Chemotherapy Induced Cardiotoxicity

1. Chemotherapy InducedCardiotoxicity Prof. Drs. Hanan Amin

2. Chemotherapy :- radiotherapy or combined use of both have the potential to cause cardiotoxicity.

3. Chemotherapy InducedCardiotoxicity • The number of long-term survivors of cancer is increasing • By 2010 1 of every 450 child may be a survivor of malignant disease • Many will have been exposed to anthracyclines – Effective in treating broad spectrum of malignancies

4. Definition : • Cardiotoxicity is defined as one or more of the following : • Cardiomyopathy in terms of reduction of left ventricular ejection fraction (LVEF) either global or more severe in the septum. • Symptoms associated with heart failure Hf e.g. pulmonary roles, peripheral oedema, hepatomegally,….. • Signs associated with Hf such as S3 , gallop, tachycardia or both. • Reduction in LVEF from baseline that is the range of less than or equal to 5% to less than 55% with accompanying signs or symptoms of Hf, or a reduction in LVEF in the range of equal to or greater than 10% to less than 55% without accompanying signs or symptoms.

5. Chemotheraphy causing cardiotoxicity 1-Anthracyclines:- -Doxorubicin -Daunorubicin - Idarubicin 2-Alkylators:- -Cyclophosphamide -Cisplatin 3-Antimetabolite:- -5 –flouracil 4-Antimicrotubule:- -Vinca Alkaloid 5-Cytokaines:- -Interlukin -Interferon 6-Atra

6. Radiation causing cardiotoxicity Cardiac doses of radiation up to 25 Gy. Are generally safe. ,However, it may involve all cardiac structures :- 1-Acute true medical and or / surgery emergencies Eg. Tamponade,Ami,Arrest. 2-Cronic due to collagen deposition.

7. Anthracycline Cardiotoxicity • Cytotoxic antibiotics • Daunorubicin, doxorubicin, epirubicin and idarubicin • Highly effective against hematologic and solid malignancies • First line defense in the management of many tumors

8. Anthracycline Cardiotoxicity Incidence:- Anthrocycline induced cardiomyopathy is related to cumulative dose. It occurs in 11% of cancer patients after a cumulative dose of less than 400 mg/m2, 23% after 400-599 mg/m2, 47% after 500-799 mg/m2 and 100% after 800 mg/m2.

10. Anthracycline Cardiotoxicity Leads to free radical formation – Molecules containing an odd number of electrons • H2O2, hydroxyl radicals, ect. – Are highly reactive and damaging to tissues • Peroxidation – Are countered by antioxidants and by intracellular enzymes

11. Anthracycline Cardiotoxicity – Cardiac degradation of anthrcyclines leads to free radical formation (enzymatic) – Anthracyline-ferric iron complex are formed in the heart – Cardiac tissue has very limited capacity to deal with free radicals – Mitochondria are particularly susceptible to free radical damage

12. Anthracycline Cardiotoxicity • Other anthracycline induced mechanisms of cell injury – Apoptosis – Elevated calcium accumulation in mitochondria – Modulation of cardiac gene expression

13. Anthracycline Cardiotoxicity Adverse effects on the heart – Electrophysiological changes – Heart failure – Reduced exercise tolerance – Cardiomyopathy – Pericarditis – Myocarditis

15. Anthracycline Cardiotoxicity Risk Factors – Dosing schedule • Single large dose > risk than smaller, frequent dosing • Bolus injection > risk than continuous infusion – Age of patient • > 65 YOA • < 4 YOA

16. Anthracycline Cardiotoxicity Risk Factors – History of mediastinal irradiation • Amplifies preexisting CAD • Exacerbation of vascular injury • Pericardial effusion • Pericardial fibrosis (restrictive disease) • Myocardial fibrosis (valvular disease) – Preexisting heart disease and arterial hypertension

17. Anthracycline Cardiotoxicity • Risk Factors – Simultaneous administration of other antineoplastic agents (cyclophosphomides, actinomycin D, bleomycin, cisplatin, methotraxate) – Poor nutrition – Diabetes – Gender

18. Anthracycline Cardiotoxicity: Stages • Acute Toxicity:- • Occur anytime from initiation of theraphy up to 2 weeks after termination of ttt • – Rare • – Directly connected with the administration of a • single dose or after a course of the antibiotic

19. Anthracycline Cardiotoxicity: Stages Acute Toxicity: – ECG changes • Often asymptomatic and rarely fatal • Synergistic action between drug and hypokalemia • Discontinue drug if occurs • Tends to be reversible • Result of an autonomic defect

20. Anthracycline Cardiotoxicity: Stages Acute Toxicity: – Cardiac monitoring during dosing? • Not typically • History • Presence of CV risk factors • Previous dosage history

21. Anthracycline Cardiotoxicity: Stages Subacute Toxicity – Occurs days to weeks post treatment – Rare and often asymptomatic – Toxic pericarditis and/or myocarditis – Appearance of CHF at this point is a harbinger of poor outcomes for the patient

22. Anthracycline Cardiotoxicity: Stages • Chronic Cardiotoxicity Early onset – < 1 yr. post treatment – Dose dependent – Manifests itself as CHF secondary to cardiomyopathy – Exact incidence unclear • 1%-18% • May miss subtle declines in LV function

23. Anthracycline Cardiotoxicity: Stages • Late onset-Cardiotoxicity – Takes years to decades to develop – Mortality estimated at 30-60%

24. Anthracycline Cardiotoxicity: Stages • Late onset-Cardiotoxicity

25. Anthracycline Cardiotoxicity: Stages • Late Cardiotoxicity – Characterized by • LV systolic failure (CHF) • Diastolic failure • Reduced cardiac contractility • Reduced cardiac compliance – Anatomic changes • Thinned ventricular walls, reduced heart weight • Cardiac fibrosis

26. Anthracycline Cardiotoxicity: Stages Late Cardiotoxicity – Monitoring/detection • Needed but problematic – Long term follow ups absent – Very subtle – Diastolic failure • Stress Angiography • Left ventricular end-systolic wall stress

27. Anthracycline Cardiotoxicity: HeartFailure

28. DEFINITION OF HEART FAILURE (HF) – “A complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or to eject blood” Braunwald – “The situation where the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic needs and venous return” Katz

29. Failed heart

30. Anthracycline Cardiotoxicity: HeartFailure • Gross Changes – Increased ventricular volume – Increased then decreased ventricular wall thickness – These geometric changes increases wall tension and decreases pumping efficiency

31. Anthracycline Cardiotoxicity: HeartFailure Microscope Changes – Mitochondrial defects – Diminished cardiac myocyte calcium handling properties – Decreased vascularization – Apoptosis – Fibrosis causing increased cardiac stiffness

33. HEART FAILURE • Cardinal symptoms – Dizziness, fainting, fatigue or weakness – Weight gain (due to fluid buildup) – Exercise intolerance – Dyspnea – Possible fluid retention/edema • JVD • Ascities – Orthopnia

35. stages ACC/AHA CLASSIFICATION – STAGE A • At high risk for developing HF, no structural damage to the heart – STAGE B • Structural damage, asymptomatic – STAGE C • Structural damage, symptomatic – STAGE D • End stage

36. Criteria for cardiac function deterioration • ECG findings : • Prolonged QT interval. • complete heart block. • Ventricular ectopy. • ST elevation or depression. • T wave changes. • 2nd degree atrioventricular AV block.,

37. Criteria for cardiac function deterioration • ECHO findings : • Fractional shortening (SF) • Left ventricular ejection fraction LVEF less than 55%. • Radioinuclide cardiac cineangiocardiography (RNA, MUGA when good ECHO can not be obtained.

38. Criteria for cardiac function deterioration Monitoring cardiovascular toxicity – Monitor for arrhythmias, ischemic cardiac events, cardinal CHF symptoms and pericardial disease

39. Treatment of congestive heart failure • Digoxin  improve vent. Contraclitiy. • Diuretics ↓NA, H2O retention • ACE inhibiting agents (captopril)  ↓ afterload. • Enalapril  ↑ contractility ↓ afterload. • Pts with cardio myopathy are at risk for vent. Arrhythmia. They should undergo a 24-hours ECG monitor on regular basis

40. Prevention of cardiotoxicity – Prolonged infusion – 2nd generation anthracyclines • Synthethic • Idarubicin, epirubicin, zorubicin • CV events comparable at similar cytotoxic levels

41. Prevention of cardiotoxicity – Use of oxygen free radical scavengers • Vitamin E, Q10-coenzyme, Vitamin C – Dexrazoxane • Chelates intracellular iron and reducing free radial levels • Reduces cardiac damage and allows higher anthracycline dosing

42. Preventing cardiotoxicity – Probucol • Vitamin E derivative • Lipid lowering • Enhances antioxidants – Liposomal formulations • Pegylated liposomal doxorubicin (Caelyx) • Drug is delivered in a liposome • Better tumor delivery and longer half life in the blood

43. Preventing cardiotoxicity Physical therapy implications – Patient education – PT awareness • History • CHF does not preclude therapeutic exercise

44. Guidelines for long-term follow up: • Frequency of testing is determined by the cumulative anthracycline doses: • Total cumulative dose (TCD)< 300 mg/m2  perform an ECHO before every other course. • TCD > 300 mg/m2 with or without mediastinal radiation  perform ECHO or MUGA every course. • After comptetion of therapy all patients should perform an ECHO at 12 months after discontinuation of therapy. • Patients with normal studies at the end of 1yr post therapy may have an ECHO, ECG every 2-3 ys. • Patients with abnormal studies should perform more follow up.

45. Cyclophosphomides • Associated with acute and subacute cardiac events • High dose regimens carry greater risk • Total dose per course best predictor of cardiotoxicity • Prior treatment with anthracycline or mediastinal irradiation increases risk • Long term affects are usually not seen in those who survive acute effects

46. 5-Fluorouracil • Acute creates ischemic insult • Clinically ranges from angina pectoris to myocardial infarction • Rechallenge generally produces same effect • Withdraw 5-FU and initiate anti-ischemic therapy • Greater risk in patients with CAD

47. Chemotherapy causing other CVeffects • Agents associated with hypotension • Etoposide (Vepesid) • Paclitaxel (Taxol) • Alemtuzumab (Campath) • Cetuximab (Erbitux) • Rituximab (Rituxan) • IL-2 • Denileukin (Ontak) • Interferon- • All-trans retinoic acid (Tretinoin) • Homoharringtonine

48. Chemotherapy causing other CVeffects • Agents associated with hypertension • Bevacizumab (Avastin) • Cisplatinin (Platinol)

49. Chemotherapy causing other CV effects • Agents associated with other toxic effects • Cardiac tamponade or endomyocardial fibrosis: busulfan (Myleran) • Hemorrhagic myocarditis: cyclophosphamide (Cytoxan) • Bradyarrhythmias: paclitaxel (Taxol), thalidomide (Thalomid) • Raynaud phenomenon: vinblastine (Velban) • Autonomic neuropathy: vincristine (Oncovin) • QT prolongation or torsades de pointes: arsenic trioxide (Trisenox) • Pulmonary fibrosis: bleomycin (Blenoxane)