Cardiovasculaire complicaties van behandeling voor kanker

Maarten van den Berg

Afdeling Cardiologie

Thoraxcentrum

Academisch Ziekenhuis Groningen

Betrokkenheid

• Persoonlijk• Cardiologisch consulent polikliniek “Late effecten”• Hoofd echoafdeling, interesse in hartfalen -

noninvasieve diagnostiek• Onderzoek -promotieonderzoek Martin Meinardi (2001):

“Long-term chemotherapy related cardiovasvular morbidity

-promotieonderzoek Geert Tjeerdsma (2001):

Value of neurohormonal and autonomic parameters for the assessment of the severity and prognosis in chronic heart failure” -promotieonderzoek Janine Nuver

Onderwerpen/indeling

2 soorten schade:• -hartfalen - myocardschade

vroegdiagnostiek:

-VO2max

-echocardiografie, inclusief diastolische functie

-neurohormonale activatie (BNP, heart rate variability)

• vaatfalen - atherosclerose-late effecten (>10 j.)

-middellange termijn effecten

-vroege effecten (mnd.)

Beperkingen

• Wel chemotherapie, radiotherapie zijdelings• Alleen cardiovasculaire effecten

• Cardiologische invalshoek, alleen eigen expertise,

geen oncologische expertise• Volwassenen (adolescenten), geen kinderen

Gemetastaseerd testiscarcinoom -model voor vaatfalen

• goede overleving (>80%), m.n. sinds introductie van cisplatinum• presentatie op jonge leeftijd (20-40 j.)

Derhalve goed model voor late effecten, o.a.

-nefrotoxiciteit

-neurotoxiciteit

-vasculaire toxiciteit (vaatfalen)

Cardiovascular morbidity in long-term survivors of metastatic testicular cancer

Journal of Clinical Oncology 2000;18:1725-32

Meinardi, Gietema, van der Graaf, van Veldhuisen, Runne, Sluiter, de Vries, Willemse, Mulder,

van den Berg, Schraffordt Koops, Sleijfer

Afd. Oncologie, Endocrinologie, Chirurgie, Cardiologie

AZG, Groningen

RationaleRationale

• Long-term survivors of testicular cancer after treatment withcisplatin based chemotherapy can develop:

– an unfavorable cardiovascular risk-profile

- hypercholesterolaemia

- hypertension

- overweight

– Raynaud’s phenomenon

Gietema, Ann Intern Med 1992

• Long-term survivors of testicular cancer after treatment withcisplatin based chemotherapy can develop:

– an unfavorable cardiovascular risk-profile

- hypercholesterolaemia

- hypertension

- overweight

– Raynaud’s phenomenon

Gietema, Ann Intern Med 1992

Aims of studyAims of study

A. Retrospective estimation of incidence ofcardiac events in long-term survivors oftesticular cancer treated with cisplatin basedchemotherapy

B. Prospective evaluation of subclinicalcardiovascular damage and the cardiovascularrisk-profile 10 years after treatment

A. Retrospective estimation of incidence ofcardiac events in long-term survivors oftesticular cancer treated with cisplatin basedchemotherapy

B. Prospective evaluation of subclinicalcardiovascular damage and the cardiovascularrisk-profile 10 years after treatment

Patients, n=87 Patients, n=87

Median (Range)

Age at chemotherapy (yrs.) 26 (17-36)

Follow-up duration (yrs.) 14 (10-20)

Chemotherapy regimen Number (%)

PVB + maintenance PV 27 (31)PVB 13 (15)PVB/BEP 15 (17)BEP 22 (25)EP 8 (9)VIP 2 (2)

Median (Range)

Age at chemotherapy (yrs.) 26 (17-36)

Follow-up duration (yrs.) 14 (10-20)

Chemotherapy regimen Number (%)

PVB + maintenance PV 27 (31)PVB 13 (15)PVB/BEP 15 (17)BEP 22 (25)EP 8 (9)VIP 2 (2)

Incidence of cardiac eventsIncidence of cardiac events

Cardiac event Age at event

(yrs.)

Years after

chemotherapy

Cardiovascular

risk factors

MI 39 12 Hypertension

MI 42 16 Hypertension, smoker,

Positive family history

AP 36 16 Hypertension, overweight

Hypercholesterolaemia

AP 39 10 Hypertension,

Hypercholesterolaemia

AP 30 9 Hypertension

Cardiac event Age at event

(yrs.)

Years after

chemotherapy

Cardiovascular

risk factors

MI 39 12 Hypertension

MI 42 16 Hypertension, smoker,

Positive family history

AP 36 16 Hypertension, overweight

Hypercholesterolaemia

AP 39 10 Hypertension,

Hypercholesterolaemia

AP 30 9 Hypertension

Observed-to-expected ratio 7.1 (CI 1.9-18.3)

Prospective evaluationProspective evaluation

Variable Normalvalue

No. of pts withabn. result (%)

Testosterone >11 nmol/L 6 (10)

FSH < 7 U/L 42 (68)

Insuline/glucose ratio <22 13 (21)

Raynaud’s Phenomenon 22 (35)

Urinary albumin excretion <20g/min 11/55 (22)

Variable Normalvalue

No. of pts withabn. result (%)

Testosterone >11 nmol/L 6 (10)

FSH < 7 U/L 42 (68)

Insuline/glucose ratio <22 13 (21)

Raynaud’s Phenomenon 22 (35)

Urinary albumin excretion <20g/min 11/55 (22)

Prospective evaluationProspective evaluation

• Echocardiography

– systolic left ventricular function:

abnormal in 2 patients

– diastolic left ventricular function:

disturbed (E/A-ratio < 1) in 19/58 (33%) patients

– LVH in 6/55 (11%) patients

• Echocardiography

– systolic left ventricular function:

abnormal in 2 patients

– diastolic left ventricular function:

disturbed (E/A-ratio < 1) in 19/58 (33%) patients

– LVH in 6/55 (11%) patients

ConclusionsConclusions

In these testicular cancer-survivors we found:

• an increased incidence of cardiac events(O/E ratio 7.1; 95% CI 1.9-18.3)

• subclinical cardiovascular damage

– cardiac damage: diastolic dysfunction, LVH– vascular damage: Raynaud, microalbuminuria

• a persistent unfavorable cardiovascular risk-profile

In these testicular cancer-survivors we found:

• an increased incidence of cardiac events(O/E ratio 7.1; 95% CI 1.9-18.3)

• subclinical cardiovascular damage

– cardiac damage: diastolic dysfunction, LVH– vascular damage: Raynaud, microalbuminuria

• a persistent unfavorable cardiovascular risk-profile

Table 1. General characteristics

Chemotherapy Stage I Controls

Number of subjects 90 44 47

Age (yrs)

Median

Range

37

20-65

36

24-63

37

22-55

Follow-up duration (yrs)a

Median

Range

7

3-13

7

3-13

n.a.

Chemotherapeutic regimenb (N,%)

BEP

EP

BEP/VIP

BOP/VIP

BEP/PVB

73 (81)

8 (9)

4 (5)

3 (3)

2 (2)

n.a. n.a.

a: years since chemotherapy or orchidectomy for chemotherapy and stage I group, respectively

b: (B)EP: (bleomycin), etoposide, cisplatin; BOP: bleomycin, vincristine, cisplatin; PVB: cisplatin, vinblastine,

bleomycin; VIP: etoposide, ifosfamide, cisplatin

n.a.: not applicable

Table 2. Cardiovascular risk factors

Chemotherapy Stage I Controls

Normal value Number (%) of persons with abnormal result

Blood pressurea <135/85 mm Hg 18 (20) 9 (20) 4 (9)

Lipid levels

Total cholesterol

LDL-cholesterol

HDL-cholesterol

Triglycerides

<5.2 mmol/l

<3.4 mmol/l

>0.9 mmol/l

<2.3 mmol/l

53 (59)

64 (71)

43 (48)

21 (23)

22 (50)

26 (59)

20 (45)

7 (16)

19 (40)

21 (45) *

14 (30)

3 (6) *

Body mass index <27.8 kg/m2 18 (22) 12 (27) 5 (11)

Insulin-to-glucose ratio < 22 15 (17) 4 (10) 2 (4)

Urinary albumin exr. <30 mg/24h 10 (12) 1 (2) 0 (0) *

Smoking status

Current smoker

Former smoker

Non-smoker

Unknown

35 (39)

6 (7)

46 (51)

3 (3)

17 (39)

8 (18)

19 (43)

13 (28)

4 (8)

30 (64)

Positive family history 18 (20) 9 (20) 17 (36)

* chemotherapy vs controls p<0.05

a: hypertension defined as high 24-hour systolic and/or diastolic blood pressure or the use of antihypertensive

medication

Table 3. Plasma levels of endothelial marker proteins

Chemotherapy Stage I Controls

Normal

value

Median

(range)

Number

(%) of

persons

with

abnormal

result

Median

(range)

Number

(%) of

persons

with

abnormal

result

Median

(range)

Number

(%) of

persons

with

abnormal

result

Fibrinogen 3.5 g/l 3.0

(1.9–4.1)

13 (14) 2.8

(1.7–3.8) ‡

2 (5) 2.5

(1.9 – 3.4)*†

0 (0)*

vWF 150 % 108

(28–296)

21 (24) 113

(52–220)

6 (14) 91

(43–304)*†

4 (9)*

PAI-1 43 ng/ml 26.5

(3.0–183.0)

25 (28) 18.8

(4.7–118.0)

10 (23) 15.5

(2.5–67.0)*

7 (15)

t-PA 10 ng/ml 7.6

(1.5–21.0)

27 (30) 6.9

(3.2–23.0)

8 (19) 5.6

(2.3–15.0)*†

3 (7)*

PAI-1/t-PA

ratio

n.a. 3.45

(0.5–31.6)

n.a. 2.76

(1.2–9.4)

n.a. 2.62

(0.7–12.1)

n.a.

* chemotherapy vs controls p<0.05

† stage I vs controls p<0.05

‡ chemotherapy vs stage I p<0.05

n.a.: not applicable

Conclusie

“Testicular cancer patients who have been treated with cisplatinum-based chemotherapy

showed a high prevalence of microalbuminuria and hypertension, and

increased endothelial marker proteins after a median follow-up of 7 years. These early vascular changes might progress to more severe endothelial dysfunction and overt

atherosclerosis several years later”

NTvG 2003:147:457

Acute effecten, mechanismen?Pilot-studie

• 25 patienten met gemetastaseerd testiscarcinoom• leeftijd gem. 28 j. (18-48)• 4 BEP kuren (bleomycine, etoposide, cisplatinum)

• Intima-media-dikte (IMT)• Flow-mediated dilation (FMD)• von Willebrand-factor

Vaatschade door testisca. + cytostatica Mechanismen?

• Direct toxisch effect op endotheel

(cisplatinum en bleomycine) - in vitro studies

(vaatspasme, hypercoagulabiliteit?)

• testosteron-deficientie, o.a. insuline-resistentie

• ongezonde leefwijze?

Vgl. metabool syndroom X

Anthracycline - myocardschade

Von Hoff, Ann Intern Med 1979;91:710

Risicofactoren

• (hoge cumulatieve dosis)• (snelle toediening - hoge piekspiegels)• vrouwelijk geslacht• oudere leeftijd• jonge leeftijd (<4 j.)!• pre-existente hartziekte• hypertensie• bestraling

Mechanisme:

directe schade aan myocytendoor vrije radicaal-vorming (ijzer), waardooroxidatieve stress

Sawyer et al.Circulation 2002;105:1551-4

Profylaxe

• cumulatieve dosis: <450-500 mg/m2;

aanpassen bij risicofactoren, kinderen <300 mg/m2• farmacokinetiek: zoveel mogelijk continue toediening

(NB gereguleerde afgifte: gepegyleerde doxorubicine)• anthracycline analogen: epirubicine en idarubicine i.p.v

doxorubicine en daunorubicine• cardioprotectiva: dexrazoxane

• cardiologische monitoring

Cardiologische vroegdiagnostiek van hartfalen

• Biopsie• Inspanningsonderzoek: VO2max • MUGA-scan• Heart rate variability • Echocardiogram• Neurohormonen: Brain natriuretic peptide (BNP)

Echocardiogram

• Patientvriendelijk, geen stralenbelasting,

algemene informatie (incl. kleppen, rechter ventrikel)

• Systolische LV functie: wandbewegingen

fractional shortening, WMSI

ejectie fractie• Diastolische LV functie

K LASSIEK E MITRALIS-INFLOW PATRONEN

NORMAALVERTRAAGDERELAXATIE

PSEUDO-

NORMALISATIERESTRICTIEF

Early detection of anthracycline induced cardiotoxicity in asymptomatic patients

with normal left ventricular systolic function: autonomic versus

echocardiographic variables

Tjeerdsma et al. Heart 1999;81:419-423

20 vrouwen, gem. 27 mnd. na mammaca. waarvoor o.a. adriamycine

• MUGA-scan: normale systolische LV-functie (EF >.50)

• Gestoorde heart rate variability• Echo:

-normale LV-dimensies, wanddikten, wandbewegingen

-E/A ratio 0.98; 10 pt. abnormaal; diastolische dysfunctie!

Prospective evaluation of early cardiac damage induced by

epirubicin-containing adjuvant chemotherapy

and locoregional radiotherapy in breast cancer patients

J Clin Oncol 2001;19:2746-53Meinardi et al.,

CONCLUSION: “Relatively low doses of epirubicin in adjuvant chemotherapy

for breast cancer results in mild subclinical myocardial damage

demonstrated by a decline in LVEF, an increase in natriuretic peptide levels,

and an increase in QTc, which may indicate a long-term risk of CHF.”

CONCLUSIONS: “The results of this prospective study show

that during the evolution of doxorubicin-induced LV dysfunction

the secretion of natriuretic peptides is more closely associated with

the impairment of left ventricular diastolic filling

than with the deterioration of LV systolic function.”

Natriuretic peptides during the development of

doxorubicin-induced left ventricular diastolic dysfunction

Nousianinen et al., J Int Med 2002;251:228-34

Plasma levels of natriuretic peptides in relation to

doxorubicin-induced cardiotoxicity and cardiac function

in children with cancer

Med Pediatr Oncol 2001;37:4-9Hayakawa et al.,

CONCLUSIONS: “These results suggest that plasma ANP and BNP levels

could be markers for doxorubicin-induced cardiotoxicity in children.

Measurement of natriuretic peptide levels during treatment may allow

earlier-identification of individuals at risk for severe cardiac damage.”

Behandeling anthracycline-geïnduceerd hartfalen, inclusief asymptomatische

LV-dysfunctie

• Geen evidence-based-medicine (geen RCT)

• Voor de praktijk: behandelen als “gewoon” hartfalen:

-asymtomatische LV-dysfunctie: ACE-remmers

-symptomatische LV-dysfunctie: -ACE-remmers

-diuretica

-betablokkers

-HTX

CARDIOTOXICIT Y ANTINEOPLASTIC AGENTS DRUG T OXIC DOSE RANGE * COMMENTS

Doxorubicin >550 mg/m2 (total dose)>550 mg/m2 (total dose)

Congestive heart failure(cumulative toxic effect ),arrhythmiasCardiac toxicity with additionalrisk factors

Daunorubicin >550 mg/m2 (total dose) Same toxicity as doxorubicinMitoxant rone >100-140 mg/m2 (total dose) Congestive heart failure,

decreases in left ventricularejection fract ion

Cyclophosphamide >100-120 mg/kg over 2 days Congestive heart failure,hemorrhagicmyocarditis/pericarditis/necrosis

5-Fluorouracil Conventional dose Angina/myocardial infarct ionVincristine Conventional dose Myocardial infarct ionVinblastine Conventional dose Myocardial infarct ionBusulfan Convent ional oral dai ly dose Endocardial fibrosisMitomycin C Conventional dose Myocardial damage similar to

radiation-induced injuryCisplatin Conventional dose Acute myocardial ischemiaAmsacrine Conventional dose Ventricular arrhythmiasTaxol Conventional dose BradycardiaInterferons Conventional dose Exacerbates underlying cardiac

diseaseInterleukin-2 Conventional dose Acute myocardial injury,

ventricular arrhythmias,hypotension

From Holland JF: Cancer Medicine. 4t h ed. Baltimore, Wi lliams & Wilkins, 1997, p 897.*Route of administrat ion is int ravenous unless otherwise indicat ed. Conventional dose is the commonlyaccepted therapeutic range.

NB Herceptin; trastuzumab: cardiotoxisch!