Ο ογκολογικός ασθενής και η καρδιά του

Δημήτρης Φαρμάκης

Αν. Καθηγητής, Πανεπιστήμιο Κύπρου

Καρδιακή Ανεπάρκεια & Καρδιο-Ογκολογία, ΠΓΝ «Αττικόν»

Disclosures

• Consultation fees, speaker honoraria or travel grants from

Boehringer-Ingelheim, Daiichi-Sankyo, Menarini, Novartis,

Pfizer, Servier.

Outline

• The burden

• The pathophysiology

• The spectrum

• The role of Cardiologist

• The open issues

The burden

Estimated and projected cancer survivors in USA

de Moor JS et al. Cancer Epidemiol Biomarkers Prev 2013

Causes of death in cancer survivors

Ning et al. Cancer Res 2012

Causes of death in 1807 cancer survivors followed for 7 years

Cancer

51%Heart disease

33%

Other

16%

Causes of death in breast cancer survivors

Patnaik et al, Breast Cancer Res 2011

Leading causes of death by time since breast cancer diagnosis

63,566 breast cancer women

Childhood cancer survivors in UK

Skinner et al. Lancet Oncol 2006

Kroll et al. Cancer Stats Monograph 2004

• In 2000, 26000 childhood cancer survivors in UK

• Childhood cancer survival rates, 25% in 1960s vs. 75% in 1990s

Mortality in childhood cancer survivors

• The Childhood Cancer Survivor Study

• 20,227 childhood cancer 5-year survivors, diagnosed 1970-

1986, up to 25 years follow-up

• Standardized mortality ratio (SMR):

– Overall mortality: 10.8 (10,3-11.3)

– Cardiac mortality: 8.2 (6.4-10.4)

Mertens et al, J Clin Oncol 2001

The pathophysiology

Farmakis et al. Eur J Heart Fail 2018

Determinants of cardiotoxicity in cancer

1. Effects of cancer therapy

Lenneman and Sawyer, Circ Res 2016

Main cardiotoxic agents

Ameri, Farmakis et al, Eur J Heart Fail 2018

Molecular pathways of anthracycline

cardiotoxicity

Lenneman and Sawyer, Circ Res 2016

Pathophysiology of anthracycline cardiotoxicity

Henriksen, Heart 2017

Increased Top2β in peripheral blood in

anthracycline-sensitive patients

• Anthracycline-sensitive (n=21): low doxo dose (10% to 450 mg/m2 and preserved

LVEF)

Vejpongsa et al, Circulation 2013 (abstr)

0,4

24%

Anthra-resistant Anthra-sensitive

Top2β >0.5 ng/μg

• Top2β levels >0.5 ng/μg a risk factor

Molecular pathways of ErbB2-targeted therapies

cardiotoxicity

Lenneman and Sawyer, Circ Res 2016

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

Ewer and Ewer, Nat Rev Cardiol 2015

Anthracycline-trastuzumab synergy

2. Effects of cancer

Farmakis et al, J Am Coll Cardiol 2014

Cancer and heart failure interaction

Ameri, Farmakis et al, Eur J Heart Fail 2018

Common risk factors in cancer and heart failure

Farmakis et al, Int J Cardiol 2016

3. Effects of RF and CV disease

Risk factors for cardiotoxicity

Farmakis et al, in press

Demographics Risk factors Heart disease Cancer therapy

Age 65 y

Diabetes Heart failure or LV

dysfunction

Prior antracyclines

Female gender

(anthracyclines)

Hypercho-

lesterolemia

CAD Prior chest

radiotherapy

Smoking Hypertensive HD

(LVH)

Combined

chemo/targeted

agents

Obesity Valvular HD

(mod./severe)

Combined chemo

and chest radiation

Sedentary life Cardiomyopathies Cumulative dose

(antrhacyclines)

Sign. arrhythmias

(AF, VT)

The spectrum

Myocardial dysfunction and heart failure:

Not just anthracyclines!

Farmakis et al, Eur J Heart Fail 2018

Class Drug Incidence

Anthacyclines Doxorubicin 3-48%

Alkylating agents Cyclophosphamide 7-28%

Antimicrotubule agents Docetaxel 2-13%

Monoclonal Ab Trastuzumab 1-20%

Tyrosine kinase inhibitors Sunitinib 3-19%

Proteasome inhibitors Carfilzomib 11-15%

Cancer therapy cardiotoxicity:

Not just LV dysfunction!

Farmakis et al. (in press)

Class Drug

Arterial hypertension VEGF inh.

Myocardial ischemia Fluopyrimidines, cisplatin

Thromboembolism Cisplatin, VEGF inh.

QT prolongation Arsenic trioxide, lapatinib, vandetanib

Arrhythmias Alkylating agents, taxanes, anthracyclines

Myocarditis Check-point inhibitors

Cardiovascular complications

in cancer

1. Myocardial dysfunction and heart failure

2. Coronary artery disease

3. Arrhythmias

4. Arterial hypertension

5. Valvular heart disease

6. Thromboembolic disease

7. Peripheral vascular disease and stroke

8. Pulmonary hypertension

9. Other: pericardial disease, ANS dysfunction

The role of cardiologist:

In whom, when and how?

In whom?

• Patients with a history of cardiotoxicity

• Patients with coexistent CV disease

• Patients with a constellation of CV risk factors

• Patients previously exposed to cardiotoxic therapies

When?

• Before cancer therapy:

– Optimal treatment of CV disease and risk factors

– Primary prevention measures

• During cancer therapy:

– Close monitoring for early detection of cardiotoxicity

– Timely implementation of therapeutic measures

• After cancer therapy:

– Long-term surveillance

How?

• Cardiovascular monitoring

• Prevention

• Treatment

• Long-term follow-up

Cardiovascular monitoring

ESC 2016

Cardinale et al, Circulation 2015

Echo monitoring for LVEF decline

• 2625 pts receiving anthracycline chemo (breast Ca or NHL)

• Close monitoring (3-monthy during chemo and 1st year, 6-monthly for 4

years, yearly afterwards)

• 9% LVEF decline (decrease >10% to

Early detection of cardiotoxicity

Ewer and Ewer, Nat Rev Cardiol 2015

Troponin predicts cardiac events and LVEF

decline

Cardinale et al, Circulation 2004

TnI measured soon after chemotherapy (early TnI) and 1 month later (late TnI).

ΝT-proBNP predicts LVEF decline

Cardinale & Sandri, Prog Cardiovasc Dis 2010

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 3rd cycle of

epirubicin was the best predictor of cardiotoxicity

after treatment

• >15% reduction in global longitudinal strain

2D strain predicts LV dysfunction early

• Global longitudinal strain >10-15% predicts future LVEF decline

Mougdil et al, Echocardiography 2018

Baseline 1 months 9 months

Primary prevention

ESC 2016

Dexrazoxane for primary prevention

• Meta-analysis, 10 RCTs, 1619 pts

• Reduction of heart failure by 70%

• No effect on tumor response rate, second malignancy or survival

• Inconclusive for adverse events

van Dalen et al, Cochrane Database Syst Rev. 2011

Treatment

• Myocardial dysfunction/heart failure:

– LVEF decrease >10% and 10% but >50%: repeated LVEF in 3 w

• Coronary artery disease/events:

– Patients on pyrimidine analogues: close ECG monitoring for ischemia

– Discontinuation of chemotherapy if ischemia occurs; re-challenge only when

no alternatives, pretreatment with nitrates and/or CCB

• Arterial hypertension:

– Start antihypertensive agents (avoid non-dihydropyridine CCB)

– Reduce dose or stop VEGF inhibitors if BP not controlled; re-challenge once BP

controlled

• QT prolongation:

– Stop treatment if QTc >500 ms or QTc prolonged >60 ms or dysrhythmias

ESC 2016

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

Cardinale et al, JACC 2010

• 201 pts, LVEF 50% - 13% LVEF incr. >10% but

ESC 2016

Long-term follow-up in cancer survivors

• Myocardial dysfunction: periodic screening (echo, biomarkers)

in patients treated with anthracyclines or with reversible LV

dysfunction during cancer therapy

• CAD: periodic screening in patients with mediastinal radiation,

starting 5 years post-treatment and at least every 5 years

thereafter

• Carotid artery disease: ultrasound scanning in patients with

previous neck irradiation

• Radiation-induced valvular heart disease: periodic screening

(echo) at 10 years post-radiation and every 5 years thereafter

Τhe open issues

Open issues

• Effectiveness of cardioactive agents in primary prevention

• Integration of biomarkers & sensitive echo techniques in

clinical practice

• Biomarker/echo-guided primary prevention

Exercise for primary prevention

• Theoretical background

• Benefit proven in pre-clinical studies (rodent/murine models)

• Poor clinical evidence (observational studies, CRF as main outcome)

Chen et al, Am J Physiol Heart Circ Physiol 2017

Scott et al, Circulation 2018

Trial Agent N Follow-up Endpoints

Kalay (2006) Carvedilol 12.5 50 6mo ↓ LVEF decline

↓ diastolic dysfunction

Bosch (2013)

OVERCOME

Carvedilol &

Enalapril

90 6mo ↓ LVEF decline

↓ Heat failure, death

Tashakori Behoshiti

(2016)

Carvedilol 6,25 70 During

chemo

No effect on LVEF

↓ LV strain decline

Avila (2018)

CECCY

Carvedilol 50 200 6mo No effect on LVEF

↓TnI increase

Guglin et al, Carvedilol CR or

lisinopril

470 24 monts ↓ LVEF decline only in

anthra-pretreated

Farmakis et al, in press

Main RCT on primary prevention:

Carvedilol

Main RCT on primary prevention:

Other CV agents

Trial Agent N Follow-up Results

Cardinale (2006) Enalapril 114 12mo ↓ LVEF decline

↓ MACE

Pituskin (2015) Bisoprolol

Perindopril

99 12mo ↓ LVEF decline

Gulati (2015) Candesartan 120 12-16mo ↓ LVEF decline

Akpek (2015) Spironolactone 83 6mo ↓ LVEF decline

↓ TNI and BNP increase

Acar (2011) Atorvastatin 40 RCT/6mo ↓ LVEF decline

Farmakis et al, in press

Ongoing trials

Meattini et al, Med Oncol 2017

Farmakis et al, in press

Trial Agent N Endpoints

SAFE Biosoprolol,

ramipril

480 Biomarkers, echo (GLS)

STOP Atorvastatin 90 CMR

McKennan Metformin 44 Echo (LVEF)

COG-ALTE1621 Carvedilol 250 Biomarkers, echo

TITAN Multidisciplinar

y care

Biomarkers, echo, MACE

Biomarker-guided prevention

Enalapril in Tn elevation

• ICOS-ONE, open-label RCT

• 21 Italian hospitals, 273 pts

• 1st–line anthra

• Enalapril in all or in Tn ↑

• Mixed Tn assays (T/I, low/high sens.)

• Primary outcome, Tn elevation > ULN

• 23% vs. 26% (p=NS)

• LVEF decline only in 1%

Cardinale et al, Eur J Cancer 2018

Antithrombotic therapy for AFib in cancer

Farmakis et al, J Am Coll Cardiol 2014

• Anticoagulation if CHA2DS2VASc >=2 and PTL >50,000/mm3

ESC 2016

Cardiac journey of cancer patients

Cardinale et al, Curr Cardiol Rep 2016

??

Thank you!