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
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!
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