1. Pathologic Response to Preoperative Chemotherapy in Colorectal Liver Metastases: Fibrosis, not Necrosis, Predicts Outcome Ann Surg Oncol (2012) 19:2797–2804 Aleksey V. George A. Poultsides, Fei Bao, Elliot L. Servais et al. Reporter: R4 李育庭 Supervisor: 鄧豪偉醫師

2. Introduction Patient and Method Result Discussion Conclusion

3. Introduction 3

4. Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients. Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients. Nordlinger B, Sorbye H, Glimelius B, et al. Lancet. Mar 22 2008;371(9617):1007-1016.

6. Systemic chemotherapy has been shown to convert initially unresectable tumors to resectable. Systemic chemotherapy has been shown to convert initially unresectable tumors to resectable.

7. Adam R, Delvart V, Pascal G, et al. Annals of surgery 2004;240:644-57.

8. Pathologic response predicts survival after preoperative chemotherapy and resection of CLM (Colorectal liver metastasis). Pathologic response predicts survival after preoperative chemotherapy and resection of CLM (Colorectal liver metastasis).

9. 9 Blazer DG, 3rd, Kishi Y, Maru DM, et al. J Clin Oncol 26:5344-51, 2008 Residual tumor complete0% major1-49% minor>50%

10. 10 Adam R, Wicherts DA, de Haas RJ, et al. J Clin Oncol 26:1635-41, 2008

11. 11 Rubbia-Brandt L, Giostra E, Brezault C, et al. Ann Oncol 18:299-304, 200 7

12. The pathologic response to neoadjuvant therapy in primary colorectal cancer is not homogeneous. Fibrosis Necrosis Acellular mucin Rubbia-Brandt L, Giostra E, Brezault C, et al. Ann Oncol 18:299-304, 200 7

13. Purpose To evaluate the prevalence of the three components of pathologic response (necrosis, fibrosis, acellular mucin) after resection of CLM, with and without preoperative chemotherapy. To evaluate the prevalence of the three components of pathologic response (necrosis, fibrosis, acellular mucin) after resection of CLM, with and without preoperative chemotherapy. To investigate the association with outcome as well as preoperative factors To investigate the association with outcome as well as preoperative factors

14. Patient and Methods 14

15. A single institution A single institution Retrospective review Retrospective review

16. Patient Preoperative chemotherapy : Systemic chemotherapy within 6 months before hepatectomy Hepatic artery infusion Non Preoperative chemotherapy Chemotherapy-naive patients chemotherapy-free interval of more than 6 months before hepatectomy Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

17. 17 Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

18. A median of 3 slides (range, 1–17) were examined for each tumor, typically one section per centimeter of tumor diameter. A median of 3 slides (range, 1–17) were examined for each tumor, typically one section per centimeter of tumor diameter. All tumors that grossly appeared to show complete or near complete response. All tumors that grossly appeared to show complete or near complete response.

19. Result 19

20. 20 Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

21. 21 Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

22. Of 21 complete pathologic responders, all but one had received preoperative chemotherapy. Of 21 complete pathologic responders, all but one had received preoperative chemotherapy. 5-year survival probability: 94% 5-year survival probability: 94% NCharacter 7>90% Necrosis 6>90% Fibrosis 3>90% Mucin 5Mixed pattern Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

23. Preoperative chemotherapy 23 Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

24. Preoperative chemotherapy 24 Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

25. 25

26. Non Preoperative chemotherapy Only 9 (8 %) and 3 (3 %) of the 117 nonchemotherapy patients had ≥75 % nonviable tumor and fibrosis ≥ 40 %. Only 9 (8 %) and 3 (3 %) of the 117 nonchemotherapy patients had ≥75 % nonviable tumor and fibrosis ≥ 40 %. Lack of association with disease-specific survival Lack of association with disease-specific survival

27. 27

28. Discussion 28

29. Fibrosis is the predominant chemotherapy- induced pathologic change in CLM. Fibrosis is the predominant chemotherapy- induced pathologic change in CLM. Necrosis in CLM is more related to spontaneous phenomena. Necrosis in CLM is more related to spontaneous phenomena. The beneficial effects of chemotherapy appear to be mainly related to the replacement of tumor by fibrosis The beneficial effects of chemotherapy appear to be mainly related to the replacement of tumor by fibrosis 29

30. The study is the first to provide a detailed quantitative analysis of the three components of overall pathologic response (fibrosis, necrosis, acellular mucin) The study is the first to provide a detailed quantitative analysis of the three components of overall pathologic response (fibrosis, necrosis, acellular mucin) Fibrosis as the main chemotherapy-induced pathologic change independently associated with survival after resection of CLM. Fibrosis as the main chemotherapy-induced pathologic change independently associated with survival after resection of CLM. 30

31. 8 % were found to have a complete absence of viable tumor cells on pathologic review 8 % were found to have a complete absence of viable tumor cells on pathologic review In the study, patients with complete pathologic response had a 94 % 5-year disease-specific survival probability. In the study, patients with complete pathologic response had a 94 % 5-year disease-specific survival probability. 31

32. It is important to identify patient or tumor characteristics that preoperatively predict higher levels of pathologic response. It is important to identify patient or tumor characteristics that preoperatively predict higher levels of pathologic response. 32 Tumor size (after treatment)< 3 cm High CEA>200ng/ml Hepatic artery infusion Bevacizumab + Oxaliplatin based chemotherapy

33. 33 Ribero D, Wang H, Donadon M, et al. Cancer 110:2761-7, 2007

34. Bevacizumab + Oxaliplatin based chemotherapy 34 Blazer DG, 3rd, Kishi Y, Maru DM, et al. J Clin Oncol 26:5344-51, 2008

35. Bevacizumab + Oxaliplatin based chemotherapy 35 Klinger M, Tamandl D, Eipeldauer S, et al. Ann Surg Oncol 17:2059-65, 2010

36. Duration of chemotherapy Longer duration of preoperative chemotherapy was not associated with pathological response Longer duration of preoperative chemotherapy was not associated with pathological response 36 Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

37. Duration of chemotherapy 37 Kishi Y, Zorzi D, Contreras CM, et al.Ann Surg Oncol 17:2870-6, 2010

38. Conclusion 38

39. Approximately 8 % of patients with CLM receiving modern combination chemotherapy can achieve complete pathologic response. Approximately 8 % of patients with CLM receiving modern combination chemotherapy can achieve complete pathologic response. Favorable overall pathologic response is associated with improved long-term survival. Favorable overall pathologic response is associated with improved long-term survival. The pathologic finding of necrosis in CLM is a nonspecific finding. The pathologic finding of necrosis in CLM is a nonspecific finding. 39

40. HAI chemotherapy and bevacizumab may be associated with higher rates of overall pathologic response and fibrosis. HAI chemotherapy and bevacizumab may be associated with higher rates of overall pathologic response and fibrosis. 40