When should we consider liver first approach in synchronous colorectal liver metastasis?

1. When should we consider liver first approach in synchronous colorectal liver metastasis? Tommy Yip Siu-man Prince of Wales Hospital

2. Introduction • Colorectal cancer is the third most common cancer worldwide 1 • ~25 % of patients have synchronous liver metastases at the time of diagnosis 2 • While surgical resection of CRLM is regarded the only potential for a cure 3,4,the simultaneous presentation of primary and secondary disease provides a unique chance in deciding the optimal therapy sequence 1 - Parkin DM 2005 2 - McMillan DC 2007 3 - Tsai MS 2007 4 - Pawlik TM, 2007

3. Surgical strategies to Synchronous CRLM • Resection of primary tumour first (Classical approach) • Resection of primary tumour and CRLM (Combined approach) • Resection of CRLM first (Liver-first approach / Reverse approach)

4. Resection of primary tumour first (Classical approach)

5. Classical approach • Resection of primary tumour  hepatectomy (if the liver metastases are resectable)  subsequent adjuvant chemotherapy • Rationale • Symptoms caused by colorectal primary tumour (bleeding, obstruction, pain) • Natural selection “window” to exclude from further liver resection 5,6 • ? Primary tumour as the likely source of subsequent metastasis 7 5 - Benoist S 2007 6 - Capussotti L 2006 7 - Peeters CF 2006

6. Limitations • Progression of CRLM beyond resectability during treatment of primary tumour, esp if complications arise from primary resection 8 or adjuvant chemotherapy 9,10 • Postoperative immunodeficiency following primary resection increases the rate of liver metastatic growth 11,12 8 – Law WL 2007 9 – Vauthey JN 2006 10- Mentha G 2006 11- de Haas RJ 2010 12 - González HD 2007

7. Resection of primary tumour and CRLM (Combined approach)

8. Combined approach • Resection of primary tumour and CRLM in the same operation • Rationale: • Adjuvant therapy can be commenced without delay 13 • Reduced total duration of surgery, total hospital stay and transfusion requirement 14,15 13 – Turrini O 2005 14 – Vassiliou I 2007 15 - Brouquet A 2010

9. Limitations • Considerable morbidity of complex liver resection combined with major bowel resection • Not for patients with • High CRLM burden who require a major liver resection 16 • Locally advanced rectal cancer 17 • Advanced age 18 • ? Risk of leaving behind undetected occult micro-metastases in the remnant liver 19 16 - Lehmann K 2012 17 - Canberra 1999 18 - Mentha G 2008 19 - Yoshidome H 2008

10. Resection of CRLM first (Liver-first approach / Reverse approach)

11. Liver-first approach / Reverse approach • First described by Mentha and colleagues in 35 patients who had a synchronous resectable primary tumour and advanced CRLM • Usually preceded by neoadjuvant chemotherapy +/- radiotherapy +/- biological agents

12. Rationale • Metastatic disease rather than primary colorectal tumour as the main determinant of survival 20 • Treatment of metastatic disease is not delayed by local therapy for primary tumour or by complications of surgical treatment of primary tumour • Primary-related complications (such as bleeding, obstruction, or perforation) are rare in patients with stage IV colorectal cancer receiving combination chemotherapy21 ; may be tackled with stenting 20 - Moher D 2010 21 – Lambert LA 2000

13. Limitations • Complication related to primary tumour progression (e.g obstruction, perforation, bleeding or pain) • Inoperability during treatment (e.g disease progression, new extra-hepatic disease Only few retrospective studies investigating this approach

14. Vincent W.T. Lam 2013

15. Santhalingam 2013

16. Vincent W.T. Lam 2013

17. Vincent W.T. Lam 2013

18. Vincent W.T. Lam 2013

19. Limitations of the studies • No randomised controlled trials • Small sample size • Different patient selection criteria • None defined resectability for the CRLM • Only one study define anatomical site of primary tumour • Different dosage and duration of preoperative chemotherapy • Only one study included response rate of CLM to chemotherapy • Lack of long-term follow-up

20. Liver-first approach in selected patients with CRLM is associated with low peri-operative morbidity & mortality, and acceptable survival outcomes

21. Patients that can be considered to “liver-first approach • Resectable primary tumour with high liver disease burden • Locally advanced primary tumour with low liver disease burden • Locally advanced primary tumour with high liver disease burden

22. Patients that can be considered to “liver-first approach • Resectable primary tumour with high liver disease burden • Locally advanced primary tumour with low liver disease burden • Locally advanced primary tumour with high liver disease burden

23. Patients that can be considered to “liver-first approach • Resectable primary tumour with high liver disease burden • Locally advanced primary tumour with low liver disease burden • Locally advanced primary tumour with high liver disease burden Crucial to control the disease with downstaging chemotherapy and potentially consider liver resection first as this can influence patient’s long-term survival

24. Patients that can be considered to “liver-first approach • Resectable primary tumour with high liver disease burden • Locally advanced primary tumour with low liver disease burden • Locally advanced primary tumour with high liver disease burden Especially for locally advanced rectal tumour, chemoRT should be considered. While waiting for rectal surgery, the liver tumours can be resected first

25. A. De Rosa 2013

26. Conclusion • The “liver-first” approach may be beneficial to a selected group of patients with synchronous CRLM • Patient selection is likely to be determined by their response to down-staging chemotherapy with or without biological agents • Need of further prospective controlled trials to determine the correct surgical sequence

27. The End

28. Questions & Answers

29. Consensus conference of CLM resectability criteria • ability to obtain a complete resection (negative margin) • ability to preserve two contiguous liver segments, with adequate vascular inflow and outflow • ability to preserve adequate future liver remnant (> 30% in a healthy liver, 40% in diseased liver)