Recent Developments in Cytotoxic Therapy for Advanced Gastric or Gastroesophageal Carcinoma: The Phase III Trials

Gastric cancer remains a significant health problem around the world. It is often diagnosed in late stages and almost 50% of patients have unresectable disease. Median survival, when cancer is in advanced stages, is often less than 9 months. Once metastatic, it is an incurable condition, and in most circumstances, fewer than 10% of patients survive 24 months. Most patients with metastatic gastric or gastroesophageal cancer have baseline symptoms, some of which are quite severe. Therapy for advanced gastric or gastroesophageal cancer is palliative in nature. For a long time, the number of randomized trials conducted in patients with gastric or gastroesophageal cancer had been unacceptably low; however, in the past 10 years, the number of phase III trials has increased and it is hoped that the momentum will continue to build and more trials will be completed. Several new classes of active agents have emerged, including taxanes, camptothecins, fluoropyrimidine analogs (particularly, capecitabine and S-1), and a platinum analog (oxaliplatin). The most recent phase III data suggest that docetaxel, when added to the reference regimen of cisplatin and 5-FU (CF), results in a statistically significant prolongation of time-to-progression and overall survival, higher response rate, doubling of the 2-year survival rate, better quality of life, improved clinical benefit, and a higher rate of complicated neutropenia. Other important phase III trials demonstrate that 5-FU can be substituted with capecitabine and cisplatin can be substituted with oxaliplatin. However, in a randomized phase III trial, irinotecan plus infusional 5-FU, when compared with CF, was not superior (it was noninferior), suggesting that irinotecan may be best suited for second-line treatment of these patients. Further developments in cytotoxic therapy will be driven by the use of more sophisticated oral agents (eg, S-1) and newer clinical algorithms that will employ therapy only until maximum response is attained. In conclusion, docetaxel should be combined with other active agents in the front-line treatment of advanced gastric or gastroesophageal cancer. When docetaxel is combined with CF, it becomes an intense regimen requiring stringent patient selection and active management including primary prophylaxis. Capecitabine is noninferior to 5-FU and oxaliplatin is noninferior to cisplatin.