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The use of perioperative chemotherapy was recently addressed in a phase III trial referred to as the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial (Table 75-5).61 A total of 503 patients with resectable adenocarcinoma of the stomach (372 patients), GEJ (58 patients), or lower esophagus (73 patients) were randomly assigned to either surgery alone or to perioperative chemotherapy with three cycles of epirubicin, cisplatin, and continuous-infusion 5-FU (ECF) before surgery and three cycles of ECF after surgery. With a median follow-up of 4 years, patients randomized to receive perioperative chemotherapy had significantly improved OS when compared with patients randomly assigned to receive surgery alone (5-year OS 36% vs. 23%, HR for death: 0.75, 95% CI: 0.60, 0.93, P = 0.009).
In general, the use of ECF was well tolerated in the preoperative setting. The incidence of overall postoperative complications was similar (45.7% vs. 45.3%) as well as 30-day mortality rates (5.6% vs. 5.9%). Of the 237 patients who started chemotherapy, 215 completed the planned three cycles of preoperative therapy. Of the 209 patients who went to surgery, 137 started postoperative chemotherapy. The most common reasons for not starting chemotherapy included disease progression, early death, postoperative complications, and patient choice. Overall, 103 patients completed all six cycles of chemotherapy.
In a separate phase III trial in France, 224 patients with potentially resectable adenocarcinoma of the lower esophagus, GEJ, or stomach were randomly assigned to either perioperative chemotherapy and surgery (n = 113) or to surgery alone (n = 111).163 Chemotherapy consisted of two or three cycles of cisplatin and infusional 5-FU prior to surgery and three to four cycles after surgery. In this trial, perioperative chemotherapy resulted in a significant improvement in 5-year OS (38 vs. 24%, HR: 0.69, 95% CI: 0.50, 0.95, P = 0.02) and DFS (34 vs. 19%, HR: 0.65, 95% CI: 0.48, 0.89, P = 0.003). Grade 3 or 4 toxicity, consisting primarily of neutropenia, occurred in 38% of the patients receiving chemotherapy.
Summary—Neoadjuvant, Adjuvant, and Perioperative Systemic Chemotherapy
The benefits of chemotherapy for potentially resectable high-risk stomach cancer have mainly been demonstrated with perioperative chemotherapy. The role of adjuvant chemotherapy for resected highrisk stomach cancer remains uncertain. Except for the Japanese trial with S-1, individual trials have generally not shown clinically meaningful benefit. Chemotherapy used alone in the postoperative setting is not of clear value. Future trial design must include adequate statistical power to detect meaningful differences in outcome. Surgery-alone control arms will probably not be feasible in future trials in view of survival benefit achieved with either perioperative chemotherapy or adjuvant combined-modality chemoradiation when compared with a surgeryalone control arm (see subsequent sections).