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Adjuvant Systemic Chemotherapy
Initial trials to assess the benefit of adjuvant chemotherapy in the United States were conducted by the Veterans Administration in 1957 testing single agents. Survival was not improved with the adjuvant use of either single-agent 5-fluorodeoxyuridine (FUDR) or triethylenethiophosphoramide (thiotepa) when compared with surgery alone.137,138
In subsequent North American and European trials, the potential benefit of multidrug regimens that had shown benefit in the metastatic setting were evaluated in the adjuvant setting. These regimens included (1) a combination of 5-FU and methyl-chloroethylcyclohexyl-nitrosourea (MeCCNU; lomustine); (2) FAM, a combination of 5-FU, doxorubicin (Adriamycin), and mitomycin C; and (3) FAMTX, a combination of 5-FU, doxorubicin, and methotrexate. Although a trial from the Gastrointestinal Tumor Study Group (GITSG) demonstrated a survival advantage for the 71 patients assigned to combination chemotherapy with 5-FU and MeCCNU when compared with an equal number of control patients assigned to surgery alone (P < 0.03),139 subsequent studies performed by the Eastern Cooperative Oncology Group (ECOG), and the Veterans Administration could not confirm a survival advantage for patients treated with the same adjuvant chemotherapy.11,12 Phase III trials testing the use of either FAM or FAMTX in an adjuvant setting also failed to demonstrate a survival advantage when compared with a surgery-alone control arm.140-148 A phase III trial of cisplatin, epirubicin, 5-FU, and leucovorin (PELF) also failed to show any significant benefit.149
Mixed results have been seen in trials performed in Asia. Nakajima and colleagues have performed a series of adjuvant trials in individuals with resected gastric cancer.150-153 In their first trial, mitomycin C was given on a twice-a-week schedule for 5 weeks, but no survival benefit was seen for the whole cohort of patients.150 In a subsequent threearm adjuvant trial, patients were randomly assigned to surgery alone, mitomycin C alone, or the combination of twice-weekly MFC (mitomycin C, 5-FU, and cytosine arabinoside).153 Forty-two patients were entered in each arm of the trial. At 5 years, a survival benefit for MFC-treated patients was seen when compared with surgical control subjects. No significant benefit was seen for the mitomycin C arm. These same investigators studied the regimen of MFC followed by either long-term oral 5-FU or ftorafur compared with surgery alone.152 A significant survival benefit was seen for individuals with stages I to III disease treated with MFC and oral 5-FU. In a fourth trial, the role of adjuvant mitomycin C and 5-FU followed by oral uracil and tegafur was evaluated in patients undergoing complete resection for early-stage gastric cancer.151 When compared with a control group, adjuvant therapy for this group of patients showed no benefit over surgery alone.
Given the success of the oral fluoropyrimidine S-1 in advanced gastric cancer, a Japanese trial of surgery followed by adjuvant S-1 for 1 year compared with surgery alone for patients with resected stage II or III gastric cancer was performed (Table 75-5).154 A total of 529 patients were randomly assigned to the S-1 group and 530 to the surgery-alone group. The 3-year and 5-year OS improved with the use of S-1 (5-year HR: 0.669; 95% CI: 0.540, 0.793).154,155
Five other phase III trials of adjuvant postoperative chemotherapy have been performed with a surgery-alone control arm, but only two demonstrated a survival benefit from the adjuvant chemotherapy (Table 75-5).156-161 Neri and associates treated surgically resected node-positive patients with the addition of adjuvant epirubicin, 5-FU, and leucovorin (68 patients) and compared them with 69 surgery-alone control patients.161 A significant improvement in 5-year OS was noted in patients receiving the adjuvant chemotherapy (30% vs. 13%, P < 0.01).
Many of the trials reported from North America, Europe, and Asia were underpowered to adequately assess any potential differences between the control and treatment arms in regard to OS. Accordingly, a clinically meaningful result may have been missed. In an attempt to better determine the benefit of adjuvant therapy after potentially curative surgery for stomach cancer, several metaanalyses have been performed. A meta-analysis of 17 phase II and III randomized trials showed a significant survival advantage (OS, DFS) to the use of chemotherapy following surgical resection of gastric cancer compared with surgery alone with a median follow-up exceeding 7 years.162