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Prevention and therapy of anthracycline cardiotoxicity Prevenzione e terapia della tossicità cardiaca da antracicline Dott. Marzia Lotrionte Università

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Presentazione sul tema: "Prevention and therapy of anthracycline cardiotoxicity Prevenzione e terapia della tossicità cardiaca da antracicline Dott. Marzia Lotrionte Università"— Transcript della presentazione:

1 Prevention and therapy of anthracycline cardiotoxicity Prevenzione e terapia della tossicità cardiaca da antracicline Dott. Marzia Lotrionte Università Cattolica del Sacro Cuore - Roma Complesso Integrato Columbus Unità per lo Scompenso Cardiaco e la Riabilitazione Cardiologica

2 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, 2005 INTRODUZIONE

3 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.

4 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

5 Impaired Cardiac Function in Cancer Survivors After Anthracyclines Steinherz LJ, et al. JAMA. 1991;266: Acute 1 Year Early Dx Severe Mild moderate 10 Years and Beyond 7-9 Years 4-6 Years Overall incidence of abnormal systolic cardiac function (%) 50

6 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 lultima somministrazione a) ad esordio precoce: - durante o entro 1 aa dal termine tp - incidenza % - 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: CLASSIFICAZIONE

7 - 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 2002 FATTORI DI RISCHIO

8 Swain SM et al. Cancer 2003;97: Von Hoff DD et al. Ann Intern Med 91: , % vs 3% 26% vs 7% 450 mg/m 2 Doxorubicina: dose cumulativa ed insufficienza cardiaca

9 J Clin Oncol 2005;23: Fattori di rischio clinico-dipendenti

10 J Clin Oncol 2005;23: Fattori di rischio clinico-dipendenti

11 MECCANISMI PATOGENETICI DI CARDIOTOSSICITA

12 Type I (eg, Doxorubicin) Type II (eg, Trastuzumab) Cellular death Biopsy change (vacuoles, necrosis, myofibrillar disarray) Damage starts with the first administration Cumulative dose-related Permanent and irreversible damage (myocyte death) Risk factors: Combination CT Prior/concomitant RT Age Previous Cardiac disease Hypertension Cellular dysfunction No typical anthracycline-like biopsy change Not-cumulative dose related Predominantly reversible (myocyte dysfunction) Risk factors: Prior/concomitant anthracyclines or paclitaxel Age Previous cardiac disease Obesity (BMI >25 kg/m 2 ) Ewer and Lippman, JCO 2005; Tipi di Cardiotossicità da chemioterapici

13 Maggioni, aprile 1998 SOPRAVVIVENZA

14 Cleland JGF Heart August 2008 Vol 94;8 Mortalità a 2 aa nei pazienti con Scompenso Cardiaco nei recneti trials clinici

15 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: MONITORAGGIO CARDIACO (1)

16 Strategie future - HEART RATE VARIABILITY - analisi spettrale e domini di tempo da ECG Holter - indice indipendente di mortalità e morbilità in CMpost-ischemica - ulteriori studi per la specificità Van de Graaf WT et al, Heat 1999;81: MARKERS BIOUMORALI - Troponine - NT-proBNP Morandi P et al, Ital Heart J 2003;4: MONITORAGGIO CARDIACO (2)

17 Cardinale et al. Circ. 2004;109: Troponin I is valuable in detecting Cardiotoxicity

18 Cipolla CM et al, Clinical Chemistry2005;51: NT-proBNP E DISFUNZIONE CARDIACA

19 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.

20 TDI E DISFUNZIONE SISTOLICA

21 TDI E DISFUNZIONE DIASTOLICA

22 Dose cumulativalimitazionilimitazioni Schedule modificatesettimanali infusioni Rilascio selettivoliposomi Agenti cardioprotettivicarvedilolo ace-inibitori suppl nutrizionali bone marrow cells Wexler, Semin Oncol 1998:25: 86 POTENZIALI STRATEGIE PREVENTIVE

23 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

24 Formulations of Liposomal Anti-Cancer Agents Clinically Tested PegylatedNon-PegylatedRegional therapyNon-cytotoxic Caelyx (PLD)MyocetDepoCyt (intrathecal)L-MTP-PE PLD with DSPCDaunoXomeL-NDDP (intrapleural)Liposomal ATRA MCC-465 Immunoliposome Liposomal Annamycin Liposomal Camptothecin (aerosol) BLP25 Liposomal Vaccine SPI-077Liposomal Vincristine Liposomal IL2 (aerosol)) Liposomal antisense ODN LipoplatinLurtotecan/ OSI-211 Liposomal E1A (intra-tumoral) S-CKD602OSI-7904L (TS inhibitor) Nanolip. CPT-11LE-Paclitaxel

25 Doxorubicina convenzionale vs Myocet (3)

26 R Ruolo della Doxorubicina liposomiale non-pegilata

27 IMPATTO DI MYOCET SU FREQUENZA CARDIACA E GITTATA CARDIACA ESC submitted

28 Ruolo protettivo degli ace-inibitori

29 Carvedilol appears protective during adriamycin based chemotherapy Kalay et al. JACC. Dec : Data expressed as mean values.

30 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

31 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

32 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

33 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.

34 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.

35 APPROCCIO PREVENTIVO E TERAPEUTICO

36

37 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 anthracyclines derivates and standard therapy of heart failure all patients in medium-high risk class.

38 MODELLO DI RISK-SCORE

39 Grazie della vostra attenzione! Per ulteriori slides:


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