1) Multimodal preoperative treatment involving chemotherapy or chemoradiation before surgery can reduce the extent of gastric cancer and allow for complete resection in some patients who otherwise may have inoperable tumors. 2) While this approach can increase the chance of complete tumor removal, it also carries risks of treatment-related toxicity, tumor progression during treatment delay, and potential increases in postoperative complications. 3) Careful patient selection and standardization of surgical and pathological evaluation after preoperative treatment is important to maximize benefits and minimize hazards for gastric cancer patients undergoing a multimodal approach.

1. prof. Domenico D’UGO Dir.: U. O. Chirurgia Generale 1 Policlinico Agostino Gemelli - Roma Università Cattolica del Sacro Cuore CENTRO DI RIFERIMENTO ONCOLOGICO ISTITUTO NAZIONALE TUMORI - AVIANO Focus sul Carcinoma Gastrico: Approccio Multidisciplinare La chirurgia dilazionata nel trattamento integrato

2. Potential Benefits of Multimodal Preoperative Treatment Locoregional reduction of tumor ( down-staging ) : chance for R0-resection on subsequent surgery Fink U, et al. World J Surg 1995, 19, p509 Eliminate or delay occult metastases ( systemic control ) T - N M 1 2

3. Toxicity of chemotherapy, with associated deterioration of the general conditions Fink U, et al. World J Surg 1995, 19, p509 Delay of definitive treatment or tumor progression Increased postoperative complications and mortality Potential Hazards of Multimodal Preoperative Treatment 1 2 3

4. Fink U, et al. World J Surg 1995, 19, p509 Potential Hazards of Multimodal Preoperative Treatment 15% 1 2

5. Fink U, et al. World J Surg 1995, 19, p509 Potential Hazards of Multimodal Preoperative Treatment 3

6. Fink U, et al. World J Surg 1995, 19, p509 Accurate pretherapeutic staging Composition of the study population controlled for performance status of the patients Standardization of surgical procedures and histopathologic evaluation of the response. Standard resection today implies extensive lymph node dissection Multimodal Preoperative Treatment: Ideal Trial Prerequisites 1 2 3

7. Songun I, et al. Eur J Canc 1999, 35 (4), p558 ≈ Neoadjuvant Chemotherapy in Operable Gastric Cancer: Preliminary results of FAMTX Trial

8. Songun I, et al. Eur J Canc 1999, 35 (4), p558 36% 78% Neoadjuvant Chemotherapy in Operable Gastric Cancer: Preliminary results of FAMTX Trial

9. Songun I, et al. Eur J Canc 1999, 35 (4), p558 “ CT scan of the abdomen and laparoscopic staging were optional . No exclusion was based on stage, among others due to the difficulty of determining stage pre-operatively” “ The standard surgical procedure was a limited lymphadenectomy (D1) ” Neoadjuvant Chemotherapy in Operable Gastric Cancer: Preliminary results of FAMTX Trial 1 3

10. Siewert JR, et al. Ann Surg 1998, 228 (4), p449 36% R0-Resection: Prognostic Considerations

11. Marrelli D, et al. Ann Surg 2005, 241 (2), p247 52% R0-Resection: Prognostic Considerations

12. 2004 2005 2006

13. Neoadjuvant Chemotherapy Staging Laparoscopy

14. Neoadjuvant Chemotherapy D2 Lymphadenectomy

15. Neoadjuvant Chemotherapy with Epirubicin, Etoposide and Cisplatin: 7-year follow-up 83% 58% 46% R0-Resections: 83%

16. 60% 36% T-downstaging: 42% Neoadjuvant Chemotherapy with Epirubicin, Etoposide and Cisplatin: 7-year follow-up

17. * One patient died after the first cycle as a result of gastrointestinal bleeding Neoadjuvant Chemotherapy with Epirubicin, Etoposide and Cisplatin: 7-year follow-up Potential Hazards 1 2 0/25 0/25 0/25 1/25* D’Ugo

18. Neoadjuvant Chemotherapy with Epirubicin, Etoposide and Cisplatin: 7-year follow-up Potential Hazards 0/24 6/24 D’Ugo 3

19. Perioperative chemotherapy : MAGIC Trial Cunningham D, et al. N Engl J Med 2006, 355, p11 “ The perioperative chemotherapy with a regimen of Epirubicin, Cisplatin and infused Fluorouracil should be considered as an option for patients with gastric adenocarcinoma”

20. Cunningham D, et al. N Engl J Med 2006, 355, p11 Perioperative chemotherapy : MAGIC Trial 1 2

21. Cunningham D, et al. N Engl J Med 2006, 355, p11 Perioperative chemotherapy : MAGIC Trial = 3 Surgery Group Perioperative-Chemotherapy Group Variable 13 days 13 days Median hospital stay 5.9% 5.6% Deaths within 30 days 45.3% 45.7% Postoperative complications

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

23. Ajani J, et al. J Clin Oncol 2006, 24, p3953 Preoperative Chemoradiation : RTOG 9904 Trial 16/32 D1 lymphadenectomy 1/36 Total esophagogastrectomy with colonic interposition 16/32 D2 lymphadenectomy 1/36 Palliative gastrojejunostomy 1/36 Proximal gastrectomy 4/36 Esophagogastrectomy 14/36 Total gastrectomy 15/36 Subtotal gastrectomy Patients Type of resection 7/43 (16%) No surgery 9/43 (21%) Palliative 27/43 (63%) Curative Patients Extent of resection 1 2

24. Ajani J, et al. J Clin Oncol 2006, 24, p3953 Preoperative Chemoradiation : RTOG 9904 Trial No deaths within 30 days 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 3

25. Preoperative Chemoradiation : RTOG 9904 Trial 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%

26. “ Preoperative chemoradiation can be performed safely in patients with gastric or gastroesophageal cancer with careful consideration of added risk ” Preoperative Chemoradiation : RTOG 9904 Trial Fujitani K, Ajani J, et al. Ann Surg Oncol 2007, 14, p1305

27. 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 long interval between the completion of therapy and surgery … doesn’t modify toxicity and early clinical results a diverting stoma should be performed to avoid major morbidity due to anastomotic leak (fatal in 0-3% of cases) but… Matthiessen P, et al. Ann Surg 2007, 246, p207

28. For Gastric Cancer Bozzetti F, et al. Ann Surg 1997, 226, p613 Multimodal Preoperative Treatment: Surgical Implications 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 There aren’t 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

29. T 3 N 2 antrum Multimodal Preoperative Treatment: FOX-RT Trial and… pT 2 N 1 (N+ 1/21)

30. Multimodal Preoperative Treatment: … Delayed Extreme Surgery FOX-RT for Previously Unresectable Disease

31. Multimodal Preoperative Treatment: … Delayed Extreme Surgery FOX-RT for Previously Unresectable Disease

32. Multimodal Preoperative Treatment: … Delayed Extreme Surgery FOX-RT for Previously Unresectable Disease

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

34. Conclusions Multimodal preoperative approach with delayed surgery… … is only seldom associated with tumor progression - accurate pretreatment staging? - radiation therapy optimization? … doesn’t increase surgical morbidity and mortality in experienced hands ( high volume – post-RT surgery ) … doesn’t modify toxicity and early clinical results 1 2 3