Kardio-onkologi Kardiale bivirkninger av kreftbehandling

Transkript

1 Kardio-onkologi Kardiale bivirkninger av kreftbehandling Torgeir Wethal

2 Google søk: Cardio-oncology

3 Årsaker til død hos HL-overlevere Aleman BMP et al. JCO 2003;21:

4 Omfanget av problemet Norge: med kreftdiagnose (Kreftregisteret, 2016) En av de ledende årsakene til død hos langtidsoverlevere Forebygging vil kunne være viktig for å redusere forekomsten av hjerte-karsykdom etter kreftbehandling.

5 Total mortalitet hos kreftoverlevere

6 Stråleterapi Nyttig hos 50% av kreftpasientene (WHO) Nest etter kirurgi den mest effektive behandlingen av lokalisert kreft. Lymfom, seminom (testikkelkreft), carcinomer DNA er målorganet Dose: Gray (Gy) = Joule/kg LD50: 4 Gy total kroppsbestråling side 6

7 Lancellotti et al. JACC 2013;26:

8 Lancellotti et al. JACC 2013;26:

9 Lancellotti et al. JACC 2013;26:

10 Systolic dysfunction

11 Coronary artery disease Bramkamp et al, Lancet 2007;369:1762

12 Valvular disorders Lenihan and Cardinale, JCO 2012;30:

13

14 Kjemoterapi

15 Type I og II kardiotoksisitet Plana et al EHJ 2014;15:

16 Hva ser vi? Myofibriller i rotete mønster Vakuoler/blærer Programmert celledød Lim et al, J Biol Chem 2004; Lightfoot et al, Circ Cardiovasc Imgaing 2010;3:550-8

17 Anthracycliner Sterba et al. Antioxidants & Redox Signalling 2013;18:

18 Anthracyclines

19 Anthracycline-mediated cardiomyopathy stratified by genotype

20 Anthracyclin-mediert hjertesvikt Felker GM et al, NEJM 2000;342:

21 Figure 1 Trastuzumab: Mode of action The Lancet Oncology , DOI: ( /S (09) )

22 Trastuzumab (Herceptin)

23 Systolic dysfunction decreased EF Events AC-T AC-T + trastuzumab Cardiac related death Congestive heart failure >10% relative reduction in EF (0.7%) 114 (11.2%) 21 (2.0%) 196 (18.6%) TCH 4 (0.4%) 97 (9.4%) Slamon et al, NEJM 2011;365:

24 Venstre ventrikkelfunksjon etter anthracyclin og trastuzumab Narayan HK et al Circulation 2017;135:

25 Viktigheten av tidlig intervensjon Cardinale D et al. Circulation 2015;131:

26 Diagnostic value of a depressed cardiac function? Cardinale et al, JACC 2010;55:213-20

27

28 Definisjoner på kardiotoksisitet Reduksjon av LVEF > 10 prosentpoeng til en verdi for LVEF < 50% målt med ekkokardiografi eller MUGA Relativ reduksjon av global longitudinell strain med over 15% fra baseline. Ny undersøkelse bør utføres etter 2 3 uker for å bekrefte funnet. Ekkokardiografi med kontrast eller MR ved tvil.

29 Risikofaktorer for kardiotoksisitet ESC position paper EHJ 2016;37:

30 Monitorering kjemoterapi Anthracyclin Ekkokardiografi før behandling og etter avsluttet behandling > 300 mg/m 2 : Ekkokardiografi før behandling, etter avsluttet behandling, 1 og 5 år etter behandling. Kardiotoksisitet under behandling: Ekkokardiografi 1 og 5 år etter behandling. Ekkokardiografi etter hver doseøkning på over 200 mg/m 2. Herceptin Ekkokardiografi (MUGA) etter hver 4. syklus.

31

32 Monitorering Strålebehandling

33 Monitorering Norge - Lymfom Før behandling: Alder < 18 år og eldre over 60 år Strålebehandling mot mediastinum Doxorubicin > 200 mg/m 2 (alder < 18 år) Doxorubicin > mg/m 2 uavhengig av behandling Under behandling: Symptomer på hjertesvikt eller koronar hjertesykdom Alder < 18 år Oppfølging etter behandling: Pasienter som allerede har hjertesykdom Symptomer eller tegn på hjertesykdom Kronisk fatigue (anbefalt) Ekkokardiografi, MUGA.

34 Monitorering Norge - Brystkreft Før behandling: Lokalavansert HER2 negativ kreft: FEC100 (epirubicine > 200 mg/m 2 ) HER2 positive kreft: FEC100 etterfulgt av Herceptin. Under behandling: HER2 positiv kreft Etter behandling: Dersom symptomer eller tegn på hjertesykdom Ekkokardiografi, MUGA.

35 Flowchart trastuzumab (Herceptin)

36 Behandling Kontroll ekkokardiografi etter 2 3 uker Seponering av kardiotoksisk terapi (dersom mulig) Dexrazoxane, beta-blokkere, angiotensin-receptor blokkere og statiner kan brukes for tidlig behandling (og som forebyggende behandling?) Herceptin (eller tyrosine kinase inhibitors): ingen behandling Anthracycliner: behandling indisert

37 Forebyggende strategier ESC position paper EHJ 2016;37:

38 Anthracycline-mediated cardiomyopathy stratified by genotype

39 Forebyggende behandling Cardinale D et al. Circulation 2006;114:

40 Forebyggende behandling II Bosch X et al JACC 2013;61:

41 Forebyggende behandling III Kalam and Marwick EJC 2013;49:

42 Forebyggende behandling III Gulati et al. EHJ 2016;37:

43 Oppstart: Budsjett: 20 millioner kroner PRADA2 Norsk multisenter randomisert dobbeltblind placebokontrollert studie (AHUS, St. Olavs, SUS, UNN). Kvinner med brystkreft mellom 18 og 80 år som skal behandles med anthracycliner (med eller uten Herceptin) Intervensjon: Entresto i 18 måneder Effektparameter: LVEF målt med ekkokardiografi og MR.

44

45 ADVERSE CARDIOVASCULAR EFFECTS OF RADIOTHERAPY AND ANTI- NEOPLASTIC DRUGS (- = none/unknown, + = < 5%incidence, ++ = > 5% incidence) Radiotherapy (mediastinal) Alkylating agents Heart failure (acute) Ischemia (cisplatin) Valvular dysfunction Pericarditis Myocarditis Anthracyclines Antimetabolites ++ (acute) +/++ (acute) Plant Alkaloids Monoclonal antibodies Tyrosine kinase inhibitors +/++ +/++ + (acute) + (acute) + (acute) ++ + (?) (acute) + (acute) Stroke Yeh and Bickford. JACC 2009;53: Jones et al, JACC 2007;50:

46 Treatment ESC Guidelines Heart Failure 2012

47 Monoklonale antistoffer Moslehi JJ. NEJM 2016;375:

48 Monoklonale antistoffer Moslehi JJ. NEJM 2016;375:

49 Forebyggende strategier Moslehi JJ. NEJM 2016;375:

50 Methods to reveal cardiovascular damage related to the heart Electrocardiogram (ECG) Exercise-Electrocardiogram Multiple Gated Acquisition scan (MUGA) Echocardiography (incl. diastolic function and strain) Stress-echocardiography Myocardial perfusion scintigraphy Computed tomography (CT) Magnetic resonance imaging (MR) Coronary angiography Cardiospecific biomarkers (troponins, BNP)

51 Hypertension Age-adjusted odds ratios (OR) of having hypertension in different treatment groups compared with healthy controls. Bars indicate 95% CIs for OR. Sagstuen H et al. JCO 2005;23: Monoclonal antibodies (bevacizumab) and tyrosine kinase inhibitors are associated with hypertension (incidence 4 47%) Chu et al, Lancet 2007;370: Yeh and Bickford. JACC 2009;53:

52 Electrocardiogram (ECG) Adverse cardiovascular effects Radiotherapy (mediastinal) Alkylating agents Anthracyclines Antimetabolites Plant Alkaloids Monoclonal antibodies Tyrosine kinase inhibitors Ischemia (cisplatin) +/++ (acute) + (acute) + (acute) + Acute iscehmia, bradycardia, QT-interval. Signs of ischemia and arrhytmia are frequent during administration of anti-neoplastic drugs. Prospective value: Unknown A normal ECG may rule out the presence of heart failure

53 Exercise-Electrocardiogram (ECG) Identify inducible ischemia if stable angina is suspected Easy to conduct and inexpensive. Problem: False-positive tests Cardiac effects of doxorubicin in patients with leukemia % (number with abnormal test/total number of patients tested) Abnormal exercise test All patients Patients with abnormality P- value Both abnormalities Increased afterload Decreased contractility 48 (39/81) 47 (24/51) 43 (20/46) 50 (10/20) 0.80 Lipschultz et al, NEJM 1991;324:808-15

54 Multiple Gated Acquisition scan Injected radioactive substances A moving image of the beating heart is produced Left Ventricular Ejection Fraction MUGA scan Radiation exposure, limited predictive value, costs, timeconsuming Walker et al, JCO 2010;28:

55 Echocardiography Widely distributed, inexpensive, portable Measurements: cardiac function (systolic and diastolic) regional deformation/wall motion (strain) valvular function pericardial effusion (restrictive) pericarditis Problems: reproducibility predictive value Department of Cardiology

56 2D and 3D TTE versus MRI Walker et al, JCO 2010;28:

57 Diastolic dysfunction preserved EF Heidenreich AHJ 2005;150:977-82

58 Strain preserved EF Deformation assessment analysis The left ventricular wall is divided into several segments The magnitude and speed of contraction and relaxation of each segment is analysed Time-consuming, data analyses and trained personel. Huey-Ru Tsai et al. AJC 2010

59 Strain an early marker of cardial dysfunction Sawaya H et al, Am J Cardiol 2011;107:

60 Coronary artery disease Stress-echocardiography Echocardiography during administration of dobutamin or combined with an exercise test. Both methods: Myocardial perfusion scintigraphy Injection of radiolabeled substances absorbed in the myocardium and visualized by SPECT While the patient is exercising (threadmill, bicycling) Regional areas of ventricular dysfunction Time-consuming, operatordependent

61 Stress-echocardiography and myocardial perfusion imaging combined Bypass graft surgery performed in 7 patients Heidenreich et al JCO 2007;25:43-49

62 Computed tomografi (CT) Coronary artery calcium score Multi-detector or multi-slice CT (MDCT). Agatston score and Volume score considering both the density and the area/volume of the calcified plaques. A score at zero can not exclude coronary artery disease

63 CT Angiography Intra-venous contrast to visualize the coronary arteries Advantage: Non-invasive. Problems: Radiation exposure, artefacts Halvorsen et al, Tidsskr Nor Legeforen 2008;128:2172-6

64 CT Angiography in Hodgkin s lymphoma survivors (HLSs) treated with mediastinal radiotherapy CT angiography performed in 119 HLSs treated with mediastinal radiotherapy. Coronary artery abnormalities in 19 patients (16%). In 15 patients conventional angiography were not required. Only one patient had significant stenosis after conventional angiography.

65 Magnetic resonance tomography (MR) A magnetic field is applied Advantage: non-invasive Disadvantages: Intravenous contrast agents, costs, avaliability Highly accurate and reproducible measures of Left and right ventricular volume Global function Regional wall motion Myocardial thickness Myocardial mass Cardiac valves Pericardial disease

66 Coronary angiography The final method to document the presence of coronary artery disease. Stenosis in the proximal LAD Both a diagnostic and therapeutic procedure. Bramkamp et al, Lancet 2007;369:1762

67 Cardiospecific biomarkers Troponin T and I, BNP, NTproBNP, cytochrome C etc. Heart Myocyte Important predictors of longterm mortality Advantages: Inexpensive, minimally invasive, lack of interobserver variability Problems: False positive values Troponin release due to myocyte death Troponin complex bound to actin filaments Days after myocardial infarction Omland T. J Intern Med 2010;268:207-17

68 Troponin I predicts cardiovascular events in anthracycline treated patients Cardinale et al. Circulation 2004;109:

69 Troponin I predicts cardiovascular events in trastuzemab treated patients Cardinale D, JCO 2010;38: Cardinale D JCO 2010;28:

70 Persistently elevated NT-proBNP after high dose chemotherapy predicts systolic and diastolic dysfunction Diastolic dysfunction Ejection fraction Sandri et al, Clin Chem 2005;8:

71 Elevated NT-proBNP also useful to measure after low-dose anthracyclines? Romano et al, BJC 2011;105:

72 Prevention and treatment of cardiac dysfunction Reduce applied dose of anthracyclines Dexrazoxane MAO-inhibitors? Calpain inhibitor? Recombinant human Neuregulin-1? Angiography and PCI in symptomatic CAD Therapy with ACE-inhibitors, A-II antagonsists, beta-blockers and diuretics at least in symptomatic heart failure with deacresed EF < 50% or with evidence of diastolic dysfunction Genetic analyses?

73 Unsolved problems Asymptomatic left ventricular dysfunction End-point analyses Inter and intra observervariablility Reversible or irreversible? Discontinuation of anti-neoplastic therapy? When to treat? Serial measurements of biomarkers

74 Diagnostic value of a depressed cardiac function? Ewer et al, JCO 2005;23:

75 Diagnostic approach CHARACTERISTICS OF COMMON METHODS USED IN CARDIOLOGY AND NEUROLOGY AND RELATIVE RATINGS OF AVAILABILITY, COST AND ACCEPTANCE (- = poor, 0 = average, + = good, ++ = excellent) Method Main application Availability Cost Acceptance and reproducibiliy ECG/E-ECG Ischemia, arrhytmia /0 Biomarkers (Troponin, BNP) Echocardiography Ischemia, myocardial infarction, heart failure EF, wall thickness/motion, valves, diastolic function, (strain) Ultrasound Carotid stenosis, IMT MUGA EF SPECT Defect size, EF CT/CTA MR/MRA EF, wall thickness/mass, pericard, CACS, stenosis EF, wall thickness/mass/motion, valves, pericard, stenosis PET EF, wall thickness, stenosis - - +

76 Diagnostic approach Symptom-guided referral from the general practioners. At referral to the Department of Cardiology the following methods may be used an (stress) echocardiographic examination exercise-ecg perfusion myocardial scintigraphy (SPECT) Troponin and BNP measurement Ultrasound of precerebral arteries

77 Diagnostic approach The use of CT/MR cor, CT/MR angiography, coronary angiography, heart biopsy may be consider if indicated. The use of CT with the measurement of coronary artery calcium score and endothelial function testing are still undefined. An increase in cardiospecific markers during or shortly after therapy may help to identify those patients at a higher risk and were close follow-up is necessary.

78 Contributors The Norwegian Radium Hospital/University of Oslo Institute for Clinical Cancer Reasearch Sophie D Fosså Siri Lothe Hess Vigdis Opperud Milada C Småstuen Cancer clinic Alexander Fosså Harald Holte Stein Kvaløy University of Tromsø Department of Oncology Hege S Haugnes Oslo University Hospital, Rikshospitalet/University of Oslo Department of Cardiology John Kjekshus Thor Edvardsen Lars Gullestad Ola Gjesdal Research Institute for Internal Medicine Pål Aukrust Thor Ueland Department of Radiology Rune Andersen Bård Nedregaard Anne Günther Department of Respiratory Medicine May-Brit Lund

79 Mechanisms of mitochondrial membrane permeabilization. Dieter A. Kubli, and Åsa B. Gustafsson Circulation Research. 2012;111: Copyright American Heart Association, Inc. All rights reserved.