Treatment Approach to Adenocarcinoma of the Ampulla of Vater.

ACs are rare tumors, and thus, there is a lack of prospective trials supporting treatment decisions. Moreover, although anatomically uniform, ACs comprise of biologically distinct entities, depending on what cell type they arise from. This makes the interpretation of limited data even more challenging. Overall, the clinical outcomes of patients with AC are better than those with pancreatic cancer. However, recurrence rates remain high after curative resection. Despite the absence of definitive evidence, we believe that these high recurrence rates are a rational justification for consideration of adjuvant therapy in resected disease, and therapy selection should take tumor biology, stage, resection margins, as well as patient comorbidities and performance status into account. Largely extrapolating from pancreas cancer, we recommend consideration of adjuvant chemotherapy with 6 months of dose-modified FOLFIRINOX in fit patients with pancreatobiliary subtype tumors. Alternative regimens include gemcitabine in combination with capecitabine. If chemoradiotherapy is being added, 6 weeks of radiotherapy in conjunction with 5-FU or capecitabine can be considered. For intestinal subtypes, we recommend 3-6 months of adjuvant FOLFOX. Future studies are needed to evaluate the role of contemporary, multi-agent chemotherapy and chemoradiotherapy in patients with resected and advanced ampullary adenocarcinoma. However, the logistics of performing large randomized trials in patients with a rare cancer is challenging, and the data collection, even in a carefully designed study, would likely take many years. As such, relying on data from basket trials and retrospective analysis will likely serve as guidance for treatment decisions in the near future. Treatment of metastatic disease should employ regimens that are typically used to treat pancreas cancer for tumors of pancreatobiliary subtype and 5-FU-based regimens for intestinal subtypes. Studies specific for patients with advanced AC are much needed. Molecular testing using next-generation sequencing and testing for microsatellite instability (MSI) should be performed on all tumors. We now have disease agnostic options based on these results. Pembrolizumab is approved for MSI-H tumors and tumors with high tumor mutational burden regardless of the primary site. Larotrectinib is approved for tumors with NTRK fusions. At a time when numerous therapeutic agents are in development, for example, those targeting specific K-RAS alterations or NRG fusions, identifying molecular aberrations can significantly impact patient outcomes as well as provide further insights into the biology of disease. In addition, based on recent data suggesting a significant prevalence of germline alterations in patients with ampullary tumors, referral to genetics counselors and germline testing is warranted in a significant proportion of patients with AC.