Gastric cancer--new therapeutic options.

Gastric and gastroesophageal adenocarcinomas are important health problems. A 2005 analysis1 of the worldwide incidence of and mortality from cancer showed that 934,000 cases of gastric cancer occurred in 2002 and that 700,000 patients die annually of this disease. The management of gastric cancer, like the management of most gastrointestinal cancers, is based on surgical resection of the primary tumor. When the cancer is localized to the stomach and is minimally invasive,2,3 surgical cure is possible in up to 90 percent of cases. However, the detection of early gastric cancer is unusual in Western countries. More commonly, resectable gastric cancer is detected when it is locally advanced — that is, when the tumor extends into or through the gastric wall and there are perigastric lymph-node metastases.4,5 Less than 30 percent of such cases are cured by gastrectomy. Because of the poor outcomes of surgery for gastric cancer, there has been much interest in adjunctive therapies that, when used in addition to surgical removal of the primary tumor, may improve survival.5-7 Adjuvant cytotoxic chemotherapy is successful in other gastrointestinal cancers,8 and many phase 3 clinical trials5,6 have explored this approach in gastric cancer. However, the survival benefit gained from the use of adjuvant chemotherapy in gastric adenocarcinoma is not clinically significant,5,6 and for this reason adjuvant chemotherapy has not become part of the standard of care in gastric cancer. Nevertheless, there are other strategies in which cytotoxic chemotherapy may be beneficial. In this issue of the Journal, Cunningham and colleagues9 present the results of a phase 3 trial in which they evaluated the role of perioperative chemotherapy in the management of resectable gastric cancer. In this trial, patients with resectable gastric cancer were randomly assigned to a combination of chemotherapy and gastric resection or to gastric resection alone. The patients in the chemotherapy group were assigned to receive both preoperative and postoperative therapy with a regimen of three drugs — epirubicin, cisplatin, and fluorouracil (ECF). Patients in the surgeryonly group underwent gastrectomy with curative intent and received no adjuvant therapy. The major outcomes were progression-free and overall survival. The trial enrolled 503 patients; 250 received perioperative chemotherapy and 253 were treated with surgical resection alone. Analysis of the results of the trial convincingly demonstrated a benefit from the use of the ECF regimen. Five-year overall survival was 36 percent in the perioperative-chemotherapy group and 23 percent in the surgery-only group (P = 0.008 by the log-rank test). This improvement in survival of 13 percentage points corresponds to a 25 percent relative reduction in the risk of death. Progressionfree survival also was improved by chemotherapy. In the perioperative-chemotherapy group, other outcomes also showed encouraging trends, such as decreased tumor size and reduction in the extent of nodal metastases. Whenever chemotherapy is used, it is important to assess drug toxicity. Neutropenia and thrombocytopenia, for example, are clinically significant complications in patients who are about to undergo a major abdominal operation. Cunningham et al. found that perioperative chemotherapy was associated with acceptable rates of adverse events. Excluding patients with neutropenia (23 percent), less than 12 percent of patients had serious (grade 3 or 4) toxic effects. Although 15 of 237 patients (6 percent) discon-