CARDIAC TOXICITY OF CANCER THERAPEUTIC AGENTS

Dr Binjo J VazhappillySenior 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

• 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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