1. Καρδιακή βλάβη από τη θεραπεία του καρκίνου Δημήτρης Φαρμάκης Ιατρική Σχολή ΕΚΠΑ

2. Cardiac injury related to cancer therapy Is this a real problem? What are the causes and forms of cardiac injury in cancer? When does the injury appear? Who is vulnerable? Risk factors and early indicators Is it a reversible injury? Is it a preventable injury? Cardiac consultation in cancer: in whom, when and how?

3. Is this a real problem?

4. Estimated and projected cancer survivors in USA de Moor JS et al. Cancer Epidemiol Biomarkers Prev 2013

5. Causes of death in cancer survivors Ning et al. Cancer Res 2012 Causes of death in 1807 cancer survivors followed for 7 years

6. Texas Heart Inst J 2011

7. What are the causes and forms of cardiac injury in cancer?

8. Bloom et al, Circ Heart Fail 2016 Mechanisms of chemotherapy cardiotoxicity

9. Direct toxic effects: – Cardiomyocytes (anthracyclines, trastuzumab) Loss (death/apoptosis) Dysfunction (mitochondria, contraction proteins) – Endothelial cells (5-FU) Indirect toxic effects: – Hypercoagulability (VEGF inh, alkylating agents ) – Hypertension (VEGF inh) – Arrhythmias, AFib (ifosfamide, gemcitabine, melphalan) Albini et al, J Natl Cancer Inst 2010

10. Cardiac manifestations of chemotherapy Suter & Ewer, Eur Heart J 2012

11. Cardiac manifestations of chemotherapy Suter & Ewer, Eur Heart J 2012

12. Smith et al, BMJ Cancer 2010 55 RCTs, the majority women with advanced breast cancer Clinical cardiotoxicity – anthracycline vs non-anthracycline regimens (OR 5.43) – bolus vs continuous infusion (OR 4.13) – lower risk with: epirubicin vs doxorubicin (OR 0.39) liposomal vs non-liposomal doxorubicin (OR 0.18) concomitant cardioprotective agent* (OR 0.21) * Dexrazoxane

13. N Engl J Med 2000 N=1230

14. Τopoisomerase-2β (Top2β) Vejpongsa & Yeh, J Am Coll Cardiol 2014

15. Top2b deletion protects mice Cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ): protects cardiomyocytes from DNA damage and transcriptome changes responsible for defective mitochondrial biogenesis and ROS formation protects mice from heart failure Zhang et al, Nat Med 2012

16. Increased Top2β in peripheral blood in anthracycline-sensitive patients Anthracycline-sensitive (n=21): low doxo dose ( 10% to <55%) Anthracycline-resistant (n=15): high doxorubicin (>450 mg/m 2 and preserved LVEF) Vejpongsa et al, Circulation 2013 (abstr) Top2β levels >0.5 ng/μg a risk factor

17. Trastuzumab (Herceptin) HER2 receptor antagonist

18. A mechanism of trastuzumab- related cardiac toxicity involves inhibition of the HER2:HER4 heterodimer that limits typical repair mechanisms during myocyte stress. Wells & Lenihan, Prog Cardiovasc Dis 2010

19. ErbB2 is essential in the prevention of dilated cardiomyopathy ErbB2-knock-out mice developed spontaneous dilated cardiomyopathy Cardiomyocytes isolated from these mice were more susceptible to anthracycline toxicity Crone et al, Nat Med 2002

20. Chemotherapy-induced cardiotoxicity Khakoo et al, Texas Heart Inst 2011

21. Ewer and Ewer, Nat Rev Cardiol 2015 Anthracycline-trastuzumab interaction

22. Seidman et al, J Clin Oncol 2002 CREC: Cardiac Review and Evaluation Committee LV dysfunction: Trastuzumab: 3-7% Trastuzumab+doxorubicin: 27% (16% HF ΝΥΗΑ ΙΙΙ/ΙV) Trastuzumab+paclitaxel: 13% (vs 1% paclitaxel)

23. Incidence of Heart Failure After Adjuvant Trastuzumab Therapy for Breast Cancer Chen et al, Circulation 2012 N=45,537 higher rates than those reported from clinical trials

24. Anthracyclines Hermann et al, Mayo Clin Proc 2014

25. Other chemotherapy agents Hermann et al, Mayo Clin Proc 2014

26. Human epidermal growth factor receptor-2 (HER2)–targeted agents Pimprapa et al, Circ Res 2013

27. Human epidermal growth factor receptor-2 (HER2)–targeted agents Pimprapa et al, Circ Res 2013

28. Angiogenesis inhibitors [VEGF] Pimprapa et al, Circ Res 2013

29. Angiogenesis inhibitors [VEGF] Pimprapa et al, Circ Res 2013

31. Radiation-induced cardiac injury Groarke et al, Eur Heart J 2014

32. Radiotherapy-induced cardiotoxicity Relative risk of fatal CV events: Total: 1,3 Left breast cancer: 1-2,2 Mediastinal Hodgkin lymphoma: 2-7

33. Pathophysiology of atrial fibrillation in cancer Farmakis, Parissis, Filippatos, J Am Coll Cardiol 2014

34. The “Multiple-Hit” Hypothesis Jones et al, J Am Coll Cardiol 2007

35. Determinants of cardiovascular injury in cancer patients Cancer Cancer therapy Pre-existing RF and CVD

36. When does the injury appear?

37. Suter & Ewer, Eur Heart J 2012 Temporal effects of cardiotoxic therapies

38. Cumulative incidence of cardiomyopathy in breast cancer survivors Doyle et al, J Clin Oncol 2005 Years since chemotherapy

39. Long-Term Outcomes of Adult Survivors of Childhood Cancer The Childhood Cancer Survivor Study: 10-fold higher overall mortality 8.2-fold higher cardiac mortality Mertens et al, J Clin Oncol 2001

40. Cardiac MRI in the Evaluation of the Late Effects of Anthracyclines Among Long-Term Survivors of Childhood Cancer 62 long-term survivors of childhood cancer mean age 15 years 8 years post-anthracycline: LVEF <45%: 18% ; LVEF 45-55%: 61% RV dysfunction: 27% J Am Coll Cardiol 2013

41. Cardinale et al, Circulation 2015 Detection of anthracycline-induced cardiotoxicity during close cardiac monitoring 2625 pts receiving anthracyclinechemo (breast Ca or NHL) Close monitoring (3-monthy during chemo and 1 st year, 6- monthly for 4 years, yearly afterwards) 9% LVEF decline (decrease >10% and <50%) 2% HF NYHA III-IV 0.3% hospitalized for AHF (0.2% died of AHF)

42. Time course of LVEF decline post-anthracycline chemotherapy Cardinale et al, Circulation 2015 Mean time to LVEF decline: 3.5 months 98% of cases within 1 st year 5 pts with LVEF decline at 5.5 years: 4 had CAD, 1 had additional Rth 1 year before

43. Who is vulnerable? Risk factors and early predictors

44. Anthracycline-induced cardiomyopathy Risk factors Age (children, >65 years) Pre-existing heart disease Cumulative dose – HF incidence: 5%, 16%, 26% for doxorubicin doses of 400, 500, and 550 mg/m 2 Combination chemotherapy Mediastinal radiation

45. Doxorubicin-induced heart failure Swain et al, Cancer 2003

46. Doxorubicin-induced heart failure by age group Swain et al, Cancer 2003

47. Doxorubicin-induced heart failure or LVEF decline Swain et al, Cancer 2003

48. Risk factors for radiotherapy-induced cardiotoxicity Therapy – Total dose >30–35 Gy – Fraction dose >2 Gy – Older techniques of radiation and protection – Cardiac mass in the radiation field – Combination with chemotherapy/trastuzumab Patient – Young age – Time interval since radiation – History of heart disease – Coexistence of CV risk factors

49. Anthracycline-induced cardiomyopathy Risk prediction tools Bloom et al, Circ Heart Fail 2016

50. Detection of doxorubicin induced cardiotoxicity Ewer and Ewer, Nat Rev Cardiol 2015

51. Troponin predicts cardiac events Cardinale et al, Circulation 2004 TnI measured soon after chemotherapy (early TnI) and 1 month later (late TnI).

52. Troponin predicts LVEF change Cardinale et al, Circulation 2004

53. ΝT-proBNP predicts LVEF change Cardinale & Sandri, Prog Cardiovasc Dis 2010

54. 2D strain predicts LV dysfunction early Stoodley et al, Eur J Echocard 2011 Florescu et al, J Am Soc Echocardiogr 2014 Α decrease in longitudinal strain after the 3 rd cycle of epirubicin was the best predictor of cardiotoxicity after treatment

55. Late gadolinium enhancement in anthracycline- induced cardiomyopathy Thavendiranathanet al, Circ Cardiovasc Imaging 2013

56. Mid-wall or subepicardial LGE Prevalence 0-100% Late gadolinium enhancement in anthracycline- induced cardiomyopathy Thavendiranathanet al, Circ Cardiovasc Imaging 2013

57. Myocardial fibrosis tends to be diffuse and may be missed by LGE Extracellular volume fraction (ECV) with pre- and post-contrast T1 mapping may illustrate diffuse myocardial injury Assessment of myocardial fibrosis in anthracycline-induced cardiomyopathy ECV values (mean/SD) were increased in the basal, mid, and apical short-axis images.

58. Is it a reversible injury?

59. Cardiotoxicity types I and II Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

60. Cardiotoxicity types I and II Early therapy Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

61. Cardiotoxicity types I and II CV disease Anthracyclines Early therapy Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

62. Cardinale et al, JACC 2010 201 pts, LVEF <45% due to anthracycline chemotherapy Enalapril +/- carvedilol Response rates: 42% LVEF incr. >50% - 13% LVEF incr. >10% but <50% - 45% LVEF incr. <10% but <50% Time of therapy onset a crucial determinant of response Effects of ACEi and BB on anthracycline-induced cardiotoxicity

63. Cardinale et al, Circulation 2015 Effects of ACEi and BB on anthracycline-induced cardiotoxicity 2625 pts receiving anthracycline chemo (breast Ca or NHL) Enalapril and carvedilol or bisoprolol: 82% LVEF recovery: – 11% full recovery (pre-chemo value) – 71% partial recovery (increase >5% and >50%) Mean time to LVEF recovery: 8 months

64. Is it a preventable injury?

65. Cumulative dose limitation (doxorubicin, 450mg/m 2 ) Antracycline structure (epirubicin) Antracycline delivery (liposomal) Antracycline administration (24–96 h iv infusion vs. bolus) Protective agents (dexrazoxane, antioxidants?) Radiation shielding, dosing and fractions Cardioactive agents (ACEi, ΒΒ, statins?) Suter & Ewer, Eur Heart J 2012 Prevention strategies

66. Vejpongsa & Yeh, J Am Coll Cardiol 2014 ACEi and B-blockers for primary prevention

67. Statins 628 women with breast cancer, treated with anthracycline Retrospective cohort Seicean et al, J Am Coll Cardiol 2012 HR=0.3, p=0.03 Heart Failure-Free Survival

68. Antioxidants Andreadou, …, Farmakis et al, J Mol Cell Cardiol 2014 Andreadou, et al, J Mol Cell Cardiol 2007 Oleuropein: a natural phenolic antioxidant of olive tree products prevents functional and cardiac histopathological effects of DXR in rats attenuates nitrosative and oxidative stress prevents NO homeostasis imbalance prevents the derangement of myocardial metabolism does not affect DXR anticancer activity

69. Antioxidants Andreadou, …, Farmakis et al, J Mol Cell Cardiol 2014

70. Cardiac consultation in cancer: in whom, when and how?

71. In whom? Potentially cardiotoxic cancer therapy Chemo plus radiotherapy of mediastinum or left breast History of heart disease Multiple risk factors Children and elderly

72. When? Before cancer therapy – Identification of high risk patients – Identification and treatment of lenient heart disease or risk factors – Prevention strategies During cancer therapy – Early identification and treatment of cardiovascular disorders – Modification of cancer therapy if needed After cancer therapy – Regular follow-up

73. Cumulative dose limitation (doxorubicin, 450mg/m 2 ) Modified antracycline structure (epirubicin), delivery (liposomal), infusion (24–96 h iv infusion instead of bolus) Sequential instead of concurrent administration (3 months between anthracycline and trastuzumab) Radiation shielding, dosing and fractions Protective agents (dexrazoxane) Cardioactive agents (ACEi, ΒΒ, statins?) Suter & Ewer, Eur Heart J 2012 How? Prevention strategies

74. AHA 2013 Primary and secondary prevention strategies

75. How? Management strategies Arterial hypertension: – Antihypertesive agents, continue cancer therapy (discontinue angiogenesis inhibitors in stage III hypertension) Left ventricular dysfunction: – ACEi, BB – LVEF: ≤15% decrease, >50%: continue cancer therapy – LVEF <50%: confirm in 3 w, temporal (40-50%) or permanent (<40%) discontinuation of cancer therapy, HF therapy Heart failure: – HF therapy – Confirm in 3 w, temporal (ΝΥΗΑ ΙΙ) or permanent (ΝΥΗΑ ΙΙΙ-ΙV) discontinuation of cancer therapy, HF therapy Exclude other causes or precipitating factors

76. Cardio-Oncology: an emerging field Cardiologists: oncology patients, a new challenge, not an annoying workload Oncologists/Haematologists: impact of CV disease on outcome, early referral when CV disease or RFs or cardiotoxic therapies This “osmosis” would gradually lead to a fruitful Cardio- Oncology service Farmakis, ArrhythmiaWatch 2013 http://arwatch.co.uk

77. Ongoing ESC initiatives EACVI/HFA Cardiac Oncology Toxicity Registry 2016 ESC Position Paper on Cardio-Oncology