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Neoadjuvant Systemic Chemotherapy

Neoadjuvant therapy has the potential advantage of downstaging gastric cancer and thereby enhancing the potential for resection. It also has the potential to eliminate micrometastatic disease prior to surgery and at a time patients may be more likely to tolerate systemic therapy. A retrospective analysis of 220 patients receiving either 5-fluorouracil (5-FU) alone or 5-FU and cisplatin prior to surgery compared with 100 patients treated with surgery alone suggested a benefit to neoadjuvant therapy.130 Patients receiving neoadjuvant therapy had a significantly longer 5-year survival. However, prospective clinical trials with neoadjuvant therapy are limited.

Several phase II trials of neoadjuvant trials have been reported and have shown mixed results. Ajani and colleagues have performed two phase II studies of preoperative chemotherapy in this setting.131,132 In their first study, 25 patients were treated with two cycles of etoposide, 5-FU, and cisplatin preoperatively.132 Three cycles were administered postoperatively if a positive response to neoadjuvant treatment could be detected endoscopically or radiographically. All 25 patients underwent surgery, and 72% were resected for cure. No pathological complete responses were seen, and the median survival was 15 months overall. Following the report of Wilke and coworkers of pathological complete response to chemotherapy with epirubicin, doxorubicin, and cisplatin (EAP),133 Ajani and associates treated 48 potentially curable patients with three cycles of preoperative EAP and two cycles following surgery if a response to preoperative treatment was observed.131 This trial failed to support the findings of the trial reported by Wilke. Of the 85% of patients who underwent exploration, 77% had resectable cancer. Although 12% of patients achieved a complete clinical response, no pathological complete responders were seen. The overall median survival was 15.5 months.

One of the few randomized trials to assess the potential benefit of preoperative chemotherapy to surgery alone in patients with potentially resectable cancer failed to show any benefit in outcomes (Table 75-5).134,135 In this Dutch trial, 59 patients were randomly assigned to either 5-FU, doxorubicin, and methotrexate (FAMTX) followed by surgery (N = 29) or surgery alone. Patients with T1 tumors, tumors arising from the gastric cardia, or evidence of distant metastases were excluded from participation. The trial was closed early as a result of poor accrual. No benefit was seen with the addition of FAMTX before surgery. In a separate phase III trial neoadjuvant chemotherapy with cisplatin, 5-FU, and leucovorin followed by surgery was compared to surgery alone.136 Patients randomly assigned to chemotherapy received two 48-day cycles of chemotherapy. The trial was closed early for poor accrual. No benefit could be demonstrated for the addition of neoadjuvant therapy as measured by OS (hazard ratio [HR]: 0.84; 95% CI: 0.52, 1.35, P = 0.466) in the 144 patients enrolled after a median follow-up of 4.4 years.