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Trattamento neoadiuvante delle metastasi epatiche resecabili Trattamento neoadiuvante delle metastasi epatiche non resec

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

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Trattamento neoadiuvante delle metastasi epatiche resecabili Trattamento neoadiuvante delle metastasi epatiche non resec

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  1. Il trattamento delle metastasi epatiche neoplasie del colon rettoFilippo de Braud MD Clinical Pharmacology and New Drugs Development UnitEuropean Institute of OncologyMilano 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 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

  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: 938 - 46, 1997)

  6. ADVANCED COLORECTAL-CANCER:LIVER RESECTION Disease Related Factors Score Surv (%)Median 1yr 5yrmonths 0 - 1 84 - 92 57 73 2 92 47 50 3 89 16 30 4 62 8 15 JCO, 15: 938 - 46, 1997

  7. Fong Y. et al, Ann Surg 1999, 230: 309-321

  8. SURGICAL RESECTION Results are very reproducible !

  9. ADVANCED COLORECTAL-CANCERRESECTION OF LIVER METS’

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

  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% 50% 0.4 27% 34% 0.2 29% 19% 0 0 1 2 3 4 5 6 7 8 9 10 Survival time (years)

  12. Never resectable N=95 Secondary resectable 11% of all patients 14% of CT-treated Resection: 266 patients (31%) Neoadjuvant chemotherapyPaul Brousse hospital study N= 872 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

  13. 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) OxaliplatinoMetastasi epatiche da Carcinoma Colon

  14. Resection rates after chemotherapyin 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 Tournigand, 2004 OxIri- based Falcone, 2004 Quenet, 2004 14% 51% 32% 36% 22% 33% 31% 9% 40% 58% 39% 50% - - - - - - - - 701 151 100 42 111 40 55 109 74 34 14% 38% 21% 33% 13% 28% - 7% 26% 27%

  15. Tournigand (JCO 2004: 22 229-237): FOLFIRIFOLFOX vs FOLFOXFOLFIRI Arm A Arm B FOLFIRI FOLFOX N° PZ 109 111 N° responders 61 59 N° resecati 8 21 R0/R1 7/1 13/8 Resecabilità metastasi epatiche dopo 1^ linea

  16. 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

  17. Metastasi epatiche nel carcinoma del colon retto

  18. 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) ? Trattamento adiuvante post-resettivo

  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

  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;20:1499-505; 3. Kemeny et al, NEJM 1999;341:2039

  22. 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

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

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

  25. 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 Phase III - Intergroup: Pre - and postoperative CT with oxaliplatin/5-FU/LV versus surgery alone in resectable liver metastases from CRC - 40983 EORTC 40983

  26. 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

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

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

  29. 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 Conclusioni

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