Although the addition of 5-FU to radiation therapy for locally advanced adenocarcinoma of the pancreas improved short-term survival (GITSG), there were no differences in patterns of failure. Hepatic metastases were equally common in both groups. Therefore, a pilot study of prophylactic hepatic irradiation was developed. Between March 1983 and May 1985, 16 patients were entered in a Phase I/II study of prophylactic hepatic irradiation with local irradiation and systemic chemotherapy for adenocarcinoma of the pancreas at the Medical College of Wisconsin Affiliated Hospitals. Megavoltage radiation (1.8 Gy/fraction) was given to the pancreas with a minimal margin (2 cm) around the tumor, localized by surgical clips or CT scan with a total dose of 61.2 Gy over 7 weeks. Prophylactic hepatic irradiation was added to the fourth week of irradiation to a total dose of 23.4 Gy over 21/2 weeks. 5-Fluorouracil, 500 mg/M2/day was given at Day 1, 2, 3, 29, 30, and 31 of radiotherapy, then a weekly maintenance for 1 year. Fifteen patients were evaluable: One patient refused chemotherapy. The follow-up period was 14 to 50 months (median 26 months). The most common side effect was nausea. Maintenance 5-FU was discontinued in one patient because of GI bleeding. Three-quarters of the patients developed temporary elevations of hepatic enzymes. No severe or life-threatening complications were observed. One, 2-, 3-, and 4-year disease-free survivals are 66.7%, 46.7%, 20% and 13.3%, respectively. Patterns of failure revealed that only two patients had hepatic metastasis as the first site of failure, five patients died of abdominal carcinomatosis, and three patients failed in the pancreas. Two patients died without evidence of cancer. Two patients are alive and well beyond 4 years after the diagnosis. This study confirms that such aggressive combined modality treatment is well tolerated and suggests that the frequency of hepatic metastasis can be reduced.