1. Is there a benefit in resection of the primary tumor in synchronous metastatic colorectal carcinoma? Carmelo Pozzo Oncologia Medica Università Cattolica del Sacro Cuore Policlinico A. Gemelli – Rome, Italy Mediterranean School of Oncology THE CURRENT MANAGEMENT OF COLORECTAL CANCER Roma 18 ottobre 2013

2. 30% synchronous metastases Additional ~50% will develop metastases 30–35% ‘liver only’ metastases 75–90% not resectable 10–25% candidates for SURGERY Aim: R0 resection 250,000 CRC cases/year (Europe) Chu, et al. Clin Colorectal Can 2006; Kemeny, et al. NEJM 1999; Pozzo, et al. Oncologist 2008; Leichman. Surg Oncol Clin N Am 2007; Leonard, et al. JCO 2005; Tomlinson, et al. JCO 2007; Van Cutsem, et al. EJC 200; Initially resectable Borderline resectable Three potential scenarios when considering treatment options

3. Resection/Ablation of CRC liver metastases Accepted standard of practice (appropriately) despite a lack of randomized trials This is due to substantial cure rate (25%-40%) reported in initial series We accepted resection/ablation as a standard due to the realistic standard for cure - Therefore, we need to accurately identify those patients who have a realistic chance for cure, and those who do not Saltz L., Educational ASCO 2012

4. Overall survival probability after a first resection for colorectal liver metastases in 14,774 patients from the LiverMetSurvey http://www.livermetsurvey.org, June 2011.

5. Overall survival probability after resection of initially resectable versus non resectable liver metastases in 10,940 patients in the LiverMetSurvey http://www.livermetsurvey.org, June 2011.

6. Overall survival in advanced CRC: Is Surgery a plus? 0 1 2 3 4 5 0 1 2 3 4 5 100 50 0 % surviving Years after diagnosis of colorectal metastases 2011 chemotherapy alone Median survival >25 months 5-yr survival 9% <1% 1987 2011 overall with addition of surgery Median survival ~40 months 5 year survival 35 % 35% Modified from Poston GJ. EJSO 2005; 31: 325-30 http://www.livermetsurvey.org, June 2011 9% 1927 1997 3% 2011 ?50% 2017

7. Changing Definition of Resectability How many metastases? 4 < lesions, with unilobar location, resectable 4 < lesions, with unilobar location, resectable How large? < 5 cm resectable < 5 cm resectable Extrahepatic disease? If none, resectable If none, resectable Old: What must come out? Can R0 resection (negative margins) be achieved? Can two contiguous liver segments be preserved? Can adequate future liver remnant (>20%) be preserved? New: What will stay in? Charnsangavej C, et al. Ann Surg Oncol. 2006; 13:1261-1268.

8. Modificato da Khatri, Petrelli e Belghiti, JCO 2005 Criteri convenzionaliCriteri moderni < 4 metastasi, unilobari

9. Criteri convenzionaliCriteri moderni < 4 metastasi, unilobariNessun limite (NeoCT, two-stage, RF) Diametro < 5 cm Modificato da Khatri, Petrelli e Belghiti, JCO 2005

10. Criteri convenzionaliCriteri moderni < 4 metastasi, unilobariNessun limite (NeoCT, two-stage, RF) Diametro < 5 cmNessun limite Metastasi metacrone Modificato da Khatri, Petrelli e Belghiti, JCO 2005

11. Criteri convenzionaliCriteri moderni < 4 metastasi, unilobariNessun limite (NeoCT, two-stage, RF) Diametro < 5 cmNessun limite Assenza di malattia extraepatica Metastasi metacroneMetastasi sincrone e metacrone Modificato da Khatri, Petrelli e Belghiti, JCO 2005

12. Criteri convenzionaliCriteri moderni < 4 metastasi, unilobariNessun limite (NeoCT, two-stage, RF) Diametro < 5 cmNessun limite Assenza di malattia extraepaticaExeresi di malattia extraepatica (adenopatie ilari, recidiva locale, mts polmonari) Margine di resezione > 1 cm Metastasi metacroneMetastasi sincrone e metacrone Modificato da Khatri, Petrelli e Belghiti, JCO 2005

13. Criteri convenzionaliCriteri moderni < 4 metastasi, unilobariNessun limite (NeoCT, two-stage, RF) Diametro < 5 cmNessun limite Assenza di malattia extraepaticaExeresi di malattia extraepatica (adenopatie ilari, recidiva locale, mts polmonari) Margine di resezione > 1 cmMargine < 1 cm, purchè negativo Adeguato parechima residuo Metastasi metacroneMetastasi sincrone e metacrone Modificato da Khatri, Petrelli e Belghiti, JCO 2005

14. Criteri convenzionaliCriteri moderni < 4 metastasi, unilobariNessun limite (NeoCT, two-stage, RF) Diametro < 5 cmNessun limite Assenza di malattia extraepaticaExeresi di malattia extraepatica (adenopatie ilari, recidiva locale, mts polmonari) Margine di resezione > 1 cmMargine < 1 cm, purchè negativo Adeguato parechima residuoPVE o legatura portale Metastasi metacroneMetastasi sincrone e metacrone Resezione radicale Modificato da Khatri, Petrelli e Belghiti, JCO 2005

15. Criteri convenzionaliCriteri moderni < 4 metastasi, unilobariNessun limite (NeoCT, two-stage, RF) Diametro < 5 cmNessun limite Assenza di malattia extraepaticaExeresi di malattia extraepatica (adenopatie ilari, recidiva locale, mts polmonari) Margine di resezione > 1 cmMargine < 1 cm, purchè negativo Adeguato parechima residuoPVE o legatura portale Metastasi metacroneMetastasi sincrone e metacrone Resezione radicale Modificato da Khatri, Petrelli e Belghiti, JCO 2005

16. Criteri convenzionaliCriteri moderni < 4 metastasi, unilobariNessun limite (NeoCT, two-stage, RF) Diametro < 5 cmNessun limite Assenza di malattia extraepaticaExeresi di malattia extraepatica (adenopatie ilari, recidiva locale, mts polmonari) Margine di resezione > 1 cmMargine < 1 cm, purchè negativo Adeguato parechima residuoPVE o legatura portale Metastasi metacroneMetastasi sincrone e metacrone Resezione radicale L’indicazione alla resezione epatica è data dalla fattibilità tecnica Modificato da Khatri, Petrelli e Belghiti, JCO 2005

17. Contraindications to hepatic resection in CRC patients: Oncosurgery Approach Adam R et al., The Oncologist 2012;17:1225-1239

18. Should the prospect of surgery influence the choice of first-line chemotherapy When should targeted therapies be used? How many cycles before assessment of response and surgery? Is there a maximum number of metastases for achieving potentially curative surgery? What to do when there is a complete response (no metastases)? How should potentially resectable synchronous metastases be managed? Questions about liver metastases from colorectal cancer: Oncosurgery Approach

19. How should potentially resectable synchronous metastases be managed? – Chemotherapy or surgery first? – One- or two-stage surgical procedures? – Is liver surgery first a valid approach? Questions about liver metastases from colorectal cancer: Oncosurgery Approach

20. Surgical resection of the primary tumor, neoadjuvant chemotherapy (?), and then liver resection as a subsequent operation Colorectal primary tumor was the usual source of symptoms Colorectal primary likely source of subsequent metastasis and thus should be removed first (limited data) Less morbidity and mortality, particularly when a major hepatectomy (> 3 segments) is needed Early progression after removal of primary can select patients who do not benefit of liver resection Synchronous resectable liver metastases of colorectal cancer: Classical Approach

21. Only one randomized peri-operative trial: EORTC 40983 (the EPOC trial) Phase III study: patients with CRC and resectable liver metastases; WHO/ECOG performance score 0-2 (N = 364) FOLFOX4 for 6 cycles (12 wks) (n = 182) Surgery (n = 182) Surgery FOLFOX4 for 6 cycles (12 wks)

22. EORTC 40983: Patients who received surgery and resection

23. EORTC 40983: RECIST Response After Pre-operative CT 12 Pts progressed during preop CT One further patient not eligible for RECIST response assess-ment progressed after 3 cycles 4 of 8 pts progressed after 3 cycles underwent resection 1 of 4 pts progressed after 6 cycles underwent resection

24. EORTC 40983: post-operative complications

25. EORTC 40983: PFS in eligible and resected patients

26. Nordlinger B et al, ASCO 2012, abstr. 3508

27. Preferred in patients with limited hepatic disease (minor hepatectomy) High risk patients with extensive metastatic disease, elderly, advanced primary tumors tend to undergo sequential resections Advantage of removing all of the macroscopic cancer during a single operation Prevents the delay of adjuvant chemotherapy Simultaneous resections may leave behind undetected occult micro- metastases (limited data) Postoperative immunodeficiency associated with the primary can lead to early tumor spread (limited data) Primary tumor resection leads to the progression of the liver metastases (limited data) Few studies with bias in interpretation of simultaneous vs staged Synchronous resectable liver metastases of colorectal cancer: Combined/Simultaneous Approach

28. Published Results of Simultaneous versus Staged Resection for Synchronous CRC Hepatic Metastasis Martin R et al., J Am Coll Surg 2009;208:842–852

29. Outcome of simultaneous resections Synchronous resectable CRC liver mets Slesser AAP, et al., Eur J Surg Oncol 2013.09.012 UK Hospitals, 112 consecutive pts From 2000 to 2012 36 simultaneous resect. 76 sequential resect No differences in intraoperative and postoperative complications

30. Outcome of simultaneous resections synchronous resectable CRC liver mets Slesser AAP, et al., Eur J Surg Oncol 2013.09.012 3 yrs OS: 75% vs 64% p = 0.3793 yrs DFS: 33% vs 32% p = 0.837

31. The majority (70–90 per cent) metastatic disease at presentation is not suitable for curative resection A mutimodal approach including chemotherapy and aggressive surgical techniques such as extended or two-stage hepatectomy has been shown to improve resectability rates by 10–50 per cent The first stage focuses on the ‘easy’ side of the liver, leaving major hepatectomy for a second specific stage (higher morbidity and mortality) This approach reduces the number of procedures and optimizes administration of chemotherapy. Synchronous resectable, borderline or unresectable liver metastases of colorectal cancer: Combined primary and two-stage hepatectomy

32. Combined first-stage hepatectomy and CRC resection in a two-stage hepatectomy strategy Karoui M et al., British Journal of Surgery 2010; 97: 1354–1362 Two Institutions (French and Italian) 33 pts with bilobar mets From 2000 to 2008

33. Combined first-stage hepatectomy and CRC resection in a two-stage hepatectomy strategy Karoui M et al., British Journal of Surgery 2010; 97: 1354–1362 - R0 resections 25/33 pts (67%) - Morbidity of first stage 21%, second stage 32% - Mortality second stage (liver-related) 4%

34. Evidence from rectal cancer supporting preoperative chemoradiotherapy Colonic stent has allowed palliation of symptoms (obstruction) so that patients can be candidates for systemic chemotherapy at an early stage Colorectal cancer is a chemosensitive disease, and thus there is a logic to early systemic treatment Potentially optimize the chance of R0 liver resection related to a better survival An early control of systemic (liver) disease can lead to a reduction of probability of distant metastases and to better outcome Synchronous liver metastases of colorectal cancer: Liver-first or Reverse Approach

35. Studies on Liver-First Approach for synchronous CRC liver mets Santhalingami J al., JAMA Surg. 2013;148(4):385-391

36. Studies on Liver-First Approach for synchronous CRC liver mets De Rosa A al., J Hepatobiliary Pancreat Sci (2013) 20:263–270

37. Studies on Liver-First Approach for synchronous CRC liver mets Santhalingami J al., JAMA Surg. 2013;148(4):385-391

38. Studies on Liver-First Approach for synchronous CRC liver mets Santhalingami J al., JAMA Surg. 2013;148(4):385-391

39. Patient-based analysis comparing Liver-First and Combined approach Skye C et al., J Am Coll Surg 2012.12.029 Four Institutions 1004 pts From 1998 to 2011

40. Patient-based analysis comparing Liver-First and Combined approach Skye C et al., J Am Coll Surg 2012.12.029 Blue bar: overall complications Red bar: severe complications Green bar: after minor resections Tan bar: after major resections No differences: all p= 0.05

41. Patient-based analysis comparing Liver-First and Combined approach Skye C et al., J Am Coll Surg 2012.12.029 No differences of complications between minor and major hepatectomy

42. Patient-based analysis comparing Liver-First and Combined approach Skye C et al., J Am Coll Surg 2012.12.029 No differences of complications in the logistic regression analysis

43. Patient-based analysis comparing Liver-First and Combined approach Skye C et al., J Am Coll Surg 2012.12.029 Only R0 resection is a predictors of survival

44. Patient-based analysis comparing Liver-First and Combined approach Skye C et al., J Am Coll Surg 2012.12.029 5 yrs Overall Survival 50.9 (44%) No differences regarding the approach (p =0.94)

45. Patient-based analysis comparing Liver-First and Combined approach Skye C et al., J Am Coll Surg 2012.12.029 In the Cox regression analysis for survival gender, rectal primary, number of mets, minor hepatectomy and combined resection and ablation are significat at univariate

46. Rectal cancer and Liver-First Approach Skye C et al., J Am Coll Surg 2012.12.029 Resection of the rectal primary is a significantly more challenging procedure by itself with well-established morbidity Patients with limited liver disease and small asymptomatic primary could benefit from a combined resection The extension of the primary tumor often do not allow a combine approach and require a neoadjuvant chemoradio In selected patients, where the primary rectal cancer is not a threat for bleeding, obstruction, or perforation, there is the option of addressing the hepatic disease first Need of selecting patients on biological features

47. Conclusions Patients managed with a staged or simultaneous approach had similar recurrence and overall survival Both minor and major hepatectomy can be performed safely with low morbidity and mortality as part of either a simultaneous or a staged operative strategy Few data available on Liver-First approach, though survival data are consistent across studies Laparoscopic rectal/colon simultaneous excision and/or other liver mets ablation technics should be further explorated Longterm outcomes among patients with sCRLM are dictated by biology (i.e. CEA, BRAF ?, RAS ? MSI, genomic, etc) not surgical strategy

48. Grazie per l’attenzione