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Adjuvant Therapies for Stomach Carcinoma: A Comprehensive Review

Explore the latest advances in adjuvant therapies for stomach carcinoma after curative resection procedures, including radiotherapy, chemoradiotherapy, chemotherapy, and the impact of Herceptin, offering crucial insights into survival benefits and treatment efficacy.

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Adjuvant Therapies for Stomach Carcinoma: A Comprehensive Review

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  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

  18. 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

  19. 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

  20. 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

  21. 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)

  22. 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)

  23. Relapse and metastasis

  24. 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

  25. 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

  26. 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

  27. 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

  28. Thank you

  29. 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

  30. 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%

  31. Herceptin

  32. ToGA Trial

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

  34. 584 patients • Herceptin + chemo: 294 • Chemo: 290 • Chemo • 3 weeks for 6 cycles • Cisplatin + capecitabine (87-88%) • Cisplatin + fluorouracil (12-13%)

  35. 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

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

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