1. 1 Surgical and Ablative Strategies for Treatment of Metastatic Colorectal Cancer Kim M. Olthoff, MD Associate Professor of Surgery Liver Transplantation and Hepatobiliary Surgery University of Pennsylvania Philadelphia, Pennsylvania, USA Penn Cancer Center

2. 2 Colorectal Cancer Demographics  Fourth most common cancer in the United States  Second leading cause of cancer death –An estimated 146,940 cases will be diagnosed, with 56,700 deaths resulting from CRC  Lifetime risk of developing CRC is 6%  90% of CRC cases occur in patients over 50 years old  Poor long-term survival in Stage IV disease (<5%)  Only 40% of patients in the United States detected through screening Cancer Facts & Figures 2004. American Cancer Society. Treatment Algorithms: Colorectal Cancer 5th Edition. Datamonitor 2003.

3. 3 CRC Stage at Diagnosis 13.7% Stage I 27.9% Stage II 37.2% Stage III 21.2% Stage IV Treatment Algorithms: Colorectal Cancer 5th Edition. Datamonitor 2003.

4. 4 CRC: Treatment by Stage  Stage I –Surgery  Stage II –Surgery, adjuvant chemotherapy (controversial)  Stage III –Surgery and adjuvant chemotherapy  Stage IV –Primary chemotherapy; resection of metastatic disease when possible Treatment Algorithms: Colorectal Cancer 5th Edition. Datamonitor 2003.

5. 5 Colorectal Metastases to the Liver  The most common site of metastases from CRC  50%-75% of patients with advanced CRC will develop liver metastases  15%-25% of patients have liver metastases at presentation  20%-35% of patients have metastatic disease confined to the liver Kemeny and Fata. J Hepatobiliary Pancreat Surg. 1999;6:39. Seifert et al. J R Coll Surg Edinb. 1998;43:141. Borner. Ann Oncol. 1999;10:623.

6. 6 Colorectal Cancer Metastatic to the Liver Outline  Surgical indications  Surgical approaches  Strategies to increase resectability –Adjuvant therapy –Ablative therapy

7. 7 Strategies for Metastatic Colorectal Cancer Surgical Decision Making Metastatic Disease Assessment of Resectability Tumor conference discussion ResectableUnresectable Neoadjuvant Surgery Chemotherapy Ablative therapy Adjuvant ?

8. 8 Strategies for Metastatic Colorectal Cancer Prognosis LobeAll n=370n=631n=1,001 Periop mortality (%)0.542.8 Median survival (mos)463942 5 year survival (%)403337 Fong et al, Ann Surg 1999; 230:309 1,001 Patients at MSKCC 1985-1998

9. 9 Hepatectomy for Colorectal Metastases Surgical Decision Making Factor%pHazard > 1 Tumor510.00041.5 CEA > 200 ng/ml90.011.5 Size > 5 cm450.011.4 Node + primary600.021.3 Dz-free interval < 1 yr490.031.3 Positive micro margin110.0041.7 Extrahepatic disease90.0031.7 Postop Preop Fong et al, Ann Surg 1999; 230:309 Multivariate Analysis of Survival (N=1,001)

10. 10 Hepatectomy for Colorectal Metastases Surgical Decision Making Survival Survival ScoreMedian5 year 074 months60% 15144 24740 33320 42025 52214 Fong et al, Ann Surg 1999; 230:309 The problem with scoring: no one preoperative factor can be used to exclude Preop Clinical Risk Score Predicts Survival

11. 11 Hepatectomy for Colorectal Metastases Surgical Decision Making Number5 year of tumorsNsurvival (%) 44933 53822 6 - 82319 9-204514 15523 Ann Surg Onc 2000; 7:643 Liver Metastases >4 Conclusion: Take an Aggressive Surgical And Adjuvant Therapy Approach!

12. 12 Hepatectomy for Colorectal Metastases Staged vs Simultaneous Operations Staged (n=106) Simultaneous (n=134) p Primary resection Right colectomy Left colectomy LAR APR 15 (14%) 31 (29%) 49 (46%) 11 (10%) 53 (40%) 30 (22%) 46 (33%) 5 (4%) 0.001 Liver resection Wedge Segmental ≥ Lobe 9 (8%) 20 (19%) 77 (73%) 49 (37%) 28 (20%) 57 (43%) 0.001 No difference in major complications or survival Martin et al JACS 2003; 197:233

13. 13 Unresectable Disease Present Identified at Laparoscopy 0 10 20 30 40 50 Score < 3Score > 3 Cancer 2001; 91:1191 Hepatectomy for Colorectal Metastases Surgical Decision Making: Laparoscopy N=45N=57 %

14. 14 Surgical Approaches: Intra-operative Ultrasound Operative U/S probes (open) T probe Finger-grip probe Microvascular flow probe Open abdomen curvilinear probe Laparoscopic U/S probes Rigid laparoscopic probe 4-way flexible laparoscopic probe End-fire probe

15. 15 Intra-op U/S of IVC and 3 hepatic veins IV C RH V MH V LH V

16. 16 Techniques for Dividing Liver Parenchyma/Achieving Hemostasis Monopolar cautery (bovie) Blunt fracture/clips Argon Beam Coagulator Ultrasonic dissector (CUSA) Harmonic scalpel Ligasure Endovascular stapler Fibrin glue Erbe Hydrojet TissueLink Floating Ball/ DS3.0/3.5

17. 17 Surgical Approaches Laparoscopic resection of liver tumor

18. 18 Hepatectomy for Colorectal Metastases Advantages of laparoscopic liver surgery  Band-aid sized incisions  Less pain  Shorter LOS  No blood transfusions  No oncological disadvantages

19. 19 Port placement: lap. resection R. lobe 11 mm 5 mm 12 mm 5 mm Old, open incision

20. 20 Port Placement for Lap. resection of R. lobe tumor Scissors TissueLink Argon Harmonic Suction irrig. X X 12 mm - Scope 12 mm - Stapler 5 mm (working) X 5 mm - retractor X lesion

21. 21 Laparoscopic partial R hepatic lobectomy 44 yo F, 5 cm lesion Ideal lesion

22. 22 Hand Assisted Laparoscopic Resection

23. 23 Port sites for Lap. hand-assisted resection R. lobe tumor lesion X X 12 mm - Scope Hand port X 12 mm - Stapler 5 mm - working

24. 24 No post-op pain, d/c’d home on POD #2 12 mm 5 mm Hand port

25. 25 Lap. hand-assisted L lateral segmentectomy 72 yo WM, met to liver tumor Resected LLS Cut edge of liver tumor

26. 26 Strategies to increase resectability of liver metastases  Portal vein embolization  2 stage hepatectomy  In situ and ex vivo resection  Downstaging chemotherapy –5-FU with leucovorin or folinic acid –Irinotecan hydrochloride (CPT-11) –Oxaliplatin  Local ablation techniques –Cryotherapy, RFA

27. 27 77 patients resected (complete and partial) after chemotherapy 58/77 patients had complete resection Topham and Adams. Semin Oncol. 2002:29:3. CRC Patients With Liver Metastasis (n=151) CRC Patients With Resected Liver Metastasis after downstaging (n=77) 5-y survival (%) 28 50 Median OS (mo) 24 48 Survival Outcomes in CRC Patients With Liver Metastasis: Role of Neoadjuvant Irinotecan- or Oxaliplatin-Based Therapy 0123456789 Years 0 20 40 60 80 100 % Survival 74 nonoperative patients

28. 28 Hepatic Resection of Colorectal Metastases Strategies to increase resectability: Ablation  Goals of Ablation in metastatic CRC –Prolong survival  No proven benefit (yet) –Treat unresectable disease  Makes us feel like we did something –In combination with resection  To clear positive or narrow margin  To ablate residual tumor

29. 29 Hepatic Resection of Colorectal Metastases Strategies to increase resectability: Ablation  Experience still limited in downstaging process  No good studies to confer benefit or increase resectability rates  Wallace et al Surgery 1999 – Cryotherapy with surgery. Two-thirds recurrence by 2 years.  Pawlik et al ASO 2003 – combined RFA with surgical resection in 172 patients. Median f/u 21 months – 56% recurrence  RFA with less EBL, shorter LOS, but longer ablation times, higher recurrence for large lesions (> 3 cm)

30. 30 Hepatic Resection of Colorectal Metastases Strategies to increase resectability  Conclusions –Be aggressive in your approach –Consider preoperative adjuvant chemotherapy to increase resectability rates –Utilize ablative techniques as a complement to surgical resection when able to completely eradicate viable tumor