Dr. LP SiTseung Kwan O Hospital

IntroductionCA stomach is the 4th most commonly

diagnosed malignancy worldwide2nd most common cause of cancer-related

mortalitySurgery (D2 gastrectomy) offers the only

hope for potential cureRecurrences after D2 gastrectomy remains

high despite good surgical skills

Adjuvant therapyRadiotherapyChemoradiotherapyChemotherapyHerceptin… after curative resection

RadiotherapyMeta-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

ChemoradiotherapyMcDonald 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 chemotherapyMedical Research Council Adjuvant

Gastric Infusional Chemotherapy (MAGIC) trial

Multi-centered RCT503 patients randomized

Perioperative chemotherapy (ECF) : 250Surgery alone: 253

Improved progression-free survivalHR 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 chemotherapyCLASSIC 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 trialMulti-centered RCT37 centers in South Korea, China and Taiwan1035 patients randomized

Surgery + adjuvant chemo: 520Surgery only: 515

Stage II to IIIB CA stomach

Curative D2 gastrectomy by experienced surgeons

Post-op chemoEight 3-week cycles of XELOXOral capecitabine (days 1-14 of each cycle)IV oxaliplatin (day 1 of each cycle)

Improved 3-year disease-free survivalChemo 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 survivalChemo 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-GCMulti-centered RCT109 centers in Japan1059 patients randomized

S-1 after surgery: 529Surgery only: 530

Stage II or III CA stomachStandardized D2 gastrectomy

S-1Oral fluoropyrimidine derivative combining 3

agentsTegafur (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 restContinued for 1 year after surgery

Overall survivalAt 3 years

S-1: 80.1%Surgery only: 70.1%HR 0.68 (95% CI 0.52–0.87, p=0.003)

At 5 yearsS-1: 71.7%Surgery only: 61.1%HR 0.669 (95% CI 0.540–0.828)

Relapse-free survivalAt 3 years

S-1: 72.2%Surgery only: 59.6%HR 0.62 (95% CI 0.50–0.77, p<0.001)

At 5 yearsS-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

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

ConclusionD2 gastrectomy is the mainstay of treatment

for CA stomachPost-op chemotherapy implies survival

benefit after curative D2 gastrectomyFurther 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-analysisGlobal Advanced/Adjuvant Stomach Tumor

Research International Collaboration Group17 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 survivalOS: HR 0.82, 95% CI 0.76-0.90, p<0.001DFS: 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 RCT122 centres in 24 countriesMetastatic / locally advanced adenoCA

stomach / OGJ with overexpression of HER2 receptors

584 patientsHerceptin + chemo: 294Chemo: 290

Chemo3 weeks for 6 cyclesCisplatin + capecitabine (87-88%)Cisplatin + fluorouracil (12-13%)

Improved median overall survivalHerceptin + chemo: 13.8 monthsChemo alone: 11.1 monthsHR 0.74, 95% CI 0.60-0.91, p=0.0046

Improved median progress-free survivalHerceptin + chemo: 6.7 monthsChemo alone: 5.5 monthsHR 0.71, 95% CI 0.59-0.85, p=0.00026

No difference in the overall rate of adverse events

Question unansweredHerceptin useful in operable CA stomach?