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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

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    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
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Outcomes of Palliative Chemotherapy for Ampulla of Vater Adenocarcinoma: A Multicenter Cohort Study

Dong Kee Jang1 , So Jeong Kim2,3 , Hwe Hoon Chung4 , Jae Min Lee5 , Seung Bae Yoon6 , Jong-Chan Lee7 , Dong Woo Shin8 , Jin-Hyeok Hwang7 , Min Kyu Jung9 , Yoon Suk Lee10 , Hee Seung Lee2 , Joo Kyung Park4 , Korean Society of Gastrointestinal Cancer

1Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, 2Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 3Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ewha Womans University College of Medicine, 4Division of Gastroenterology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 5Department of Internal Medicine, Korea University Anam Hospital, 6Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 7Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 8Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, 9Division of Gastroenterology, Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, and 10Division of Gastroenterology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea

Correspondence to: Joo Kyung Park
ORCID https://orcid.org/0000-0002-9652-5287
E-mail mdsophie@gmail.com

Hee Seung Lee
ORCID https://orcid.org/0000-0002-2825-3160
E-mail lhs6865@yuhs.ac

Dong Kee Jang, So Jeong Kim, and Hwe Hoon Chung contributed equally to this work as first authors.

Received: April 30, 2023; Revised: September 7, 2023; Accepted: October 11, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver.

Published online December 22, 2023

Copyright © Gut and Liver.

Background/Aims: Palliative chemotherapy (PC) is not standardized for patients with advanced ampulla of Vater adenocarcinoma (AA). This multicenter, retrospective study evaluated first-line PC outcomes in patients with AA.
Methods: Patients diagnosed with AA between January 2010 and December 2020 who underwent PC were enrolled from 10 institutions. Overall survival (OS) and progression-free survival (PFS) according to the chemotherapy regimen were analyzed.
Results: Of 255 patients (mean age, 64.0±10.0 years; male, 57.6%), 14 (5.5%) had locally advanced AA and 241 (94.5%) had metastatic AA. Gemcitabine plus cisplatin (GP) was administered as first-line chemotherapy to 192 patients (75.3%), whereas capecitabine plus oxaliplatin (CAPOX) was administered to 39 patients (15.3%). The median OS of all patients was 19.8 months (95% confidence interval [CI], 17.3 to 22.3), and that of patients who received GP and CAPOX was 20.4 months (95% CI, 17.2 to 23.6) and 16.0 months (95% CI, 11.2 to 20.7), respectively. The median PFS of GP and CAPOX patients were 8.4 months (95% CI, 7.1 to 9.7) and 5.1 months (95% CI, 2.5 to 7.8), respectively. PC for AA demonstrated improved median outcomes in both OS and PFS compared to conventional bile duct cancers that included AA.
Conclusions: While previous studies have shown mixed prognostic outcomes when AA was analyzed together with other biliary tract cancers, our study unveils a distinct clinical prognosis specific to AA on a large scale with systemic anticancer therapy. These findings suggest that AA is a distinct type of tumor, different from other biliary tract cancers, and AA itself could be expected to have a favorable response to PC.

Keywords: Ampulla of Vater, Biliary tract neoplasms, Chemotherapy, Survival

Cancer of the ampulla of Vater (AoV) is a rare malignancy.1-3 Unfortunately, approximately 50% of patients with AoV cancer are not diagnosed until they are in an advanced stage, and as such, only 40% of patients can be treated surgically.1,4 AoV adenocarcinoma (AA) is a predominant type of AoV cancer and can be classified into intestinal, pancreaticobiliary, and mixed histologic subtypes.1-3 Although the 5-year survival rate is approximately 50% following curative-intent resection, the 2-year survival rate is only 5% to 10% in patients with relapse or metastasis.5-8 Therefore, appropriate chemotherapy is the most crucial factor for prognosis in patients with recurrence following surgery or initially palliative treatment. However, due to the rarity of AA, there is currently no standard chemotherapy in use, and it is difficult to select an appropriate chemotherapy regimen due to limited data.

Most of the research on palliative treatment of AA has been performed in concurrence with biliary tract cancer or small intestine cancer research.9-14 The ABC-02 trial was the largest clinical trial of biliary tract cancer, including AA, in which gemcitabine plus cisplatin (GP) demonstrated an increased survival benefit compared with gemcitabine monotherapy (11.7 months vs 8.7 months, p<0.001).15 The GP regimen was also effective compared to gemcitabine alone in Eastern patients with biliary tract cancer (median survival, 11.2 months vs 7.7 months).16 Gemcitabine plus oxaliplatin (GEMOX) combination therapy can also be considered as an alternative option to GP therapy, but no large-scale study has been performed so far. The GEMOX regimen has been evaluated as a control group for some combination trials or in single-arm trials.17-21 However, like the other studies mentioned above, most of the GEMOX studies included only small AAs, making it difficult to generalize the results.

Based on the ABC-02 trial, gemcitabine-platinum doublets were adopted in the international guidelines as the treatment of choice for advanced AA, as for the other primary sites of biliary tract cancer.15,22,23 However, the evidence from this trial that suggests that GP treatment for AA is effective is tenuous, with only 20 (4.9%) participants with AA included in the study. While several studies on AA have been conducted based on either gemcitabine-based or fluorouracil-based regimens, a regimen more effective than GP has yet to be established.8,15,24-26

AA shows independent histological features and clinical courses compared with pancreaticobiliary or small intestine cancer.9,27,28 When taking into consideration its complex histologic characteristics, even if the location of the AoV is near the biliary tract and small intestine, it is clear that a large-scale, independent study is required to evaluate the efficacy of specific chemotherapy regimens for AA. To date, there has been a limited number of studies regarding the effectiveness of the most common GP regimen for AA compared with other regimens. This study therefore aimed to evaluate the overall outcomes of palliative chemotherapy (PC) for AA in a large, multicenter, retrospective cohort.

1. Study design and patients

The Korean Society of Gastrointestinal Cancer Research initially established a multicenter cohort of patients with AoV tumors in 2021. This retrospective cohort consisted of patients diagnosed with AoV tumors between January 2010 and December 2020 from nine institutions in Korea. A total of 1,607 patients with pathologically confirmed AoV tumors were included in the cohort. Patients diagnosed with the following diseases were excluded from those with AA: (1) neuroendocrine tumors (n=20); (2) adenomas (n=640); and (3) cancer types other than adenocarcinoma (n=34). A total of 913 patients with AA were identified, and patients with either of the following conditions were excluded as a means of identifying those who underwent PC for AA: patients who (1) did not receive chemotherapy (n=21) and (2) did not recur after resection (n=637). Ultimately, 255 patients who received PC for AA were included in the analysis (Fig. 1).

Figure 1.Study flow.
AoV, ampulla of Vater.

This study conformed with the ethical guidelines of the Declaration of Helsinki (1975), and the institutional review boards approved the studies conducted in all participating centers. The requirement for written informed consent was waived due to the retrospective nature of the study. The approval numbers from the institutional review boards of the participating hospitals are as follows: KC21RCDI0217 for Seoul St. Mary’s Hospital, 2021-177-001 for Severance Hospital, 2020AN0078 for Korea University Anam Hospital, ISPAIK 2021-03-036-001 for Ilsan Paik Hospital, SMC 2021-3-202 for Samsung Medical Center, 2021-03-031 for Kyungpook National University Hospital, B-2104-689-104 for Seoul National University Bundang Hospital, DUIH 2021-04-012 for Dongguk University, and 2021-03-057 for Keimyung University.

2. Chemotherapy regimen

In GP chemotherapy, each cycle comprised cisplatin (25 mg/m2 of body-surface area) followed by gemcitabine (1,000 mg/m2), each administered on days 1 and 8 every 3 weeks.15 In capecitabine plus oxaliplatin (CAPOX) chemotherapy, oxaliplatin 130 mg/m2 was given on day 1 while capecitabine 750 mg/m2 was given twice a day on days 1 through 14- as a 21-day cycle.25 In Korea, the choice of regimen was left to the free decision of the clinicians, and the GP regimen has been approved for reimbursement since July 2012 and has been mainly used since then.

3. Clinical variables

We collected clinical and laboratory characteristics (age, sex, body mass index, serum carcinoembryonic antigen, carbohydrate antigen 19-9, and total bilirubin at diagnosis and follow-up period) and chemotherapy-related factors (chemotherapy indications, first-line regimen of chemotherapy, and second-line chemotherapy). Overall survival (OS) and progression-free survival (PFS) for each regimen, including GP and CAPOX, were evaluated. OS was defined as the number of days from the start date of chemotherapy until the last follow-up or death, and PFS was calculated as the number of days from the start date of chemotherapy until the confirmation of progression.

4. Tumor response

Based on the revised Response Evaluation Criteria in Solid Tumors guideline version 1.1, the overall best response to the first-line regimen of chemotherapy was divided into four categories: complete response, partial response, stable disease, and progressive disease.29 The objective response was defined as the sum of the complete and partial responses. Disease control rate was defined as the sum of the rates of complete response, partial response, and stable disease.

5. Statistical analysis

All analyses were performed using IBM SPSS statistical software version 26 (IBM Corp., Armonk, NY, USA). The chi-square test was used to compare discrete variables, and the independent t-test was used to compare continuous variables. We performed the Kaplan-Meier analysis to compare OS and PFS.

1. Clinical and chemotherapy-related features of participants

A total of 255 patients who received PC for AA were analyzed. The mean age of the participants was 64.0±10.0 years, and 57.6% (147/255) were male. The initial palliative disease and recurrence following resection as chemotherapy indications were 23.1% and 76.9%, respectively. The median time to recurrence was 11.2 months (interquartile range, 6.6 to 18.9 months) in recurrent cases. With regard to first-line chemotherapy, 75.3% (192/255) of patients received GP therapy, 15.3% (39/255) received CAPOX therapy, and 9.4% (24/255) received other therapies. There was no significant difference between the GP and CAPOX groups in terms of baseline characteristics. Second-line chemotherapy was administered to 47.8% (122/255) of patients. The most common second-line regimen was CAPOX (63/122, 51.6%), followed by 5-fluorouracil/leucovorin combined with oxaliplatin or irinotecan (12/122, 9.8%). The median follow-up period was 25.3 months (interquartile range, 16.1 to 38.1 months) (Table 1).

Table 1. Baseline Characteristics

CharacteristicTotal (n=255)GP (n=192)CAPOX (n=39)p-value*
Age, yr64.0±10.064.1±9.762.4±10.40.334
Male sex147 (57.6)113 (58.9)20 (51.3)0.383
BMI, kg/m223.6±3.323.8±3.323.3±2.80.428
CEA, ng/mL8.0±35.96.5±30.718.9±61.00.220
CA19-9, U/mL949±5,2111,023±5,920962±2,1780.949
Total bilirubin, mg/dL5.0±5.84.9±5.64.8±6.60.921
Cancer status0.526
Initial palliative
Locally advanced14 (5.5)11 (5.7)1 (2.6)
Metastatic45 (17.6)34 (17.7)10 (25.6)
Recurrent196 (76.9)147 (76.6)28 (71.8)
First-line chemotherapy
GP192 (75.3)192 (100)0-
CAPOX39 (15.3)039 (100)-
Others24 (9.4)00-
Second-line chemotherapy122 (47.8)91 (47.4)16 (41.0)0.467
Follow-up duration, mo25.3 (16.1–38.1)27.0 (17.3–39.1)18.8 (13.5–32.0)0.441

Data are presented as mean±SD, number (%), or median (interquartile range).

BMI, body mass index; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin.

*Comparison between GP and CAPOX group.



2. Survival and disease progression

The median OS of all patients was 19.8 months (95% CI, 17.258 to 22.282), and the median PFS for first-line chemotherapy was 7.6 months (95% CI, 6.370 to 8.770) (Fig. 2). No difference in OS and PFS between the GP and CAPOX groups (20.4 months vs 16.0 months, p=0.341; 8.4 months vs 5.1 months, p=0.279, respectively) was observed, despite the survival duration being longer in the GP group compared with the CAPOX group (Fig. 3).

Figure 2.Overall survival (OS) and progression-free survival (PFS) of the study group. (A) OS of the study group (median, 19.8 months; 95% confidence interval [CI], 17.258 to 22.282). (B) PFS of study group (median, 7.6 months; 95% CI, 6.370 to 8.770).

Figure 3.Overall survival (OS) and progression-free survival (PFS), GP versus CAPOX. (A) OS of study group (GP median 20.4 months, 95% CI 17.213 to 23.587; CAPOX median 16.0 months, 95% CI 11.235 to 20.705; log rank test p=0.341). (B) PFS of the study group (GP median 8.4 months, 95% CI 7.139 to 9.721; CAPOX median 5.1 months, 95% CI 2.467 to 7.793; log rank test p=0.279).
GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin; CI, confidence interval.

3. Tumor response

The best tumor response was evaluated in 180 out of the 255 patients, allowing for exclusion of those who were lost to follow-up or were impossible to evaluate (n=75). A complete response was observed in four patients (4/180, 2.2%), all of whom received GP treatment. The objective response rate was 25.6% (46/180), and the disease control rate was 72.2% (130/180). No statistically significant differences were noted in the tumor response, objective response, and disease control rate between the GP and CAPOX groups (p=0.195, p=0.287, and p=0.287, respectively) (Table 2).

Table 2. Best Response According to Response Evaluation Criteria in Solid Tumors Version 1.1

Total (n=180)GP (n=141)CAPOX (n=22) p-value
Tumor response0.195
CR4 (2.2)4 (2.8)0
PR42 (23.3)32 (22.7)8 (36.4)
SD84 (46.7)69 (48.9)6 (27.3)
PD50 (27.8)36 (25.5)8 (36.4)
Objective response46 (25.6)36 (25.5)8 (36.4)0.287
Disease control130 (72.2)105 (74.5)14 (63.6)0.287

Data are presented as number (%).

GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin; CR, complete response; PR, partial response; SD, stable disease; PD; progressive disease.



4. Comparison with previous clinical trials

Previous studies on AA included patients who were diagnosed with small bowel cancer and biliary tract cancer.24-26 A CAPOX trial was conducted for advanced small bowel cancer, whereas the ABC-02 and FUGA-BT trials were conducted for advanced and recurrent biliary tract cancer. In contrast, our study focused only on unresectable AA. The number of patients with AA were 12 (40.0%), 20 (4.9%), and 13 (3.7%) in the CAPOX trial, ABC-02 trial, and FUGA-BT trial, respectively. Our study included 255 patients who were pathologically diagnosed with AA.24-26

Each study used the following regimens: (1) the CAPOX trial evaluated the CAPOX regimen only (single arm);25 (2) the ABC-02 trial compared gemcitabine treatment and GP regimen;15 and (3) the FUGA-BT trial compared GP regimen and gemcitabine in addition to S-1 therapy.26 The current study evaluated various regimens including GP (75.3%), CAPOX (15.3%), and others (9.4%). The median OS observed in this study was similar to the CAPOX trial, which included patients with advanced small bowel cancer and AA, median OS of 16.0 and 20.4 months, respectively. In particular, the median OS of patients who underwent GP chemotherapy was the same as that of the CAPOX trial at 20.4 months. In addition, the median PFS of the GP regimen appeared low, as compared to those of previous trials, at 8.4 months in this study, 8.0 months in the ABC-02 trial, and 5.8 months in the FUGA-BT trial (Table 3).15,25,26

Table 3. Comparison between the Present Study and Previous Clinical Trial Results

Korean Society of Gastrointestinal CancerCAPOX25ABC-0215FUGA-BT26
PatientsAdvanced and recurrent AoV cancerAdvanced small bowel and AoV cancerAdvanced and recurrent biliary tract cancerAdvanced and recurrent biliary tract cancer
Total patients25530410354
No. of AoV adenocarcinoma (%)255 (100)12 (40.0)20 (4.9)13 (3.7)
Regimen for AoV adenocarcinoma, No. (%)

GP 192 (75.3)

CAPOX 39 (15.3)

CAPOX 12 (100)

Gem 11 (55.0)

GP 9 (45.0)

GS 6 (46.2)

GP 7 (53.8)

Median overall survival, mo

GP 20.4

CAPOX 16.0

CAPOX 20.4

Gem 8.1

GP 11.7

GS 15.1

GP 13.4

Median progression-free survival, mo

GP 8.4

CAPOX 5.1

CAPOX 11.3

Gem 5.0

GP 8.0

GS 6.8

GP 5.8

CAPOX, capecitabine plus oxaliplatin; AoV, ampulla of Vater; GP, gemcitabine plus cisplatin; Gem, gemcitabine; GS, gemcitabine plus S-1.


Biliary tract cancer has a high degree of heterogeneity in terms of clinical features and prognosis depending on location. Moreover, some types of advanced AA are similar to small intestine or pancreatic cancer and have very diverse clinical prognoses.14,15,30,31 Therefore, research to confirm the independent characteristics of AA is urgently required. To date, existing studies on palliative treatment for AA have not included sufficient patients to allow for evaluation of the heterogeneous nature of its clinical course and to subsequently derive meaningful treatment options.24-26 This study therefore aimed to determine independent clinical courses of PC for AA and propose reasonable treatment options based on a large patient cohort consisting entirely of AA.

AA is a disease with a recurrence rate of 40% to 50%.1,4 Even after surgery, most patients with AA experience recurrence and undergo PC.5-8 In this study, 76.9% of AA patients received PC due to recurrence. However, PC for AA resulted in longer OS and PFS compared to those of other biliary tract cancers. This suggests that PC for AA possesses distinct characteristics, different from other bile duct cancers. Further research is needed to elucidate this distinction.

Our results show that the GP regimen was most frequently used for our cohort of patients (75.3%), which indicates that most palliative treatments have potentially been administered based on the ABC-02 trial.24,28 Notably, the median OS and PFS in the present cohort were high, as compared to the FUGA-BT and ABC-02 trials, which utilized the same regimen.24,26 It is likely that this result could be attributed to the restriction of our study population to those patients with AA only. In addition, we included more patients who had recurrence or received second-line chemotherapy in our study, which ultimately may have contributed to an increased survival benefit.24,26 This result therefore indicates the potential of the GP regimen as a standard treatment option for advanced or recurrent AA.

Moreover, we found that CAPOX was the second most commonly used therapy following the GP regimen. However, we were able to demonstrate that the prognosis for the CAPOX group, including OS, treatment response, and objective response, was not significantly different from that of the GP group. These results may have differed if more patients treated with CAPOX were included, as several studies have shown differences in therapeutic response as determined by a pathological subgroup.9-14 Therefore, taking the diversity of AA into consideration, additional large-scale, comparative studies are required to provide appropriate treatment options.

Recently, it is essential to differentiate between the two primary histological subtypes, namely pancreatobiliary and intestinal in AA. The pancreatobiliary subtype is characterized by histological features that resemble pancreatic and biliary ducts. It often exhibits aggressive behavior and a poorer prognosis due to its invasive nature and a higher incidence of lymph node involvement. In contrast, intestinal subtype displays histological characteristics like the intestinal lining. It is generally associated with a more favorable prognosis and a better response to surgery and adjuvant therapies. Recognizing these histological subtypes is crucial for tailoring treatment strategies and predicting patient outcomes in the management of AA. In the updated National Comprehensive Cancer Network guidelines, pancreatic cancer regimens such as oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine-based chemotherapy are recommended for pancreatobiliary type, while CAPOX, FOLFOX (folinic acid, fluorouracil, and oxaliplatin), and FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) are recommended for intestinal type. Although not included in this study, we believe that further analysis is needed to assess the treatment prognosis based on the histological classification of AA in the future.

Recently, two studies demonstrated putative associations between gene mutations and histological subtypes, with reported increases in the incidence of KRAS, TP53, and SMAD4 mutations in the pancreaticobiliary type and APC mutations in the intestinal type.32,33 More specifically, the presence of KRAS and TP53 mutations is potentially associated with a more aggressive clinical course regardless of histology, which suggests that these mutations represent drivers of early cancer progression.34 It is therefore possible for molecular and genetic studies to provide additional information on targeted therapy and immunotherapy as alternatives to conventional chemotherapy. Despite advances in targeted therapy and immunotherapy, conventional chemotherapy remains the primary treatment for unresectable or metastatic AA. As such, the present study is of particular significance as we analyzed the largest number of AA patients who received palliative conventional chemotherapy to date.

Despite our interesting results, this study had several limitations. First, given the rarity of AA, we were unable to plan a prospective study for our research and had to instead rely on a retrospective study. Second, subtyping and genetic and molecular profiling were not performed in this study. It was challenging to confirm the heterogeneous characteristics of AA in a multicenter study as each institution utilized a different evaluation method. Third, our study included a large number of recurrent cases, which may have resulted in a better prognosis. Nevertheless, we believe that this study reflects a more realistic clinical situation as we analyzed the results of conventional PC for AA over the past decade, which for the most part has been performed without additional subtyping. Lastly, in Korea, the choice of regimen is determined by the chemotherapy reimbursement policy, and the preferred regimens are different for each institution. Therefore, it is highly likely that there was selection bias in this study.

In conclusion, while previous studies have shown mixed prognostic outcomes when considering the combination of biliary tract cancer and AA, our study demonstrates the clinical prognosis specific to AA on a large scale with systemic anticancer therapy. This result suggests that AA is a distinct type of tumor, different from other biliary tract cancers, and AA itself could be expected to have a favorable response to PC. Nevertheless, both conventional GP and CAPOX regimens proved effective in treating AA. Large-scale prospective studies are required in the future to identify more effective regimens targeting the individual characteristics of AA.

This study was conducted with financial support from the Korean Society of Gastrointestinal Cancer Research.

Study concept and design: J.K.P., H.S.L. Data acquisition: D.K.J., S.J.K., H.H.C., J.M.L., S.B.Y., J.C.L., D.W.S., J.H.H., M.K.J., Y.S.L., H.S.L., J.K.P. Data analysis and interpretation: D.K.J., S.J.K., H.H.C. Drafting of the manuscript: D.K.J., S.J.K., H.H.C. Approval of final manuscript: all authors.

The data used to support the findings of this study are included within the article.

  1. Hong SS, Han SS, Kwon W, et al. Comparison of oncologic outcomes between transduodenal ampullectomy and pancreatoduodenectomy in ampulla of Vater cancer: Korean Multicenter Study. Cancers (Basel) 2021;13:2038.
    Pubmed KoreaMed CrossRef
  2. Ahn DH, Bekaii-Saab T. Ampullary cancer: an overview. Am Soc Clin Oncol Educ Book 2014:112-115.
    Pubmed KoreaMed CrossRef
  3. Zheng-Pywell R, Reddy S. Ampullary cancer. Surg Clin North Am 2019;99:357-367.
    Pubmed CrossRef
  4. O'Connell JB, Maggard MA, Manunga J Jr, et al. Survival after resection of ampullary carcinoma: a national population-based study. Ann Surg Oncol 2008;15:1820-1827.
    Pubmed CrossRef
  5. Bouvet M, Gamagami RA, Gilpin EA, et al. Factors influencing survival after resection for periampullary neoplasms. Am J Surg 2000;180:13-17.
    Pubmed CrossRef
  6. van Geenen RC, van Gulik TM, Offerhaus GJ, et al. Survival after pancreaticoduodenectomy for periampullary adenocarcinoma: an update. Eur J Surg Oncol 2001;27:549-557.
    Pubmed CrossRef
  7. Woo SM, Ryu JK, Lee SH, et al. Recurrence and prognostic factors of ampullary carcinoma after radical resection: comparison with distal extrahepatic cholangiocarcinoma. Ann Surg Oncol 2007;14:3195-3201.
    Pubmed CrossRef
  8. Czaykowski P, Hui D. Chemotherapy in small bowel adenocarcinoma: 10-year experience of the British Columbia Cancer Agency. Clin Oncol (R Coll Radiol) 2007;19:143-149.
    Pubmed CrossRef
  9. Kohler I, Jacob D, Budzies J, et al. Phenotypic and genotypic characterization of carcinomas of the papilla of Vater has prognostic and putative therapeutic implications. Am J Clin Pathol 2011;135:202-211.
    Pubmed CrossRef
  10. Westgaard A, Tafjord S, Farstad IN, et al. Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. BMC Cancer 2008;8:170.
    Pubmed KoreaMed CrossRef
  11. Ruemmele P, Dietmaier W, Terracciano L, et al. Histopathologic features and microsatellite instability of cancers of the papilla of Vater and their precursor lesions. Am J Surg Pathol 2009;33:691-704.
    Pubmed CrossRef
  12. Fischer HP, Zhou H. Pathogenesis of carcinoma of the papilla of Vater. J Hepatobiliary Pancreat Surg 2004;11:301-309.
    Pubmed CrossRef
  13. Zhou H, Schaefer N, Wolff M, Fischer HP. Carcinoma of the ampulla of Vater: comparative histologic/immunohistochemical classification and follow-up. Am J Surg Pathol 2004;28:875-882.
    Pubmed CrossRef
  14. Roh YH, Kim YH, Lee HW, et al. The clinicopathologic and immunohistochemical characteristics of ampulla of Vater carcinoma: the intestinal type is associated with a better prognosis. Hepatogastroenterology 2007;54:1641-1644.
    Pubmed CrossRef
  15. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-1281.
    Pubmed CrossRef
  16. Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 2010;103:469-474.
    Pubmed KoreaMed CrossRef
  17. Leone F, Marino D, Cereda S, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer 2016;122:574-581.
    Pubmed CrossRef
  18. Malka D, Cervera P, Foulon S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol 2014;15:819-828.
    Pubmed KoreaMed CrossRef
  19. Lee J, Park SH, Chang HM, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2012;13:181-188.
    Pubmed CrossRef
  20. Sharma A, Mohanti B, Raina V, et al. A phase II study of gemcitabine and oxaliplatin (Oxigem) in unresectable gall bladder cancer. Cancer Chemother Pharmacol 2010;65:497-502.
    Pubmed CrossRef
  21. André T, Reyes-Vidal JM, Fartoux L, et al. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J Cancer 2008;99:862-867.
    Pubmed KoreaMed CrossRef
  22. Jung K, Park J, Jung JH, Lee JC, Kim J, Hwang JH. Real-world outcomes of gemcitabine, cisplatin, and nab-paclitaxel chemotherapy regimen for advanced biliary tract cancer: a propensity score-matched analysis. Gut Liver 2022;16:798-805.
    Pubmed KoreaMed CrossRef
  23. Kwon SC, Bang S, Park YN, et al. The Expression of programmed death-ligand 1 on immune cells is related to a better prognosis in biliary tract cancer. Gut Liver 2023;17:933-941.
    Pubmed KoreaMed CrossRef
  24. Jiang ZQ, Varadhachary G, Wang X, et al. A retrospective study of ampullary adenocarcinomas: overall survival and responsiveness to fluoropyrimidine-based chemotherapy. Ann Oncol 2013;24:2349-2353.
    Pubmed KoreaMed CrossRef
  25. Overman MJ, Varadhachary GR, Kopetz S, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 2009;27:2598-2603.
    Pubmed CrossRef
  26. Morizane C, Okusaka T, Mizusawa J, et al. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol 2019;30:1950-1958.
    Pubmed CrossRef
  27. Perkins G, Svrcek M, Bouchet-Doumenq C, et al. Can we classify ampullary tumours better? Clinical, pathological and molecular features: results of an AGEO study. Br J Cancer 2019;120:697-702.
    Pubmed KoreaMed CrossRef
  28. Kim WS, Choi DW, Choi SH, Heo JS, You DD, Lee HG. Clinical significance of pathologic subtype in curatively resected ampulla of Vater cancer. J Surg Oncol 2012;105:266-272.
    Pubmed CrossRef
  29. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
    Pubmed CrossRef
  30. Westgaard A, Pomianowska E, Clausen OP, Gladhaug IP. Intestinal-type and pancreatobiliary-type adenocarcinomas: how does ampullary carcinoma differ from other periampullary malignancies?. Ann Surg Oncol 2013;20:430-439.
    Pubmed CrossRef
  31. Hansel DE, Maitra A, Lin JW, et al. Expression of the caudal-type homeodomain transcription factors CDX 1/2 and outcome in carcinomas of the ampulla of Vater. J Clin Oncol 2005;23:1811-1818.
    Pubmed CrossRef
  32. Gingras MC, Covington KR, Chang DK, et al. Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. Cell Rep 2016;14:907-919.
    Pubmed KoreaMed CrossRef
  33. Yachida S, Wood LD, Suzuki M, et al. Genomic sequencing identifies ELF3 as a driver of ampullary carcinoma. Cancer Cell 2016;29:229-240.
    Pubmed KoreaMed CrossRef
  34. Mafficini A, Amato E, Cataldo I, et al. Ampulla of Vater carcinoma: sequencing analysis identifies TP53 status as a novel independent prognostic factor and potentially actionable ERBB, PI3K, and WNT pathways gene mutations. Ann Surg 2018;267:149-156.
    Pubmed CrossRef

Article

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Gut and Liver

Published online December 22, 2023

Copyright © Gut and Liver.

Outcomes of Palliative Chemotherapy for Ampulla of Vater Adenocarcinoma: A Multicenter Cohort Study

Dong Kee Jang1 , So Jeong Kim2,3 , Hwe Hoon Chung4 , Jae Min Lee5 , Seung Bae Yoon6 , Jong-Chan Lee7 , Dong Woo Shin8 , Jin-Hyeok Hwang7 , Min Kyu Jung9 , Yoon Suk Lee10 , Hee Seung Lee2 , Joo Kyung Park4 , Korean Society of Gastrointestinal Cancer

1Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, 2Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 3Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ewha Womans University College of Medicine, 4Division of Gastroenterology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 5Department of Internal Medicine, Korea University Anam Hospital, 6Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 7Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 8Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, 9Division of Gastroenterology, Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, and 10Division of Gastroenterology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea

Correspondence to:Joo Kyung Park
ORCID https://orcid.org/0000-0002-9652-5287
E-mail mdsophie@gmail.com

Hee Seung Lee
ORCID https://orcid.org/0000-0002-2825-3160
E-mail lhs6865@yuhs.ac

Dong Kee Jang, So Jeong Kim, and Hwe Hoon Chung contributed equally to this work as first authors.

Received: April 30, 2023; Revised: September 7, 2023; Accepted: October 11, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Palliative chemotherapy (PC) is not standardized for patients with advanced ampulla of Vater adenocarcinoma (AA). This multicenter, retrospective study evaluated first-line PC outcomes in patients with AA.
Methods: Patients diagnosed with AA between January 2010 and December 2020 who underwent PC were enrolled from 10 institutions. Overall survival (OS) and progression-free survival (PFS) according to the chemotherapy regimen were analyzed.
Results: Of 255 patients (mean age, 64.0±10.0 years; male, 57.6%), 14 (5.5%) had locally advanced AA and 241 (94.5%) had metastatic AA. Gemcitabine plus cisplatin (GP) was administered as first-line chemotherapy to 192 patients (75.3%), whereas capecitabine plus oxaliplatin (CAPOX) was administered to 39 patients (15.3%). The median OS of all patients was 19.8 months (95% confidence interval [CI], 17.3 to 22.3), and that of patients who received GP and CAPOX was 20.4 months (95% CI, 17.2 to 23.6) and 16.0 months (95% CI, 11.2 to 20.7), respectively. The median PFS of GP and CAPOX patients were 8.4 months (95% CI, 7.1 to 9.7) and 5.1 months (95% CI, 2.5 to 7.8), respectively. PC for AA demonstrated improved median outcomes in both OS and PFS compared to conventional bile duct cancers that included AA.
Conclusions: While previous studies have shown mixed prognostic outcomes when AA was analyzed together with other biliary tract cancers, our study unveils a distinct clinical prognosis specific to AA on a large scale with systemic anticancer therapy. These findings suggest that AA is a distinct type of tumor, different from other biliary tract cancers, and AA itself could be expected to have a favorable response to PC.

Keywords: Ampulla of Vater, Biliary tract neoplasms, Chemotherapy, Survival

INTRODUCTION

Cancer of the ampulla of Vater (AoV) is a rare malignancy.1-3 Unfortunately, approximately 50% of patients with AoV cancer are not diagnosed until they are in an advanced stage, and as such, only 40% of patients can be treated surgically.1,4 AoV adenocarcinoma (AA) is a predominant type of AoV cancer and can be classified into intestinal, pancreaticobiliary, and mixed histologic subtypes.1-3 Although the 5-year survival rate is approximately 50% following curative-intent resection, the 2-year survival rate is only 5% to 10% in patients with relapse or metastasis.5-8 Therefore, appropriate chemotherapy is the most crucial factor for prognosis in patients with recurrence following surgery or initially palliative treatment. However, due to the rarity of AA, there is currently no standard chemotherapy in use, and it is difficult to select an appropriate chemotherapy regimen due to limited data.

Most of the research on palliative treatment of AA has been performed in concurrence with biliary tract cancer or small intestine cancer research.9-14 The ABC-02 trial was the largest clinical trial of biliary tract cancer, including AA, in which gemcitabine plus cisplatin (GP) demonstrated an increased survival benefit compared with gemcitabine monotherapy (11.7 months vs 8.7 months, p<0.001).15 The GP regimen was also effective compared to gemcitabine alone in Eastern patients with biliary tract cancer (median survival, 11.2 months vs 7.7 months).16 Gemcitabine plus oxaliplatin (GEMOX) combination therapy can also be considered as an alternative option to GP therapy, but no large-scale study has been performed so far. The GEMOX regimen has been evaluated as a control group for some combination trials or in single-arm trials.17-21 However, like the other studies mentioned above, most of the GEMOX studies included only small AAs, making it difficult to generalize the results.

Based on the ABC-02 trial, gemcitabine-platinum doublets were adopted in the international guidelines as the treatment of choice for advanced AA, as for the other primary sites of biliary tract cancer.15,22,23 However, the evidence from this trial that suggests that GP treatment for AA is effective is tenuous, with only 20 (4.9%) participants with AA included in the study. While several studies on AA have been conducted based on either gemcitabine-based or fluorouracil-based regimens, a regimen more effective than GP has yet to be established.8,15,24-26

AA shows independent histological features and clinical courses compared with pancreaticobiliary or small intestine cancer.9,27,28 When taking into consideration its complex histologic characteristics, even if the location of the AoV is near the biliary tract and small intestine, it is clear that a large-scale, independent study is required to evaluate the efficacy of specific chemotherapy regimens for AA. To date, there has been a limited number of studies regarding the effectiveness of the most common GP regimen for AA compared with other regimens. This study therefore aimed to evaluate the overall outcomes of palliative chemotherapy (PC) for AA in a large, multicenter, retrospective cohort.

MATERIALS AND METHODS

1. Study design and patients

The Korean Society of Gastrointestinal Cancer Research initially established a multicenter cohort of patients with AoV tumors in 2021. This retrospective cohort consisted of patients diagnosed with AoV tumors between January 2010 and December 2020 from nine institutions in Korea. A total of 1,607 patients with pathologically confirmed AoV tumors were included in the cohort. Patients diagnosed with the following diseases were excluded from those with AA: (1) neuroendocrine tumors (n=20); (2) adenomas (n=640); and (3) cancer types other than adenocarcinoma (n=34). A total of 913 patients with AA were identified, and patients with either of the following conditions were excluded as a means of identifying those who underwent PC for AA: patients who (1) did not receive chemotherapy (n=21) and (2) did not recur after resection (n=637). Ultimately, 255 patients who received PC for AA were included in the analysis (Fig. 1).

Figure 1. Study flow.
AoV, ampulla of Vater.

This study conformed with the ethical guidelines of the Declaration of Helsinki (1975), and the institutional review boards approved the studies conducted in all participating centers. The requirement for written informed consent was waived due to the retrospective nature of the study. The approval numbers from the institutional review boards of the participating hospitals are as follows: KC21RCDI0217 for Seoul St. Mary’s Hospital, 2021-177-001 for Severance Hospital, 2020AN0078 for Korea University Anam Hospital, ISPAIK 2021-03-036-001 for Ilsan Paik Hospital, SMC 2021-3-202 for Samsung Medical Center, 2021-03-031 for Kyungpook National University Hospital, B-2104-689-104 for Seoul National University Bundang Hospital, DUIH 2021-04-012 for Dongguk University, and 2021-03-057 for Keimyung University.

2. Chemotherapy regimen

In GP chemotherapy, each cycle comprised cisplatin (25 mg/m2 of body-surface area) followed by gemcitabine (1,000 mg/m2), each administered on days 1 and 8 every 3 weeks.15 In capecitabine plus oxaliplatin (CAPOX) chemotherapy, oxaliplatin 130 mg/m2 was given on day 1 while capecitabine 750 mg/m2 was given twice a day on days 1 through 14- as a 21-day cycle.25 In Korea, the choice of regimen was left to the free decision of the clinicians, and the GP regimen has been approved for reimbursement since July 2012 and has been mainly used since then.

3. Clinical variables

We collected clinical and laboratory characteristics (age, sex, body mass index, serum carcinoembryonic antigen, carbohydrate antigen 19-9, and total bilirubin at diagnosis and follow-up period) and chemotherapy-related factors (chemotherapy indications, first-line regimen of chemotherapy, and second-line chemotherapy). Overall survival (OS) and progression-free survival (PFS) for each regimen, including GP and CAPOX, were evaluated. OS was defined as the number of days from the start date of chemotherapy until the last follow-up or death, and PFS was calculated as the number of days from the start date of chemotherapy until the confirmation of progression.

4. Tumor response

Based on the revised Response Evaluation Criteria in Solid Tumors guideline version 1.1, the overall best response to the first-line regimen of chemotherapy was divided into four categories: complete response, partial response, stable disease, and progressive disease.29 The objective response was defined as the sum of the complete and partial responses. Disease control rate was defined as the sum of the rates of complete response, partial response, and stable disease.

5. Statistical analysis

All analyses were performed using IBM SPSS statistical software version 26 (IBM Corp., Armonk, NY, USA). The chi-square test was used to compare discrete variables, and the independent t-test was used to compare continuous variables. We performed the Kaplan-Meier analysis to compare OS and PFS.

RESULTS

1. Clinical and chemotherapy-related features of participants

A total of 255 patients who received PC for AA were analyzed. The mean age of the participants was 64.0±10.0 years, and 57.6% (147/255) were male. The initial palliative disease and recurrence following resection as chemotherapy indications were 23.1% and 76.9%, respectively. The median time to recurrence was 11.2 months (interquartile range, 6.6 to 18.9 months) in recurrent cases. With regard to first-line chemotherapy, 75.3% (192/255) of patients received GP therapy, 15.3% (39/255) received CAPOX therapy, and 9.4% (24/255) received other therapies. There was no significant difference between the GP and CAPOX groups in terms of baseline characteristics. Second-line chemotherapy was administered to 47.8% (122/255) of patients. The most common second-line regimen was CAPOX (63/122, 51.6%), followed by 5-fluorouracil/leucovorin combined with oxaliplatin or irinotecan (12/122, 9.8%). The median follow-up period was 25.3 months (interquartile range, 16.1 to 38.1 months) (Table 1).

Table 1 . Baseline Characteristics.

CharacteristicTotal (n=255)GP (n=192)CAPOX (n=39)p-value*
Age, yr64.0±10.064.1±9.762.4±10.40.334
Male sex147 (57.6)113 (58.9)20 (51.3)0.383
BMI, kg/m223.6±3.323.8±3.323.3±2.80.428
CEA, ng/mL8.0±35.96.5±30.718.9±61.00.220
CA19-9, U/mL949±5,2111,023±5,920962±2,1780.949
Total bilirubin, mg/dL5.0±5.84.9±5.64.8±6.60.921
Cancer status0.526
Initial palliative
Locally advanced14 (5.5)11 (5.7)1 (2.6)
Metastatic45 (17.6)34 (17.7)10 (25.6)
Recurrent196 (76.9)147 (76.6)28 (71.8)
First-line chemotherapy
GP192 (75.3)192 (100)0-
CAPOX39 (15.3)039 (100)-
Others24 (9.4)00-
Second-line chemotherapy122 (47.8)91 (47.4)16 (41.0)0.467
Follow-up duration, mo25.3 (16.1–38.1)27.0 (17.3–39.1)18.8 (13.5–32.0)0.441

Data are presented as mean±SD, number (%), or median (interquartile range)..

BMI, body mass index; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin..

*Comparison between GP and CAPOX group..



2. Survival and disease progression

The median OS of all patients was 19.8 months (95% CI, 17.258 to 22.282), and the median PFS for first-line chemotherapy was 7.6 months (95% CI, 6.370 to 8.770) (Fig. 2). No difference in OS and PFS between the GP and CAPOX groups (20.4 months vs 16.0 months, p=0.341; 8.4 months vs 5.1 months, p=0.279, respectively) was observed, despite the survival duration being longer in the GP group compared with the CAPOX group (Fig. 3).

Figure 2. Overall survival (OS) and progression-free survival (PFS) of the study group. (A) OS of the study group (median, 19.8 months; 95% confidence interval [CI], 17.258 to 22.282). (B) PFS of study group (median, 7.6 months; 95% CI, 6.370 to 8.770).

Figure 3. Overall survival (OS) and progression-free survival (PFS), GP versus CAPOX. (A) OS of study group (GP median 20.4 months, 95% CI 17.213 to 23.587; CAPOX median 16.0 months, 95% CI 11.235 to 20.705; log rank test p=0.341). (B) PFS of the study group (GP median 8.4 months, 95% CI 7.139 to 9.721; CAPOX median 5.1 months, 95% CI 2.467 to 7.793; log rank test p=0.279).
GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin; CI, confidence interval.

3. Tumor response

The best tumor response was evaluated in 180 out of the 255 patients, allowing for exclusion of those who were lost to follow-up or were impossible to evaluate (n=75). A complete response was observed in four patients (4/180, 2.2%), all of whom received GP treatment. The objective response rate was 25.6% (46/180), and the disease control rate was 72.2% (130/180). No statistically significant differences were noted in the tumor response, objective response, and disease control rate between the GP and CAPOX groups (p=0.195, p=0.287, and p=0.287, respectively) (Table 2).

Table 2 . Best Response According to Response Evaluation Criteria in Solid Tumors Version 1.1.

Total (n=180)GP (n=141)CAPOX (n=22) p-value
Tumor response0.195
CR4 (2.2)4 (2.8)0
PR42 (23.3)32 (22.7)8 (36.4)
SD84 (46.7)69 (48.9)6 (27.3)
PD50 (27.8)36 (25.5)8 (36.4)
Objective response46 (25.6)36 (25.5)8 (36.4)0.287
Disease control130 (72.2)105 (74.5)14 (63.6)0.287

Data are presented as number (%)..

GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin; CR, complete response; PR, partial response; SD, stable disease; PD; progressive disease..



4. Comparison with previous clinical trials

Previous studies on AA included patients who were diagnosed with small bowel cancer and biliary tract cancer.24-26 A CAPOX trial was conducted for advanced small bowel cancer, whereas the ABC-02 and FUGA-BT trials were conducted for advanced and recurrent biliary tract cancer. In contrast, our study focused only on unresectable AA. The number of patients with AA were 12 (40.0%), 20 (4.9%), and 13 (3.7%) in the CAPOX trial, ABC-02 trial, and FUGA-BT trial, respectively. Our study included 255 patients who were pathologically diagnosed with AA.24-26

Each study used the following regimens: (1) the CAPOX trial evaluated the CAPOX regimen only (single arm);25 (2) the ABC-02 trial compared gemcitabine treatment and GP regimen;15 and (3) the FUGA-BT trial compared GP regimen and gemcitabine in addition to S-1 therapy.26 The current study evaluated various regimens including GP (75.3%), CAPOX (15.3%), and others (9.4%). The median OS observed in this study was similar to the CAPOX trial, which included patients with advanced small bowel cancer and AA, median OS of 16.0 and 20.4 months, respectively. In particular, the median OS of patients who underwent GP chemotherapy was the same as that of the CAPOX trial at 20.4 months. In addition, the median PFS of the GP regimen appeared low, as compared to those of previous trials, at 8.4 months in this study, 8.0 months in the ABC-02 trial, and 5.8 months in the FUGA-BT trial (Table 3).15,25,26

Table 3 . Comparison between the Present Study and Previous Clinical Trial Results.

Korean Society of Gastrointestinal CancerCAPOX25ABC-0215FUGA-BT26
PatientsAdvanced and recurrent AoV cancerAdvanced small bowel and AoV cancerAdvanced and recurrent biliary tract cancerAdvanced and recurrent biliary tract cancer
Total patients25530410354
No. of AoV adenocarcinoma (%)255 (100)12 (40.0)20 (4.9)13 (3.7)
Regimen for AoV adenocarcinoma, No. (%)

GP 192 (75.3).

CAPOX 39 (15.3).

CAPOX 12 (100)

Gem 11 (55.0).

GP 9 (45.0).

GS 6 (46.2).

GP 7 (53.8).

Median overall survival, mo

GP 20.4.

CAPOX 16.0.

CAPOX 20.4

Gem 8.1.

GP 11.7.

GS 15.1.

GP 13.4.

Median progression-free survival, mo

GP 8.4.

CAPOX 5.1.

CAPOX 11.3

Gem 5.0.

GP 8.0.

GS 6.8.

GP 5.8.

CAPOX, capecitabine plus oxaliplatin; AoV, ampulla of Vater; GP, gemcitabine plus cisplatin; Gem, gemcitabine; GS, gemcitabine plus S-1..


DISCUSSION

Biliary tract cancer has a high degree of heterogeneity in terms of clinical features and prognosis depending on location. Moreover, some types of advanced AA are similar to small intestine or pancreatic cancer and have very diverse clinical prognoses.14,15,30,31 Therefore, research to confirm the independent characteristics of AA is urgently required. To date, existing studies on palliative treatment for AA have not included sufficient patients to allow for evaluation of the heterogeneous nature of its clinical course and to subsequently derive meaningful treatment options.24-26 This study therefore aimed to determine independent clinical courses of PC for AA and propose reasonable treatment options based on a large patient cohort consisting entirely of AA.

AA is a disease with a recurrence rate of 40% to 50%.1,4 Even after surgery, most patients with AA experience recurrence and undergo PC.5-8 In this study, 76.9% of AA patients received PC due to recurrence. However, PC for AA resulted in longer OS and PFS compared to those of other biliary tract cancers. This suggests that PC for AA possesses distinct characteristics, different from other bile duct cancers. Further research is needed to elucidate this distinction.

Our results show that the GP regimen was most frequently used for our cohort of patients (75.3%), which indicates that most palliative treatments have potentially been administered based on the ABC-02 trial.24,28 Notably, the median OS and PFS in the present cohort were high, as compared to the FUGA-BT and ABC-02 trials, which utilized the same regimen.24,26 It is likely that this result could be attributed to the restriction of our study population to those patients with AA only. In addition, we included more patients who had recurrence or received second-line chemotherapy in our study, which ultimately may have contributed to an increased survival benefit.24,26 This result therefore indicates the potential of the GP regimen as a standard treatment option for advanced or recurrent AA.

Moreover, we found that CAPOX was the second most commonly used therapy following the GP regimen. However, we were able to demonstrate that the prognosis for the CAPOX group, including OS, treatment response, and objective response, was not significantly different from that of the GP group. These results may have differed if more patients treated with CAPOX were included, as several studies have shown differences in therapeutic response as determined by a pathological subgroup.9-14 Therefore, taking the diversity of AA into consideration, additional large-scale, comparative studies are required to provide appropriate treatment options.

Recently, it is essential to differentiate between the two primary histological subtypes, namely pancreatobiliary and intestinal in AA. The pancreatobiliary subtype is characterized by histological features that resemble pancreatic and biliary ducts. It often exhibits aggressive behavior and a poorer prognosis due to its invasive nature and a higher incidence of lymph node involvement. In contrast, intestinal subtype displays histological characteristics like the intestinal lining. It is generally associated with a more favorable prognosis and a better response to surgery and adjuvant therapies. Recognizing these histological subtypes is crucial for tailoring treatment strategies and predicting patient outcomes in the management of AA. In the updated National Comprehensive Cancer Network guidelines, pancreatic cancer regimens such as oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine-based chemotherapy are recommended for pancreatobiliary type, while CAPOX, FOLFOX (folinic acid, fluorouracil, and oxaliplatin), and FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) are recommended for intestinal type. Although not included in this study, we believe that further analysis is needed to assess the treatment prognosis based on the histological classification of AA in the future.

Recently, two studies demonstrated putative associations between gene mutations and histological subtypes, with reported increases in the incidence of KRAS, TP53, and SMAD4 mutations in the pancreaticobiliary type and APC mutations in the intestinal type.32,33 More specifically, the presence of KRAS and TP53 mutations is potentially associated with a more aggressive clinical course regardless of histology, which suggests that these mutations represent drivers of early cancer progression.34 It is therefore possible for molecular and genetic studies to provide additional information on targeted therapy and immunotherapy as alternatives to conventional chemotherapy. Despite advances in targeted therapy and immunotherapy, conventional chemotherapy remains the primary treatment for unresectable or metastatic AA. As such, the present study is of particular significance as we analyzed the largest number of AA patients who received palliative conventional chemotherapy to date.

Despite our interesting results, this study had several limitations. First, given the rarity of AA, we were unable to plan a prospective study for our research and had to instead rely on a retrospective study. Second, subtyping and genetic and molecular profiling were not performed in this study. It was challenging to confirm the heterogeneous characteristics of AA in a multicenter study as each institution utilized a different evaluation method. Third, our study included a large number of recurrent cases, which may have resulted in a better prognosis. Nevertheless, we believe that this study reflects a more realistic clinical situation as we analyzed the results of conventional PC for AA over the past decade, which for the most part has been performed without additional subtyping. Lastly, in Korea, the choice of regimen is determined by the chemotherapy reimbursement policy, and the preferred regimens are different for each institution. Therefore, it is highly likely that there was selection bias in this study.

In conclusion, while previous studies have shown mixed prognostic outcomes when considering the combination of biliary tract cancer and AA, our study demonstrates the clinical prognosis specific to AA on a large scale with systemic anticancer therapy. This result suggests that AA is a distinct type of tumor, different from other biliary tract cancers, and AA itself could be expected to have a favorable response to PC. Nevertheless, both conventional GP and CAPOX regimens proved effective in treating AA. Large-scale prospective studies are required in the future to identify more effective regimens targeting the individual characteristics of AA.

ACKNOWLEDGEMENTS

This study was conducted with financial support from the Korean Society of Gastrointestinal Cancer Research.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study concept and design: J.K.P., H.S.L. Data acquisition: D.K.J., S.J.K., H.H.C., J.M.L., S.B.Y., J.C.L., D.W.S., J.H.H., M.K.J., Y.S.L., H.S.L., J.K.P. Data analysis and interpretation: D.K.J., S.J.K., H.H.C. Drafting of the manuscript: D.K.J., S.J.K., H.H.C. Approval of final manuscript: all authors.

DATA AVAILABILITY STATEMENT

The data used to support the findings of this study are included within the article.

Fig 1.

Figure 1.Study flow.
AoV, ampulla of Vater.
Gut and Liver 2023; :

Fig 2.

Figure 2.Overall survival (OS) and progression-free survival (PFS) of the study group. (A) OS of the study group (median, 19.8 months; 95% confidence interval [CI], 17.258 to 22.282). (B) PFS of study group (median, 7.6 months; 95% CI, 6.370 to 8.770).
Gut and Liver 2023; :

Fig 3.

Figure 3.Overall survival (OS) and progression-free survival (PFS), GP versus CAPOX. (A) OS of study group (GP median 20.4 months, 95% CI 17.213 to 23.587; CAPOX median 16.0 months, 95% CI 11.235 to 20.705; log rank test p=0.341). (B) PFS of the study group (GP median 8.4 months, 95% CI 7.139 to 9.721; CAPOX median 5.1 months, 95% CI 2.467 to 7.793; log rank test p=0.279).
GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin; CI, confidence interval.
Gut and Liver 2023; :

Table 1 Baseline Characteristics

CharacteristicTotal (n=255)GP (n=192)CAPOX (n=39)p-value*
Age, yr64.0±10.064.1±9.762.4±10.40.334
Male sex147 (57.6)113 (58.9)20 (51.3)0.383
BMI, kg/m223.6±3.323.8±3.323.3±2.80.428
CEA, ng/mL8.0±35.96.5±30.718.9±61.00.220
CA19-9, U/mL949±5,2111,023±5,920962±2,1780.949
Total bilirubin, mg/dL5.0±5.84.9±5.64.8±6.60.921
Cancer status0.526
Initial palliative
Locally advanced14 (5.5)11 (5.7)1 (2.6)
Metastatic45 (17.6)34 (17.7)10 (25.6)
Recurrent196 (76.9)147 (76.6)28 (71.8)
First-line chemotherapy
GP192 (75.3)192 (100)0-
CAPOX39 (15.3)039 (100)-
Others24 (9.4)00-
Second-line chemotherapy122 (47.8)91 (47.4)16 (41.0)0.467
Follow-up duration, mo25.3 (16.1–38.1)27.0 (17.3–39.1)18.8 (13.5–32.0)0.441

Data are presented as mean±SD, number (%), or median (interquartile range).

BMI, body mass index; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin.

*Comparison between GP and CAPOX group.


Table 2 Best Response According to Response Evaluation Criteria in Solid Tumors Version 1.1

Total (n=180)GP (n=141)CAPOX (n=22) p-value
Tumor response0.195
CR4 (2.2)4 (2.8)0
PR42 (23.3)32 (22.7)8 (36.4)
SD84 (46.7)69 (48.9)6 (27.3)
PD50 (27.8)36 (25.5)8 (36.4)
Objective response46 (25.6)36 (25.5)8 (36.4)0.287
Disease control130 (72.2)105 (74.5)14 (63.6)0.287

Data are presented as number (%).

GP, gemcitabine plus cisplatin; CAPOX, capecitabine plus oxaliplatin; CR, complete response; PR, partial response; SD, stable disease; PD; progressive disease.


Table 3 Comparison between the Present Study and Previous Clinical Trial Results

Korean Society of Gastrointestinal CancerCAPOX25ABC-0215FUGA-BT26
PatientsAdvanced and recurrent AoV cancerAdvanced small bowel and AoV cancerAdvanced and recurrent biliary tract cancerAdvanced and recurrent biliary tract cancer
Total patients25530410354
No. of AoV adenocarcinoma (%)255 (100)12 (40.0)20 (4.9)13 (3.7)
Regimen for AoV adenocarcinoma, No. (%)

GP 192 (75.3)

CAPOX 39 (15.3)

CAPOX 12 (100)

Gem 11 (55.0)

GP 9 (45.0)

GS 6 (46.2)

GP 7 (53.8)

Median overall survival, mo

GP 20.4

CAPOX 16.0

CAPOX 20.4

Gem 8.1

GP 11.7

GS 15.1

GP 13.4

Median progression-free survival, mo

GP 8.4

CAPOX 5.1

CAPOX 11.3

Gem 5.0

GP 8.0

GS 6.8

GP 5.8

CAPOX, capecitabine plus oxaliplatin; AoV, ampulla of Vater; GP, gemcitabine plus cisplatin; Gem, gemcitabine; GS, gemcitabine plus S-1.


References

  1. Hong SS, Han SS, Kwon W, et al. Comparison of oncologic outcomes between transduodenal ampullectomy and pancreatoduodenectomy in ampulla of Vater cancer: Korean Multicenter Study. Cancers (Basel) 2021;13:2038.
    Pubmed KoreaMed CrossRef
  2. Ahn DH, Bekaii-Saab T. Ampullary cancer: an overview. Am Soc Clin Oncol Educ Book 2014:112-115.
    Pubmed KoreaMed CrossRef
  3. Zheng-Pywell R, Reddy S. Ampullary cancer. Surg Clin North Am 2019;99:357-367.
    Pubmed CrossRef
  4. O'Connell JB, Maggard MA, Manunga J Jr, et al. Survival after resection of ampullary carcinoma: a national population-based study. Ann Surg Oncol 2008;15:1820-1827.
    Pubmed CrossRef
  5. Bouvet M, Gamagami RA, Gilpin EA, et al. Factors influencing survival after resection for periampullary neoplasms. Am J Surg 2000;180:13-17.
    Pubmed CrossRef
  6. van Geenen RC, van Gulik TM, Offerhaus GJ, et al. Survival after pancreaticoduodenectomy for periampullary adenocarcinoma: an update. Eur J Surg Oncol 2001;27:549-557.
    Pubmed CrossRef
  7. Woo SM, Ryu JK, Lee SH, et al. Recurrence and prognostic factors of ampullary carcinoma after radical resection: comparison with distal extrahepatic cholangiocarcinoma. Ann Surg Oncol 2007;14:3195-3201.
    Pubmed CrossRef
  8. Czaykowski P, Hui D. Chemotherapy in small bowel adenocarcinoma: 10-year experience of the British Columbia Cancer Agency. Clin Oncol (R Coll Radiol) 2007;19:143-149.
    Pubmed CrossRef
  9. Kohler I, Jacob D, Budzies J, et al. Phenotypic and genotypic characterization of carcinomas of the papilla of Vater has prognostic and putative therapeutic implications. Am J Clin Pathol 2011;135:202-211.
    Pubmed CrossRef
  10. Westgaard A, Tafjord S, Farstad IN, et al. Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. BMC Cancer 2008;8:170.
    Pubmed KoreaMed CrossRef
  11. Ruemmele P, Dietmaier W, Terracciano L, et al. Histopathologic features and microsatellite instability of cancers of the papilla of Vater and their precursor lesions. Am J Surg Pathol 2009;33:691-704.
    Pubmed CrossRef
  12. Fischer HP, Zhou H. Pathogenesis of carcinoma of the papilla of Vater. J Hepatobiliary Pancreat Surg 2004;11:301-309.
    Pubmed CrossRef
  13. Zhou H, Schaefer N, Wolff M, Fischer HP. Carcinoma of the ampulla of Vater: comparative histologic/immunohistochemical classification and follow-up. Am J Surg Pathol 2004;28:875-882.
    Pubmed CrossRef
  14. Roh YH, Kim YH, Lee HW, et al. The clinicopathologic and immunohistochemical characteristics of ampulla of Vater carcinoma: the intestinal type is associated with a better prognosis. Hepatogastroenterology 2007;54:1641-1644.
    Pubmed CrossRef
  15. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-1281.
    Pubmed CrossRef
  16. Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 2010;103:469-474.
    Pubmed KoreaMed CrossRef
  17. Leone F, Marino D, Cereda S, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer 2016;122:574-581.
    Pubmed CrossRef
  18. Malka D, Cervera P, Foulon S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol 2014;15:819-828.
    Pubmed KoreaMed CrossRef
  19. Lee J, Park SH, Chang HM, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2012;13:181-188.
    Pubmed CrossRef
  20. Sharma A, Mohanti B, Raina V, et al. A phase II study of gemcitabine and oxaliplatin (Oxigem) in unresectable gall bladder cancer. Cancer Chemother Pharmacol 2010;65:497-502.
    Pubmed CrossRef
  21. André T, Reyes-Vidal JM, Fartoux L, et al. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J Cancer 2008;99:862-867.
    Pubmed KoreaMed CrossRef
  22. Jung K, Park J, Jung JH, Lee JC, Kim J, Hwang JH. Real-world outcomes of gemcitabine, cisplatin, and nab-paclitaxel chemotherapy regimen for advanced biliary tract cancer: a propensity score-matched analysis. Gut Liver 2022;16:798-805.
    Pubmed KoreaMed CrossRef
  23. Kwon SC, Bang S, Park YN, et al. The Expression of programmed death-ligand 1 on immune cells is related to a better prognosis in biliary tract cancer. Gut Liver 2023;17:933-941.
    Pubmed KoreaMed CrossRef
  24. Jiang ZQ, Varadhachary G, Wang X, et al. A retrospective study of ampullary adenocarcinomas: overall survival and responsiveness to fluoropyrimidine-based chemotherapy. Ann Oncol 2013;24:2349-2353.
    Pubmed KoreaMed CrossRef
  25. Overman MJ, Varadhachary GR, Kopetz S, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 2009;27:2598-2603.
    Pubmed CrossRef
  26. Morizane C, Okusaka T, Mizusawa J, et al. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol 2019;30:1950-1958.
    Pubmed CrossRef
  27. Perkins G, Svrcek M, Bouchet-Doumenq C, et al. Can we classify ampullary tumours better? Clinical, pathological and molecular features: results of an AGEO study. Br J Cancer 2019;120:697-702.
    Pubmed KoreaMed CrossRef
  28. Kim WS, Choi DW, Choi SH, Heo JS, You DD, Lee HG. Clinical significance of pathologic subtype in curatively resected ampulla of Vater cancer. J Surg Oncol 2012;105:266-272.
    Pubmed CrossRef
  29. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
    Pubmed CrossRef
  30. Westgaard A, Pomianowska E, Clausen OP, Gladhaug IP. Intestinal-type and pancreatobiliary-type adenocarcinomas: how does ampullary carcinoma differ from other periampullary malignancies?. Ann Surg Oncol 2013;20:430-439.
    Pubmed CrossRef
  31. Hansel DE, Maitra A, Lin JW, et al. Expression of the caudal-type homeodomain transcription factors CDX 1/2 and outcome in carcinomas of the ampulla of Vater. J Clin Oncol 2005;23:1811-1818.
    Pubmed CrossRef
  32. Gingras MC, Covington KR, Chang DK, et al. Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. Cell Rep 2016;14:907-919.
    Pubmed KoreaMed CrossRef
  33. Yachida S, Wood LD, Suzuki M, et al. Genomic sequencing identifies ELF3 as a driver of ampullary carcinoma. Cancer Cell 2016;29:229-240.
    Pubmed KoreaMed CrossRef
  34. Mafficini A, Amato E, Cataldo I, et al. Ampulla of Vater carcinoma: sequencing analysis identifies TP53 status as a novel independent prognostic factor and potentially actionable ERBB, PI3K, and WNT pathways gene mutations. Ann Surg 2018;267:149-156.
    Pubmed CrossRef
Gut and Liver

Vol.18 No.1
January, 2024

pISSN 1976-2283
eISSN 2005-1212

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