HEMONC: Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma ================================================================================

Gaurav Goel, Mayank Jauhri, Anita Negi, Shyam Aggarwal

on 14/06/2010 06:53:00 Gastric cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer deaths worldwide.1 Patients with gastric cancer typically present with advanced disease and it continues to carry a poor prognosis. The role of palliative chemotherapy is therefore of utmost importance. Single agents with activity in advanced gastric cancer include 5-fluorouracil (5FU), cisplatin, the anthracyclines (doxorubicin and epirubicin), mitomycin C, and etoposide, with pooled response rates in the range of 10% to 20%.2 Various combinations of these agents have been tried to improve upon these response rates. These include 5FU, doxorubicin and mitomycin (FAM); 5FU, doxorubicin and high-dose methotrexate (FAMTX); epirubicin, cisplatin and 5FU (ECF); etoposide, leucovorin and 5FU (ELF). As compared to best supportive care (BSC), combination chemotherapy has yielded significantly superior overall survival (OS) rates.3 However, no single regimen has claimed precedence over the others, and currently there is no universal standard regimen for the treatment of gastroesophageal cancer.4 Thus, new treatment protocols are warranted to achieve better disease control while maintaining a tolerable toxicity profile. The V-325 trial, the largest international phase III trial, showed that adding docetaxel to cisplatin and 5FU improves the time-to-progression (TTP), survival, and response rate in gastric cancer patients, but resulted in increase in toxicity.5 Current reports suggest that substituting capecitabine for 5FU, and oxaliplatin for cisplatin, prolongs OS as well as improves safety, quality of life (QOL) and efficacy.6 Oxaliplatin is a third-generation diaminocyclohexane platinum compound, which is an alkylating agent inhibiting DNA replication by forming adducts between two adjacent guanines, or guanine and adenine molecules. Adducts of oxaliplatin appear to be more effective than cisplatin adducts with regard to the inhibition of DNA synthesis and it has a more favorable toxicity profile. Capecitabine is an oral fluoropyrimidine that is activated to 5FU preferentially in tumor tissue by a three-step enzymatic conversion culminating with thymidine phosphorylase (TP).7 In phase III trials, efficacy data for capecitabine compared favorably with that of parenteral 5FU in the first-line metastatic setting, and resulted in a consistently lower frequency of grade 3 or 4 toxic effects.8 Docetaxel has shown promising activity in gastric cancer, both as monotherapy and in combination with other agents.9 Moreover, docetaxel shows synergy with capecitabine, as it upregulates TP enzyme in tumor cells. Encouraged by the high efficacy of DCF and the better safety profile of capecitabine and oxaliplatin when used in place of 5FU and cisplatin, respectively, we designed this study to test the safety and efficacy of the DOX combination.