Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group.

The incidence of pancreatic cancer still seems to be increasing, and it is the fifth most common cause of cancer death in the United States. The prognosis is one of the most dismal of all cancers: approximately 95% of all patients diagnosed with pancreatic cancer will die within 1 year. 1 To date, the only potentially curative therapy is radical surgical resection. After potentially curative resection for cancer of the pancreatic head, the 1-year survival estimate is 50% to 60%, 2-year survival is 15% to 35%, and 5-year survival is 5% to 20%. In patients with periampullary carcinoma in the ampulla of Vater, distal common bile duct, or duodenum, a much better survival rate is obtained after surgical resection, with a 5-year survival rate of 40% to 60%. 2–7 After radical resection, pancreatic cancer recurs primarily within the abdominal cavity; most failures are locoregional and in the liver. Distant metastases in the lung or peritoneal cavity are seldom seen without local tumor recurrence and are characteristic of late recurrence. Therefore, a treatment approach combining local and systemic adjuvant treatment in pancreas and periampullary cancer seems interesting. Radiation therapy with or without chemotherapy has been extensively studied in locoregional advanced disease, especially the combination of external radiotherapy combined with 5-fluorouracil (5-FU). 8–11 The possible benefit of chemoradiotherapy resulted in the use of radiotherapy combined with 5-FU as adjuvant treatment in a prospective randomized multicenter study performed by the Gastrointestinal Tumor Study Group (GITSG), in which 14 institutes participated. 12 The high incidence of pancreatic cancer and the relatively large group of participating institutions was intended to guarantee sufficient patient accrual. Radiotherapy consisted of a split course of 40 Gy—two courses of 20 Gy with an interval of 2 weeks. 5-FU was given concomitantly during the first week of radiotherapy and during 2 years thereafter. The 21 patients who received adjuvant treatment had a 2-year survival rate of 43%, significantly better than the 18% found in the control group (p < 0.03). The trial was prematurely closed because the interim analysis showed a statistically significant difference in favor of the treatment arm. Another 30 patients were treated with the same adjuvant treatment and studied by the GITSG with similar results (2-year survival rate 46%). This trial demonstrated for the first time that prolonged survival could be obtained with adjuvant treatment after surgical resection of pancreatic cancer, although this was demonstrated in only a small number of patients. 13 However, a nonrandomized study showed no significant difference in survival after adjuvant treatment as given in the GITSG trial. 14 At present, no other prospective randomized trial in pancreatic or periampullary cancers has been reported in the United States or Europe. Recently, Yeo et al 15 described the beneficial effect of adjuvant radiotherapy and 5-FU treatment. However, in that nonrandomized study, there seemed to be a selection of patients. Patients who had a satisfactory recovery by postoperative day 60 were encouraged to accept adjuvant therapy. Patients declining radiotherapy were significantly older and had a significantly longer postoperative stay, more intensive care therapy, and a significantly greater incidence of postoperative complications. The GITSG trial led to the use of standard adjuvant radiotherapy with 5-FU in the United States. In 1987, we initiated a prospective randomized clinical trial in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) to study the effect of adjuvant radiotherapy and 5-FU.