Randomized Trial Shows No Survival Benefit with Adjuvant Chemotherapy in Ampullary Cancer

Adjuvant chemotherapy provides no clear survival Benefit in patients with resected ampullary cancer, suggest results of the multicenter, international, open-label, randomized, controlled ESPAC- 3(v2) trial. Results of this trial — the largest of its kind in patients with adenocarcinoma of the ampulla of Vater — were presented by John P. Neoptolemos, MD, of the University of Liverpool, United Kingdom, in the Gastrointestinal (Noncolorectal) Cancer Oral Abstract Session (Abstract LBA4006).

	"Regarding future approaches, combination chemotherapy may provide better results. The role of adjuvant therapy in ampullary cancer remains uncertain." — John P. Neoptolemos, MD

Adenocarcinoma of the ampulla of Vater, the second most common cancer in patients with resectable tumors in the head of the pancreas, is an aggressive malignancy, with fewer than half of patients alive 5 years after resection. The role of adjuvant chemotherapy in patients with ampullary cancer is unknown, and no standard adjuvant treatment has been established. A previous single study showed no Benefit with adjuvant chemoradiotherapy.

The European Study Group for Pancreatic Cancer undertook the ESPAC-3(v2) trial to compare adjuvant chemotherapy with observation after resection, and to compare 5-fluorouracil (5-FU)/folinic acid with gemcitabine for adjuvant chemotherapy.

Between July 2000 and April 2008, the trial enrolled 304 patients with ampullary cancer, an R0 or R1 resection, a World Health Organization performance status of 0 to 2, no previous or concurrent malignancy, and a life expectancy of at least 3 months. Patients could not have ascites, liver, or peritoneal metastasis or other distant abdominal or extra-abdominal organ spread. The trial also enrolled 130 patients with periampullary cancers, although the analysis focused on the patients with ampullary adenocarcinoma. The study was powered to detect a 15% difference in survival at 5 years.

Patients were stratified by resection margins (R0/R1) and randomly assigned to 5-FU/folinic acid (101 patients), gemcitabine (98 patients), or observation (105 patients). The median maximum tumor diameter was 20 mm (range, 2 to 70 mm). Tumors were moderately differentiated in 63% of patients; 57% had lymph node involvement, and 91% of patients had negative margins after resection. significant prognostic factors included disease grade, disease stage, lymph node status, and resection margin status (R0/R1).

Adjuvant chemotherapy did not significantly improve survival in this trial. After a median follow-up of 66 months, the median overall survival (OS) was 57.1 months with chemotherapy and 43.0 months with observation (hazard ratio [HR]: 0.85; 95% CI [0.61,1.18]; p = 0.322); 5-year OS rates were 47.6% and 42.1%, respectively. In the 276 patients with clear (R0) resections, median overall survival was 58.4 months with chemotherapy compared with 45.1 months with observation (p = 0.171).

	Dan Leheru, MD

A Cox proportional hazards analysis also failed to show a survival Benefit with chemotherapy in the overall population. However, among patients with an R0 resection, chemotherapy was associated with a trend toward a survival benefit over observation (HR: 0.71; p = 0.057).

Regarding the type of chemotherapy administered, no significant survival differences were noted with gemcitabine compared with 5-FU/folinic acid, although gemcitabine was better tolerated.

Although the trial was not positive, Dr. Neoptolemos concluded that it provides “an important benchmark” for expected outcomes following modern surgery. However, in his discussion of the results, Dan Laheru, MD, of The Johns Hopkins University School of Medicine, argued that this was a “trend toward an improvement in survival” study that was ultimately underpowered.

Regarding future approaches, Dr. Neoptolemus suggested that combination chemotherapy may provide better results. The role of adjuvant therapy in ampullary cancer remains uncertain.