Cardiotoxicity in Drug Development: Cardiac Function Monitoring

Nuclear Core Lab Imaging

Diwakar Jain MD, FRCP, FACC, FASNCProfessor of Medicine and Director of Nuclear

Cardiovascular Imaging LaboratoryDrexel University College of Medicine

Philadelphia

Oncology and Cardiology Cardiologists and oncologists often share the same pt

population Another shared concern: cardiotoxicity associated with

cancer chemotherapy Several forms of cancer therapy can affect

cardiovascular system Two groups of agents are well known for cardiotoxicity:

Anthracyclines HER2 receptor monoclonal antibody (Trastuzmab,

Herceptin) and other TK inhibitors

Anthracyclines Anthracycline glycoside antibiotics are potent broad spectrum

anticancer agents. Doxorubicin (DOX), or adriamycin is the most widely used agent in this category

Cardiotoxicity, characterized by progressive LV dysfunction & CHF which in extreme cases can be fatal is a well recognized clinical entity limiting the use of all anthracyclines

Dose related with significant inter-individual variability

Life-time cumulative dose the best predictor for CHF:

3% at 300mg/m2, 7% at 450mg/m2, 20% at 600mg/m2

Risk factors: age, pre-existing heart disease, thoracic irradiation, combined use of other agents: high dose cyclophosphemide, taxanes, herceptin

Anthracyclines Mechanism of cardiotoxicity:

Sarcoplasmic Ca++ overload Binding to topoisomerases

Oxidative damage: Redox cycling Approaches to reduce cardiotoxicity:

newer DOX analogues slow iv infusion over 24-72 hrs iron chelators (Zinecard) and antioxidants liposome-incorporated DOX

Close LVEF monitoring and prompt discontinuation at the appearance of a predetermined fall in LVEF

Cum Dox dose and lowest LVEF

10

20

30

40

50

60

70

80

Low

est

LVEF

0 100 200 300 400 500 600 700 800 900Adria final dosage

CHFNo CHF

n=265

At-Risk v Non-Risk Pts

Variables

nAge (yrs) FemalesPrior CV Dis (Hypertension, MI)Dox Total Dose (mg/m2)Overt CHFHosp admission for CHFCardiac DeathCancer Related DeathsFollow up from last DOX DoseNumber of ERNAsBaseline LVEF (%)Lowest EF During Follow up(%)

At-Risk41 (15% )53±1428 (68% )12 (29% )304±1245 (12% )2 ( 5% )1 (2.5%)24 (59% )691±4453.9±1.558±842±8

Non-Risk224 (85% )54±16173 (78% )

39 (17% )284±110

2 ( 1% )1 (0.4%)066 (30% )

676±4243.2±1.364±857±7

P0.6

0.20.060.3<0.00010.010.020.00030.80.002<0.0001<0.0001

No difference in D Mellitus, Prior DOX Therapy Cytoxan Therapy, Dexrazoxane Therapy & Mediastinal Irradiation

0

50

100

150

200

250

300

ERNA#1ERNA#2ERNA#3ERNA#4ERNA#5ERNA#6ERNA#7ERNA#8ERNA#9ERNA#10

RiskNon-Risk

Sequential ERNA and pts at risk

Mitani I et al. JNC 2000

Overt CHF preceded by subclinical LV dys, which is rapidly progressive with continuation of therapy, but can be arrested by prompt discontinuation of offending agent

Need for close LV function monitoring during therapy using a technique which can reliably detect subclinical LV dysfunction

Serial LVEF monitoring with ERNA continues to be the only cost effective approach for the prevention of cardiac morbidity and mortality from DOX chemotherapy

LV Function Monitoring

Guidelines for LVEF Monitoring during Dox Therapy

Bsl EF

Bslat 250-300mg/m2

At 450 mg/m2 *Prior to each subsequent dose

BslPrior to each subsequent dose

Avoid doxorubicin

At Risk for CHF

Nl≥50%

ERNAs

* At 400 mg/m2 with Known heart disease, hypertension, radiation exposure, ab ECG, cyclophosphamide therapy

30- <50%

<30%

≥10% EF Fallto <50%

≥10% EF fall or EF <30%

Schwartz R et al. Ann of Int Med 1985

Prevention of DOX Cardiotoxicity

Free radical injury mediated mechanism thought to contribute towards DOX cardiotoxicity

Iron forms a complex with drug resulting in generation of free radicals

Contribution of body iron stores towards DOX cardiotoxicity is not clear

Higher body iron stores are strongly suspected to potentiate DOX cardiotoxicity

5

Inj

wks 0 4

Sacrifice

Multi DOX Dose (2.5 mg ip twice/wk x 4 wks, cum 20 mg/Kg)

Inj

wks 0 3

Sacrifice

2

Single 6mg iv DOX Dose

DOX cardiotoxicity in Iron Loaded rats

Imaging

Mortality,wt. change &histology

Imaging

Mortality,wt. change &histology

Panjrath G et al JACC 2007

Body wt. Changes

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Multi DoseSingle Dose

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

0.2

% b

ody

wt.

chan

ge

1 2 3

saline iron DOX DOX + iron

wks

% b

ody

wt.

chan

ge5

saline iron DOX DOX + iron

wks

EM

Caspase-3

Saline DOX

DOXIron

DOX + iron

DOX + iron

Saline (single)

(multi)

(single)

(multi)

Body Iron and Dox Cardiotoxicity

Body iron stores and iron bioavailability may be important determinants of DOX cardiotoxicity

HFE+/+ 1 in 250 but HFE+/- 7%, HD+/- 20%

Blood transfusions, iron supplementations common in cancer pts

More appropriate and logical use of iron chelators for preventing DOX cardiotoxicity

Trastuzumab• Humanized monoclonal antibody• Binds selectively to human epidermal growth factor-2

(HER2 also known as ErbB2) • Amplification of HER2 gene in ≈20% of breast Ca• HER2 encodes a membrane transporter belonging to

the family of tyrosine kinases• Used to treat HER2 over-expressing metastatic breast

Ca as a monotherapy or with anthracyclines• efficacious in increasing median survival times• Given as weekly iv injections starting during the

course of chemotherapy or soon after the completion of initial chemotherapy for 9-12 months

Mechanism of Trastuzumab Induced Cardiac Dysfunction

• Not fully known• Important difference with anthracycline cardiotoxicity• HER receptors form a group of receptors present on the

myocardium, involved in cell survival under stress challenge

• Blockage of cell survival receptors predispose myocytes to apoptosis particularly when challenged by other cardiotoxic agents

• This property may be shared with other TK receptor blocking agents

• Recently Gleevec another TK inhibitor has been found to have cardiotoxicity

Panjrath G et al NMC 2006

Cardiotoxicity of TK inhihitors Over-expression of PDGFR in several cancers, which

promotes cell growth Several chemotherapeutic agents imatinib (Gleevec),

Sunitnib (Sutent), Sorafinib (Nexavar) target tumor PDGFR receptors, which slows tumor growth

PDGFR expression and activation in the myocardium is also associated with angiogenesis

PDGFR expression increases in response to pressure overload

Cardiac PDGFR KO mice developed heart failure on pressure overload with aortic banding

Khakoo A et al. JCI 2010

Conclusion Cardiotoxicity continues to be a major issue with

the use of anthracyclines: Body iron content is an important determinant of DOX cardiotoxicity

Newer anticancer drugs such as trastuzumumab also have significant cardiotoxicity

Need for closer observation of newer monoclonal antibodies and TK inhibitors for potential cardiotoxicity

Need for further research to better understand the mechanisms and prevention of cardiotoxicity

Conclusions Meanwhile close LV function monitoring with

serial ERNA using the recommended guidelines can be used to effectively reduce the incidence of overt CHF

Currently no large central data bases exist regarding LV function, cancer chemotherapy and cardiotoxicity

There is a critical need for the creation of such data bases to gain better insight into therapy induced cardiotoxicity and to keep up with the changing trends in this field