Adjuvant therapy in biliary tract cancers: oral fluoropyrimidine as a beginning

Biliary tract cancer is a group of malignant tumours, mostly adenocarcinoma, arising from different sites of the biliary tract with diverse aetiology, molecular profiling, TNM classification, and surgical procedures and outcomes of resectable diseases. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (264) Google Scholar Radical surgical resection remains the only curative treatment, but postoperative relapse is common. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (264) Google Scholar Developing effective adjuvant therapy is mandatory. However, two modern observation-controlled phase 3 trials, the BCAT trial 2 Ebata T Hirano S Konishi M et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018; 105: 192-202 Crossref PubMed Scopus (224) Google Scholar and the PRODIGE 12-ACCORD 18 trial, 3 Edeline J Benabdelghani M Bertaut A et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019; 37: 658-667 Crossref PubMed Scopus (278) Google Scholar did not show the benefit of adjuvant gemcitabine-based chemotherapy in resected biliary tract cancers. BILCAP 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Scopus (615) Google Scholar was the first phase 3 study to support the role of adjuvant chemotherapy, with oral capecitabine, for resected biliary tract cancers. 5 Shroff RT Kennedy EB Bachini M et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019; 37: 1015-1027 Crossref PubMed Scopus (244) Google Scholar , 6 Yoo C Jeong H Kim KP et al. Adjuvant gemcitabine plus cisplatin (GemCis) versus capecitabine (CAP) in patients (pts) with resected lymph node (LN)-positive extrahepatic cholangiocarcinoma (CCA): a multicenter, open-label, randomized, phase 2 study (STAMP). Proc Am Soc Clin Oncol. 2022; 404019 Google Scholar , 7 Stein A Arnold D Bridgewater J et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015; 15: 564 Crossref PubMed Scopus (146) Google Scholar The recommendation mainly relied on a significant improvement in overall survival by the prespecified sensitivity analysis (hazard ratio [HR]=0·71, 95% CI 0·55–0·92) but not on overall survival (ie, the primary endpoint; HR=0·81, 95% CI 0·63–1·04) in the primary, intention-to-treat analysis, 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Scopus (615) Google Scholar and is thus debatable. The adjusted HR for overall survival increased to 0·84 (95% Cl 0·67–1·06) and the HR for recurrence-free survival was 0·81 (95% Cl 0·65–1·01) in the extension report, 8 Bridgewater J Fletcher P Palmer DH et al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. J Clin Oncol. 2022; 40: 2048-2057 Crossref PubMed Scopus (31) Google Scholar which further weakened the recommendation. 9 Edeline J Malka D Capecitabine: still a standard option in the adjuvant setting of biliary tract cancer?. J Clin Oncol. 2022; 40: 3667-3668 Crossref PubMed Scopus (2) Google Scholar Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trialAlthough long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. Full-Text PDF