1. Taiwan 2000 Should all patients be treated with adjuvant and/or neoadjuvant treatment? Arnaud Roth MD Oncosurgery Geneva Switzerland Gastric Barcelona 2012

2. Gastric Cancer Surgery Survival US vs. Japanese Centers US (1982 – 1987) Japan (1971 – 1985) Stage (%) 5-yr OS (%) 5-yr OS I 2004 (18.1) 50% 1453 (45.7) 91% II 1976 (16.2) 29% 377 (11.9) 72% III 3945 (35.6) 13% 693 (21.8) 44% IV 3342 (30.1) 3% 653 (20.6) 9% Maruyama et al., World J Surg 1987;11:418-25

3. Gastric Barcelona 2012 We need to help our surgeons!

4. Gastric Barcelona 2012 Curative treatment programs Neoadjuvant TTT (Chemotherapy and/or Radiation therapy) Main TTT (SURGERY) Adjuvant TTT (Chemotherapy and/or Radiation therapy)

5. Gastric Barcelona 2012 YES! Finally adjuvant chemotherapy in gastric cancer seems to work!

6. Gastric Barcelona 2012 Biostatistical constraints 5 years OS relative # events total patients accrual* Arm A Arm B OS ratio per arm 3y-2y (accr-fup) 5y-5y 20% 35% 1.533 93 298 pts 206 pts 20% 30% 1.337 193 614 pts 434 pts 40% 55% 1.533 93 440 pts 264 pts 40% 50% 1.332 209 964 pts 590 pts * Two-sided alpha error = 0.05, beta error = 0.2

7. Gastric Barcelona 2012 Biostatistical constraints consequences Minimal accrual = 300 patients (for a 5 year study with relative OS ratio = 1.5) The required accrual increases when the prognosis of the control arm increases. A negative study with a power to observe a relative OS ratio of 1.5 does not reject a clinically meaningfull smaller difference.

8. Gastric Barcelona 2012 Gastric Cancer 1993 - 2003 4 Meta-Analysis on Adjuvant Chemotherapy # of studies # of patients ODDs ratio/hazard ratio for death (95% CI) Author 112,0960.88 (0.78-1.08)Hermans (1993) 131,9900.80 (0.66-0.97)*Earle (1999) 213,6580.82 (0.75-0.89)*Mari (2000) 173,1180.72 (0.62-0.84)*Panzini (2002) *: p<0.05 => 3 / 4 positive and one ongoing with the « gastric » Meta-analysis group

9. Gastric Barcelona 2012 JAMA. 2010;303(17):1729-1737 Adjuvant chemotherapy in gastric: OS Individual patient data meta-analysis

10. Gastric Barcelona 2012 JAMA. 2010;303(17):1729-1737 Adjuvant chemotherapy in gastric: OS Individual patient data meta-analysis

11. Gastric Barcelona 2012 Adjuvant radio-chemotherapy in gastric cancer: INT 0116 –Long standing effect –Robust treatment effect in subset analysis with an exception for diffuse histology BUT –54% of patients with insufficient surgery (<D1) –Grade 3/4 toxicity 41%/32%! –33% of inadequate RxTTT planning (corrected by central review) Smalley JS, JCO May 14th 2012, ahead of print

12. Gastric Barcelona 2012 Lee J et al. JCO 2012;30:268-273 The ARTIST trial: adjuvant XP ± RxTTT All patients N+ patients 458 patients 60% stage IB –II DFS significant in N+ patients

13. Gastric Barcelona 2012 Be patient, CRITICS and other trials are coming up!

14. Gastric Barcelona 2012 Nutritional status after total gastrectomy: A nightmare for adjuvant chemotherapy 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)

15. Gastric Barcelona 2012 Adjuvant treatment in gastric cancer: The reality! CONTROL SURGERY ADJUVANT TREATMENT R - Delayed surgical recovery - Poor food intake - Dumping syndrome etc. - Poor performance status - Treatment refusal (~50%?) BUT: frequent poor patient tolerance with - Retreatment delays - Dose reductions - Early termination => Adjuvant TTT for fit patients only!

16. Gastric Barcelona 2012 What about neoadjuvant or perioperative chemotherapy?

17. Gastric Barcelona 2012 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

18. Gastric Barcelona 2012 MAGIC trial

19. Gastric Barcelona 2012 Ychou M et al. JCO 2011;29:1715-1721 FNCLCC 94012 - FFCD 9703 Trial in gastric

20. Gastric Barcelona 2012 The Truth about 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 40-50%

21. Gastric Barcelona 2012 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 Biffi, R. World j Gastroenterol 18;868 2010

22. Gastric Barcelona 2012 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 Biffi, R. World j Gastroenterol 18;868 2010

23. Gastric Barcelona 2012 Multidisciplinary approach for the cure of localised gastric cancer Conclusions Adjuvant treatment is efficient but cumbersome and badly tolerated after gastrectomy The role of XRT in (neo)adjuvant TTT of gastric cancer is still unclear Peri-operative or neoadjuvant chemotherapy are better tolerated and leave less patients behind We needed huge meta-analyses to be convinced of adjuvant therapy while only few studies were sufficient for the peri-operative strategy!