Antracyclines et sujet âgé

Transcription

1 Antracyclines et sujet âgé Etienne GC Brain, MD PhD Medical Oncology Hôpital René Huguenin / Institut Curie Saint-Cloud, France

2 Facts about anthracyclines Cornerstone for treatment of MBC and EBC No. Relapse Relative Absolute Death Relative Absolute Anthracyclines > CMF 6, ± ± ± ± 1.2 However, mostly < 60 years since very few data beyond Chemotherapy < 5% 1,224/28,764 Anthracyclines < 2% 213/14,971 EBCTCG. Lancet 1998 & 2005

3 CHOP q3w x 8 (197) DLBCL L A CHOP q3w + rituximab x 8 (202) GELA & LNH98-5

4 Fig 1. (A) Event-free survival, (B) progression-free survival, and (C) overall survival with a median followup of 5 years in patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and rituximab plus CHOP (R-CHOP) Feugier, P. et al. J Clin Oncol; 23: Copyright American Society of Clinical Oncology

5 CHF induced by anthracyclines Cause HR (95%CI) P Idiopathic 1.00 Peripartum 0.31 ( ) 0.05 Hypertension 0.74 ( ) 0.42 Myocarditis 1.05 ( ) 0.82 Connective disease 1.75 ( ) 0.04 Ischemic heart 1.52 ( ) 0.02 Anthracyclines 3.46 ( ) HIV 5.86 ( ) <0.001 Infiltrative myocardial disease 4.40 ( ) <0.001 Median OS if A-related = 1 yr (age: +20%/decade) Felker. New Engl J Med 2000

6 Doxorubicine, CHF and age 630 patients (3 phase III) with 32 CHF 26% >550 mg/m² >50%: reduction of LVEF <30% w/ct HR age 2.25 ( ) vs 3.28 ( ) if >400 mg/m² Cumulative proportion with event 1.0 Hazard ratio (>65: 65) = % CI of (>65: 65) = ( ) Log rank p-value = Wilcoxon p-value = 0.78 > *Patients at risk * >65* 172! Cumulative dose of doxorubicin (mg/m 2 ) Swain. Cancer 2003

7 Onset & dose Heterogeneous cohort of 2,625 patients receiving A Cardiotoxicity: LVEF decrease >10 absolute points and <50% Median follow-up 5.2 ( ) years Overall incidence of cardiotoxicity = 9% (n=226) Median time between end of chemo and cardiotoxicity: 3.5 (3-6) mths In 98% of cases (n=221): within the first year Recovery Partial (LVEF increase >5 absolute points and >50%) 160 (71%) patients Full (LVEF increase to the baseline value) 25 (11%) patients Multivariable analysis End of chemo LVEF (HR 1.37; 95%CI ) Cumulative DXR dose (HR 1.09; 95%CI, ) Cardinale. Circulation 2015

8 Anthracyclines cardiotoxicity 3 types of anthracycline-induced cardiotoxicity Acute (ECG, arrhythmia, pericarditis, myocarditis) rare and usually reversible Early-onset and late-onset chronic Oxydative stress multiple non reversible & cumulative damage to myocytes 1. Free radicals 2. Induction of apoptosis 3. Changes in intracellular ATP production (contractility) 4. Depression of cardiac glutathion peroxydase activity 5. Mitochondrial damage (respiratory defects and interaction w/ topo-ii) 6. Down regulation of mrna production for sarcoplasmic reticulum calcium ATPase Dilated cardiomyopathy Insidious subclinical Systolic dysfunction Left sided CHF 2-5 years > treatment Median survival ~ 1 year Early signs Impaired diastolic function Biomarkers (CK-MB, NT-proBNP) Ewers. J Clin Oncol 2008; Singal. New Engl J Med 1998 Dodos. Clin Res Cardiol 2008

9 DXR, PK and age 37 patients w/ DXR Early clearance 1.h -1, m patients w/dxr CL 63.6+/-22.7 L/h Decreased w/ age p< Age (years) Robert. Cancer Res 1983; Rudek. Eur J Cancer 2004

10 The incidence of CHF from the Finnish Herceptin Study (FINHER), Herceptin Adjuvant trial (HERA), Breast Cancer International Collaborative Group trial 006 (006) with TCH and AC-TH analyzed separately, the North Central Cancer Treatment Group trial 9831 (N9831), and NSABP B-31 (B-31). Bird B R H, Swain S M Clin Cancer Res 2008;14:14-24 NSABP B31 Age 2% < 50 yo vs 5.4% > 60 yo LVEF > 4 AC 12% if LVEF < 55%) Concomitant > sequential Hypertension comedications B31/N % pts who had completed AC had a lower LVEF or developed cardiac symptoms preventing the initiation of TZT 1/3 pts who started TZT discontinued it: 4.7% with symptomatic CHF, 14.2% with confirmed asymptomatic decline in LVEF, and the rest for noncardiac reasons 2008 by American Association for Cancer Research

11 SEER database and NHL 6,388 patients 65+ w/ DLBCL , SEER 31.9% diabetes, 73.1% high blood pressure (HBP), 53.6% hyperlipidemia, 2.1% myocardial infarction, 22.2% pre-existing CHF, 50.9% pre-existing heart disease 4,001 (42%) w/ DXR Increase in risk of CHF w/ DXR (HR 1.29, 95% CI, ) Age Prior heart disease Comorbidities Diabetes HBP (HR 1.8; P <.01) 8-yr CHF-free survival: 74% (+DXR) vs 79% (no chemo) Hershmann. J Clin Oncol 2008

12 Weighted Kaplan-Meier curve of congestive heart failure (CHF) free survival in patients treated with doxorubicin compared with patients receiving no chemotherapy (P =.001). Dawn L. Hershman et al. JCO 2008;26: by American Society of Clinical Oncology

13 Decrease risk of CHF Infusion ( 6 hr vs shorter) HR 0.27 (95% CI ) Analogs (epirubicin) HR 0.36 (95%CI ) Efficacy dose/dose? Liposomal formulations HR 0.20 (95% CI ) HR 0.38 (95%CI ) subclinical Iron chelating agent dexrazoxane HR 0.29 (95% CI ) β- and ACE inhibitors Replace AC in adjuvant and metastatic settings van Dalen. Cochrane Database Syst Rev 2006 & 2008

14 Anthacyclines and schedules Metanalysis 6 randomised controlled trials 625 patients (adults and children) Results Lower rate of CHF if infusion duration 6 hours vs shorter infusion duration: HR 0.27; 95% CI No difference for RR: HR 0.83; 95% CI OS: HR 1.42; 95% CI Weekly: no answer van Dalen. Cochrane Database Syst Rev 2006

15 Liposomal DXR AC MC p Cardiotoxicity (%) Median cumulative DXR dose (mg/m²) 480 2, Median TTP (mth) NS Median TTF (mth) NS Maintenance of anti-tumour effect Privileged position given the combination w/other targeted cardiotoxic agents (HER2+) Lower rate of CHF HR 0.38; 95% CI Batist. J Clin Oncol 2001; Chan. Ann Oncol 2004 van Dalen. Cochrane Database Syst Rev 2006

16 PLD & EBC: CAPRICE study Phase II single-arm primary chemo PLD 35 mg/m² + CPA 600 mg/m/² x 4 Cy PTX 80 mg/m/² qw x pts w/ 1 risk factor for developing cardiotoxicity 84% 65+, 64% HBP, 10% cardiac disease Close cardiac monitoring & pcr (primary endpoint) pcr breast 32% (95 % CI %) pcr + axilla 24% (95 % CI %) Conservative surgery: 26% 58.7% No significant decrease in LVEF Gil Gil. BCRT 2015

17 PLD & NHL 80 patients 60+ (median 69) R-CHOP + PLD All except 1 had additional cardiac risk factors for DXRinduced cardiac toxicity Cardiac events Grade 3: 3 pts (4%) Grade 1-2 (~ asymptomatic LVEF declines): 16 pts (20%) 1 death Oki. Clin Lymphoma Myeloma Leuk. 2015

18 Fig 1. Disease-free survival (DFS) and overall survival (OS) (A) DFS by treatment; (B) DFS by treatment and age; (C) OS by treatment: 1 day; (D) OS by treatment and age Jones, S. et al. J Clin Oncol; 27: Copyright American Society of Clinical Oncology

19 Cardiac events BCIRG 006 Slamon. NEJM 2011

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21 «Standards» HER2- HER2+ Séquentiel A T Séquentiel A T 3 FEC TXT 3 FEC TXT + TRASTU 4 AC + 4 TXL 4 AC + 4 TXL + TRASTU Combinaison A + T «Mono» 6 TAC 4 TC + TRASTU «Mono» 4-6 FEC 100 (PACS 05?) 4 TC TXL hebdo + TRASTU Alternatif 6 TCH 4 AC et 6 CMF 4 TC + TRASTU 4 TC TXL hebdo + TRASTU? Anthracyclines liposomales?

22 CHOP & dexrazoxane Retrospective series 180 patients treated between , R-CHOP Prognostic factors for CHF and impact of empirical cardioprotection by dexrazoxane (45% of patients in second period ) Cardiac events: decline in resting LVEF <50%, decline in LVEF of 20% from baseline Results 5-year cumulative risks of cardiac events: 29% vs 8% Clinical CHF: 17% vs 1 5% Multivariate analysis: protective factors of cardiac events Use of dexrazoxane (HR = 0 1 [ ], P = 0 02) Age < 60 years (HR = 0 4 [ ], P = 0 03) Lima. J Clin Pharm Ther. 2014

23 Prophylactic interventions vs control Review from 14 published articles (n=2,015 paediatric and adult patients, 12 RCT + 2 observational studies) Patients with normal LVEF and no past history of CHF Control vs prophylaxis Cardiac events: 304 vs 83 (RR=0.31 [95% CI: ], p< ) Cardio protection Dexrazoxane (RR=0.35 [95% CI ], p< ) Beta-blockade (RR=0.31 [95% CI ], p=0.001) Statin (RR=0.31 [95% CI ], p=0.01) Angiotensin antagonists (RR=0.11 [95% CI ], p<0.0001) Kalam. EJC 2013

24 High blood pressure and LVEF 208 patients w/ NHL receiving conventional DXR LV systolic dysfunction (LVSD) Decrease of LVEF < 50% and > 10% from baseline Pre-existing HBP LVSD (19.7% vs. 6.6%; P =.004) More delays of chemo cycles (26.8% vs. 14.6%; P =.03) More DXR dose reductions (18.3% vs. 8.8%; P =.05) More chemo discontinuation (16.9% vs. 7.3%; P =.03) The most important risk factor for developing new LVSD after (R)-CHOP chemotherapy Szmit. J Am Soc Hypertens. 2014

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28 SIOG Treviso Advanced Post Graduate Course 2 editions in 2014 & rd edition 29/6-2/7/2016 Course Director: S. Monfardini (IT) Course Coordinator: G. Colloca (IT) Young Geriatricians and Oncologists will be the messengers of the integrated approach Clinical Oncology Faculty (TBC): M. Aapro (CH),R. Audisio (UK), L. Balducci (USA), E. Brain (FR), A. Brunello (IT), A. Hurria (US), L. Lozza (IT), A. Luciani (IT), P. Soubeyran (FR), T. Wildes (US) Geriatric Faculty (TBC): M. Hamaker (NL), S. Rostoft (NO), E. Marzetti (IT) Study Centre Achille & Linda Lorenzon

29 FEC, AACR, FAC, ASCO, anti-pdl1, anti-pd1, CMF, DXR, PK/PD, CEX, 5FU CDDP, Calvert AUC, ESMO, Chatelut AUC, CTC, TILs, population PK, EORTC, FOLFIRI, ctdna, FOLFOX 7, CPA, DFS, CALGB, DDFS, OS, TTP, NCI, CYP P450, JCO, JNCI, HER2, PI3K, mtor, Phase 0, ECCO, ib and ab, Unicancer, etc. Charlson, CIRSG, CGA, MNA, GDS, MMS, ADL, IADL, GFI, CMR2, JAGS, EUGMS, G8, CARG, Oncodage, VES-13, TRFs, JGO, NIA, SoFOG, Walter s score, Lee s score, CRASH, etc.

30 FEC, FAC, SoFOG, ADL, IADL, CMF, DXR, PK/PD, CEX, G8, EORTC, 5FU CDDP, Calvert and Chatelut AUC, GDS, population PK, FOLFIRI, MMS, FOLFOX, CPA, CRASH, DFS, OS, TTP, NCI, GERICO, TILs, CARG, anti-pdl1, anti-pd1, EORTC TFE, JCO, JNCI, Charlson, JGO, CIRSG, ctdna, EGS, EGA, MNA, GFI, Unicancer, Lee s score, JAGS, etc. Let us make together hear the voice of elderly!

31 Geriatric oncology: a multidisciplinary approach in a global environment SAVE THE DATE & JOIN US IN MILAN

32 DXR, tolerance and age MDA MDA patients >50 yo EBC DXR 40 mg/m² 325 patients years FU 185 months ( ) 65 patients >65 years FU 169 months ( ) No difference according to age PS, HR, pt, pn, surgery Relapse, DFS, OS Nadirs neutrophils + platelets at C 1,3,6 Cumulated haematological toxicity Doses really administered? Parameter 1011 MBC DXR 50 mg/m² Difference according to age RR, fever (12% vs 17%) No difference according to age OS, TTP, DI Nadirs neutrophils and platelets, FN (16%), toxic deaths/infection (3.2%) years >65 years n % median dose administered >85% dose received (%) Ibrahim. Ann Oncol 2000 & Arch Med Int 1996

33 Biomarkers Multicenter cohort of 78 BC patients w/ DXR & trastuzumab therapy 8 biomarkers evaluated at baseline + every 3 mths over 15 months High-sensitivity cardiac troponin I (hs-ctni) High-sensitivity CRP (HsCRP) N-terminal pro-b-type natriuretic peptide (NT-proBNP) Growth differentiation factor 15 (GDF-15) Myeloperoxidase (MPO) Placental growth factor (PlGF) Soluble fms-like tyrosine kinase receptor-1 (sflt-1) Galectin 3 (gal-3) Increase ± persistent of all biomarkers except NT-proBNP and gal-3 Association w/ cardiotoxicity MPO HR 1.38 (95% CI ), P = 0.02 PlGF HR 3.78 ( ), P = GDF-15 HR 1.71 ( ), P = 0.01 Putt. Clin Chem 2015

34 LVEF 5,027 adult patients treated w/ anthracyclines 124 (2,4%) MACEs: symptomatic CHF and death Predictive value of LVEF and LV dimensions (US) 2,285 patients w/ US < chemo MACE Older (p <0.0001), Predominantly men (p = 0.03), Higher incidence of CV risk factors and cardiac treatments Haematological cancers vs BC (4.2% vs 0.7%, p <0.0001) Predictors: LVEF baseline, 5 points, internal diameter Wang. Am J Cardiology 2015