1. Oesophageal and Gastric cancer: neo-adjuvant therapy
Prof Eric Van Cutsem, MD, PhD
Gastroenterology/Digestive Oncology
Leuven, Belgium

2. Gastro-esophageal Cancer
Only 10-25% are long-term survivors
De Angelis et al., Lancet Oncol 2014 Jan;15(1):23-34

3. Oesophageal cancer: does one fit all ?
SCC
Difference in :
Pathogenesis
Epidemiology
Tumor biology
Pattern of recurrence
Prognosis
different TNM staging
ADC
At least 2 different diseases, but most clinical studies have not differentiated

4. Oesophageal, GEJ and gastric tumours
Studies on treatment: not always perfect:
heterogeneous populations: various stages;
Squamous Cell cancer and oesophageal / GEJ adenocarcinoma;
GEJ and gastric adenocarcinoma
Heterogeneous regimens: CT, CRT

5. Is oesophageal cancer one disease? Survival in resected patients
FUTURE: trials focussing on each tumor type
Stein/Siewert World J Surg 2004; 28:

6. Adeno-CA neo Chemo or neo ChemoRadio
Oesophageal Cancer
Staging (EUS / CT / PET)
T 1/(2) Category
T(2),3,4 Category
Multimodal Therapy
Primary Resection
Squamous CA
ChemoRadio T
Adeno-CA neo Chemo or neo ChemoRadio
Neoadjuvant
Definitive
Lordick F et al. Langenbecks Arch Surg 2013;398:177-87

7. Gastric Cancer Staging (CT Chest/Abdo, EUS, Laparoscopy) cT1m
cT1sm/2 cN0
cT(2)/3/4 cNx
Endoscopic Resection
Gastrectomy
Perioperative Chemotherapy + Gastrectomy
EORTC Recommendations Eur J Cancer 2012 Nov;48(16):

8. Preoperative treatment
Rationale/potential advantages
Enhance resectability
Assess response in primary tumour
Improve local control
Treat micrometastases early
Better tolerance than postoperative treatment
Potential disadvantages
Staging less adequate
Increased postoperative morbidity
Disease progression

9. (Neo)-adjuvant treatment options for patients with oesophageal cancer and GEJ cancers
Preoperative chemotherapy
Preoperative chemoradiotherapy
Locally advanced oesophagogastric
adenocarcinomas
T3 – 4
AND/OR
Node-positive

10. Large metaanalysis on neoadjuvant treatment for oesophageal cancer
17 trials included with 4188 patients and ~3500 events
Neoadjuvant CRT vs surgery: 12 trials; N=1854
HR 0.78 (95% CI )
squamous HR 0.80 (95% CI )
adenocarcinoma HR 0.75 (95% CI )
Neoadjuvant CT vs surgery: 9 trials; n=1981
HR 0.87 (95% CI )
squamous HR 0.92 (95% CI );
adenocarcinoma HR 0.75 (95% CI )
Neoadjuvant CRT vs CT: 2 trials; n=194
HR 0.88 (95% CI ; p=0.07)
Sqoquist K et al, Lancet 2011

11. Large metaanalysis on neoadjuvant treatment for oesophageal cancer: CRT
Sqoquist K et al, Lancet 2011

12. Large metaanalysis on neoadjuvant treatmen in oesophageal cancer: chemotherapy
Sqoquist K et al, Lancet 2011

13. Large metaanalysis on neoadjuvant treatment in oesophageal cancer: CRT vs CT
Sqoquist K et al, Lancet 2011

14. Chemoradiotherapy?
Postoperative Mortality

15. 30 day in hospital mortality
chemoradiotherapy
chemotherapy
Sqoquist K et al, Lancet 2011

16. Large metaanalysis on neoadjuvant treatment for oesophageal cancer
Neoadjuvant CRT vs surgery: 12 trials; N=1854
HR 0.78 (95% CI )
survival benefit at 2 years of 8.7% and numbers to treat of 11
Neoadjuvant CT vs surgery: 9 trials; n=1981
HR 0.87 (95% CI )
survival benefit at 2 years of 5.1% and numbers to treat of 19
Neoadjuvant CRT vs CT: 2 trials; n=194
HR 0.88 (95% CI ; p=0.07)
weak evidence in favour CRT
Sqoquist K et al, Lancet 2011

17. Chemo(radio)therapy +/- Surgery: Regimens
5-FU/Cisplatin
Paclitaxel/Cisplatin RTOG
Paclitaxel/Carboplatin CROSS
Irinotecan/Cisplatin MSKCC, CALGB
Docetaxel containing
Irinotecan/Cisplatin platform +
bevacizumab MSKCC
cetuximab
Irinotecan/Cisplatin ECOG
vs. paclitaxel/Cisplatin
Oxaliplatin/5-FU SWOG, ACOSOG

18. Adjuvant strategies in advanced gastric cancer
postoperative chemotherapy
perioperative chemotherapy
postoperative chemoradiotherapy
Preoperative chemoradiotherapy

19. Gastric Cancer 2015 Staging (CT Chest/Abdo, EUS, Laparoscopy) cT1m
cT1sm/2 cN0
cT(2)/3/4 cNx
Endoscopic Resection
Gastrectomy
Perioperative Chemotherapy + Gastrectomy
EORTC St. Gallen Recommendations Eur J Cancer 2012 Nov;48(16):

20. Peri-/Preoperative Therapy Gastric Adenocarcinoma (including GEJ cancers)
3 Randomized Phase-III-Studies
UK: MAGIC (n=503)
France: FNCLCC (n=224)
Germany: EORTC (n=144)
Cunningham D et al. N Engl J Med 2006;355:11-20
Ychou M. et al. JCO 2011; 29:
Schuhmacher C. et al. JCO 2010; 28:

21. Peri-/Preoperative Therapy Esophago-Gastric Adenocarcinoma
Tumor localization
MAGIC
FNCLCC
EORTC
Stomach EGJ
74% 26%
25% 75%
47% 53%

22. Peri-/Preoperative Therapy Esophago-Gastric Adenocarcinoma
Postoperative Mortality
MAGIC (n=503)
FNCLCC (n=224)
EORTC (n=114)
CTX
SURG 6% 5% 4% 2%

23. Peri-/Preoperative Therapy Esophago-Gastric Adenocarcinoma
MAGIC + FNCLCC
CTx
Surgery
CTx
St. II + III
Stomach + Cardia + Dist. Eso
RANDOM
Primary endpoint: survival
Surgery

24. Peri-/Preoperative Therapy Esophago-Gastric Adenocarcinoma
UK MAGIC 2006
5-y-OS 36%
23%
ECF
Surgery alone
Stomach Cancer 74% EGJ Cancer 26%
Cunningham D et al. N Engl J Med 2006;355:11-20

25. Peri-/Preoperative Therapy Esophago-Gastric Adenocarcinoma
France FNCLCC 2011
Cisplatin/5-FU 8 weeks peri-op.
5-y-OS 38%
24%
Surgery alone
Stomach Cancer 25% EGJ Cancer 75%
Ychou et al. J Clin Oncol 2011; 29:

26. Postoperative Therapy Gastric Adenocarcinoma
Multiple Adjuvant Studies
Surgery
CTx
St. II + III
Stomach Cancer
RANDOM
Primary endpoint: survival
Surgery

27. GASTRIC METAANALYSIS : Overall Survival for adjuvant chemotherapy compared to surgery alonse)
Paoletti X… Van Cutsem E et al. The Gastric Group- JAMA, 2010

28. GASTRIC Group Meta-analysis
6% difference at 5 years
HR = 0.82; p < 0.001
Paoletti X… Van Cutsem E et al. The Gastric Group- JAMA, 2010

29. Postoperative Therapy Gastric Adenocarcinoma
Japan ACTS-GC 2007 (1 year S-1)
Korea/China/Taiwan Classic 2012
(Cape/oxali) (6 mon Cape-Ox.)
Overall Survival
HR = 0,669 (95% CI, to 0.828)
P = 0,003
Overall Survival (preliminary)
HR = 0,72 (95% CI, 0.52 to 1.00)
P < 0,0493
Sakuramoto S et al. N Engl J Med 2007;357:
Sasako et al. J Clin Oncol 2011; 29:
BangYJ et al. Lancet 2012; 379:

30. Postoperative Therapy Gastric Adenocarcinoma
Adjuvant chemotherapy is effective
Gain in overall survival ~ 5 %
More effectiv in N+ disease

31. Current Western Studies Eso-gastric Cancer
CTx + Bev
Resection
CTx + Bev
MAGIC B (UK) R
CTx
Resection
CTx
CTx
Resection
Radio-CTx
CRITICS (NL, Skandinavia) R
CTx
Resection
CTx
Radio-CTx
Resection
CTx
TOPGEAR (AUS, CAN, EORTC) R
CTx
Resection
CTx

32. (trend to perioperative CT
Neo-adjuvant and adjuvant therapy for gastric cancer: different strategies
Peri-operative
Chemotherapy
(ECF- 5FU/cisplatin)
Post-operative
Chemoradiotherapy
(trend to perioperative CT
in academic centers)
Postoperative CT
Post-operative
Chemotherapy
(S-1 or combination)
Van Cutsem E et al; expert discussion Barcelona; Ann Oncol 2011 32