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Review
. 2025 May 2:220:115342.
doi: 10.1016/j.ejca.2025.115342. Epub 2025 Mar 7.

Adjuvant chemotherapy compared to observation in resected biliary tract cancers: Survival meta-analysis of phase-III randomized controlled trials

Erman Akkus  1 , Angela Lamarca  2
Affiliations
Review

Adjuvant chemotherapy compared to observation in resected biliary tract cancers: Survival meta-analysis of phase-III randomized controlled trials

Erman Akkus et al. Eur J Cancer. .

Abstract

Background: A limited number of randomized controlled trials (RCTs) investigated adjuvant chemotherapy in biliary tract cancers (BTCs). Recurrences and deaths are common in the first 2 years and survival remains poor despite adjuvant treatment.

Methods: Phase-III RCTs were included comparing adjuvant chemotherapy and observation in resected BTCs. The primary endpoints were recurrence-free (RFS) and overall survival (OS). Proportional hazard results were used for trial-based analyses. Patient data was curated from published Kaplan-Meier curves to analyze short-term (2-year) hazards. The Parmar and generic inverse variance methods were used.

Results: 1308 patients in 4 trials (BILCAP, ASCOT, BCAT, PRODIGE-12) were included. Capecitabine (BILCAP) and S-1 (ASCOT) were grouped as 5-FU-based, gemcitabine (BCAT) and gemcitabine-oxaliplatin (PRODIGE-12) were grouped as gemcitabine-based chemotherapy. Adjuvant 5FU-based chemotherapy improved RFS [HR: 0.80 (95 % CI:0.68-0.95), p = 0.012] and OS [HR: 0.78 (95 % CI:0.65-0.94), p = 0.009]. However, gemcitabine-based chemotherapy did not provide benefit in RFS [HR: 0.90 (95 % CI:0.70-1.15), p = 0.428] and OS [HR: 1.03 (95 % CI:0.78-1.36), p = 0.794]. The benefit of 5-FU-based chemotherapy was more apparent in the short-term (2-year hazards) (RFS: [HR: 0.67 (95 %CI:57-0.79), p < 0.001] and OS: [HR: 0.61 (95 % CI:59-0.64), p < 0.001]). However, gemcitabine-based chemotherapy did not provide RFS benefit in the short term either [HR: 0.80 (95 % CI:0.64-0.1.01), p = 0.067] and seemed to be even detrimental for OS [HR: 1.22 (95 % CI:1.14-1.31), p < 0.001] in the first 2 years.

Conclusion: This study confirms using 5FU-based monotherapy in the adjuvant treatment of resected BTCs. The more prominent benefit in the first 2 years emphasizes that more effective adjuvant treatments with sustained long-term benefits are needed. Two-year proportional hazards OS and RFS are proposed here as an additional secondary end-point to consider in future clinical trials. in this setting. Registration ID (PROSPERO): CRD42024614444.

Keywords: Adjuvant; Biliary tract cancers; Capecitabine; Chemotherapy; Cholangiocarcinoma; Survival.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Erman Akkus declares no conflict of interest. Dr. Angela Lamarca declares Travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, Delcath Advanz Pharma and Roche; Speaker honoraria from Merck, Pfizer, Ipsen, Incyte, AAA/Novartis, QED, Servier, Astra Zeneca, EISAI, Roche, Advanz Pharma and MSD; Advisory and consultancy honoraria from EISAI, Nutricia, Ipsen, QED, Roche, Servier, Boston Scientific, Albireo Pharma, AstraZeneca, Boehringer Ingelheim, GENFIT, TransThera Biosciences, Taiho and MSD; Principal Investigator-associated Institutional Funding form QED, Merck, Boehringer Ingelheim, Servier, Astra Zeneca, GenFit, Panbela Therapeutics, Novocure GmbH, Camurus AB, Albireo Pharma, Taiho, TransThera, Jazz Therapeutics and Roche; Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen.

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