ADJUVANT CHEMOTHERAPY HAS MODEST BENEFIT IN PERIAMPULLARY CANCER

July 10, 2012 — Adjuvant chemotherapy is already of proven benefit in pancreatic cancer. Now it has also shown a survival advantage for cancer located in the periampullary region, in and near the head of the pancreas. These periampullary cancers are rare, with an incidence of 0.49 per 100,000 (the incidence of pancreatic cancer is 11.7 per 100,000).

The finding of a survival advantage comes from the largest randomized trial of periampullary cancers, conducted by the European Study Group for Pancreatic Cancer (ESPAC), and published in the July 11 issue of JAMA.

The phase 3 ESPAC-3 trial showed that adjuvant chemotherapy with either fluorouracil or gemcitabine improved overall survival, compared with surgery alone.

However, the effect was "modest," say the authors, and they emphasize the need for improvements in and testing of combination chemotherapies.

Chemotherapy After Resection

ESPAC-3, headed by John Neoptolemos, MD, from the Liverpool Cancer Trials Unit based at Liverpool University in the United Kingdom, was conducted at 100 centers in Australia, Canada, Europe, and Japan. A total of 428 patients were enrolled, 297 of whom had cancer in the ampulla, the region where the bile and pancreatic ducts join up to empty into the duodenum. Another 96 patients had cancer in the bile duct, and the remaining 35 had cancer elsewhere in the periampullary region.

Around 80% of all periampullary cancers are resectable, the authors note. All the participants in this trial had undergone a complete resection and were then randomized to be followed by observation or to receive chemotherapy.

Chemotherapy was either an intravenous infusion of gemcitabine 1000 mg/m² once a week every 3 of 4 weeks for 6 months, or an intravenous bolus injection of fluorouracil 425 mg/m² administered on days 1 to 5 every 28 days. (The fluorouracil was preceded by folinic acid 20 mg/m²).

Median follow-up for the patients who lived was nearly 60 months. However, 61% of patients in the observation group died, as did 58% in the fluorouracil group and 52% in the gemcitabine group.

Median overall survival was 35.2 months in the observation group and 43.1 months in the 2 chemotherapy groups. On multiple regression analysis, after adjustment for independent prognostic variables, the hazard ratio for chemotherapy, compared with observation, was 0.75 (P = .03).

Further analysis suggested that there was a significant survival benefit specifically with gemcitabine, which has a better safety profile than fluorouracil plus folinic acid, but the authors note that "these results should be considered hypothesis generating."

They point out that a parallel trial conducted in ductal adenocarcinoma of the pancreas found that gemcitabine was not superior to fluorouracil plus folinic acid in improving overall survival (JAMA. 2010;304:1073-1081).

Some analysis was carried out on the different types of cancers the trial participants had, but because of the small numbers involved, no clear survival advantage for any specific type of cancer was observed. However, the authors note that intrapancreatic bile duct cancer is particularly challenging, and might need to be considered as a separate entity from periampullary cancers. These intrapancreatic bile duct cancers also seem to be different from the more proximal bile duct cancers, they add.

"Although this study found support for the use of adjuvant chemotherapy to improve survival in patients with periampullary cancers, this effect was modest," the authors conclude, and they call for more research.

The trial was funded by various cancer charities and research institutions in Australia, Canada, France, Italy, and the United Kingdom.

JAMA. 2012;308:147-156. Abstract