Dr. LP Si Tseung Kwan O Hospital

Introduction CA stomach is the 4 th most commonly diagnosed malignancy worldwide 2 nd 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

Adjuvant therapy Radiotherapy Chemoradiotherapy Chemotherapy Herceptin … after curative resection

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

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

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

Chemotherapy

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

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

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

Post-op chemotherapy CLASSIC trial ACTS-GC

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

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

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)

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 , 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 , p=0.0493)

Disease-free survival

Overall survival

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

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

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

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 (95% CI 0.540–0.828)

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 (95% CI 0.537–0.793)

Relapse and metastasis

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

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

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

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: 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): Edge et al. AJCC Cancer staging manual. 7 th edition. New York, NY:Springer 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: 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: 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: Waddell et al. Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 24: vi57-vi63, 2013

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

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

Herceptin

ToGA Trial

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

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

Improved median overall survival Herceptin + chemo: 13.8 months Chemo alone: 11.1 months HR 0.74, 95% CI , p= Improved median progress-free survival Herceptin + chemo: 6.7 months Chemo alone: 5.5 months HR 0.71, 95% CI , p= No difference in the overall rate of adverse events

Question unanswered Herceptin useful in operable CA stomach?