Il trattamento delle metastasi epatiche neoplasie del colon retto Filippo de Braud MD Clinical Pharmacology and New Drugs Development Unit European.

Presentazione sul tema: "Il trattamento delle metastasi epatiche neoplasie del colon retto Filippo de Braud MD Clinical Pharmacology and New Drugs Development Unit European."— Transcript della presentazione:

1 Il trattamento delle metastasi epatiche neoplasie del colon retto Filippo de Braud MD Clinical Pharmacology and New Drugs Development Unit European Institute of Oncology Milano Italy

2 Trattamento neoadiuvante delle metastasi epatiche resecabili
Trattamento neoadiuvante delle metastasi epatiche non resecabili Trattamento adiuvante post-resettivo Trattamento delle metastasi epatiche sincrone da cancro del retto Trattamento delle metastasi epatiche con “minima” malattia extraepatica

3 ADVANCED COLORECTAL-CANCER: DISEASE LIMITED TO THE LIVER
SURGICAL RESECTION 10 STUDIES > 2500 PTS Mortality % 1 yr surv 80 % 5 yrs surv % Sem. Oncol. 26, 5: , 1999

4 ADVANCED COLORECTAL-CANCER: DISEASE LIMITED TO THE LIVER
SURGICAL RESECTION WHEN IT IS POSSIBLE BUT….. WHEN IS IT POSSIBLE ?

5 ADVANCED COLORECTAL-CANCER: LIVER RESECTION
Disease Related Factors AGE IS NOT (Fong et al, Ann Surg 222: 426, 1995) MARGINS : It does not make sense Size of Largest Met > 5 cm Disease Free Interval < 12 mos Number of Mets > 3 Primary Node Positive CEA > 200 ng/mg (JCO, 15: , 1997)

6 ADVANCED COLORECTAL-CANCER: LIVER RESECTION
Disease Related Factors Score Surv (%) Median 1yr 5yr months JCO, 15: , 1997

7 Fong Y. et al, Ann Surg 1999, 230:

8 Results are very reproducible !
SURGICAL RESECTION Results are very reproducible !

9 ADVANCED COLORECTAL-CANCER RESECTION OF LIVER METS’
Study # pts 5-yrs OS Median Survival months Hughes 1986 607 33% - Scheele 1995 434 40 Nordinger 1996 1568 28% Jamison 1997 280 27% 33 Fong 1999 1001 37% 42

10 Metastasi epatiche nel carcinoma del colon retto
Malattia solo epatica non operabile Chemioterapia intraarteriosa? Chemioterapia sistemica? Chemioterapia sistemica + intraarteriosa? Terapia neo-adiuvante?

11 Survival after primary and secondary resection of liver metastases
Adam R, Ann Oncol 2003;14: ii13-ii16 Surviving (%) 1.0 Resectable (n=425) Initially unresectable (n=95) 0.8 54% 0.6 34% 0.4 50% 27% 34% 0.2 29% 19% 1 2 3 4 5 6 7 8 9 10 Survival time (years)

12 Neoadjuvant chemotherapy Paul Brousse hospital study
Adam R et al., Ann Surg Oncol 8:347-53, 2001 Initially unresectable N=701 N=171 Primary resectable 20% of all patients Oxaliplatin/5FU/LV Never resectable N=95 Secondary resectable 11% of all patients 14% of CT-treated Resection: 266 patients (31%)

13 Oxaliplatino Metastasi epatiche da Carcinoma Colon
Bismuth 1996 330 pazienti con metastasi epatiche inoperabili N. pz. operati 53 (16%) Resezione curativa 46 (75%) OS a 3 anni 54% a 5 anni 40% Giacchetti, Ann Oncol. 1999 151 pz. con metastasi epatiche inoperabili trattati con Oxa + 5FU (83% con cronoterapia): 59% RP OS casistica 24 mesi (28% vivi a 5 aa) 51% operati (38% resezione radicale) OS operati 48 mesi (50% vivi a 5 aa)

14 Resection rates after chemotherapy in initially inoperable patients
Chemotherapy Pts Surgery R yr OS rate Oxaliplain- based Adam, 2001 Giacchetti, 1999 Giacchetti, 2000 Alberts, 2003 Tournigand, 2004 Irinotecan- based Pozo, 2004 Ducreux, 2003 OxIri- based Falcone, 2004 Quenet, 2004 701 151 100 42 111 40 55 109 74 34 14% 51% 32% 36% 22% 33% 31% 9% 40% 58% 14% 38% 21% 33% 13% 28% - 7% 26% 27% 39% 50% -

15 Resecabilità metastasi epatiche dopo 1^ linea
Tournigand (JCO 2004: ): FOLFIRIFOLFOX vs FOLFOXFOLFIRI Arm A Arm B FOLFIRI FOLFOX N° PZ N° responders N° resecati R0/R1 7/1 13/8

16 Metastasi epatiche nel carcinoma del colon retto
Malattia solo epatica operata Cosa fare dopo resezione? Solo follow up? Chemioterapia locoregionale? Chemioterapia sistemica? Chemioterapia locoregionale + sistemica?

17 Metastasi epatiche nel carcinoma del colon retto

18 Trattamento adiuvante post-resettivo
Necessario in ogni paziente resecato ? Dopo CT neoadiuvante sistemica ? Sola terapia sistemica ? Alternanza di CT sistemica di ultima generazione / CT i.a. meno tossica (5-FU) ?

19 Terapia sistemica CT sistemica con schedule basate sul 5-FU sembra
poter dare beneficio ma le casistiche sono troppo limitate per dare risultati significativi

20 ADJUVANT THERAPY AFTER RESECTION OF LIVER METS’ FROM COLORECTAL-CANCER
Author # pts Regimens Surv Hepatic Rec Free Lorenz 1998 226 HAI (LV/5-FU) Vs Control 47% 30% At 5 yrs - Kemeny N 1999 156 HAI (FuDR) + iv LVFU vs iv LVFU 61% 49% 74% 44% Kemeny M (4 yrs F.up) 75/109 63.7/47mos 49/34 mos 67% 43%

21 Chemotherapy for resectable liver metastases
German phase III1 (N=34 evaluable/226 enrolled) HAI: 5FU/LV Observation S No difference in TTP and OS, but results difficult to interpretate as only 30% of patients completed ECOG/SWOG phase III2 (N=75 evaluable/109 enrolled) HAI FUDR+ Systemic 5FU Observation S 4-yr liver PFS: 67% vs 43 (p=0.03) 4-yr OS: 62% VS 53% (NS) MSKCC phase III3 (N=156) HAI FUDR+Systemic 5FU/LV Systemic 5FU/LV 2-yr liver PFS: 90% vs 60 (p=0.03) 2-yr OS: 86% vs 72% (p=0.03) 5-yr OS: 61% vs 45% S 1.Lorenz et al, Ann Surg 1998;228:756; 2. Kemeny et al, J Clin Oncol 2002;20: ; Kemeny et al, NEJM 1999;341:2039

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23 MJ O’Connel, Proc ASCO, Abs 3527, 2004
Adjuvant HAI + SYS chemotherapy dopo metastasectomie multiple epatiche . Studio Fase II NCCTG 44 % > 4 mets 78 % bilobar disease 12 % cryoablation 49 pts resected 36 treated FUDR 0.2 mg / kg die wks 0-2, 5-7, 10-12, 15-17 Alternante MAYO “classica” wks 3 – 8 – Median FU = 6.2 yrs Liver only 9 Extraliver only 10 Both 9 25 / 36 recurred 5 yrs OS = 31 % 5 yrs liver free survival = 25 % MJ O’Connel, Proc ASCO, Abs 3527, 2004

24 Chemioterapia neoadiuvante nelle metastasi epatiche resecabili
Fattibile…ma a cosa serve ? “Finestra biologica” ? Ottimizzazione della durata del trattamento

25 Chemotherapy for resectable liver metastases: ongoing trials
NSABP-C-09 phase III Systemic XELOX S Systemic XELOX + HAI FUDR EORTC/EPOC phase III Observation R S FOLFOX FOLFOX Accrual completed (N=360) Preliminary results will be communicated at ASCO 2005

26 R Surgery LV5FU2+L-OHP (6 cycles) surgery LV5FU2+L-OHP (6 cycles)
Phase III - Intergroup: Pre - and postoperative CT with oxaliplatin/5-FU/LV versus surgery alone in resectable liver metastases from CRC LV5FU2+L-OHP (6 cycles) surgery LV5FU2+L-OHP (6 cycles) R Surgery Objectives: PFS, OS, Resection Rate, Toxicity Sample Size: 330 pts in 3 y y follow-up Start: June-July 2000 EORTC 40983

27 Contraindications for resection
Unresectable extrahepatic disease Extensive liver involvement - > 6 segments involved - >70% liver parenchyma involved, or - all three hepatic veins involved Major liver insufficiency Patient unfit for or declining surgery Analysis of appropriateness Immediate resection Resection after pre-operative chemotherapy LOCAL DESTRUCTION CHEMOTHERAPY

28 Sinchronous or metachronous
LIVER M+ of CRC Unresectable Sinchronous or metachronous Responsive unresectable further CT I.A. I.V. CT Responsive resectable SURG Unresponsive 2nd-line CT

29 Minimal residual unresectable
LIVER M+ of CRC Further CT Follow-up Phase I trial Minimal residual unresectable liver disease after CT Radiofrequency TACE or TAE Surg + RF

30 Conclusioni Le metastasi epatiche non sono tutte uguali e neppure i pazienti e neppure i medici Indispensabile la valutazione multidisciplinare di ogni caso Studio organico delle caratteristiche biologiche e di quelle cliniche

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