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. Cardiotoxicity of 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 Tamponade and endomyocardial fibrosis Busulfan Haemorrhagic myocarditis: Cyclophosphamide

6. Bradyarrhythmias : Paclitaxel Raynaud’s phenomenon Vinblastine, bleomycin QT prolongation or Torsades de 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/m 2 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/ 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.

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/m 2 of epirubicin produces cardiotoxicity comparable to 450 to 500 mg/m 2 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 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/m 2 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: 9 th edition Hurst’s The Heart : 13 th 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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