Two-Stage Hepatectomy for Unresectable Metastases : R. Adam, D.A. Wicherts, R. Miller, R.J. de Haas, G. Bitsakou, E. Vibert, L.A. Veilhan, D. Azoulay, H. Bismuth, D. Castaing Hôpital Paul Brousse, Université Paris-Sud, France

Survival benefit 40% at 5 yrs Resectable 10–20% Non resectable 80–90% 15–30 % 1-2% Survival benefit 40% at 5 yrs RESECTABILITY: a new end point of the strategy

MULTINODULAR COLORECTAL LIVER METASTASES HOW TO MAKE A COMPLETE RESECTION WHILE SAVING 30% LIVER REMNANT ?

BILATERAL HUGE LIVER METASTASES HOW TO MAKE A COMPLETE RESECTION ?

TWO-STAGE HEPATECTOMY Concept Two sequential liver resections aiming to resect multinodular hepatic tumors irresectable by a single procedure Regeneration following hepatectomy Planned strategy at the time of 1st hepatectomy - (1) Adam R, et al. Ann Surg 2000; 232:777-85

Two-Stage Hepatectomy (1) Adam R, et al. Ann Surg 2000; 232:777-85 155 cc 1 I 440 cc IV I 2 (1) Adam R, et al. Ann Surg 2000; 232:777-85

262 Pts initially Unresectable Two-Stage Hepatectomy: Patients and Methods Oct. 1992 - Oct. 2006: 817 pts resected for CLM 100% 32% 262 Pts initially Unresectable 100% 51 Pts 2-stage hepatectomy 20% 6%

Two-Stage Hepatectomy: Evolution in time % Conventional Hepatectomy Two-stage 14% 8% 5% 7% 2%

Two-Stage Hepatectomy: Results Feasibility 35/51 (69%) 16 patients ineligible for a second resection because: Disease Progression - Intrahepatic - Intra- and extrahepatic Bad Performance Status 15 (29%) 6 (12%) 9 (18%) 1 (2%)

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Outcome of failed patients (N = 16) Alive with disease (13%) (N=2) Dead (88%) (N=14) Median time to death 12.3 mo (3.6 - 18.8)

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Patient and Primary tumor characteristics N = 35 57.5 + 10.3 17 (49%) 18 (51%) 27 (77%) 8 (23%) 5 (26%) 14 (74%) 4 (22%) 14 (78%) Mean age + SD Female Male Colon Rectum T - 0-2 T - 3-4 N - 0 N - 1-2

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Liver Metastases Diagnosis N = 35 28 (80%) 7 (20%) 9.6 + 5.4 50.2 + 25.1 290.6 + 655.4 187.2 + 320.0 6 (17%) Synchronous Metachronous Mean number + SD Mean max size + SD Mean CEA + SD Mean CA 19.9 + SD Extrahepatic disease

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Chemotherapy N =35 1.5 + 0.7 11.0 + 3.8 4.2 + 1.8 Before 1st Hepatectomy (N = 34) (97%) Mean number of lines + SD Mean number of cycles + SD Before 2nd Hepatectomy (N = 27) (77%) All patients received 1 line. After 2nd Hepatectomy (N = 26) (74%)

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Time interval between 1st and 2nd hepatectomy Mean + SD (months) < 3 months 3-6 months > 6 months N = 35 4.3 + 3.1 13 (37%) 17 (49%) 5 (14%)

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Hepatic resection 1st 4 (11%) 0 (0%) 2 (6%) 27 (77%) 2nd 26 (74%) 1 (3%) 4 (11%) - P < 0.001 0.41 - Major resection (> 3 segm) Local treatment RFA Cryotherapy Portal Vein Embolization

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Short-term outcome 1st - 8 (23%) 3 (9%) 6 (17%) 1 (3%) 11.7 + 4.2 2nd 3 (9%) 22 (63%) 10 (29%) 20 (57%) 2 (6%) 9 (26%) 20.6 + 17.1 P - < 0.01 0.03 0.56 60-day Mortality Morbidity General complications Hepatic complications Relaparotomy Percutaneous drainage Mean hospital stay + SD

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Recurrences after second hepatectomy N = 19 (54%) Intra- and Extrahepatic (31%) No (46%) Extrahepatic (9%) Hepatic (14%) Median follow-up 26.0 months (range: 3.7 - 130.3)

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Repeat hepatectomy Extrahepatic resection Both Recurrence N = 19 (54%) 6 (32%) 4 (21%) 3 (16%)

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Total number of procedures 35 Pts 81 Hepatectomies 34 Adjuvant Procedures (PVE + Local Ablation) 15 EH Resections 130 Procedures in 35 Patients 3,7 Procedures per Patient

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Overall Survival - Intention to treat (N = 51) .2 .4 .6 .8 1 Overall Survival 2 3 4 5 Years 44% 30% Patients at risk Total 1 yr 2 yrs 3 yrs 4 yrs 5 yrs 51 34 19 10 6 4

Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Overall Survival .2 .4 .6 .8 1 Overall Survival 2 3 4 5 Years Two-stage effective (N = 35) Two-stage failed (N = 16) Log rank P < 0.001 57% 39% Patients at risk Total 1 yr 2 yrs 3 yrs 4 yrs 5 yrs Two-stage 35 27 19 10 6 4 Failed 16 7 -

Prognostic Factors of Overall Survival Two-Stage Hepatectomy (Oct 1992 - Oct 2006) Multivariate Analysis Prognostic Factors of Overall Survival after effective Two-Stage procedure HR [95% CI] P > 6 Metastases at diagnosis Concomitant Extrahepatic Disease No chemotherapy after second hepatectomy 0.01 0.02 < 0.01 18.4 [2.1-161.3] 5.3 [1.3-21.0] 12.8 [2.9-56.0]

Two-Stage Hepatectomy Conclusions 1) Established strategy to increase resectability in selected patients with advanced bilobar disease 2) Feasibility rate: 69% 3) Second resection (more extensive) had higher morbidity than first resection 4) Five-year survival 39% for patients that completed the total strategy, close to that of patients with a single procedure.

Portal Embolization Hepatectomy + RxF or Cryo 2-Stage Hepatectomy NON RESECTABLE « HEPATIC » PATIENTS Multi Unilobar Multi Bilobar Multi Bilobar Remnant Liver<30% ≤3 nod. ≤30 mm >3 nod >30 mm Portal Embolization Hepatectomy + RxF or Cryo 2-Stage Hepatectomy