1) Neoadjuvant chemotherapy and preoperative chemoradiation can help increase the rate of R0 resection for gastric cancer by downstaging the tumor. 2) Multimodal preoperative treatment with delayed surgery between completion of therapy and surgery increases the probability of tumor downstaging but does not increase surgical morbidity or mortality when performed by experienced surgeons. 3) Preoperative chemoradiation has shown pathologic complete response rates of over 25% in clinical trials for gastric cancer.

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