Just When You Thought the Fluorouracil Debate Was Over: S-1 and Gastric Cancer

Despite a decline in incidence in the United States and Western Europe, gastric cancer is common worldwide and remains the second leading cause of cancer-related death. In a shift in the epidemiology of gastric cancer, adenocarcinomas of the esophagus and gastroesophageal junction are increasing at a dramatic rate in the United States and Western Europe, and represent an even more virulent disease entity. The pattern of more distal gastric cancer elsewhere in the world may be a function of rates of infection by Helicobacter pylori, dietary practices, and potential dietary deficiency in micronutrients such as selenium and vitamin C. The predominance of adenocarcinoma of the esophagus and gastroesophageal junction in the West may reflect population trends in obesity and tobacco abuse, and paradoxically, a decrease in Helicobacter infection that may increase the risk of esophageal reflux disease. Because of the absence of effective screening, patients with gastric cancer in the United States usually present with symptomatic and either locally advanced or metastatic disease. High rates of recurrence after surgery have engendered decades of clinical trials evaluating the use of adjuvant chemotherapy, with or without radiation. Fortunately, recent clinical trials have made advances with the validation of the use of systemic chemotherapy to improve survival. Intergroup trial 116 showed that postoperative bolus fluorouracil (FU), leucovorin, and radiation therapy improved survival compared with surgery alone, despite the relative inactivity for FU and leucovorin in metastatic disease. Although postoperative adjuvant chemotherapy alone has failed to affect survival in gastric cancer, preand postoperative chemotherapy with epirubicin, cisplatin, and protracted-infusion FU (ECF) without the use of radiation, as recently reported in the MAGIC trial from the United Kingdom, significantly improved survival compared with surgery alone. The improvement in survival in recent adjuvant trials, however, is marginal, and the key to further progress is the identification of more active systemic agents in gastric cancer. The evaluation of a novel combination chemotherapy regimen, S-1 and cisplatin, is the focus of the phase I trial reported by Ajani et al in the current issue of the Journal of Clinical Oncology. This trial raises important issues about the pace of progress of chemotherapy development in gastric cancer, including the role of oral agents as a replacement for intravenous drugs. The trial also, for better or for worse, rekindles the time-worn debate of how best to administer fluoropyrimidines as part of combination chemotherapy. Conventional chemotherapy used in the treatment of gastric cancer has limited effectiveness and significant toxicity, depending on the dose and schedule of agents used. If we are searching for direction in gastric cancer drug development, colorectal cancer should clearly serve as a model. Progress has been made in colorectal cancer in the identification of new chemotherapy agents, optimal dosing and scheduling of agents, and the incorporation of targeted therapies. Colorectal cancer trials have firmly established that, in comparison with bolus FU, the use of continuous-infusion FU administered as a biweekly 48-hour infusion results in superior antitumor efficacy, longer patient survival, and improved therapy tolerance. The debate about the optimal schedule of FU has largely been replaced by discussion of the best sequencing of available therapies and the addition of targeted agents. The substitution of oral agents for continuous-infusion FU is a topic of more secondary interest given the accumulating data from phase III trials that show equivalence, but not necessarily superiority, of oral drugs. Whereas response, survival, and toxicity benefits have all been accomplished in colorectal cancer trials, such advances have eluded gastric cancer investigators. In gastric cancer, there has been a seeming reluctance to incorporate lessons learned from the trial experience in colorectal cancer. There is continued acceptance of the combination of a 5-day infusion of FU in combination with every 3to 4-week dosing of relatively high doses of cisplatin. The toxicity and limited efficacy of this regimen was underscored in a phase III JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 28 OCTOBER 1 2005