1. Treatment of hepatic metastases in colorectal cancer French consensus conference 2003

3. Liver metastases from colorectal cancer 1. Kemeny et al (1999); 2. Seifert (1998); 3. Borner ( 1999) Liver, the most common site of metastases from CRC – 50 to 75% of patients with advanced CRC will develop liver metastases 1 – 15 to 25% of patients of any stage have liver metastases at presentation 1, 2 – 20 to 35% of patients with metastatic disease confined to the liver 3 Surgery of liver metastases is at a turning point

8. Evidence base levels Grade A : scientific diagnosis established : (gradeA) Level 1 of scientific evidence Trial and meta-analyses and comparative randomised studies Analyses conducted on well organised studies Grade B : scientific diagnosis presumption: (grade B) Level 2 cohort studies, low level randomised comparative trials , non randomised controlled clinical trial well performed Grade C, low scientific diagnosis level : (grade C) Level 3 Case report, control-tests Level 4 Retrospective and comparative studies with important bias, case series, developped studies of epidemiology ….. consensus

9. 1 What investigations ? Complete physical examination ( OMS 3> Stop) Colonoscopy CEA useful after therapeutic response ( grade C) Ultrasound: Limits T< 1cm differentiate metastases (MRI) from other benign tumors CT with contrast > ultrasound ( gradeB ) MRI with liver contrast agents = CT scan ( grade B) MRI + gadolinium if doubt on CT or if CT not possible ( grade B) 1.McCall JL Dis Colon Rectum 1994 - 2. Renehan AG méta-analyse BM J2002

10. It is mandatory to look for a local reccurence and extra hepatic metastases

12. PETscan (FDG) within evaluation patients with high risks of dissemination (grade B) métastases Se 88-90% Sp 95> (méta-Analyses: Huebner RH J Nucl Med 2000 Kinkel K Radiology 2002)

13. 2 What metastases are immediately resectable ?

14. Resection for CRC liver metastases: the traditionally perceived criteria Metachronous detection Unilobar disease < 4 metastases > 1 cm resection margin If we accept these criteria, then very few patients are eligible for surgery

16. 1.Technical criteria : per-operative Visual and manual exploration ( grade C) Per-operative ultrasonography ( grade C) Modify therapeutic data in 10 to 42% of cases(1) More efficient than porto-scan and helical (2) Can be done by laparoscopy (3) Avoid useless laparotomy Technical efficiency but less reliable for node evaluation and posterior liver segments exploration (consensus) 1 Castaing 1986, Boutkan 1992, Machi 1993, Kane 1995 2 TDMBloed W 2000, Schmidt J 2000, Jamagin WR 2001 - 3 Milsom JW 2000, Jarnagin WR 2000

17. Resectable yes but? Reserve of hepatic tissue adequate (hepatic insufficiency) ? functional (vascularization and biliary drainage ) ? Anticipated mortality and minimal morbidity? Global morbidity 8-23% (1) Global mortality 1-2% (2) 1 Aaron R. Seminar in oncology 2002 – 2 Belghiti J. Am Coll Surg 2000)

18. Anatomic possibility of resection : Solitary or multiple unilobular tumors Irresectability : rare Size: no problem Location (caudate lobe) (1) Vascular limits : Involving the portal confluence : rare, no posterior approach Involving inferior veina cava : Hepatic vascular exclusion (TVE) With (2) or without preservation of caval flow ( 3) Replacement (4) of veina cava Vascular reconstruction(5) of hepatic vein Ex-situ in- vivo liver surgery (6) 1 Launois B. Ann Chirg 1990, Tono T Int Surg 2000 - 2 Cherqui D Ann Surg 1999 - Torzilli G Ann Surg 2001 - 3 Edmond JC 1996, Evans PM 1998, Huguet C 1992 - 4 Torzilli G Ann Surg 2001, Miyasaki M Am J Surg 1999 - 5 Nakamura S 1997 - 6 Hannoun L lancet 1991

19. Anatomic possibility of resection Bilateral multiple tumors Several segmentectomies with respected vascularisation of remnant liver Limitation: Number and areas of metastases More than 6 segments involved or 5 separated Vascular connections : involving 2 portal pedicles Liver transplantation not advisable (ANAES 1993)

20. Is hepatic resection safe ? Risk evaluation Hepatocellular insufficiency : 1- 5% of major hepatectomies Depend on remnant hepatic parenchyma and its pre and post-operative condition Remnant hepatic mass : prediction scoring system : liver volume by CT Okhamato (1984) or URATA (1995) Hepatology Resection limits : HCI risk for a healthy liver when >40% no risk remnant 25-40% increased liver <25% hepatectomy contra-indicated (C,4)

22. To summarize : Anatomic possibility of resection Simple resectability : classic hepatectomy leaving 40%> of liver parenchyma (resectability class I ) : (I*) Possible resectability : hepatectomy difficult or very large requesting a risky and/or a difficult procedure (resectability class II) : ( II*)

24. Initial pathology : Synchronic metastases No increase risk for combined resection (1) Pro: Non randomized series (2) and comparative series (3) Con: Sequential resection does increase the survival : 5 years survival: 35%/13%)(3) Allows appropriate selection of the patients. Recommendation: Combined resection is possible except for complex resection, advanced disease or emergency case (consensus) 1. Elias D. Am J Surg 1995, Jaeck D. Ann Chir 1996 – 2. Scheele J. Chirurg 2001, Lyass S. J Surg Oncol 2001. – 3. Vogt P. World J Surg 1991 – 3 Jenkins LT. Am Surg 1997, Lambert LA. Arch Surg 2000

25. Initial pathology : Metachronic metastases Advanced stage of colon cancer is not a contra-indication to resection (1) Quality of colon surgery has his own prognosis (2) Local recurrenc is not a contra-indication if resected at the same time (3) Recommendation: The tumor stage should not change the indication 1.Jamison RL Arch Surg 1997, Doci R Tumori 1995 - 2. Wigmore SJ. Ann Surg 1999 3. Scheele J. surgery 1991

27. Hepatic disease : Relapses after liver resection 1 - R. Adam et al., Ann. Surg., 1997 - 2 - B. Nordlinger et al., Cancer, 1996 - 3 - HJ. Wanebo, et al., Surgery, 1996 Tumor relapse will occur in 60-70% of resected patients (1, 2) Recurrences are confined to the liver in 20-30% of cases (3) Iterative resection is possible in 10-25% of patients (1, 3) Long-term results after iterative resection are comparable to those obtained after a first hepatectomy (1) The relevance of rehepatectomy is based on the arguments listed to the initial hepatectomy ( grade C )

28. Results of iterative resections Author, year N. of Operative 5-yr patient mortality survival rate Nordlinger, 1994 (1) 130 0.9% - Fernandez Trigo, 1995 (2) 170 - 32% Pinson, 1996 (3) 134 1.9% 40% Adam, 1997 (4) 64 0% 41% 1 - B. Nordlinger et al., JCO 1994 3 - CW. Pinson et al., Ann. Surg., 1996 2 - V. Fernandez Trigo et al., Surgery 1995 4 - R. Adam et al., Ann. Surg., 1997

29. Oncological resection possibility Recommendation If easy (class I : I*), resection must be done (whatever number, size, vascular or biliary invasion, ECA level) (grade C) If possible but risky (class II : II*), relevance of neo-adjuvant chemotherapy (clinical trial) (consensus)

30. Carcinological resection possibility Related factors to surgical technique Security margin resection: 1 cm-5 mn, (consensus) 2mn (1) Margin non independent prognosis factor (2) Importance of Ro. surgery (3) Type of exeresis : anatomical or nonanatomical resection: no recommendation If possible: liver sparing approach (4) so to enable repeated resection of the liver. importance of resection margin ++ 1 Makuuchi Arch Surg 2002 - 2 Elias D. J Surg Oncol 1998 – 3 Weber SM Ann Surg Oncol 2000, Scheele J Chirurg 2001 – 4 Kokudo N.am J Surg 2001

31. Related factors to extra hepatic disease Lymph node involvement : Hepatic pedicle involvement Rare 1-12.5% microscopic 11-19% (1) 5 years survival = 0(2), 3.4% (3) even if microscopic involvement (4). French register : 5 years 12% Regional lymph nodes ? If microscopic involvement = chemotherapy ? Pre-operative coeliac lymph node involvement : no exeresis Per-op: I* : exeresis can be considered. but within multidisciplinary decision ( grade C) II* : no exeresis ( grade C) 1 Elias D. Br J Surg 1996. Gibbs JF Cancer 1998. Ekberg H. Br J Surg 1986 – 2 Ekberg H. Br J Surg 1986 3 Rodgers MS Br J Surg 2000 - 4 Beckurts KT Br J Surg 1997 .

32. Related factors to extra hepatic disease : Other intra-abdominal localizations If resectable : yes 21% to 5 years. (1) 18% (2) But increased risk if operation combined If two surgical procedures : treat the liver first If high risk of resection (II*) or factors of poor prognosis : chemotherapy 1° If non resectable : surgical contra-indication (consensus) 1 Makuuchi Ann Surg 2000 - 2 Blumgart LH. Ann Surg 1999

33. Related factors to extra hepatic disease : Other intra-abdominal localizations Peritoneal disease 3.3% (1) : no resection laparoscopy if suspicion and/or large laparotomy (2) On trials : cyto reductive surgery followed by immediate intraperitoneal chemotherapy: 3 years survival : 40% (3) 1 Jarnagin WR. Am Coll Surg 1999 - 2 Gibbs JF. Cancer 1998 - 3 Elias D. J Surg Invest 2001, Sugarbaker PH. Ann Ital Chir 1996.

34. Related factors to extra hepatic disease : Extra-abdominal localizations Pulmonary metastases resected : 5 years survival rate of 28-52% (1,4) If resection, treat thtee liver first after brain CT scan (2) ( grade C) Other metastases : contra-indication (gradeC) 1 Murata S. Cancer 1998. Robinson BJ. J Thorac Cardiovasc Surg 1999. - 2 Wronski M. Cancer 1999 - 3 Nagakura S. J Am Coll Surg 2001 – 4 Headrick JR. An Thorac Surg 2001

36. H.A.I. after RO resection H.A.I.C./ O randomised prospective (1) : 5Fu- Folinic Ac/control (n=226 ) therapeutic inefficiency and important toxicity . H.A.I.C. + I.V.C. / O randomised ECOG-SOG (2) : Fin favour of chemotherapy (M: 63.7 /49 mois) H.A.I.C. + I.V.C./ I.V.C. Memorial (3) :In favour of combined arm (M: 72.2/59.3 mois) . Prospective (4) : In favour of combined treatment H. A.I.C. ( FUDR)+ I.V.C. favorable ( grade B) but high cost and high morbidity, not available in Europe 1 Lorenz M Ann Surg 1998 - 2 Kemeny MM. J Clin Oncol 2002 - 3 Kemeny N Engl J Med 1999 4 Lygidakis Hepatogastroenterolgy 2001

37. I.V.C. after RO resection Retrospective studies: FFCD (Portier G. J Clin Oncol 2002) I.V.C. /control : N.S. Study inter-group europeo-canadian (Langer B. J Clin Oncol 2002) N.S. After Ro resection : Testing of new molecules : yes if no testing: no evidence of benefit (grade B,C) but the consensus suggest a sytemic association 5Fu-folinic ac

38. Intravenous chemotherapy after RO resection Resectable metastases after neoadjuvant chemotherapy. To continue chemotherapy according to : importance of response, cumulative toxicity, post-operative course (Consensus) After local ablation (RF, cryotherapy): no consensus multidisciplinary decision

45. Local ablation of hepatic metastases (consensus) Indications: T. <3cm R.F. or laser or cryotherapy but if 3 cm> cryotherapy (1) Nb < 4 In proximity of a vessel 4mn > temporary occlusion Contra-indications: Next to the biliary duct or 1 cm< hilar Patients with a biliodigestive anastomosis Risk of septic complications ++ Next to the digestive- tract if per-cutaneous 1. Bilchick AJ 2000

46. Radiofrequency Nb Pts  moyen Survival 3 y Per cutaneous : Solbiati 1999 120 3,1 cm 38 % Gillams 1999 69 3,9 cm 54 % Per operative : RF 14 2,7 14% Resection 16 3,4 23% NS (prospective, non randomized) Shibata et al. Cancer 2000; 89: 276-84

47. Cryotherapy - 196° . Respect of vessels

54. Adam et al (2001) 300 250 200 150 100 50 0 95/701 (11%) 171 (20%) No. of pts Oxali/5-FU/LV increased the proportion of patients resected by 55% Initially resectable Initially non-resectable, resectable with oxaliplatin Ability of oxaliplatin-based chemotherapy to allow secondary surgery in metastatic CRC

55. Five-year survival following secondary surgery in metastatic CRC Survival time (years) 1.0 0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 Proportion surviving 91% 50% 34% n=95 Survival of patients initially non-resectable, made resectable with oxali/5-FU/LV Adam et al (2001)

56. Survival according to categories of initial non resectability (n=95) Adam et al (2001) 18% Extrahepatic (26) Proportion surviving 1.0 0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 Survival time (years) 34% Multinodular (48) 60% Large (9) 49% -located (12)

57. Survival after oxaliplatin-based chemotherapy and surgery 58 patients: macroscopically complete resection 74 non-operated patients 30% 50% Giacchetti et al (1999) Time (years) Patients (%) 100 0 80 60 40 20 0 1 2 3 4 5 6 7 8 9 77 operated patients 151 patients with initially unresectable liver metastases

58. Impact of oxaliplatin on resection of colorectal liver metastases: Liverpool experience July 2001 CEA 997 Jan 2002 CEA 3

59. Resection rates after FOLFOX in initially inoperable patients Patients 51% 32% 13.6% 35.7% 18.9% resected (%) Complete 38% 21% 13.6% 28.5% 11.7% resection 5-year 50% – 35% – – survival (%) Study Giachetti Giachetti Adam Alberts Tournigand

62. Portal vein embolization to Induce hypertrophy of the remnant liver

64. Right portal vein embolization P.E. (D0) Hépatectomy (D50-60) (Small left lobe)

65. Portal vein embolization Indications : depends on the rate of remnant functional liver parenchyma (CT) < 25% : essential > 40% : not advisable 25-40% : treatment’prescriptions to be treated separately according to the duration of neoadjuvant chemotherapy, the possible ischemic operation time and the complexity of the resection surgery (grade C) Survival up to 5 years : 40% (Azoulay D. Ann Surg 2000) 37% (Elias D. Surgery 2002)

67. Right portal vein embolization and two stage hepatectomy Right P.E. (D14) Right hepatectomy (D70-80) 1° step (D0) Résection of left liver metastases  3 nodules