Ampullary adenocarcinoma is a rare gastrointestinal malignancy, with limited evidence to guide systemic treatment in patients with metastatic disease. Although fluoropyrimidine-based and gemcitabine-based chemotherapy regimens are commonly used, the optimal first-line treatment approach remains uncertain.
On October 9, 2026, a study titled “First-Line Fluoropyrimidine- versus Gemcitabine-Based Chemotherapy for Metastatic Recurrence After Resection of Ampullary Adenocarcinoma: a Real-World Analysis of the FFCD-AC Cohort” was published online in the European Journal of Cancer.
This post hoc analysis of the prospective French FFCD-AC cohort evaluated outcomes with first-line fluoropyrimidine-based versus gemcitabine-based chemotherapy in patients who developed metastatic recurrence following curative-intent resection. The investigators also examined clinical and histological factors associated with survival.
The study was conducted by Erwan Vo-Quang, Vincent Hautefeuille, Olivier Bouché, Karine Le Malicot, David Tougeron, Stéphanie Truant, Anna Pellat, Morgane Amil, Gael Roth, Marine Jary, Sylvain Manfredi, Marielle Guillet, Olivier Glehen, Julien Taieb, and Claire Gallois.
Study Design and Patient Characteristics
The analysis included patients from the French national prospective FFCD-AC cohort (NCT03800212), which enrolled 370 patients who underwent resection for localized ampullary carcinoma between July 2014 and June 2023 across 50 centers.
Among these patients, 108 (29.2%) developed disease recurrence, of whom 85 (78.7%) received at least one cycle of systemic chemotherapy and were included in the analysis. The median age at metastatic recurrence was 70 years. The most common histological subtype was biliopancreatic (50.6%), followed by mixed, undifferentiated, or undetermined tumors (34.1%) and intestinal tumors (15.3%). The liver was the most frequent metastatic site, reported in 62.4% of patients, while 64.7% had only one metastatic site.
Progression-free survival (PFS) and overall survival (OS) were calculated from the initiation of first-line chemotherapy. Prognostic factors were evaluated using univariable and multivariable Cox proportional hazards models.
First-Line Treatment Patterns
Of the 85 patients, 55 (64.7%) received fluoropyrimidine-based chemotherapy, while 30 (35.3%) received gemcitabine-based regimens. The most frequently administered treatments were FOLFIRINOX (22.4%), FOLFOX (17.6%), FOLFIRI (16.5%), and gemcitabine plus nab-paclitaxel (14.1%).
Treatment selection differed across histological subtypes. Fluoropyrimidine-based regimens were used in 92.3% of patients with intestinal-type tumors, compared with 60.5% of patients with biliopancreatic tumors and 58.6% of those with mixed, undifferentiated, or undetermined tumors. Overall, 58 patients (68.2%) received at least one subsequent line of systemic therapy.
Treatment Response and Survival
Among 72 patients with available RECIST assessments, the overall objective response rate (ORR) was 34.7%, and the disease control rate (DCR) was 70.8%. Response rates were similar between the two treatment groups:
- ORR: 36.2% with fluoropyrimidine-based chemotherapy versus 32.0% with gemcitabine-based chemotherapy (p=0.73).
- DCR: 72.3% versus 68.0%, respectively (p=0.78).
After a median follow-up of 65.4 months, median PFS in the overall population was 6.7 months (95% CI, 4.8–8.9), while median OS was 15.6 months (95% CI, 11.9–18.2).
Patients treated with fluoropyrimidine-based regimens had a median PFS of 7.7 months (95% CI, 4.6–12.2), compared with 5.4 months (95% CI, 3.5–10.1) among those receiving gemcitabine-based chemotherapy. In multivariable analysis, fluoropyrimidine-based treatment was independently associated with longer PFS (adjusted HR 0.53; 95% CI, 0.32–0.88; p=0.01).
However, no statistically significant difference in OS was observed. Median OS was 15.9 months (95% CI, 10.6–22.3) in the fluoropyrimidine-based group versus 15.2 months (95% CI, 9.6–18.2) in the gemcitabine-based group (p=0.10). The association between chemotherapy regimen and OS also remained nonsignificant in multivariable analysis (adjusted HR 0.63; 95% CI, 0.36–1.10; p=0.10).
Prognostic Factors and Histological Subtypes
The investigators identified several factors independently associated with longer PFS. In addition to fluoropyrimidine-based chemotherapy, having only one metastatic site was associated with improved PFS compared with two or more metastatic sites (adjusted HR 0.43; 95% CI, 0.26–0.70; p<0.01).
Similarly, patients receiving bi- or triplet chemotherapy had longer PFS than those receiving monotherapy (adjusted HR 0.25; 95% CI, 0.12–0.52; p<0.01). For OS, the absence of liver metastases was the only independently associated favorable prognostic factor (adjusted HR 0.58; 95% CI, 0.34–0.97; p=0.04). The analysis also evaluated outcomes according to histological phenotype.
Median OS was 18.2 months for intestinal-type tumors, 10.61 months for biliopancreatic tumors, and 25.82 months for mixed, undifferentiated, or undetermined tumors. Despite these numerical differences, no statistically significant association between histological subtype and survival outcomes was demonstrated. The investigators noted that the limited number of patients within each histological subgroup restricted the interpretation of these findings.
Clinical Implications and Limitations
The FFCD-AC analysis provides real-world evidence on chemotherapy outcomes in patients with metastatic recurrence of ampullary adenocarcinoma, a population for which prospective treatment data remain scarce. Although fluoropyrimidine-based chemotherapy was associated with longer PFS, the absence of a statistically significant OS difference prevents conclusions regarding the overall survival superiority of either chemotherapy backbone.
Treatment intensity may also have influenced the observed PFS difference. Combination regimens were more frequently administered in the fluoropyrimidine-based group, and the number of chemotherapy agents was independently associated with PFS. Although treatment intensity was included in the multivariable analysis, residual confounding could not be excluded.
The findings should also be interpreted in the context of several limitations. The post hoc analysis included a relatively small population, particularly in the gemcitabine-based group, limiting comparisons between individual chemotherapy regimens. Treatment allocation was not randomized, and selection bias may have influenced the results.
Furthermore, the study included only patients who developed metastatic recurrence after curative-intent resection and received systemic treatment. Patients presenting with synchronous metastatic disease or those unable to receive chemotherapy were not represented. Important clinical and molecular variables were unavailable, and no central pathology review was performed. Treatment-related toxicity data were also not prospectively collected, preventing a comprehensive assessment of the benefit–risk balance of different chemotherapy strategies.
Conclusion
The FFCD-AC analysis demonstrated an association between fluoropyrimidine-based first-line chemotherapy and longer PFS compared with gemcitabine-based regimens in patients with metastatic recurrence of ampullary adenocarcinoma after resection. However, no statistically significant OS difference was observed.
The absence of liver metastases emerged as the only independent favorable prognostic factor for OS, while histological subtype was not significantly associated with survival outcomes.
These findings do not establish the superiority of one chemotherapy backbone over another in terms of overall survival. The investigators emphasized the need for larger prospective studies incorporating comprehensive histological and molecular characterization to better define treatment strategies for metastatic ampullary adenocarcinoma.
The full article is available in European Journal of Cancer.
