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
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
ADVANCED COLORECTAL-CANCER: DISEASE LIMITED TO THE LIVER SURGICAL RESECTION 1984 - 1997 10 STUDIES > 2500 PTS Mortality 1- 5 % 1 yr surv 80 % 5 yrs surv 25 - 37 % Sem. Oncol. 26, 5: 514-523, 1999
ADVANCED COLORECTAL-CANCER: DISEASE LIMITED TO THE LIVER SURGICAL RESECTION WHEN IT IS POSSIBLE BUT….. WHEN IS IT POSSIBLE ?
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: 938 - 46, 1997)
ADVANCED COLORECTAL-CANCER: LIVER RESECTION Disease Related Factors Score Surv (%) Median 1yr 5yr months 0 - 1 84 - 92 57 73 2 92 47 50 3 89 16 30 4 62 8 15 JCO, 15: 938 - 46, 1997
Fong Y. et al, Ann Surg 1999, 230: 309-321
Results are very reproducible ! SURGICAL RESECTION Results are very reproducible !
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
Metastasi epatiche nel carcinoma del colon retto Malattia solo epatica non operabile Chemioterapia intraarteriosa? Chemioterapia sistemica? Chemioterapia sistemica + intraarteriosa? Terapia neo-adiuvante?
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)
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%)
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)
Resection rates after chemotherapy in initially inoperable patients Chemotherapy Pts Surgery R0 5-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% -
Resecabilità metastasi epatiche dopo 1^ linea Tournigand (JCO 2004: 22 229-237): FOLFIRIFOLFOX vs FOLFOXFOLFIRI Arm A Arm B FOLFIRI FOLFOX N° PZ 109 111 N° responders 61 59 N° resecati 8 21 R0/R1 7/1 13/8
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?
Metastasi epatiche nel carcinoma del colon retto
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) ?
Terapia sistemica CT sistemica con schedule basate sul 5-FU sembra poter dare beneficio ma le casistiche sono troppo limitate per dare risultati significativi
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%
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;20:1499-505; 3. Kemeny et al, NEJM 1999;341:2039
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 1 14 wks 0-2, 5-7, 10-12, 15-17 Alternante MAYO “classica” wks 3 – 8 – 13 - 18 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
Chemioterapia neoadiuvante nelle metastasi epatiche resecabili Fattibile…ma a cosa serve ? “Finestra biologica” ? Ottimizzazione della durata del trattamento
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
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 - 40983 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 + 3.5 y follow-up Start: June-July 2000 EORTC 40983
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
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
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
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