Prevention and therapy of

anthracycline cardiotoxicity

Prevenzione e terapia della tossicità

cardiaca da antracicline

Dott. Marzia LotrionteUniversità Cattolica del Sacro Cuore - Roma

Complesso Integrato ColumbusUnità per lo Scompenso Cardiaco e la Riabilitazione Cardiologica

mlotrionte@gmail.com

Le antracicline, antibiotici glicosidici, rappresentano una classe di agenti citotossici efficaci nel trattamento di un ampio spettro di neoplasie tra cui il carcinoma della mammella

Il loro potenziale terapeutico è limitato dallo sviluppo di cardiotossicità, che può indurre a scompenso cardiaco irreversibile

Ne consegue un aumento della morbilità e mortalità dei pazienti sottoposti a tale trattamento chemioterapico

Lipshultz et al, 2005Lipshultz et al, 2005

INTRODUZIONE

DEFINIZIONE The cardiac review and evaluation committee supervising

trastuzumab clinical trials, which defined drug-associated cardiotoxicity as one or more of the following:

– 1) cardiomyopathy in terms of a reduction in left ventricular ejection fraction (LVEF), either global or more severe in the septum;

– 2) symptoms associated with heart failure (HF);

– 3) signs associated with HF, such as S3 gallop, tachycardia, or both;

– 4) reduction in LVEF from baseline that is in the range of less than or equal to 5% to less than 55% with accompanying signs or symptoms of HF, or a reduction in LVEF in the range of equal to or greater than 10% to less than 55%, without accompanying signs or symptoms.

This definition does not include subclinical cardiovascular damage that may occur early in response to some chemotherapeutic agents.

Thus, to date, an ideal definition is lacking.

And the estimated risk of anthracycline-induced clinical heart failure increased with time to 5.5% at 20 years after the start of anthracycline therapy.

In patients treated with a cumulative anthracycline dose of 300mg/m² or more the risk was even higher, almost 10%.

The incidence of anthracycline-induced asymptomatic cardiac dysfunction has been reported to be more than 57% at a median of 6.4 years after treatment.

INCIDENZA

Impaired Cardiac Function in Cancer Survivors After

Anthracyclines

Steinherz LJ, et al. JAMA. 1991;266:1672-1677

0

20425

60

875

10100

Acute 1 Year

Early DxSevere

Mild moderate

10 Years and Beyond

7-9 Years

4-6 Years

Ove

rall

inci

denc

e of

ab

norm

al s

ysto

lic c

ardi

ac

func

tion

(%)

50

ACUTA: subito dopo la prima somministrazione

- età più avanzata

- singola grossa dose

- spesso reversibile

-palpitazioni, dolore toracico, anomalie ECG, aritmie SV e V, ipotensione, mio-

pericardite

SUBACUTA: da giorni a settimane dopo il trattamento

- rara e spesso asintomatica

- percicardite tossica e/o miocardite

CRONICA: mesi o anni dopo l’ultima somministrazione

a) ad esordio precoce: - durante o entro 1 aa dal termine tp

- incidenza 1.6-2.1%

- più maligna

- sintomi e segni clinici di SCC

b) ad esordio tardivo: - decenni per svilupparsi

- incidenza a 6 aa: 65%

- mortalità 30-60%

- 4 volte più frequente sesso F

- sintomi e segni clinici di SCC

Lipshultz SE et al. BJH 2005; 131:561-Lipshultz SE et al. BJH 2005; 131:561-578578

CLASSIFICAZIONE

- fattori legati al farmaco: combinazione con altri chemioterapici

sequenza di somministrazione

modalità di somministrazione

dose cumulativa somministrata

- fattori legati al paziente: età > 60 anni

sesso F

RT mediastinica

pregressa chemiotp con Ant

valvulopatie e/o cardiomiopatie pregresse

ipertensione arteriosa

disordini elettrolitici

predisposizione genetica

Kremer LC, et al. Ann Oncol 2002Kremer LC, et al. Ann Oncol 2002

FATTORI DI RISCHIO

Swain SM et al. Cancer 2003;97:2869-2879 Swain SM et al. Cancer 2003;97:2869-2879

Von Hoff DD et al. Ann Intern Med 91:710-717, 1979Von Hoff DD et al. Ann Intern Med 91:710-717, 1979

5%

vs

3%

26%

vs

7%

450 mg/m2

Doxorubicina: dose cumulativa ed insufficienza

cardiaca

J Clin Oncol 2005;23:7811-19J Clin Oncol 2005;23:7811-19

Fattori di rischio clinico-dipendenti

J Clin Oncol 2005;23:7811-19J Clin Oncol 2005;23:7811-19

Fattori di rischio clinico-dipendenti

MECCANISMI PATOGENETICI DI

CARDIOTOSSICITA’

Type I (eg, Doxorubicin)Type I (eg, Doxorubicin) Type II (eg, Trastuzumab)Type II (eg, Trastuzumab)

Cellular deathCellular death

Biopsy change (vacuoles, Biopsy change (vacuoles, necrosis, myofibrillar disarray)necrosis, myofibrillar disarray)

Damage starts with the first Damage starts with the first administrationadministration

Cumulative dose-relatedCumulative dose-related

Permanent and irreversible Permanent and irreversible damage (myocyte death)damage (myocyte death)

Risk factors:Risk factors:Combination CT Combination CT

Prior/concomitant RTPrior/concomitant RTAgeAge

Previous Cardiac diseasePrevious Cardiac diseaseHypertensionHypertension

Cellular dysfunctionCellular dysfunction

No typical anthracycline-like No typical anthracycline-like biopsy changebiopsy change

Not-cumulative dose relatedNot-cumulative dose relatedPredominantly reversible Predominantly reversible

(myocyte dysfunction)(myocyte dysfunction)

Risk factors:Risk factors:Prior/concomitant anthracyclines Prior/concomitant anthracyclines

or paclitaxelor paclitaxelAgeAge

Previous cardiac diseasePrevious cardiac diseaseObesity (BMI >25 kg/mObesity (BMI >25 kg/m22))

Ewer and Lippman, JCO 2005;2900-02Ewer and Lippman, JCO 2005;2900-02

Tipi di Cardiotossicità da chemioterapici

Maggioni, aprile 1998Maggioni, aprile 1998

SOPRAVVIVENZA

Cleland JGF Heart August 2008 Vol 94;8Cleland JGF Heart August 2008 Vol 94;8

Mortalità a 2 aa nei pazienti con Scompenso Cardiaco nei recneti trials clinici

Strategie convenzionali:- ELETTROCARDIOGRAMMA

alterazioni ST-T, aritmie SV e V, anomalie QRS, dispersione

QTc bassa sensibilità e specificità

- ECOCARDIOGRAMMA

- MUGA

EF, funz diastolica, dimensioni V

influenzata da pre e post-carico

buona sensibilità, bassa specificità

associata a radionuclidi o dobutamina

- BIOPSIA ENDOMIOCARDICA VENTRICOLARE

alta sensibilità e specificità

invasiva

errori di campionamento

mancanza di expertise universali

Morandi P et al, Ital Heart J 2003;4:655-667Morandi P et al, Ital Heart J 2003;4:655-667

MONITORAGGIO CARDIACO (1)

Strategie future

- HEART RATE VARIABILITY

- analisi spettrale e domini di tempo da ECG Holter

- indice indipendente di mortalità e morbilità in CM post-ischemica

- ulteriori studi per la specificità

Van de Graaf WT et al, Heat 1999;81:419-23

-MARKERS BIOUMORALI

- Troponine

- NT-proBNP

Morandi P et al, Ital Heart J 2003;4:655-667

MONITORAGGIO CARDIACO (2)

Cardinale et al. Circ. 2004;109:2749-2754

Troponin I is valuable in detecting Cardiotoxicity

Cipolla CM et al, Clinical Chemistry2005;51:1405-1410Cipolla CM et al, Clinical Chemistry2005;51:1405-1410

NT-proBNP E DISFUNZIONE CARDIACA

POSSIBILI FUTURI MARKERS

The diagnostic and prognostic value of other biomarkers used to monitor cardiovascular damage, such as myeloperoxidase should also be validated for clinical use in cardio-oncology.

Genomics, proteomics, and/or recently identifi ed oligoclonal B-cell repertoires may provide us with genomic profiLes and serological biomarkers for assessment of cardiotoxicity in the foreseeablE future.

TDI E DISFUNZIONE SISTOLICA

TDI E DISFUNZIONE DIASTOLICA

Dose cumulativa limitazioni limitazioni

Schedule modificate settimanali

infusioni

Rilascio selettivo liposomi

Agenti cardioprotettivi carvedilolo

ace-inibitori

suppl nutrizionali

bone marrow cells

Wexler, Semin Oncol 1998:25: 86Wexler, Semin Oncol 1998:25: 86

POTENZIALI STRATEGIE PREVENTIVE

DERIVATI LIPOSOMIALI DELLE ANTRACICCLINE

Liposomal preparations of athracyclines also show promise in reduction of cardiac toxicity

Liposomes are preferentially taken up by tissues enriched in phagocytic reticuloendothelial cells

In a retrospective analysis of 8 phase I and II clinical trials, there was not a clinically significant decrease in EF in 41 patients treated with 500 mg/m2

In many trials, it appears to be as effective as standard doxorubicin

Formulations of Liposomal Anti-Cancer Agents Clinically Tested

Pegylated Non-Pegylated Regional therapy Non-cytotoxic

Caelyx (PLD) Myocet DepoCyt (intrathecal) L-MTP-PE

PLD with DSPC DaunoXome L-NDDP (intrapleural) Liposomal ATRA

MCC-465 Immunoliposome

Liposomal Annamycin

Liposomal Camptothecin (aerosol)

BLP25 Liposomal Vaccine

SPI-077 Liposomal Vincristine

Liposomal IL2 (aerosol))

Liposomal antisense ODN

Lipoplatin Lurtotecan/OSI-211

Liposomal E1A (intra-tumoral)

S-CKD602 OSI-7904L (TS inhibitor)

Nanolip. CPT-11 LE-Paclitaxel

Doxorubicina convenzionale vs Myocet (3)

R

Ruolo della Doxorubicina liposomiale non-pegilata

IMPATTO DI MYOCET SU FREQUENZA CARDIACA E

GITTATA CARDIACA

ESC 2010 - submitted

Ruolo protettivo degli ace-inibitori

Carvedilol appears protective during adriamycin based chemotherapy

Kalay et al. JACC. Dec 2006. 48:2258-62Data expressed as mean values.

DEXRAZOXANE

Dexrazoxane is an oral iron chelator

It prevents the formation of the semiquinone-iron which leads to reactive oxygen production

It has been tested in multiple clinical trials and has been shown to reduce cardiac toxicity

In 2 randomized controlled trials performed in metastatic breast cancer, 289 patients being treated with FDC and 249 were FDC + dexrazoxane.

Symptomatic CHF developed in 8% of the placebo group versus 1% of the dexrazoxane group

Similar results were seen in other trials using FEC for metastatic breast cancer and epirubicin for sarcoma

RACCOMANDAZIONI ASCO

Not recommended for initial therapy

Breast patients receiving more than 300 mg/m2 of doxorubicin

Consideration in patients with other malignancies receiving more than 300 mg/m2 of doxorubicin

Cardioprotective agent coenzyme Q10.

-one small RCT

-only asymptomatic cardiac dysfunction was assessed, which occurred in none of the children

-Tumor response, survival and adverse effects were not evaluated in this study

AGENTI ANTIOSSIDANTI

POSSIBILI FUTURI FARMACI CARDIOPROTETTIVI (1)

Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, Kanamori H, KhaiNC, Maruyama R, Ogino A, Minatoguchi S, Fujiwara T, Fujiwara H. Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin induced cardiomyopathy. Circulation. 2006;113:535–543.

Li K, Sung RY, Huang WZ, Yang M, Pong NH, Lee SM, Chan WY, Zhao H, To MY, Fok TF, Li CK, Wong YO, Ng PC. Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin. Circulation. 2006;113:2211–2220.

Neilan TG, Jassal DS, Scully MF, Chen G, Deflandre C, McAllister H, Kay E, Austin SC, Halpern EF, Harmey JH, Fitzgerald DJ. Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without ompromising tumour suppression. Eur Heart J. 2006;27:1251–1256.

POSSIBILI FUTURI FARMACI CARDIOPROTETTIVI (2)

Lipid-lowering agents have been indicated as protective agents against anthracycline-mediated cardiotoxicity ( 92 ), and, in particular, statins seem to have a chemopreventive and direct antitumor effect ( 93 , 94 ).

Whether statins may have protective or harmful effects on cancer risk is still a matter of debate, but the most recent reviews of the literature suggest that these drugs do not have short-term negative consequences on cancer risk ( 95 ).

Moreover, they can have an antithrombotic effect ( 96 ) that could lower the risk of thrombosis induced by anticancer treatment.

APPROCCIO PREVENTIVO E TERAPEUTICO

CONCLUSIONI

To date, no guidelines have been developed specifically for the definition, detection, or therapy of cardiotoxicity from antineoplastic therapy, so it is imperative that these guidelines be defined.

Meanwhile, cancer patients with cardiovascular diseases should be treated based on the guidelines published by the American College of Cardiology and American Heart Association ( www . acc . org / quality and science / clinical / statements . htm ).

We suggest the need to develop a clinical risk-score of an integrated multidisciplinary approach to treat with lyposomal anthracycline’s derivates and standard therapy of heart failure all patients in medium-high risk class.

MODELLO DI RISK-SCORE

Grazie della vostra attenzione!

Per ulteriori slides:http://www.metcardio.org/slides.html