CARDIAC TOXICITY OF CANCER THERAPEUTIC AGENTS

1. CARDIAC TOXICITY OF CANCER THERAPEUTIC AGENTS Dr Binjo J Vazhappilly Senior Resident

2. 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.

3. 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.

4. Cardiotoxicityof chemotherapeutic agents • Drugs associated with CHF Anthracyclines , Cyclophosphamide, Taxanes Monoclonal Ab: Trastuzumab , Bevacizumab Tyrosine Kinase inhibitors: imatinib , desatinib , sunitinib

5. Drugs associated with Ischaemia Fluorouracil, Capecitabine ,Paclitaxel, Docetaxel , Cisplatin ,Thalidomide • Hypertension Bevacizumab , Cisplatin , Sunitinib, sorafenib • Tamponadeand endomyocardial fibrosis Busulfan • Haemorrhagicmyocarditis: Cyclophosphamide

6. Bradyarrhythmias : Paclitaxel • Raynaud’sphenomenon Vinblastine, bleomycin • QT prolongation or Torsadesde pointes Arsenic trioxide • Venous Thrombosis Cisplatin , Thalidomide

7. 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%

8. 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.

9. Doxorubicin induced HF & cumulative dose

10. 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 .

11. HF incidence and cumulative dose

12. Mechanisms of Anthracycline toxicity • Intercalation into DNA and inhibit topoisomerase II • Preventing macromolecule synthesis • ROS leading to DNA damage or lipid peroxidation

13. 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.

15. Acute/ subacutecardiotoxicity 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.

16. Chronic progressive cardiotoxicity Early onset : presenting with in 1 yr of chemotherapy completion. Late onset : presenting after 1 yr.

17. 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.

18. 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 .

19. 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.

20. Cisplatin • Used for testicular germ cell cancer • Causes hypertension • Acute chest pain syndromes ,including MI, can occur due to coronary spasm.

21. 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.

22. 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.

23. 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%.

24. 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)

25. Mechanisms of action Monoclonal antibodies (mAbs) Tyrosine kinase inhibitors (TKIs)

27. 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.

28. Mechanism of Action

29. 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.

30. 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.

31. Bevacizumab associated with 2 fold increase in arterial thromboembolic events. • Sorafenib is associated with acute coronary syndromes (2.9% vs 0.4% in placebo)

32. 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

33. 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.

34. 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.

35. 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.

36. 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.

37. 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

38. 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.

39. Comparison of Therapies for Prevention of Cardiac Toxicity

40. 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.

41. 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.

42. 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.

43. 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

44. 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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