1. GASTRIC CANCER A MODEL FOR MULTIDISCIPLINARY TEAM APPROACH

2. Gastric cancer is a significant problem in some countries GLOBOCAN (2002) Incidence of gastric cancer (crude rate in males [all ages] per 100,000 population) <3.1 <7.0 <13.8 <22.2 <118.6

7. Years after surgery Gastric Cancer Survival by stage CADO,1985 0 50 100% 5 10 years Stage III Stage II Stage I Stage 0 21.9 47.6 79.2 91.6 82.0 66.9 36.4 14.7

8. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA No relevant past history, excepting overweight No peptic ulcer disease. Ocasional dyspepsia and gastroesophageal reflux Active smoker. No previous surgery CURRENT DISEASE: He consulted due to haematemesis. No weight loss or anorexia.

9. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA Physical exam: No pallor or icteric collour No hepatomegaly. No ascitis. No edema. No supraclavicullar lymph nodes Cardiopulmonar and neurological without findings of interest A DIAGNOSTIC TEST WAS PERFORMED A FIBEROPTIC ESOPHAGO-GASTROSCOPY

10. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA A FIBEROPTIC ESOPHAGO-GASTROSCOPY WAS DONE: Two cm. above the gastroesophageal junction, an ulcerated circumferential mass with elevated and hard borders with some rigidity and moving in block with surrounding tissues was observed. A biopsy showed a diffuse gastric adenocarcinoma poorly differentiated STAGING

11. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA Systemic and local staging: Thorax and abdominopelvic CT scan : No liver mets nor lung mets were detected. Thickness of the gastroesophageal union area. Some locoregional lymph nodes of more than 1 cm. size were detected at the perigastric area. Endoscopy with ultrasonography : Tumor fully involving the muscular layer of the stomach antrum with invasion of the serosa. At least four lymph nodes of significant size were observed (uT3uN1) Laparoscopy was not recommended

15. Years after surgery Gastric Cancer Survival by stage CADO,1985 0 50 100% 5 10 years Stage III Stage II Stage I Stage 0 21.9 47.6 79.2 91.6 82.0 66.9 36.4 14.7

16. META-ANALYSIS OT TRIALS INVOLVING ADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE FOR GASTRIC CANCER-1 0.44-076 0.58 Asian 0.83-1.12 0.96 Western Very heterogeneous group of trials 0.74-0.96 0.84 3962 21 2002 Januger Eur J Surg Small survival benefit 0.75-0.89 0.82 3658 20 2000 Mari Ann Oncol Small survival benefit In N+ patients 0.66-0.97 0.80 1990 13 1999 Earle Eur J Cancer No benefit 0.78-1.08 0.88 2096 11 1993 Hermanns J Clin Oncol Conclusions 95% CI Odds Ratio Nr. Pts Nr. Trials Year Meta-analysis

17. META-ANALYSIS OT TRIALS INVOLVING ADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE FOR GASTRIC CANCER-2 Marginal, though significant benefit P< 0.0001 0.80-0.90 0.85 2286 19 2008 Liu et al Eur J Surg Oncol Marginal, though significant benefit P: 0.001 0.84-0.96 0.90 3212 15 2008 Zhao et al Cancer Investigation Conclusions 95% CI Odds Ratio Nr. Pts Nr. Trials Year Meta-analysis

18. RECENTLY PUBLISHED TRIALS OF ADJUVANT CHEMOTHERAPY FOR LOCALIZED GASTRIC CANCER 0.91 0.69-1.21 48% 43.5% 113 113 No CT ELFE De Vita Ann Oncol 2007 0.95 0.70-1.29 52% 50% 201 196 FU-LV PELFw Cascinu JNCI 2007 0.93 0.65-1.34 52% 48% 137 137 No CT EAP 5FU-LV Bajetta Ann Oncol 2002 0.90 0.64-1.26 47.6 % 48.7% 130 128 No CT PELF Di Constanzo JNCI 2008 HR (CI at 95%) Median Survival CT 5-year Survival Control Nr. Pts CT Nr. Pts Control CT Trial

19. WHY HAS ADJUVANT CHEMOTHERAPY FAILED TO SHOW ANY POSITIVE EFFECT AFTER SURGERY IN GASTRIC CANCER? NON STANDARD SURGERY HIGH RISK OF LOCAL RELAPSE CHEMOTHERAPY NOR VERY ACTIVE IN ADVANCED DISEASE: COMPLETE RESPOSE RATE LESS THAN 10% HETEREOGENEOUS SAMPLES, LOW SIZE SAMPLES, MOST PATIENTS N- INADEQUATE ESTATISTICAL DESIGN PROLONGUED AND SLOW ACCRUAL

20. STUDY DESIGN SURGERY NO TREATMENT STRATIFICATION T 1-4 NODES CT+ CT-RT + CT 0, 1-3, >3

23. LOCALIZED GASTRIC CANCER MOST PATIENTS ARE: T3 N+ METASTATIC PATTERN MAY BE PREDICTED FROM CLINICAL FACTORS BIOLOGICAL PARAMETERS MAY BETTER PREDICT OUTCOME

24. LOCALIZED GASTRIC CANCER AIMS OF NEOADJUVANT THERAPY TO INCREASE R0 RESECTION RATE EARLY TREATMENT OF MICROMETASTAES TO REDUCE LOCOREGIONAL RELAPSES BIOLOGICAL STUDIES

26. Pre-operative chemotherapy and surgery trial profile Cunningham et al NEJM 2006 CSC N=250 Commenced pre-operative chemotherapy N=237 (95%) Completed pre-operative chemotherapy N=215 (86%) Proceeded to surgery N=219 (88%) Proceeded to surgery N=240(95%) S N=253

27. Postoperative morbidity/mortality Cunningham et al NEJM 2006 CSC S Postoperative deaths 6% (14/219) 6% (15/24 0) Postoperative complications 46% 46% Median duration of post - operative hospital stay 13 days 13 days

30. Can MAGIC be compared to INT0116? Direct comparison of results is difficult due to different inclusion criteria and different time of randomization. * Estimated from curve 1 Cunningham NEJM 2006 2 MacDonald NEJM 2001; 2004 GI Cancers Symposium 0.76 (0.62-0.93) P=0.006 0.75 (0.60-0.93) P=0.009 Hazard ratio (95% CI) 27 months 35 months 20 months 24 months Median survival 26%* 40%* 23% 36% 5 year survival 50%* 58%* 41% 50% 2 year survival Surgery only N=277 Post-op chemoRT + surgery N=282 Surgery only N=253 Peri-op chemo + surgery N=250 INT116 2 (N=556) MAGIC 1 (N=503)

31. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA After a multidisciplinary team discussion: Preoperative chemotherapy was recomended Three courses of Oxaliplatin and capecitabine (XELOX) were given. Only grade 1 Nausea and grade 1 cold related dysestehesia were reported

32. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA After 3 courses a surgical procedure was performed: Esophagogastric resection with partial gastrectomy with lymphadenectomy The histopathological report showed: Absence of neoplastic cells or remaining tumors areas in the surgical specimen. None of 15 nodes proximal to the stomach and none of the 12 nodes resected at extraperigastric sites were involved with tumor. ypT0pN0 M0

33. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA POSTOPERATIVE THERAPY WITH THREE MORE COUSES OF THE SAME CHEMOTHERAPY WAS RECOMMENDED No evidence of disease relapse 40 months after surgery.

34. LOCALIZED GASTRIC CANCER POST- OR PREOPERATIVE TREATMENT CONCLUSIONS-1 POSTOPERATIVE CT IS NOT STANDARD THERAPY POSTOPERATIVE CT+ RT MAY BENEFIT PATIENTS WITH STAGE II-III AND R0 RESECTION (PROLONGATION OF SURVIVAL) PREOPERATIVE CT HAS SHOWN BENEFIT IN SURVIVAL IN SEVERAL RANDOMIZED TRIAL (MAGIC-1, FFCD)

35. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER She had no previous signs of disease Consulted due to weight loss of 10% (8 Kg), anorexia, vomiting, dispepsia and constant dull pain in her right upper abdomen. Performance status was 1 Blood tests revealed: Mild anemia, increased LDH and Alkaline Phospatase A gastroscopy was done: Polipoid, ulcerated and infiltrating tumor in gastric fundus of 4 cm. Biopsy: Diffuse gastric adenocarcinoma poorly differentiated STAGING

36. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER LOCAL AND SYSTEMIC STAGING: Thorax and abdominopelvic CT: No lung mets. Multiple nodes in both liver lobes showing hypodensity indicating liver mets. Multiple perigastric and paraortic lymph nodes of 15 to 27 mm. Thickened wall of stomach at fundic area with suspected invasion of splenic hilum and tail of pancreas

37. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: This is a not curable disease The main aim of therapy is palliation SURGERY IS NOT RECOMENDED IN PATIENTS WITH METASTATIC DISEASE EXCEPTING FOR SYMPTOM CONTROL DO CONSIDER PROGNOSTIC FACTORS PALLIATIVE CHEMOTHERAPY WAS RECOMENDED

41. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: PALLIATIVE CHEMOTHERAPY WAS RECOMENDED THREE COURSES OF DOCETAXEL, CISPLATIN AND 5-FU WERE GIVEN GCSF SUPPORT ORAL CIPROFLOXACINE RECOMMENDED ASSESSMENT OF RESPONSE

42. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: ASSESSMENT OF RESPONSE PERFORMANCE STATUS 0, 6 KG WEIGHT GAIN MILD TOXICITY: GRADE 2 ALOPECIA GRADE 1 DIARRHEA NO FEVER, NO MUCOSITIS NO DOSE REDUCTION REQUIRED CT-SCAN: PARTIAL RESPONSE

46. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: UP TO SIX COURSES OF DOCETAXEL, CISPLATIN AND 5-FU WERE COMPLETED ASSESSMENT OF RESPONSE PERFORMANCE STATUS 0, WEIGHT STABLE MILD TOXICITY: NO DOSE REDUCTION REQUIRED CT-SCAN: PERSISTENT PARTIAL RESPONSE STOP CHEMOTHERAPY

47. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: ASSESS THE PATIENT CLINICALLY EVERY 6-8 WEEKS NO SYMPTOMATIC PROGRESSION DURING SIX FURTHER MONTHS PS 0, NO WEIGT LOSS, SOCIAL LIFE OK. WHAT ARE OUR PLANS IN CASE OF DISEASE PROGRESSION?

49. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER WHAT ARE OUR PLANS IN CASE OF DISEASE PROGRESSION? SECOND LINE CHEMOTHERAPY: - RETREAT WITH DCF - FOLFIRI - FOLFOX vs XELOX - CLINICAL TRIAL CONSIDER EXPERIMENTAL APPROACHES IN CLINICAL TRIALS OPTIMAL APPROACH: SEQUENTIAL DOUBLETS?

50. RANDOMIZED TRIALS COMPARING CT VERSUS BEST SUPPORTIVE CARE IN ADVANCED GASTRIC CANCER CT RR-PD TTP OS (%) (months) PYRÖNEN FAMTX 29-24 5.4 12.3 (1995) BSC 0-80 1.7 3.1 MURAD FAMTX 50- -- 10.0 (1993) BSC 0- -- 3.0 SCHEITAUER FU-LV-EPI 38- 4 >5 >7.5 (1995) BSC 0-53 2 4.0 GLIMELIUS ELF-FULV 23-30 5 8.0 (1997) VS BSC 0- 2 5.0

51. RANDOMIZED TRIAL OF EARLY CT VS AT SYMPTOMATIC PROGRESSION IN ADVANCED GASTRIC CANCER PATIENTS WITHOUT SYMPTOMS EARLY ELF-FULV CT AT PROGR. CT 100% 50% TIME TO CT 8 DAYS 82 DAYS SYMPTOMATIC IMPROVEMENT 70% 25% QoL IMPROVEMENT 70% 25% SURVIVAL 10 MONTHS 4 MONTHS GLIMELIUS, ANN ONCOL 1994

57. Primary end point: OS Time (months) 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 0 1 0 0 0 No. at risk 11.1 13.8 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Event FC + T FC Events 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 Median OS 13.8 11.1 T, trastuzumab

58. OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) 11 3 1.0 0.8 0.6 0.4 0.2 0.0 36 34 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 Time (months) 11.8 16.0 FC + T FC Events 120 136 HR 0.65 95% CI 0.51, 0.83 Median OS 16.0 11.8 Event 0.1 0.3 0.5 0.7 0.9 218 198 4 0 5 3 12 4 20 11 228 218 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 1 0 0 0 No. at risk 39 20 28 13