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

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

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

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

Is oesophageal cancer one disease? Survival in resected patients FUTURE: trials focussing on each tumor type Stein/Siewert World J Surg 2004; 28: 520-525

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

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):2941-53

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

(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

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 0.70-0.88) squamous HR 0.80 (95% CI 0.68-0.93) adenocarcinoma HR 0.75 (95% CI 0.59-0.95) Neoadjuvant CT vs surgery: 9 trials; n=1981 HR 0.87 (95% CI 0.79-0.96) squamous HR 0.92 (95% CI 0.81-1.04); adenocarcinoma HR 0.75 (95% CI 0.71-0.95) Neoadjuvant CRT vs CT: 2 trials; n=194 HR 0.88 (95% CI 0.76-1.01; p=0.07) Sqoquist K et al, Lancet 2011

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

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

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

Chemoradiotherapy? Postoperative Mortality

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

Large metaanalysis on neoadjuvant treatment for oesophageal cancer Neoadjuvant CRT vs surgery: 12 trials; N=1854 HR 0.78 (95% CI 0.70-0.88) 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 0.79-0.96) 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 0.76-1.01; p=0.07) weak evidence in favour CRT Sqoquist K et al, Lancet 2011

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

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

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):2941-53

Peri-/Preoperative Therapy Gastric Adenocarcinoma (including GEJ cancers) 3 Randomized Phase-III-Studies UK: MAGIC (n=503) France: FNCLCC (n=224) Germany: EORTC 40954 (n=144) Cunningham D et al. N Engl J Med 2006;355:11-20 Ychou M. et al. JCO 2011; 29: 1715-21 Schuhmacher C. et al. JCO 2010; 28: 5210-5218

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

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

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

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

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: 1715-21

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

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

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

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, 0.540 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;357:1810-1820 Sasako et al. J Clin Oncol 2011; 29: 4387-4393 BangYJ et al. Lancet 2012; 379: 315-21

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

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

(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