2. The latest changes in surgery of liver metastatic colorectal cancer. Preoperative evaluation of the patient with hepatic metastases Treatment of liver metastatic colorectal cancer –Surgical, chemotherapy and biological.

3. General Information Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States. CRC is the second-most common cause of cancer death in western countries.

4. In approximately 50% of patients with CRC liver metastatic, the metastatic disease is confined to the liver. The liver is the most frequent site of metastasis in CRC, both at the time of diagnosis (20–25% of cases) or after an apparently radical surgery on the primary tumor (40% of cases).

5. 0 1 2 3 4 5 100 50 0 % surviving Years after diagnosis of colorectal metastases 3% 19881998 Rougier P et al. Brit J Surg 1995 1928 0% 1943 First hepatectomy for colorectal liver metastasis 1957 Introduction of 5-fluorouracil <1% Wider acceptance of role of liver surgery Overall survival in advanced colorectal cancer 1928-1998

6. Sylvain Manfredi et al. Ann Surg 2006

7. The Benefits and Side effects of Surgery Recent reports- 5 years overall survival >28%. Low mortality-1.5% (high volume), and 9.6% (low volume) but higher morbidity- 15-30% : hemorrhage, abscess, bile leaks, hepatic failure.

8. Hepatic resection for colorectal metastases, limited to the liver, has become the standard of care. Surgery currently remains the only potentially curative therapy.

11. Multidisciplinary approach Patient Surgeon Oncologist Gastroenterologist Anaesthesiologist radiologist

12. Preoperative Evaluation of the Patient with Hepatic Metastases Easily resectable disease Initially unresectable disease Unresectable

13. “Defining Resectability” Criteria for surgery Imaging.

15. Old approach criteria for surgery(1989, Steele et al): Less then four lesions in the same lobe. Maximum lesion dimensions<5cm. Non metachornous. Absence of extra-hepatic spread. More then 1 cm margin of healthy liver tissue Adequate liver remnant. Radical resection(R0).

16. Current approach for liver surgery New approach criteria for surgery(2006,Vauthey et al): Complete Radical resection(less then 1cm margin). Preservation of two adjacent liver segments. adequate vascular inflow and outflow and biliary drainage can be preserved Future liver remnant(total volume>20%). Aggressive approach More then one hepatectomy Resecting metastases in other sites as well(lungs, adrenal etc…)

17. Contra-indications: Radiographic evidence of involvement of the common hepatic artery, common hepatic or common bile duct, or main portal vein Extensive liver involvement (>70 percent, more than six segments, or involvement of all three hepatic veins) Inadequate predicted post resection functional hepatic reserve

19. Normal Underlying Liver  20% of TLV Kubota, Hepatology 1997 Azoulay, Ann Surg 2000 Abdalla, Arch Surg 2002 Vauthey, Ann Surg 2004 High Dose Chemotherapy  30% of TLV Chronic Liver Disease  40% of TLV Azoulay, Ann Surg 2000 Adam, Ann Surg 2004  Liver Remnant Volume

20. Liver Volumetry

21. Minimized the postoperative mortality- preserving a liver remnant that is >20% of the total liver volume. pre-operative portal vein embolization (PVE) to initiate compensatory hypertrophy of the future remnant liver. Atrophy of embolized lobe. Hypertrophy of non embolized lobe- Increasing Remnant liver. More potential surgical candidates Preoperative portal vein embolization

23. Imaging – CT CT is the staging modality most widely used in CRC Widespread availability and relatively low cost in comparison with MRI or PET/CT. In a study with surgically proven liver lesions, a sensitivity of 69% to 73% and a specificity of 86% to 91% was shown.* Limitations: steatosis, lesions smaller than 1 cm, Hemangiomas. *Kamel et el.J comput 2003, Kinkel et el. Radiology 2002, Bhattacharjya et al.Br J Surg. 2004.

24. Imaging – FDG-PET/CT Evaluation of patients with known or suspected recurrent colorectal cancer. Most sensitive method for detecting extra-hepatic disease in patients with CLM. Alters surgical management in 23% to 29% of patients. Measures the responsiveness of the tumor to preoperative treatment. For hepatic lesions compared with CT, it has a Sensitivity - 91–100 % and Specificity- 75-100% (Patel S et el. Ann Surg 2011). Limitations: Correlation of pathological response and metabolic response, detecting lesions smaller than 1 cm, expansive.

25. Imaging – MRI Sensitivity 81.1% and specificity of 97.2%. mangafodipir trisodium imaging has a sensitivity of 100%, a specificity of 92%. Better sensitivity with patients that have steatosis, lesions smaller than 1cm. Best preoperative imaging technique for CLM detection, but not used routinely. Used to differentiate metastatic findings from benign findings such as- cysts, adenomas, and hemangiomas. Limitations: length of the scan time, patient compliance and higher costs.

26. Imaging – US Widespread availability. Sensitivity is in the range of 36 to 61% in small liver lesions. Limitations: lesions> 2cm, experience of the operator, impaired accuracy with: obese patients, liver steatosis. Used for surveillance and liver lesion biopsy.

27. Imaging- Intraoperative US Intraoperative US- most sensitive technique for detecting liver lesions (sensitivity 93 to 94%). Discovers 25 – 30 % new lesions. May change planning of the operation.

28. Imaging- Summary CT scan is an essential tool in the optimal imaging of the majority of CLM. MRI : for patients with liver damage owing to prolonged treatment or co-morbidities. For lesions smaller than 1cm, the sensitivity estimates for MRI were higher than those for CT. (Niekel et al 2010). PET/CT is extremely useful to exclude extrahepatic disease. Intraoperative evaluation by IOUS, mandatory in all patients undergoing surgical resection of CLM.

30. Overall survival in advanced colorectal cancer in 2008: The impact of multi-disciplinary management 0 1 2 3 4 5 100 50 0 % surviving Years after diagnosis of colorectal metastases 2008 chemotherapy Median survival >24 months 5 year survival 9 % 3% <1% 19881998 2008 overall (Surgery + Chemo) Median survival ~36 months 5 year survival 20 % 20% Poston GJ. EJSO 2005; 31: 325-30 1928 9%

31. The Arsenal Of Treatment Systemic chemotherapy Intra-hepato-arterial chemotherapy Biologic treatment New surgery techniques Radiofrequency ablation/Cryosurgery.

32. Converting The “Unresectable” Unresectable systemic chemotherapy (CT) Biologic treatment Preoperative portal vein embolization

33. Systemic chemotherapy (CT) FOLFOX: oxaliplatin, 5-FU, leucovorin. FOLFORI: irinotecan, 5-FU, leucovorin. XELOX/CapeOx: capecitabine(xeolda), oxaliplatin CT as a “conversion therapy”,preoperative chemo: Bismuth et al (1996): conversion rate- 16%, 5yr survival- 40%. Adam et al(2001)- conversion rate- 13.5%, 5yr survival- 38%. Alfaro et al(2002)- conversion rate- 23%. Limitations: liver toxicity and postoperative complications.

35. Biologic treatment Anti VEGF -Bevacizumab Anti-EGFR Agents Cetuximab Panitumumab

36. Bevacizumab (Avastin) humanized monoclonal antibody. angiogenesis inhibition by inhibiting vascular endothelial growth factor A (VEGF-A). Main side effects- hypertension and heightened risk of bleeding. Bevacizumab moderately improved resectability rates (8.4 versus 6.1 percent with chemotherapy alone) when added to XELOX or FOLFOX.

37. Anti-EGFR Agents EGFR plays a crucial role in multiple cellular processes, such as cell proliferation, migration, survival and adhesion. KRAS mutational status as a key determinant of sensitivity to anti- EGFR treatment in mCRC. Cetuximab(Erbitux) A chimeric IgG1 antibody Folprecht et al (2010) - retrospective review, resectability rates increased from 32% to 60% after chemotherapy with cetuximab. Van Cutsem et al (2011)- KRAS wild-type patients, radical surgery was achieved in 5.1% of patients treated with cetuximab compared with 2.1% of patients treated with chemotherapy alone, in liver-only metastases the percentages raise to 13.2 and 5.6%, Panitumumab(Vectibix) A fully human IgG2 antibody PRIME trail (Douillard et el 2010) – panitumumab+FOLFOX4 did not improve secondary resection rate over FOLFOX4 alone.

38. Combination therapy + a biologic ? StudyRegimenNResponse rate (%) Resection rate all pts % Survival (mos) PozzoFOLFIRI40483331.3 AlbertsFOLFOX442604026 Folprecht5-FU/FA (AIO) + iri +cetuximab21671933 CervantesFOLFOX4 + cetuximab4379 19 (23)30 PeetersFOLFIRI + cetuximab42452423 KopetzFOLFIRI + Bevacizumab237417NR HurwitzIFL + Bevacizumab IFL 402 411 45 35 <2%20.3 15.6 HechtIFL + panitumumab FOLFIRI + panitumumab 19 24 47 33 NR16.8 23/24 alive

39. Surgery

40. Adjuvant The role of adjuvant chemotherapy is not clearly defined. Portier et al (2006) –post-opreative 5-FU/leucovorin vs surgery alone – 5 year survival: 34% vs 27%. UpToDate: best postoperative strategy is uncertain we suggest completion of a full six month course of oxaliplatin plus 5FU/capecitabine. NCCN: FOLFOX/CapeOx.

41. Radiofrequency ablation (RFA) Needle probe under image guidance generating heat and thus destroying the interstitial. Temperatures >60° results in cell necrosis

42. Others Cryosurgery Yittrium 90

44. Hepatic resection for colorectal metastases that are limited to the liver is a standard of care. Preoperative Evaluation of the Patients is vital. Each patient needs a different care. The future is promising.