ace/BB?

Continue Chemo

Cycle 4BNP/Troponin

(-) proceed,

(+) Echo(strain), Consider Ace/BB?

Continue Chemo

Heart Failure Specialist Perspective Continuum of Cancer

Intervention

Lymphoma Patient-R-Chop

ECG HR<60 (Qtc)Any symptoms

Stop dox LVEF<40%

MUGA• Accurate for low

ejection fraction • Less accurate with

rhythm disorders• No information on

valvular disorders• Little information on

wall motion abnormalities

Echo• Valvular heart disease• Wall motion

abnormalities• Pulmonary pressures• Hemodynamics• Diastology• Strain

Echo Versus MUGA?

Class I Indications Assessment of LV Function

• Suspected cardiomyopathy or CHF• Edema with clinical signs of increased CVP• Dyspnea or clinical signs of heart disease• Unexplained hypotension• Exposure to cardiotoxic agents• “Pre-chemo”• Re-evaluation change in status or Rx

ACC/AHA/ASE Guidelines of Echo 2003

Cardiotoxicity occurs earlier than change in EF

3

2

1

0

Mackay — MDAH

Billingham — Stanford

200 –400 401 – 500 >500

Cumulative Doxorubicin Dose (mg/m2)

Doxorubicin was given IV every 3 to 4 weeks.Biopsy specimens were taken approximately 3 weeks following last therapy.

Mea

n B

iops

y G

rade

n=8n=18

n=22 n=8

n=3

n=7

Adapted from Ewer et al. J Clin Oncol 1984;2:112-117.

5% *

*Risk of CHF

Committee for Proporietary Medicinal Products . The European Agency for the Medicinal Products .London 17th Dec 1997.

http://www.emea.eu.int/pdfs/human/swp/098696en.pdf

Termination of T-wave; In the Eyes of the Beholder

Cancer patients: risks for prolonged QTc .

ECG Percent Reference

Prolonged QTc 10.6% Barbey et al 2003

Borderline or prolonged QTc

15% Vaterasian, et al. 2003

any ECG anomaly 36% Barbey et al 2003

• molecularly targeted agents with QTc• adjuvant regimens, long treatment periods• survival emphasis toxicity reduction

WHEN TO WORRY ABOUT QT?

• More than 25% prolongation of QTc interval from the baseline or a QTc interval longer than 500 ms increases the risk of precipitation of drug-induced torsade de pointes

• More than 90% of incidences of drug-induced torsade de pointes occur with QTc values of more than 500 ms

Bednar MM et al. Am. J. Cardiol 2002;89:1316–1319 Gowda RM et al. Int J Cardiol 2004;96:1-6

TREATMENT

• Discontinuation of the offending agent: Any offending agent should be withdrawn. Predisposing conditions such as hypokalemia, hypomagnesaemia, and bradycardia should be identified and corrected.

• (>90% of time, we just stop supportive cast of medications)

PROGNOSIS

• Because Long QT interval is primarily an electrical disorder, in the absence of structural heart disease and LV dysfunction, the long-term prognosis is good as long as the offending agents and risk factors are corrected and arrhythmia is controlled.

Things to Consider

• More than 500 known tyrosine kinases from Human Genome Project– Over 250 of these tyrosine kinases are cloned,

and expressed– 7 Tyrosine kinases are FDA approved– 4 Tyrosine kinases targeted (17 kinases in vivo)– How many kinases in the human genome are

cardiac specific?

Kinase-binding profiles of the ABL inhibitors imatinib (upper panel), dasatinib (middle panel), and bosutinib (bottom panel) across a set of protein kinases simultaneously identified from K562 cells. The bars indicate the IC50 values, defined as the concentration of drug at which half-maximal competition of kinobead binding is observed.

Nature Biotechnology 25(9)2007

Selective vs. Non-Selective Kinase Binding Profiles

Drug-Induced HF of FDA Approved Targeted Cancer Therapies

Sorafenib 2007 VEGF1,2,3/PDGF 1%

Dasatinib 2006 BCR-ABL/SRC C-Kit, PDGF

4%

Sunitinib 2006 VEGF/PDGF/ C-KIT

3-14%

Bevacizumab 2004 VEGF 2-14%

Trastuzumab 2000 ErbB-2/TKI 3-27%

Imatinib 2001 C-ABL, C-Kit 1%

Drug Approval Action CHF

FDA Approved Targeted Therapies

Sorafenib CMP Yes SHF

Dasatinib CMP Yes SHF

Sunitinib HTN/CMP Yes SHF/DHF

Bevacizumab HTN/CMP Yes SHF/DHF

Trastuzumab CMP Yes SHF

Imatinib CMP Yes SHF

Drug HTN/CMPResponds to

ACE/BB SHF/DHF

38

Hypertension is a Biomarker of Efficacy in Patients with Metastatic Renal Cell

Carcinoma Treated with Sunitinib

BI Rini,1 DP Cohen,2 DR Lu,2 I Chen,2 S Hariharan,3 RA Figlin,4

MS Baum,5 RJ Motzer5

1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Pfizer Oncology, 2La Jolla, CA, 3New York, NY;

4City of Hope National Medical Center, Duarte, CA; 5Memorial Sloan-Kettering Cancer Center, New York, NY, USA

39

Clinical Outcome by HTN StatusMax. SBP

≥140 mmHg (n=441)

Max. SBP <140 mmHg

(n=93) P-valueObjective response, n (%) 241 (54.6%) 9 (9.7%) <0.0001Progression-free survival, months 12.5 2.5 <0.0001Overall survival, months 30.5 7.8 <0.0001

Max. DBP ≥90 mmHg

(n=362)

Max. DBP <90 mmHg

(n=172) P-valueObjective response, n (%) 207 (57.2%) 43 (25.0%) <0.0001Progression-free survival, months 13.4 5.3 <0.0001Overall survival, months 32.1 15.0 <0.0001

40

Median OS by Use of Anti-HTN Agents, HTN-induced Dose Reductions and HTN Status as

Defined by Maximum SBP ≥140 mmHg on Sunitinib

1.00.90.80.70.60.50.40.30.20.10.0P

roba

bilit

y of

ove

rall

surv

ival

0 5 10 15 20 25 30 35 40 45 50Time (months)

Dose reduction onlyAnti-HTN drug onlyBothNeitherNo HTN

Powe, D. G. & Entschladen, F. Nature Reviews Clinical Oncology 8, 511-512 (2011)

Binding to specific adrenergic receptors, β‑blockers inhibit cancer cell migration and metastasis, suggesting a novel targeted therapeutic application in protecting against breast cancer disease progression

J Clin Oncol 29;2645-2652

Oncotarget 2010; 1:628-638

Baseline Hypertensive BC Patients Treated with Beta Blockers Live Longer

Heart Success

• Organizations for future:• Conquer, MD Anderson Cancer Center, 2001• Cardiology Oncology Partnership Vanderbilt

USA, 2004• International Society for Cardioncology, Milan,

Italy, 2009• Brazilian Cardiology Oncology, Sao Paulo,

Brazil, 2009• Canadian Cardioncology, 2010

Conclusions• Cardiologists and oncologists must collaborate

• Exciting new cancer therapies are being discovered, however, in order to maximize their potential, cardiac toxicities need to be identified and addressed upfront

• Although recent clinical experience has shown significant cardiotoxicity post-trial with cancer therapies, we have also seen resolution of toxicity using evidence-based cardiology guidelines (beta blockers need further study)

• More collaborative work with biomarkers/cardiac imaging for early detection and treatment

Thank you!

• TwitterJean-Bernard Durand@oncocardiology

jdurand@mdanderson.org

Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months; placebo (n=84), carvedilol (n=261).*Multicenter Oral Carvedilol Heart Failure Assessment.Adapted from Bristow MR et al. Circulation. 1996;94:2807–2816.

Carvedilol

Placebo0

1

2

3

4

5

6

7

8

LV

EF

(EF

units

)

Changes in LVEF

P<.001

‡

‡

‡

‡P<.05 vs placebo.

25 mg bid6.25 mg bid 12.5 mg bid

Carvedilol Dose-Response Trial (MOCHA*):Effect on Ejection Fraction and Mortality