Adjuvant Therapy for Carcinoma of Stomach

1. Adjuvant Therapy for Carcinoma of Stomach Dr. LP Si Tseung Kwan O Hospital

2. Introduction • CA stomach is the 4th most commonly diagnosed malignancy worldwide • 2nd most common cause of cancer-related mortality • Surgery (D2 gastrectomy) offers the only hope for potential cure • Recurrences after D2 gastrectomy remains high despite good surgical skills

3. Adjuvant therapy • Radiotherapy • Chemoradiotherapy • Chemotherapy • Herceptin … after curative resection

4. Radiotherapy • Meta-analysis in 2007 showed significant improvement in survival at 3 years (OR 0.57) and 5 years (OR 0.62) • Significant heterogeneity among different studies on RT regime • High risk of local and distant recurrence • Out of clinical and research interest now Fiorica et al. The impact of radiotherapy on survival in resectable gastric carcinoma: a meta-analysis of literature data. Cancer Treat Rev. 2007;33(8):729-40

5. Chemoradiotherapy • McDonald et al showed post-op chemoRT significantly improved 3-year overall (41% vs 50%) and relapse-free survival rate (31% vs 48%) • Criticized for inadequacy of lymphadenectomy (only 10% patients received D2 dissection) • Benefits of post-op chemoRT probably compensate for inadequacy of surgery McDonald et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal juction. N Engl J Med 2001; 345:725-30

6. McDonald regime of adjuvant chemoRT is only popular in certain part of the North America

7. Chemotherapy

8. Peri-op chemotherapy • Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial

9. Multi-centered RCT • 503 patients randomized • Perioperative chemotherapy (ECF) : 250 • Surgery alone: 253 • Improved progression-free survival • HR for progression 0.66 (95% CI 0.53-0.81, p<0.001) • Improved overall survival • HR for death 0.75 (95% CI 0.59-0.93, p=0.009)

10. ~74% patients had CA stomach • ~40% patients received a standard D2 lymphadenectomy • Apparent survival benefit may only a compensation for inadequacy of lymphadenectomy

11. Post-op chemotherapy • CLASSIC trial • ACTS-GC

12. Included patients with histologically proven adenoCA of stomach • All patients received standardized D2 gastrectomy • Survival benefits solely due to the addition of adjuvant chemotherapy

13. CLASSIC trial • Multi-centered RCT • 37 centers in South Korea, China and Taiwan • 1035 patients randomized • Surgery + adjuvant chemo: 520 • Surgery only: 515 • Stage II to IIIB CA stomach

14. Curative D2 gastrectomy by experienced surgeons • Post-op chemo • Eight 3-week cycles of XELOX • Oral capecitabine (days 1-14 of each cycle) • IV oxaliplatin (day 1 of each cycle)

15. Improved 3-year disease-free survival • Chemo group: 74% (95% CI 69-79%) • Surgery alone group: 59% (95% CI 53-64%) • HR 0.56 (95% CI 0.44-0.72, p<0.0001) • Improved 3-year overall survival • Chemo group: 83% (95% CI 79-87%) • Surgery alone group: 78% (95% CI 74-83%) • HR 0.72 (95% CI 0.52-1.00, p=0.0493)

16. Disease-free survival

17. Overall survival

19. Survival benefits observed in all stages of CA stomach • Safety profile consistent with XELOX for CA colon • XELOX is an effective adjuvant chemo regime for resectable CA stomach

20. ACTS-GC • Multi-centered RCT • 109 centers in Japan • 1059 patients randomized • S-1 after surgery: 529 • Surgery only: 530 • Stage II or III CA stomach • Standardized D2 gastrectomy

21. S-1 • Oral fluoropyrimidine derivative combining 3 agents • Tegafur (prodrug of 5-FU) • Gimeracil (inhibits DPD enzyme activity) • Oteracil (prevents GI side effects from 5-FU) • S-1 for 4 weeks, followed by 2 weeks of rest • Continued for 1 year after surgery

22. Overall survival • At 3 years • S-1: 80.1% • Surgery only: 70.1% • HR 0.68 (95% CI 0.52–0.87, p=0.003) • At 5 years • S-1: 71.7% • Surgery only: 61.1% • HR 0.669 (95% CI 0.540–0.828)

24. Relapse-free survival • At 3 years • S-1: 72.2% • Surgery only: 59.6% • HR 0.62 (95% CI 0.50–0.77, p<0.001) • At 5 years • S-1: 65.4% • Surgery only: 53.1% • HR 0.653 (95% CI 0.537–0.793)

26. Relapse and metastasis

27. Grade 3 or 4 adverse events occurred in less than 5% of patients in the S-1 group • Anorexia (6% incidence) was the only increased side effect when compared to surgery-alone group • S-1 is an effective adjuvant oral chemo agent for resectable CA stomach

28. McDonald CLASSIC / S-1 ToGA MAGIC Waddell et al. Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 24: vi57-vi63, 2013

29. Conclusion • D2 gastrectomy is the mainstay of treatment for CA stomach • Post-op chemotherapy implies survival benefit after curative D2 gastrectomy • Further research is needed to find the optimal agent and regime as adjuvant therapy

30. References • McDonald et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal juction. N Engl J Med 2001; 345:725-30 • Cunningham et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355:11-20 • Fiorica et al. The impact of radiotherapy on survival in resectable gastric carcinoma: a meta-analysis of literature data. Cancer Treat Rev. 2007;33(8):729-40 • Edge et al. AJCC Cancer staging manual. 7th edition. New York, NY:Springer 2010. • Bang et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone or treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687-97 • Sasako et al. Five-year outcome of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alon ein stage II or III gastric cancer. J Clin Oncol 2011; 29: 4387-93 • Bang et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012; 379: 315-21 • Waddell et al. Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 24: vi57-vi63, 2013

31. Thank you

35. GASTRIC Group meta-analysis • Global Advanced/Adjuvant Stomach Tumor Research International Collaboration Group • 17 RCTs up to 2009 • CLASSIC and S-1 trial not included

36. Adjuvant chemo was associated with a significant improvement in overall survival and disease-free survival • OS: HR 0.82, 95% CI 0.76-0.90, p<0.001 • DFS: HR 0.82, 95% CI 0.75-0.90, p<0.001 • 5-year overall survival increased from 49.6% to 55.3%

37. Herceptin

38. ToGA Trial

39. Multi-centered RCT • 122 centres in 24 countries • Metastatic / locally advanced adenoCA stomach / OGJ with overexpression of HER2 receptors

40. 584 patients • Herceptin + chemo: 294 • Chemo: 290 • Chemo • 3 weeks for 6 cycles • Cisplatin + capecitabine (87-88%) • Cisplatin + fluorouracil (12-13%)

41. Improved median overall survival • Herceptin + chemo: 13.8 months • Chemo alone: 11.1 months • HR 0.74, 95% CI 0.60-0.91, p=0.0046 • Improved median progress-free survival • Herceptin + chemo: 6.7 months • Chemo alone: 5.5 months • HR 0.71, 95% CI 0.59-0.85, p=0.00026 • No difference in the overall rate of adverse events

42. Question unanswered • Herceptin useful in operable CA stomach?