1. Taiwan 2000 Comparative evaluation in tolerance of neoadjuvant versus adjuvant docetaxel based chemotherapy in resectable gastric cancer in a randomized trial of the Swiss Group for Clinical Cancer Research (SAKK) and the European Institute of Oncology (EIO) A.D. Roth, R. Biffi, R. Stupp, R. Morant, J.C. Schuller, F. De Braud, O. Huber, N. Fazio SAKK 43/99 Barcelona 2007

2. Background Adjuvant chemotherapy has been reported as minimally effective in the curative treatment of gastric cancer Adjuvant chemotherapy is often difficult to start on time and to conduct after gastrectomy because of delayed recovery Neoadjuvant chemotherapy has been shown to be feasible and to induce tumor response before surgery (Van Cutsem et al, Ann Oncol 2006) Very short time to response are highly desirable in this setting and can be obtained with docetaxel containing regimens (Roth AD et al, J Clin Oncol 2007)

3. SAKK 43/99 Barcelona 2007 Objectives To compare the feasibility in term of tolerance and toxicity of the same chemotherapeutic regimen administered in an adjuvant and neoadjuvant setting in a randomized phase III trial To evaluate the efficacy and tolerance of a docetaxel based combination used with surgery in the curative treatment of locally advanced gastric cancer

4. SAKK 43/99 Barcelona 2007 Methods Patient inclusion criteria –Locally advanced resectable gastric cancer (LARGC) T2N+M0 or T3-4anyN M0 –PS ≤2, normal blood count, normal renal and hepatic functions –Absence of macroscopic peritoneal carcinomatosis Staging work up –Body CT-scan –Gastroscopy with echoendoscopy –Bone scintigraphy –Peritoneal lavage and/or laparoscopy

5. SAKK 43/99 Barcelona 2007 Treatment TCF X 4 Surgery (arm A) T2N+M0 T3-4anyN M0 Surgery TCF X 4 (arm B) TCF: –Docetaxel 75mg/m2 d1 –Cisplatin 75 mg/m2 d1 –5-Fluouracyl 300mg/m2 in continuous infusion d1-14 Repeat cycle every 3 weeks R

6. SAKK 43/99 Barcelona 2007 Statistical considerations The trial was planned to recruit 252 patients allowing to detect 15% difference in event free rate at 3 years (arm A 35%, arm B 20%) but was interrupted due to slow accrual after 70 patients were enrolled Tolerance and toxicity results are compared between the 2 arms. Analyses are exploratory, p-value are two sided and not adjusted for multiple testing

7. SAKK 43/99 Barcelona 2007 Patient Characteristics Arm A (n=34)Arm B (n=35) Age (y): median (range)57 (25-75)59 (39-76) Male (%)6871 PS 0/1/2 (%)91/6/386/14/0 Tumor Localization (%) Cardia2120 Fundus/corpus3840 Antrum/pylorus4140 Stage (by echoendoscopy + CTscan) IB 21 II1413 III1821

8. SAKK 43/99 Barcelona 2007 TCF => S N = 34 Preop CT (4 cycles) (97%) Started N=33 (97%) (74%) Completed N= 25 (74%) Surgery (94%) N = 32 (94%) Postop CT (4 cycles) (66%) Started N = 23 (66%) (34%) Completed N = 12 (34%) S =>TCF N = 35 Surgery (100%) N = 35 (100%) Trial profile pCR in 4 patients (12.9%)

9. SAKK 43/99 Barcelona 2007 Intensity of treatment administered per arm ‡ p<0.05, € p=0.07, # p<0.001, + p<0.003, * p<0.0003 ¥ Dose intensity corrected to actually given cycles

10. SAKK 43/99 Barcelona 2007 Hematotoxicity (NCIC grade 3/4) Arm AArm B (% per patient / % per cycle) Neutropenia 79%/41%61%/34% Thrombocytopenia 0% 4%/1% Febrile neutropenia15%/8% 9%/3%

11. SAKK 43/99 Barcelona 2007 Non-hematological toxicity (NCIC grade 3/4) Arm AArm B (% per patient / % per cycle) Nausea/vomiting3%/1%13%/4% Alopecia55%/ -35%/ - Diarrhea 9%/3% 4%/3% Stomatitis 0% 9%/3% Neurosensory 0% 0% Neuromotor 0% 0% Plantar-palmar 0% 0% Other skin 0% 0%

12. SAKK 43/99 Barcelona 2007 Discussion This is the only available trial comparing head to head the feasibility and tolerability of the same systemic regimen in a neoadjuvant and adjuvant setting Neoadjuvant chemotherapy is feasible in gastric cancer while adjuvant chemotherapy is difficult to conduct after gastrectomy Our data are consistent with the results of the published trials of perioperative chemotherapy in gastric cancer (MAGIC trial [NEJM july 2006] and FNLCC-ACCORD trial [ASCO 2007 abstr #4510])

13. SAKK 43/99 Barcelona 2007 Perioperative chemotherapy for locally advanced Gastric Cancer: The MAGIC and the French trials Surgery alone Stage ≥II Chemoth Surgery Chemoth MAGIC trial: ECF x 3 => Surgery => ECF x 3 (Total 503 pts) French trial: FuP x 2 => Surgery => FuP x 4 (Total 224 pts) R

14. SAKK 43/99 Barcelona 2007 MAGIC trial: Compliance to chemotherapy (Cunningham, D. NEJM 355: 11-20 2006) Preop. chemotherapy: –Started: 237 pts –Completed 3 cycles:215 pts (90.7%) Surgery:209 pts Postop. Chemotherapy: –Started:137 pts (65.6%) –Completed 3 cycles:104 pts (49.7%)

15. SAKK 43/99 Barcelona 2007 CT + S N = 113 Preop CT (2-3 cycles) N = 98 (87%) Surgery N = 109 (96%) Postop CT (1-4 cycles) N = 54 (50%) S N = 111 Surgery N = 110 (99%) Trial profile (Boige V. ASCO 2007, abstr #4510)

16. SAKK 43/99 Barcelona 2007 Nutritional status after total gastrectomy 23 patients followed during 6 mois after gastrectomy 1st month6th month Mean calory intake (kcal/j) 1 ’458 2 ’118 Insufficient intake * (patients) 23/23 9/23 * according to RDA (Recommended dietary allowance) Braga M. et al Br. J. Surg. 75:477-80 (1988)

17. SAKK 43/99 Barcelona 2007 Conclusions In the multidisciplinary approach to the cure of locally advanced gastric cancer a neo- adjuvant strategy should be preferred to an adjuvant strategy whenever possible Additional trials establishing the role of neoadjuvant (radio-)chemotherapy in the curative approach of gastric cancer are warranted