Authors: David Cunningham et al Date posted: April 3, 2008 Capecitabine and Oxaliplatin for Advanced Esophagogastric Cancer NEJM January 3, 2008 Authors: David Cunningham et al Date posted: April 3, 2008

R Epirubicin 50 mg/m2 IV q 3 weeks Cisplatin 60 mg/m2 IV q 3 weeks Treatment A: ECF Epirubicin 50 mg/m2 IV q 3 weeks Cisplatin 60 mg/m2 IV q 3 weeks 5-FU 200 mg/m2 per day continuous infusion Treatment B: ECX Epirubicin 50 mg/m2 IV q 3 weeks Cisplatin 60 mg/m2 IV q 3 weeks Capecitabine 625 mg/m2 bid continously R Treatment C: EOF Epirubicin 50 mg/m2 IV q 3 weeks Oxaliplatin 130 mg/m2 IV q 3 weeks 5-FU 200 mg/m2 per day continuous infusion 1002 patients locally advanced (inoperable) or metastatic (80%) cancer esophagus, GE junction,gastric - Adenocarcinoma, squamous cell, or undiff. carcinoma - 2x2 non-inferiority design - Primary Enpoint: non inferiority in OS Treatment D: EOX Epirubicin 50 mg/m2 IV q 3 weeks Oxaliplatin 130 mg/m2 IV q 3 weeks Capecitabine 625 mg/m2 bid continously

RESULTS Patients 85-90% in all groups were adenocarcinoma Relatively even distribution among: esophagus, GE junction, stomach ECF ECX EOF EOX p-value Response Rate (%) 41% 46% 42% 48% NS PFS (median, mos) 6.2 mos 6.7 mos 6.5 mos 7.0 mos OS (median, mos) 9.9 mos 9.3 mos 11.2 mos Non-inferiority of 5-FU/cape and cis/oxali established

STUDY COMMENTARY This large RCT demonstrated non-inferiority for 5-FU/capecitabine and cisplatin/oxaliplatin when given with epirubicin in patients with advanced esophagogastric cancer. In planned survival analysis among 4 groups, survival in EOX group was improved compared to ECF (HR 0.80, 95%CI 0.66-0.97 – Median Survival improved from 9.9 to 11.2 mos). No significant difference in overall toxicity or QOL between the 4 arms. Oxaliplatin had more grade 3-4 diarrhea and neuropathy than cisplatin but less neutropenia and alopecia greater grade 3-4 neutropenia (but no higher rates of febrile neutropenia) and HFS (10% vs 4%) in ECX group versus ECF High rate of thromboembolism 11.4% overall rate was significantly greater in cisplatin group compared to oxaliplatin group (15.% vs 7.6%, P<0.001).

CANADIAN MEDICAL ONCOLOGISTS BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS In many Canadian centres the standard of care for this patient population is ECF. This study shows that capecitabine can be safely substituted for infusional 5-FU in patients with advanced esophagogastric cancer. This provides a treatment option for patients which is free of pumps and venous access devices – the only downside being slightly higher rates of Gr 3/4 HFS. The use of oxaliplatin avoids the requirement of IV hydration used with cisplatin and there is a signal of improved efficacy with this agent. However, the overall toxicity and QOL was not improved with the substitution of oxaliplatin for cisplatin. Given the greater ease of delivery it is likely that EOX and/or ECX will emerge in the future as preferred standards compared to ECF but access to oxaliplatin and capecitabine for advanced gastric cancer will likely depend on funding of these agents in most parts of Canada.