Download CARDIAC TOXICITY OF CANCER THERAPEUTIC AGENTS

CARDIAC TOXICITY OF CANCER
THERAPEUTIC AGENTS
Dr Binjo J Vazhappilly
Senior Resident
• New anticancer therapies have led to long life
expectancy for many patients.
• Treatment related co morbidities have become an
issue for cancer survivors.
• Cardiac toxicity vary from mild ECG changes to
serious arrhythmias, myocarditis, pericarditis, MI &
heart failure.
Factors influencing cardiotoxicity
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Type of drug.
Dose administered during each cycle.
Cumulative dose.
Combination of other cardiotoxic drugs.
Associated radiotherapy.
Pt’s age, presence of CV risk factors, previous CV
disease, prior radiation therapy.
Cardiotoxicity of chemotherapeutic
agents
• Drugs associated with CHF
Anthracyclines , Cyclophosphamide, Taxanes
Monoclonal Ab : Trastuzumab ,
Bevacizumab
Tyrosine Kinase inhibitors: imatinib ,
desatinib , sunitinib
• Drugs associated with Ischaemia
Fluorouracil, Capecitabine ,Paclitaxel,
Docetaxel , Cisplatin ,Thalidomide
• Hypertension
Bevacizumab , Cisplatin , Sunitinib, sorafenib
• Tamponade and endomyocardial fibrosis
Busulfan
• Haemorrhagic myocarditis:
Cyclophosphamide
• Bradyarrhythmias : Paclitaxel
• Raynaud’s phenomenon
Vinblastine, bleomycin
• QT prolongation or Torsades de pointes
Arsenic trioxide
• Venous Thrombosis
Cisplatin , Thalidomide
Definition for Cardiotoxicity causing
LV dysfunction
• No universally accepted definition.
• Definition in various trials are
≥ 10% LVEF decline from baseline to 55%
≥ 10% LVEF decline from baseline to 50%
20% or 15% LVEF decline from baseline but
remaining > 50%
Any LVEF decline to < 50%
Anthracyclines
• Most cardiotoxic agents to date.
• Chemotherapeutic agents used in lymphomas and
solid tumors (breast, SCLC) .
• Acute toxicity : arrhythmias, LV dysfunction, and
pericarditis
• Chronic : produce LV dysfunction and HF.
• Toxicity is strongly dose related.
Doxorubicin induced HF & cumulative
dose
• In initial retrospective analyses incidence of HF is
2.2% overall & 7.5% in pts receiving
dose of
550 mg/m2
• Incidence is higher in newer studies .
HF incidence and cumulative dose
Mechanisms of Anthracycline toxicity
• Intercalation into DNA and inhibit topoisomerase II
• Preventing macromolecule synthesis
• ROS leading to DNA damage or lipid peroxidation
Mechanisms of Anthracycline toxicity
• Reactive oxygen species is the central mediator of
adverse myocardial consequences
• Accelerate apoptosis by activation of p53 & suppress
sarcomere protein synthesis through depletion of
GATA-4 & cardiac progenitor cells.
• This imbalance b/w sarcomere synthesis &
degradation results in myocardial dysfunction.
• Acute/ subacute cardiotoxicity
Occur within a week.
May occur after a single dose.
Transient ECG changes seen in 20 – 30%.
Arrhythmias seen in 0.5 - 0.7%.
ECG changes or arrhythmias are not related
to chronic cardiomyopathy.
• Chronic progressive cardiotoxicity
Early onset : presenting with in 1 yr of
chemotherapy completion.
Late onset : presenting after 1 yr.
Epirubicin
• Stereoisomer of doxorubicin
• Less cardiotoxicity than doxorubicin at comparable
doses.
• 900 -1000 mg/m2 of epirubicin produces
cardiotoxicity comparable to 450 to 500 mg/m2 of
doxorubicin.
• Efficacy of both agents are comparable at equivalent
doses.
Taxanes :Paclitaxel, Docetaxel
• Disrupt microtubular networks.
• Relatively less cardiotoxicity .
• Cardiac toxicity occurred in 14% ( 76% of events were
asymptomatic bradycardia )
• When combined with doxorubicin : 18% developed
HF
• Due to retardation of doxorubicin metabolism
• Docetaxel does not retard metabolism of doxorubicin
hence less toxic .
Cyclophosphamide
• Well tolerated at conventional doses.
• High doses used in pre-transplant conditioning regimens are
toxic
• Dose > 170 -180 mg/kg per course is a risk factor.
• Causes myopericarditis
• Incidence is 22 %
• Who survive acute phase do not have residual LV dysfunction.
Cisplatin
• Used for testicular germ cell cancer
• Causes hypertension
• Acute chest pain syndromes ,including MI, can occur
due to coronary spasm.
Fluorouracil
• Cause a/c ischemic syndromes ranging from angina to MI
• Can occur in pts without CAD ( 1% )
• In pts with pre-existing CAD ( 4% to 5% )
• Vasospasm is the mechanism of ischemia.
• Capecitabine is metabolized to fluorouracil, preferentially
in tumor cells and is less toxic.
Tamoxifen
• Widely used in treatment of breast cancer.
• Was proposed to have cardioprotective effects
• Studies showed tamoxifen did not reduce or
increase cardiovascular events.
• Stroke risk is increased.
Bortezomib : Proteasome Inhibitor
• Degrade improperly folded proteins and proteins
that are no longer needed in the cell.
• Cardiomyocytes also have proteasome system and its
inhibitors may be cardiotoxic.
• Used in pts with multiple myeloma and heart failure
is reported in 5%.
Targeted drug cardiotoxicity
• Targeted drugs are compounds acting through
inhibition of specific target molecules
• In anticancer therapy, protein kinases, are the
targets
• 2 classes of drug targeting tyrosine kinase
Monoclonal antibodies (trastuzumab,
bevacizumab)
Tyrosine kinase inhibitors ( lapatinib,
imatinib,sorafenib, sunitinib)
Mechanisms of action
Monoclonal antibodies (mAbs)
Tyrosine kinase inhibitors (TKIs)
Trastuzumab
• 3% - 7% developed LV dysfunction
• Incidence increase to 27% by concomitant use of
doxorubicin (16% NYHA III or IV).
• When used with paclitaxel, 13% developed
cardiotoxicity vs 1% with paclitaxel alone.
• Trastuzumab toxicity is not dose related and is
frequently reversible.
Mechanism of Action
Bcr-Abl Inhibitors
• Imatinib ,Dasatinib and Nilotinib
• HF is uncommon with imatinib & nilotinib
• HF or LV dysfunction can occur in 4% with
dasatinib
• Nilotinib prolongs QT interval by 15 to 30msec.
VEGF Inhibitors
• Bevacizumab , Sunitinib and Sorafenib
• Hypertension is class effect of VEGFR inhibition.
• HT can be severe in 8% to 20% pts.
• All 3 drugs are associated with HF.
• In sunitinib treated pts, 8% developed NYHA III or IV HF
& additional 10% suffered asymptomatic decline in EF.
• Bevacizumab associated with 2 fold increase in
arterial thromboembolic events.
• Sorafenib is associated with acute coronary
syndromes (2.9% vs 0.4% in placebo)
Cardiotoxicity Detection
• Endomyocardial biopsy : most sensitive
typical findings are cytosolic vacuolization, lysis of
myofibrils & cellular swelling.
• Serial determination of LV function : less sensitive
but currently accepted method.
• Decrease in LVEF becomes evident only after
significant myocardial damage
Role of biomarkers
• Rise in troponin I predict the occurrence and the
magnitude of LVEF decline in pts receiving high-dose
anthracyclines.
• The natriuretic peptides are less reliable than
troponins in predicting LVEF decline.
• Biomarkers are not recommended for routine
screening.
ESMO recommendations for
cardiotoxicity monitoring
• Baseline clinical & ECG evaluation in all pts
undergoing anthracycline therapy.
• Baseline DEcho before treatment with monoclonal
Ab or anthracyclines and their derivates in pts aged
>60 yrs or with CV risk factors or previous thoracic
radiotherapy.
Further LVEF evaluations
• After half the planned dose of anthracycline or
cumulative dose of doxorubicin 300 mg/m2, epirubicin
450 mg/m2 or
• Doxorubicin of 240 mg/m2 or epirubicin 360 mg/m2 in
pts aging <15 or >60 yrs
• Before every next administration of anthracycline
• After 3, 6 and 12 months from the end of therapy with
anthracycline.
• Assessment of cardiac function 4 & 10 yrs after
anthracycline therapy in pts treated at <15 yrs.
• LVEF reduction of ≥ 20% from baseline or LVEF
decline to <50% necessitate discontinuation of
therapy.
Prevention and treatment
• CV risk factors should be identified and corrected.
• Dexrazoxane : Iron chelator
Reduce incidence of doxorubicin toxicity
American Society of Clinical Oncology recommends
its use to pts received ≥ 300 mg/m2 of doxorubicin
• Several small trials showed efficacy of ACE I, ARB , β
blockers & statins in reducing anthracycline induced
LV dysfunction & HF.
• Carvedilol , Enalapril & atorvastatin reduced
incidence of systolic dysfunction.
Comparison of Therapies for
Prevention of Cardiac Toxicity
Treatment
• Symptomatic HF is treated with ACE inhibitors & β
blockers.
• Recommendations are based on limited data and
guidelines derived from findings in noncancer heart
failure.
Summary
• Cardiactoxicity is seen with many chemotherapeutic
agents , among which anthracyclines are most toxic.
• Anthracycline toxicity depends on cumulative dose.
• Hypertension is class effect of VEGFR inhibition.
• Biomarkers are not recommended for routine
screening.
• Accepted method for toxicity determination is serial
monitoring of LVEF.
• ACE I , ARB , β blockers and statins reduce
anthracycline induced HF.
References
• Braunwald’s Heart Disease: 9th edition
• Hurst’s The Heart : 13th edition
• Cardiotoxicity of chemotherapeutic agents and radiotherapy
related heart disease: ESMO Clinical Practice Guidelines :D.
Bovelli, G. Plataniotis & F. Roila: Annals of Oncology 21
(Supplement 5): v277–v282, 2010
• Cancer Therapy-Induced Cardiac Toxicity in Early Breast
Cancer : Michel G. Khouri, Pamela S et al : Circulation.
2012;126:2749-2763
• Cardiotoxicity :I. Brana & J. Tabernero : Annals of Oncology 21
(Supplement 7): vii173–vii179, 2010
• Cardiotoxicity of cytotoxic drugs :Cancer Treatment Reviews
2004;30:181–191
• Chemotherapy-induced cardiotoxicity: current practice and
prospects of prophylaxis: M.I. Gharib, A.K. Burnett: European
Journal of Heart Failure 4 (2002) 235 – 242.
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