Klinik und Poliklinik für Kinderchirurgie · 2017-06-06 · Smith, L. A., V. R. Cornelius, et al. (2010). BMC Cancer 10: 337 CARDIOTOXICITY OF ANTHRACYCLINES 0 10 20 30 40 50 60

Klinik und Poliklinik für Kinderchirurgie

THOMAS M. SUTER

KARDIOLOGIE UND KARDIO-ONKOLOGIE

UNIVERSITÄTSSPITAL BERN, SCHWEIZ

KARDIO-ONKOLOGIE

KARDIO-ONKOLOGIE [email protected]

ONCO-CARDIOLOGY

A cardiovascular sub-specialty focused on

identifying, preventing, and treating

cardiovascular complications of cancer therapy

www.cancerandtheheart.org


CV SIDE EFFECTS OF MODERN CANCER THERAPY

„…you need to cure first…

…before you should be concerned about cardiotoxicity“

Emil J. Freireich, M.D., D.Sc. Oncologist


Arrhythmia

QT-Prolong

AP / MICardiac Dysfunction

Cardiotoxicity

Thromboembolism

Hypertension

PAODPleural EffusionPulmonary

Hypertension

SYSTEMIC CANCER THERAPY RELATED CARDIOVASCULAR SIDE EFFECTS


Arrhythmia

QT-Prolong

AP / MICardiac Dysfunction

Cardiotoxicity

Hypertension

PAODPleural EffusionPulmonary

Hypertension

Thromboembolism

SYSTEMIC CANCER THERAPY RELATED CARDIAC DYSFUNCTION/CARDIOMYOPATHY


CARDIOVASCULAR SIDE EFFECTS OF CANCER TREATMENT

Cancer Therapy

Efficacy

Side Effects

Toxicity


Suter, T. M. and M. S. Ewer, Eur Heart J 2013; 34(15): 1102-1111


Modified; Hill JA, Olson EN-.N Engl J Med 2008;358:1370-80

THE HEART – A POSTMITOTIC, COMPLEX ORGAN


INTRACELLULAR SIGNAL-TRANSDUCTION PATHWAYS MODULATING CARDIAC PROTEIN SYNTHESIS

Heineke J, Molkentin Nat Rev Mol Cell Biol 2006;7:589-600

Ras Inhib

TGF-b Inhib

Anti VEGF

Tyrosine Kinase Inh

EGFR Inhib

IGF 1 Inhib

Anti HER2

Raf Inhib

MEK Inhib

Farnesyl Transf Inhib

p38 Inhib

mTOR Inhib

HSP Inhib

Anti-Cyclin D1Anti HIF-1

HDAC Inhib


WHAT IS CARDIOTOXICITY?

• Heart Failure • Cardiac Dysfunction

• Systolic Heart Failure (HFrEF)

asymptomatic


SYSTEMIC THERAPY RELATED CARDIAC DYSFUNCTION / HEART FAILURE

Chemotherapeutics Cardiac Dysfunction Heart Failure

Anthracyclines

- Doxorubicin

- Epirubicin

2 – 12 %

4 – 15 %

Cyclophosphamide 1 %

Signaling Inhibitors

Trastuzumab 3-18 % 4 %

Lapatinib 10 % 2 %

Pertuzumab 3 – 18% 0 - 2% (9%)

Bevacizumab 3- 10 % 2-4 %

Sunitinib 8 -15 % 10 %

Sorafenib 1%

Pazopanib 7% 1%

Imatinib 2 % <1 %

Carfilzomib 19-25%

HE

R2

-In

hA

nti-V

EG

FB

cr-

Ab

l

Pro

t-

Inh

ib


Anthracyclines (-like) Toxicity Intensifiers

Doxorubicin Cyclophosphamide

Indarubicin Mitamycin-C

Epirubicin Etoposide

Daunorubicin Vincristine

Bleomycin

Mitoxantrone Ifosfamide

Signaling Inhibitors

Trastuzumab

Pertuzumab

Lapatinib

Sunitinib


days -weeks

1 y 2 y 3 y 4 y 5 y 6 y 7 y 8 y 9 y 10 y ...

ANTHRACYCLINE CARDIOTOXICITY – TIME COURSE

Early

Toxicity

Late Toxicity

Acute

Toxicity

Anthra

Heart Failure Treatment (ACE-I; BB)


Heart Failure in RTCs

Smith, L. A., V. R. Cornelius, et al. (2010). BMC Cancer 10: 337

CARDIOTOXICITY OF ANTHRACYCLINES

0

10

20

30

40

50

60

70

80

90

100

0 100 200 300 400 500 600 700 800 900

Swain et al.

Von Hoff

CH

F (

%)

Doxorubicin Cumulative Dose (mg/m2)

Von Hoff D et al. Am J Med 1977;62:200-208

Swain S et al. Cancer 2003.Singal PK et al. NEJM 1998, 339, 900-5

• Cumulative dose of doxorubicin

• Combination therapy (CT and Sig Inhibitors)

• Prior/concomitant mediastinal radiotherapy

• Age

• Previous cardiac disease

• Hypertension

• Genetic predisposition

Risk Factors


Normal

Myocyte

cytosol

extracellular

[Ca2+]i

Protein

Degradation

Protein

Synthesis

Myofibrillar

DisorganizationMyocyte

Necrosis

Myocyte

Apoptosis

[Ca2+]i [Ca2+]i

Protein

Degradation

Protein

Synthesis

Proteases Caspases

Sawyer DB, Suter TM: Circulation 2002Lim CC, Suter TM, Sawyer DB: J Biol Chem. 2004 Salvatorelli E, Minotti G: J Pharmacol Exp Ther 2013

Doxorubicin


• Dose limitation

• Continuous infusion

• Liposomal delivery systems

• Less toxic anthracyclines

• Dexrazoxane

• ACE inhibition

CARDIOTOXICITY OF ANTHRACYCLINES- PREVENTION



de Azambuja, E., Suter T.M. et al J Clin Oncol. 2014 Jun 9

ANTI-HER2 CARDIOTOXICITY


TRASTUZUMAB CARDIOTOXICITY - MECHANISMS

Strasser F, Suter TM.: NEJM 2001, 345(13): 996

HER2 in Human Heart

Force T , and Wang Y Circulation 2013;128:98-100


REVERSIBLE CARDIAC DYSFUNCTION –

CLINICAL IMPLICATIONS


PROGRESS IN CARDIO-ONCOLOGY

Slamon D. et al. N Engl J Med, 2001; 344 Piccart-Gebhart, M., et al. J Clin Oncol. 2015Romond EH et al. N Engl J Med 2005;353:1673-84

2001 Metastatic HER2 pos 2005 Adjuvant HER2 pos 2014 Adjuvant HER2 pos

0%

5%

10%

15%

20%

25%

30%

Metastatic HER2pos

HERA NSABP B-31 NCCTG N 9831 BCIRG006_Anthra

BCIRG 006_Taxo ALTTO L+T ALTTO T->L Trast

Severe Heart Failure

Card Dysfunction


Prior RX

Risk Assessment

During Rx

Avoid Toxicity

Survivor

Surveillance

CV SIDE EFFECTS – PREVENTION/REDUCTION


Prior RX

Risk Assessment

CARDIOTOXICITY – PREVENTION/REDUCTION


Prior RX

Risk Assessment



SCH-R. S. 14.07.1980

• 01.13 Mamma-Ca re pT1c,pN0(0/2),cM0,R0,G2

Ablatio re, LK-Entfernung

ER>90%, PR<1%, Hercep Test <10%,

«Luminal B, HER2-neg»

• 01.13 TTE normal

• 02.-05.13 EC x 4

• 06.13 Tamoxifen

- Dyspnoe – Spiral-Thorax-CT

- «Tamoxifen Hypersensivitätspneumonitis»

- Stopp Tamoxifen, Steroide

- Appetitlosigkeit, Dyspnoe, Abgeschlagenheit


SCH-R. S. 14.07.1980

• 01.07.13 Spital Davos - ambulant

Progrediente Symptome

- CK 68, TnI 0.311 (<0.013), ASAT 122

• 03.07.13 Tachypoe, tachykard, hypoton

IMC Spital Davos

aBGA unter 8 l O2

- pH 7.2, pO2 78, pCO2 15.6 BE -19 Lact 9.1

- CK 824, TnI 2.32, ASAT 2943


During Rx

Avoid Cardiotoxicity

Nature Medicine; 2011: 304–312



0

10

20

30

40

50

60

Pre Pre 26.10.2015 23.12.2015 13.01.2016 17.02.2016

LVEF

LVEDD

O.S. 24.10.1952

A/C Ptx+Trast Trast

Heart Failure

ACE-Inhibitor

Beta-Blocker

Heart Failure

• Invasiv ductal Breast Cancer

• pT1c (16mm) N0(0/3)(sn)(i-)cM0

• Breast conserving surgery 08.11

–ER y1%, PR <1%, Ki-67 30-35%

HER-2/neu Score +++


0

10

20

30

40

50

60

70

LV

EF

(%

) / LV

ED

D (

mm

)

LVEF

LVEDD

• Invasiv ductal Breast Cancer

• pT2 N0(0/5)(sn)(i-)M0, R0, G3

• Breast conserving surgery 08.11

–ER y1%, PR <1%, Ki-67 20%, p53-Expression <10%,

HER-2/neu 100%, Score ++

S.R. 19.11.1971

Epi/Endo Ptx+Trast Trast

Heart Failure

ACE-Inhibitor


Survivor

Surveillance



CARDIAC DYSFUNCTION / HEART FAILURE DURING AND AFTER

CANCER THERAPY

Suter, T. M. and M. S. Ewer, Eur Heart J 2013; 34(15): 1102-1111

• Anthracycline

• Risk Factors– Cumulative Dose

– Combination chemotherapy

– Prior/concomitant

mediastinal

radiotherapy

– Age

– Previous cardiac disease

– Hypertension

010203040506070

Pre 6

12

18

24

30

36

42

48

54

60

66

72

LV

EF

%

Months

Rx

010203040506070

Pre 6

12

18

24

30

36

42

48

54

60

66

72

LV

EF

(%

)

Months

Rx

• Signaling Inhibitors

• Risk Factors– Prior / concomitant anthracyclines

– Age > 50 y/o

– Previous cardiac disease

– Hypertension

– Higher BMI


CARDIOVASCULAR SIDE EFFECTS OF RADIATION THERAPY

Ischemia

Cardiac Dysfunction

Valvular Disease Pericardial Disease

Conduction Disease


THE HEART – A POSTMITOTIC, COMPLEX ORGAN


Survivor

Surveillance


Childhood Cancer Survivors

• signs of cardiotoxicity

• within 10 years after therapy

Lipshultz SE et. al. Circulation. 2013;128(17):1927-95

Van der Pal HJ J Clin Oncol. 2012 May 1;30(13):1429-37


Heart Failure

Patient

Oncology

Patient

Heart Failure

Patient

Oncology

Patient


Prior RX

Risk Assessment

• Conventional RF

• Novel RF

• Rx Preexisting Dz

ROLE OF CARDIO-ONCOLOGIST

During Rx

Avoid Cardiotoxicity

Manage Side Effects

• Co-Medication

• Early Detection

• Risk Assessment

Survivor

Surveillance

• Early Detection

• Early Treatment


CARDIAC MONITORING OF CANCER PATIENTS DURING

CANCER THERAPY

• «normal» LVEF ≥ 55%

• decrease in LVEF of >10 % points, to a value < 50%

• repeat study 3 weeks after baseline study

• LVEF with best method available (ideally 3DE)

• myocardial deformation using 2D speckle-tracking

• combination with biomarkers


CARDIO-ONCOLOGY BERN UNIVERSITY HOSPITAL

Tel. +41 31 632-5173

Email [email protected]

http://www.google.ch/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=OoUmtn6BOtJZYM&tbnid=E9qn8xRqNT2UfM:&ved=0CAUQjRw&url=http://www.kardiologie.insel.ch/de/ueber-uns/team/dr-michael-schmid/&ei=dWTWUpm0POKy0QWmkICwAg&bvm=bv.59378465,d.ZGU&psig=AFQjCNG-AxZHcg8CdSsqivEfFWmhrUIIpA&ust=1389868225863183

http://www.google.ch/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=OoUmtn6BOtJZYM&tbnid=E9qn8xRqNT2UfM:&ved=0CAUQjRw&url=http://www.kardiologie.insel.ch/de/ueber-uns/team/dr-michael-schmid/&ei=dWTWUpm0POKy0QWmkICwAg&bvm=bv.59378465,d.ZGU&psig=AFQjCNG-AxZHcg8CdSsqivEfFWmhrUIIpA&ust=1389868225863183

Klinik und Poliklinik für Kinderchirurgie · 2017-06-06 · Smith, L. A., V. R. Cornelius, et al. (2010). BMC Cancer 10: 337 CARDIOTOXICITY OF ANTHRACYCLINES 0 10 20 30 40 50 60

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