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Chemotherapy and Radiation
In Western countries, approximately 75% of patients with gastric cancer have disease that has spread to the perigastric lymph nodes or have distant metastases at the time of diagnosis.372 Patients presenting at early stages are often treated with surgery plus perioperative or adjuvant chemotherapy with curative intent. Unfortunately, gastric cancer appears to be fairly resistant to conventional chemotherapy. Numerous clinical trials have been performed evaluating the role of adjuvant chemotherapy after curative resection for gastric cancer.373 The majority of the studies were inconclusive, but a series of meta-analyses of these trials suggested a 15% to 20% reduction in the risk of death in patients who received adjuvant chemotherapy.374,375 More recent randomized trials of cisplatin- or epirubicin-based adjuvant chemotherapy have largely failed to show a benefit.376,377 The optimal regimen for first-line chemotherapy has yet to be clearly established. Whether a 3-drug regimen is more effective than a potentially less toxic doublet is a point of controversy. Historically, clinical trials have included as a group esophageal, EGJ, and gastric adenocarcinomas. Pooling these conditions may have hidden relevant location-dependent outcomes, although Chau and coworkers demonstrated that, despite a slightly better outcome in esophageal and EGJ adenocarcinomas, no statistical differences were found in terms of overall survival or response rates in the 3 groups.378 The European Organization for Research and Treatment of Cancer Expert Panel differentiated treatment and staging recommendations for tumors near the GE junction. Preoperative chemoradiation was recommended for adenocarcinoma of the esophagogastric junction (AEG) type I and II tumors. For AEG type III (cardia) tumors, perioperative chemotherapy was suggested as the best choice.
Neoadjuvant chemotherapy appears to benefit patients with resectable disease. In the U.K. MAGIC trial, 503 patients with gastric, gastroesophageal, or distal esophageal cancer were randomly assigned to undergo surgery alone or surgery following neoadjuvant epirubicin, cisplatin, and 5-fluorouracil (5FU). Compared to surgery alone, the neoadjuvant group had significantly improved 5-year (36% vs. 23%), progression-free, and overall survival.379 As a result, preoperative chemotherapy is now considered an acceptable treatment option prior to surgery for gastric cancer.
Combined chemoradiation after surgical resection appears to be effective at improving progression-free and overall survival in gastric cancer. The Intergroup Trial 0116 randomized 603 patients with gastric or gastroesophageal cancer to undergo surgery alone or surgery followed by 5FU, leucovorin, and radiation therapy. Subjects in the surgery alone group had a shorter median survival time (27 months vs. 36 months) and a worse overall and relapse-free survival.380 Following publication of the results of this study, adjuvant chemoradiation became the standard of care in the USA, although the optimal chemotherapy regimen is not yet clear. Early studies of the use of neoadjuvant chemoradiation have also shown promising results.381
Because systemic chemotherapy is ineffective for peritoneal metastasis, intraperitoneal (IP) chemotherapy can be considered in patients whose tumors are resected for cure but have a high likelihood of microscopic residual disease. In a randomized trial of 248 patients with gastric cancer, postoperative hyperthermic IP chemotherapy was associated with improved overall survival compared to surgery alone.382 The treatment benefits were most pronounced in patients with stage III and IV disease, serosal invasion, and lymph node metastases. Although a second clinical trial reported similar results,383 other studies have failed to demonstrate a benefit of hyperthermic IP chemotherapy.384,385 A meta-analysis of studies of IP chemotherapy for patients with resectable gastric cancer reported a significantly reduced risk of death in patients who received hyperthermic IP chemotherapy (odds ratio, 0.60).386 At present, the use of hyperthermic IP chemotherapy should be confined to patients enrolled in clinical trials, especially in Western countries.