1. The road to R0 Several paths for one goal ? Domenico D’UGO Full Professor of Surgery Catholic University - Rome

2. Survival after R0-Resection 36.1% German Gastric Cancer Study (1654 pts); Ann Surg, 1998 5 yrs

3. Memorial Sloan-Kettering Cancer Center, New York (1172 pts); Ann Surg, 2004 7% 92% Recurrence after R0-Resection

4. Personal Series (294 pts) – D. D’Ugo 2009 Risk factors pT3-4 pN+ diffuse type G3 larger size proximal site Time to recurrence months 19.0% 16.7% 39.3% 25.0% Peritoneal Lymph nodal Haematogenous Locoregional 60.7% Recurrence after R0-Resection Locoregional 19.1 Lymph nodal 24.2 Peritoneal 19.9 Haematogenous 25.9

5. or Recurrence (of disease) Failure (of treatment) “ It’s what the surgeon doesn’t see that kills the patients” Sugarbaker PH J Nippon Med Sch. 2000 Feb;67(1):5-8 ?

6. No residual disease , “ high probability” of cure The curative potential of gastric resection T1 or T2 N0 treated by D1, 2, 3 resection N1 treated by D2, 3 resection M0, P0, H0, CY0 Proximal and Distal margins >10 mm CRITERIA Japanese Gastric Cancer Association, 1998 D>N

7. Nishi M, et al. Gastric Cancer, 1993 1962 General Rules for Gastric Cancer Study in Surgery and Pathology Survival after R0-Resection according to the “Japanese Rules”

8. N0 patients N+ Patients

9. Randomized Controlled Trials No survival benefit Dutch MRC

11. Maruyama Index: paradigm of tailored extension of LND Median MI = 26

12. Chance of detecting lymph node metastases “ Calculating the probability of detecting metastases ... this probability increased steeply in the lower range and more gradually in the higher range yield”

13. Overall survival: p=0.041 Disease-free survival: ns Cancer specific survival: ns Per-protocol analysis: OS, CSS, DFS: p=ns

14. Overall survival: p=ns Disease-free survival: p= ns

15. 36.1% Siewert 1998 64.8% Kim 1998 ≈ ≈ German Gastric Cancer Study (1654 pts); Ann Surg, 1998 Korea Gastric Cancer Center (10783 pts); Gastric Cancer, 1998 The E/W Survival Gap

16. Magic Trial INT-0116 ACTS-GC CH-RT ECF courtesy by : T. SANO (2009) The E/W Survival Gap

17. 2004 2005 2006 2008 “ Induction ” of R0

18. “ Induction” of R0 by Neoadjuvant Chemotherapy Staging Laparoscopy

19. D2 Lymphadenectomy “ Induction” of R0 by Neoadjuvant Chemotherapy

20. Neoadjuvant Chemotherapy with Epirubicin, Etoposide and Cisplatin: 7-year follow-up 84% 58% 46% R0-Resection Rate: 83%

21. 60% 36% T-downstaging: 42% = Induction of R0 Resection ? Neoadjuvant Chemotherapy with Epirubicin, Etoposide and Cisplatin: 7-year follow-up

24. Circumferential Margin at EGJ The high proportion of “open & close” laparotomies” (12%) and of positive circumferential resection margin (32-47%) highlights limitations in the current staging techniques for identifying patients at risk for potential CRM involvement. Davies et al., Dis Esoph (2008) Dexter et al., GUT (2001)

25. Preoperative radiotherapy : RCT – chinese report, 1998 “ Preoperative radiation therapy is able to improve the results of surgery for adenocarcinoma of the gastric cardia” Treatment: 40 Gy / 4 weeks by 2 Gy qd x 20 OS: 30% vs 19% Zhang, et al. Int. J. Radiation Oncology Biol. Phys., 1998

26. Arm A : 2.5 PLF(cisplatin+fluorouracil+leucovorin) Arm B : 2 PLF+ cisplatin+etoposide+30 Gy “ Although the study was closed early and statistical significance was not achieved, results point to a survival advantage for preoperative chemo-radiotherapy compared with preoperative chemotherapy in adenoca. of the EGJ ” Preoperative Chemoradiation

27. Preoperative Chemoradiation : RTOG 9904 Trial Ajani J, et al. J Clin Oncol 2006, 24, p3953 Pathologic Complete Response : 26%

28. Ajani J, et al. J Clin Oncol 2006, 24, p3953 “ With some guideline refinements, the preoperative chemoradiotherapy strategy is poised for a comparison with postoperative chemoradiotherapy in patients with localized gastric cancer” 71% Preoperative Chemoradiation : RTOG 9904 Trial

29. Preoperative Chemoradiation Fujitani K, Ajani J, et al. Ann Surg Oncol 2007, 14, p1305 Morbidity rate: 38.0% (27 patients) Mortality rate: 2.8% (2 patients) Prospectively collected database on 71 consecutive patients Induction chemotherapy chemo-radiotherapy (45 Gy) Postoperative results (…careful consideration of added risk…)

30. Tran CL, et al. Am J Surg 2006, 192, p873 For Colorectal Cancer Francois Y, et al. J Clin Oncol 1999, 8, p2396 Multimodal Preoperative Treatment: Surgical Implications Delayed surgery… … increases probability of downstaging of the tumor when there is a correctly long interval between the completion of therapy and surgery … doesn’t modify toxicity and early clinical results diverting stoma avoids major morbidity due to anastomotic leak (fatal in 0-3% of cases) but… Matthiessen P, et al. Ann Surg 2007, 246, p207

32. For Gastric Cancer Bozzetti F, et al. Ann Surg 1997, 226, p613 Delayed surgery… … increases probability of downstaging of the tumor when there is a long interval between the completion of therapy and surgery … doesn’t modify toxicity and early clinical results No tools to avoid major morbidity due to anastomotic leak (fatal up to 1/3 of cases!) but… Sauvanet A, et al. J Am Coll Surg. 2005, 201 (2):p253 Multimodal Preoperative Treatment: Surgical Implications

33. Multimodal Preoperative Treatment: Extreme Salvage Surgery FOX-RT for Previously Unresectable Disease

34. Conclusions Multimodal preop. approach with delayed surgery… … is only seldom associated with tumor progression - accurate pretreatment staging? - radiation therapy optimization? … no increase of surgical morbi/ /mortality in experienced hands - high volume – post-RT surgery … doesn’t modify toxicity and early clinical results