The National Comprehensive Cancer Network (NCCN) has released new guidelines for ampullary adenocarcinoma, a disease accounting for just 0.2% of all gastrointestinal malignancies.

Physicians determine treatment for ampullary adenocarcinomas depending on whether the tumor histology is pancreatobiliary, intestinal, or mixed. E. Gabriela Chiorean, MD, colead of the NCCN Ampullary Adenocarcinoma committee and medical director of gastrointestinal medical oncology with Fred Hutchiinson Cancer Center, said the NCCN wanted to help physicians make those treatment decisions and classify optimal local treatments.

The ampulla of Vater region, or just “ampulla,” is the crossroad of the intestinal, ductal pancreatic, and biliary epithelia.

 It has 4 parts in a narrow area of the ampulla, including tissue of the periampullary pancreas. “Because it’s basically the nexus of between the biliary and pancreatic ducts with the small intestine, the ampulla it has a very complex histology," Chiorean said. 

Most ampullary adenocarcinomas are intestinal or pancreatobiliary. In 2019, German investigators published findings from a retrospective analysis of 170 patients with ampullary cancer who received pancreatic resection from 1999 to 2016. Fifty percent of patients harbored the pancreatobiliary subtype, 34.5% had intestinal disease, and 7.6% had mixed subtype.

Survival analysis from that study showed a significantly worse 5-year overall survival (OS) rate for the pancreatobiliary subtype compared with intestinal at 27.5% vs 61%, respectively (

<.001). The mean overall survival for patients with the pancreatobiliary subtype was 52.5 months, compared with 115 months for intestinal subtype, and 94.7 months for the mixed subtype (

Chiorean said that physicians use regimens for pancreatic cancer to treat patients with ampullary adenocarcinomas of pancreaticobiliary subtype. However, the 5-year OS rate for all forms of pancreatic cancer is just 11% compared with 30% to 67% for ampullary adenocarcimomas.

The current standard of care for localized ampullary cancer is pancreaticoduodenectomy, also known as the Whipple procedure, in which a surgeon removes the head of the pancreas, part of the duodenum, the common bile duct, and the gallbladder. The procedure is a common treatment for patients with pancreatic cancers. However, by one estimate, approximately 50% of patients with ampullary cancer can receive curative surgery compared with less than 10% of those with pancreatic adenocarcinoma.

Neoadjuvant therapy is an option for patients with localized pancreatic cancer because those tumors are more commonly closed to the celiac arterial axis, but the guidelines say that there is limited evidence supporting such treatment for ampullary cancers and most such patients proceed straight to surgery.

“After surgical resection, we consider administering adjuvant therapy to reduce the odds of recurrence based, again, on the histology,” Chiorean said.

The guidelines suggest FOLFIRINOX or modified FOLFIRINOX with or without subsequent chemoradiation, or gemcitabine-based regimens with cisplatin, capecitabine, or nab-paclitaxel (Abraxane), all with or without subsequent chemoradiation for those with pancreatobiliary or mixed disease. FOLFOLX, FOLFIRINOX, or capecitabine/oxaliplatin with or without subsequent chemoradiation are options for intestinal subtype ampullary cancers.

In the adjuvant setting, the guidelines specifically cite the phase 3 ESPAC-3 trial (NCT00058201), which included patients with ampullary cancers, to support the use of postoperative gemcitabine or 5-fluorouracil (5-FU). In that trial, investigators assigned 143 patients to 20 mg/m

 fluorouracil every 1 to 5 days in 28-day cycles,141 patients to 1000 mg/m

 gemcitabine once weekly for 3 of every 4 weeks for 6 months, and 140 patients to observation.

 Eligible patients had undergone complete macroscopic (R0 or R1) resection for nonpancreatic ductal periampullary adenocarcinoma of the head of the pancreas and had no evidence of malignant ascites, peritoneal metastasis, or spread to the liver or other distant abdominal or extraabdominal organs.

At a median follow-up of more than 2 years, the median OS was 35.2 months (95% CI, 27.2-43.0) in the observation group and 43.1 months (95% CI, 34.0-56.0 months) in the chemotherapy groups (HR, 0.86; 95% CI, 0.66-1.11; 

 = .25). Median OS for the ampullary pancreatobiliary group was 56.0 months (95% CI, 36.0-not estimable) and 43.1 months (95% CI, 25.5-58.4) for the ampullary intestinal group (

Recurrence is common following surgery at 89.6% at 3 years in one study.

 The choice of second-line therapy depends on both disease subtype and the regimen used in up front. For instance, guideline recommendations suggest 5-FU plus leucovorin and liposomal irinotecan, FOLFIRI, FOLFOX, modified FOLFIRINOX, oxaliplatin plus 5-FU and leucovorin, capecitabine/oxaliplatin, capecitabine alone, or 5-FU plus leucovorin for patients with pancreatobiliary/mixed disease who received gemcitabine-based therapy in first line.

"On the other hand, for intestinal subtypes, if a patient was originally managed with a FOLFOX, we would offer FOLFIRI in second line,” Chiorean said. "The subtype makes a difference, and we use standard regimens that are otherwise used for colorectal, pancreatic, or biliary tumors."

Similar to other solid tumor indications, the guidelines recommend genetic testing for hereditary cancer genes, as well as tumor genomic and molecular profiling, the latter for patients with advanced disease. This information can identify patients who could benefit from immunotherapies or molecularly targeted therapies, she added.


For the most part, the guidelines are classified as 2A, meaning that there is uniform NCCN consensus that a given treatment is appropriate, but that the recommendations are based on “lower-level evidence.” Chiorean noted that there are no current clinical trials looking at ampullary cancers exclusively, and she sees these guidelines as a way to boost interest and attention to this malignancy.

“With guidelines in place, it will definitely [be easier] moving forward for researchers and investigators to develop the new generation of clinical trials specifically for ampullary cancers, including for molecular subtypes,” she said.

National Comprehensive Cancer Network. NCCN guidelines version 1.2022 for ampullary adenocarcinoma. Published March 9, 2022. Accessed March 10, 2022. https://bit.ly/3rJA933

Ahn DH, Bekaii-Saab T. Ampullary cancer: an overview. 

. 2014:112-5. doi:10.14694/EdBook_AM.2014.34.112

Pea A, Riva G, Bernasconi R, et al. Ampulla of Vater carcinoma: molecular landscape and clinical implications. 

Zimmermann C, Wolk S, Aust DE, et al. The pathohistological subtype strongly predicts survival in patients with ampullary carcinoma. 

. 2019;9:12676. doi: /10.1038/s41598-019-49179-w

Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 Periampullary Cancer randomized trial. 

. 2012;308(2):147–156. doi:10.1001/jama.2012.7352

Kim KJ, Choi DW, Kim WS, et al. Adenocarcinoma of the ampulla of Vater: predictors of survival and recurrence after curative radical resection. 

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