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Efficacy of Preoperative Chemotherapy in Resectable Adenocarcinoma of the Stomach and Esophagus

This study investigates the potential benefits of preoperative chemotherapy with 5FU and cisplatin in patients with resectable adenocarcinoma of the stomach and lower esophagus. The primary endpoint is overall survival (OS), while secondary endpoints include disease-free survival (DFS) and R0 resection rates. With a sample size of 250 patients, the analysis aims to determine whether preoperative treatment improves surgical outcomes and reduces recurrence rates. Results indicate that preoperative chemotherapy significantly enhances survival and resection rates.

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Efficacy of Preoperative Chemotherapy in Resectable Adenocarcinoma of the Stomach and Esophagus

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  1. Background • 1995: no standard adjuvant or neoadjuvant treatment in resectable adenocarcinoma of the stomach and the lower esophagus (ASLE) • 5FU in continuous infusion plus cisplatin (FP) = one of the most effective regimens in advanced ASLE • Potential benefits of preoperative (preop) chemotherapy (CT) in resectable ASLE: • increases likelihood of curative surgery by tumor downstaging • eliminates micrometastases • assesses tumor chemosensitivity

  2. Objectives • To determine whether preop FP improves the outcome of resectable ASLE • Primary endpoint: overall survival (OS) • Secondary endpoints: • disease-free survival (DFS) • R0 resection rate • safety

  3. Eligibility Criteria • Histologically-proven adenocarcinoma of the lower third of the esophagus or esogastric junction or stomach • Suitable for curative resection • Age: 18-75 years • WHO performance status (PS): 0 or 1 • Stage II or greater • Non-metastatic disease • Adequate renal and hematological functions • Informed consent

  4. Staging • Endoscopy • Barium meal study • Abdominal and thoracic CT scans • Endoscopic ultrasonography : optional

  5. Study Design Randomization S CT + S FP (*) x 2/3 every 28 days Within 4 weeks 4 - 6 weeks Resection Resection 4 – 6 weeks FP x 3/4 or no treatment Follow-up (*) FP = 5FU: 800 mg/m² CI x 5 days - CDDP: 100 mg/m² at d1 or d2, 1-hr infusion

  6. Postoperative CT: protocol guidelines • Curative surgery • Tumor response* or stabilization after preop CT • pT3 and/or pN+ tumor • No grade 3-4 toxicity under preop CT * based on symptoms (dysphagia, weight loss), endoscopy, CT-scan and +/- endoscopic ultrasonography

  7. Statistical methods • Central randomization stratified on center, PS and tumor site • Sample size: 250patients (178 deaths) to detect an increase from 20% to 35% in 5-yr OS (two-sided logrank test,  = 5 %,  = 20%) • DFS calculated with a 6 months landmark time to take into account the difference in timing of surgery between the 2 groups • Intent-to-treat analysis • Kaplan-Meier survival curves and two-sided logank-rank test

  8. Recruitment • Open to accrual: November 1995 • Closed to accrual: December 2003 • 224 patients randomized • Eligibility criteria extended in March 1998 to include adenocarcinoma of the stomach

  9. Patient characteristics S CT + S n = 111 n = 113 Median age (yrs) 63 63 (range) (38-75) (36-75) Sex (%) Male 91 (82) 96 (85) Female 20 (18) 17 (15) WHO PS (%) 0 83 (75) 84 (74) 1 28 (25) 29 (26)

  10. Patient characteristics S CT + S n = 111 n = 113 nb pts (%) Site Esophagus 10 (9) 15 (13) Esogastric junction 74 (67) 70 (62) Stomach 27 (24) 28 (25) > 10% weight loss Yes 16 (15) 21 (19) No 88 (79) 87 (77) ND 7 (6) 5 (4)

  11. S N = 111 Preop CT (2-3 cycles) N = 98 (89%) Surgery N = 109 (96%) Surgery N = 110 (99%) Postop CT (1-4 cycles) N = 54 (51%) Trial profile CT + S N = 113

  12. Preoperative CT: Toxicity Grade 3-4 Nb of pts (%) • Neutropenia 22 (20) • Nausea/Vomiting 10 (9) • Thrombocytopenia 6 (5) • Diarrhea 2 (1) • Neurotoxicity 1 (1) • Nephrotoxicity 1 (1) • Mucositis 4 (4) Toxic death 1 (1) Total 40 (37)

  13. Surgery S CT + S n = 111 n = 113 No surgery 1 4* Surgery (%) 110 (99) 109 (96) Median time to surgery (days) 13 78 Postoperative mortality (%) 5 (4) 5 (5) Postoperative morbidity (%) 21 (19) 28 (26) * toxic death (n = 1), disease progression (n = 3)

  14. Type of surgery S CT + S n = 110 n = 109 nb pts (%) No resection 10 (9) 7 (6) Transthoracic esophagectomy 47 (43) 46 (42) Transhiatal esophagectomy 9 (8) 10 (9) Extended gastrectomy 7 (6) 9 (8) Total gastrectomy 21 (20) 23 (21) Distal gastrectomy 14 (13) 15 (14) Other 1 (1) -

  15. Surgical and pathological results S CT + S n = 110 n = 109 nb pts (%) Extent of resection No resection 10 (9) 7 (6) R0 81 (74) 95 (87) p = 0.04 R1 6 (5) 4 (4) R2 12 (11) 2 (2) RX 1 (1) 1 (1)

  16. Pathological results S CT + S p n = 85 n = 98 Tumor stage (%) T0 0 (0) 3 (3) T1, T2 27 (32) 38 (39) T3, T458 (68)57 (58) 0.16  Nodal status (%) N- 17 (20) 32 (33) N+ 68 (80) 66  (67) 0.054 Nb nodes removed median  19 19 range (2 - 82) (1 - 49)

  17. Postoperative CT

  18. Follow-up and patterns of recurrence • Median follow-up: 5.7 years [2.4-10.4] S CT + S Site of recurrence n = 111 n = 113 nb pts (%) Locoregional only 9 (8) 14 (12) Systemic only 42 (38) 34 (30) Both 20 (18) 14 (12) Total 71 (64) 62 (55)

  19. Logrank p value = 0.0033 Hazard Ratio = 0.65 (95% CI 0.48-0.89) ___ S ___ CT + S years 0-0.5 1 2 3 4 5 6 7 111 57 35 28 21 14 11 6 113 77 53 44 34 25 17 14 At risk Disease-free survival 5-year DFS: 21% (14-30%) vs 34% (26-44%)

  20. Overall survival Logrank p value = 0.021 Hazard Ratio = 0.69 (95% CI 0.50-0.95) ___ S ___ CT + S years At risk 5-year OS: 24% (16-33%) vs 38% (28-47%)

  21. Multivariate & subset analyses • Cox model including: age, gender, PS, tumor site, allocated treatment • Prognostic factors (multivariate analysis): • preop CT (p<0.013) • tumor site (stomach, p <0.01) • No variation of treatment effect according to tumor site (test of interaction, p = 0.26)

  22. Summary of results In resectable gastroesophageal adenocarcinoma,preoperative CT with 5FU/cisplatin: significantly increases curative resection rate significantly improves disease-free survival significantly improves overall survival

  23. Conclusion Our results confirm those of the MAGIC trial* in a slightly different patient population with a non anthracyclin-based CT * Cunningham D et al. N Engl J Med 2006;355:11-20

  24. Participating centers (n=25) Amiens Clermont-Ferrand Montpellier Angers Clichy Nancy Bayonne Colmar Nantes Bicêtre Dijon Reims Bichat Eaubonne Rennes Boulogne Laennec Toulouse Bourg en Bresse Lille Vichy Bourgoin-Jallieu Marseille Villejuif Caen

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