Download Adjuvant Therapy for CA Stomach

Dr. LP Si
Tseung Kwan O Hospital
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
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 0.53-0.81, p<0.001)
 Improved overall survival
 HR for death 0.75 (95% CI 0.59-0.93, 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 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)
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 0.669 (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 0.653 (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
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
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; 345:725-30

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
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 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%
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 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
Question unanswered
 Herceptin useful in operable CA stomach?