When it comes to chemotherapy for locally invasive gastric cancer, results from an international clinical trial published in the July 6 New England Journal of Medicine suggest that timing can make all the difference.

"Adjuvant chemotherapy has not become part of the standard of care in gastric cancer," explains Dr. John Macdonald in an editorial, because previous studies have not shown a clinical benefit for postoperative chemotherapy for this disease. But since fewer than 30 percent of patients with locally invasive gastric cancer can be cured with surgery alone, new treatment strategies are of urgent interest to researchers.

A previous large, phase III trial, the U.S. GI Intergroup Study led by the Southwest Oncology Group (INT 0116), demonstrated improved survival with a combination of postsurgical radiation therapy and chemotherapy consisting of fluorouracil and leucovorin, which has since become a standard treatment. The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial has now shown that perioperative chemotherapy - chemotherapy given both before and after surgery - can also provide a significant survival benefit.

The investigators predicted that a perioperative chemotherapy regimen would have advantages over postoperative chemotherapy alone, including "increasing the likelihood of curative resection by downstaging the tumor, eliminating micrometastases, rapidly improving tumor-related symptoms, and determining whether the tumor is sensitive to chemotherapy."

The MAGIC trial enrolled patients with adenocarcinoma of the stomach, the lower third of the esophagus, and the esophagogastric junction; about 74 percent of the patients had tumors in the stomach. Participants were recruited from medical centers in Europe, South America, Asia, and New Zealand. Investigators randomly assigned patients to receive either surgery alone or surgery and perioperative chemotherapy with the drugs epirubicin, cisplatin, and fluorouracil (ECF).

Perioperative chemotherapy consisted of three cycles preoperatively and three cycles postoperatively. Epirubicin and cisplatin were given intravenously on the first day of each cycle, and fluorouracil was given daily for 21 days as a continuous intravenous infusion through a catheter attached to a portable infusion pump. The trial protocol allowed for dose modifications in the event of specific side effects.

Surgery was scheduled to take place within 6 weeks of assignment to the surgery-only group, or 3 to 6 weeks after completion of the preoperative chemotherapy cycles in the perioperative chemotherapy group. Patients were followed for a median of almost 50 months.

Only 42 percent of patients in the chemotherapy group completed all pre- and postoperative cycles according to protocol. However, the authors report that despite the low completion rate, "patients assigned to perioperative chemotherapy had a significant survival advantage over those who underwent surgery alone."

At surgery, tumors were significantly smaller in the chemotherapy group. Patients receiving perioperative chemotherapy had a significantly higher likelihood of both progression-free and overall survival. Five-year survival was 36 percent in the chemotherapy group compared with 23 percent in the surgery-only group.

Patients awaiting surgery for gastric cancer now have more than one treatment option, explains Dr. Margaret Mooney of NCI's Cancer Therapy Evaluation Program. "There is effective adjunct therapy for patients with resectable gastric cancer," she says. "The option that this trial tested is to receive chemotherapy with ECF before and after surgery. There is also an option to receive chemotherapy consisting of fluorouracil and leucovorin with radiation therapy after surgery. Both provide survival advantages over resection alone."

By Sharon Reynolds