Current insights and future perspectives of treatment strategies for biliary tract cancer

Table 1 Cancer types and candidate risk factors

Cancer type	Candidate risk factors	Ref.
Intrahepatic cholangiocarcinoma	Liver fluke infection (Opisthorchis, Clonorchis); chronic liver disease (HBV, HCV, cirrhosis); PSC; hepatolithiasis; exposure to thorotrast or chemicals	[4,5]
Gallbladder cancer	Gallstones; large gallbladder polyps (> 10 mm); porcelain gallbladder; PBM; chronic Salmonella infection	[4,6-9,11]
Extrahepatic cholangiocarcinoma	PSC; PBM; liver fluke infection; chronic biliary inflammation or strictures	[4,5,10,11]
Ampullary cancer	FAP; Lynch syndrome; PBM	[4,11]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; PSC: Primary sclerosing cholangitis; PBM: Pancreaticobiliary maljunction; FAP: Familial adenomatous polyposis.

Table 2 Adjuvant chemotherapy trials for biliary tract cancer

Trial	Regimen	Country/no. of sites	Sample size	Primary endpoint	Enrollment period	Results	Ref.
BILCAP	Capecitabine	United Kingdom/44	447	OS	2006-2014	No OS difference in ITT (HR = 0.81, P = 0.097); sensitivity and PPS analysis suggested that capecitabine can improve OS (HR = 0.71, P = 0.01)	[35]
BCAT	GEM	Japan/33	225	OS	2007-2011	No OS or RFS difference (HR = 1.01, P = 0.964)	[32]
PRODIGE 12-ACCORD 18	GEMOX	France/33	196	RFS	2009-2014	No RFS benefit (HR = 0.88, P = 0.48)	[38]
JCOG1202 (ASCOT)	S-1	Japan/38	440	OS	2013-2018	OS benefit (HR = 0.69, P = 0.008); RFS not significant	[37]
ACTICCA-1	GEM + CDDP vs capecitabine	Germany, United Kingdom, Netherlands, Austria, Denmark/90+	594	DFS	2014-2022	Follow-up ongoing1	[39]

¹The original trial was designed to verify the efficacy of the initial surgery alone. Following the results of the BILCAP trial, the trial was modified to verify the superiority of gemcitabine + cisplatin therapy over capecitabine therapy (ACTICCA-1 Protocol V7.0, University of Birmingham, 2022).

GEM: Gemcitabine; GEMOX: Gemcitabine + oxaliplatin; CDDP: Cisplatin; OS: Overall survival; RFS: Recurrence-free survival; DFS: Disease-free survival; HR: Hazard ratio; ITT: Intention-to-treat; PPS: Per protocol set.

Table 3 Phase III trials in advanced biliary tract cancer

Trial	Sample size	Primary endpoint	Regimen and median OS	Enrollment period	Results	Ref.
ABC-02	410	OS	GC: 11.7 months; GEM: 8.1 months	2005-2008	Significant OS benefit with GC (HR = 0.64, P < 0.001)	[30]
JCOG1113	354	OS	GS: 15.1 months; GC: 13.4 months	2013-2017	GS noninferior to GC (HR = 0.945, P = 0.046)	[40]
KHBO1401	246	OS	GCS: 13.5 months; GC: 12.6 months	2013-2017	OS benefit with GCS (HR = 0.79, P = 0.046)	[41]
TOPAZ-1	685	OS	D + GC: 12.8 months; GC: 11.5 months	2019-2021	OS benefit with D + GC (HR = 0.80, P = 0.021)	[44]
KEYNOTE-966	1069	OS	P + GC: 12.7 months; GC: 10.9 months	2019-2022	OS benefit with P + GC (HR = 0.83, P = 0.0034)	[46]

OS: Overall survival; GC: Gemcitabine + cisplatin; GEM: Gemcitabine; GS: Gemcitabine + S1; GCS: Gemcitabine + cisplatin + S1; D: Durvalumab; P: Pembrolizumab; HR: Hazard ratio.

Table 4 Fibroblast growth factor receptor inhibitors in cholangiocarcinoma

Drug name	Target FGFR	Clinical status (for CCA)	Type
Pemigatinib	FGFR1-3	Approved (United States/European Union/Japan)	Reversible
Infigratinib	FGFR1-3	Withdrawn (formerly approved in United States)	Reversible
Zoligratinib (Debio 1347)	FGFR1-3	Phase 2 ongoing	Reversible
Fexagratinib (AZD4547)	FGFR1-3	Phase 1-2 completed	Reversible
Erdafitinib	FGFR1-4	Approved (bladder CA); exploratory in CCA	Reversible
Derazantinib	FGFR1-3	Phase 2 (FIDES-01)	Reversible
Tasurgratinib (E7090)	FGFR1-3	Approved (Japan); phase 2 completed	Reversible
Futibatinib	FGFR1-4	Approved (United States/Japan)	Irreversible
Lirafugratinib (RLY-4008)	FGFR2 selective	Phase 1/2 with high ORR	Irreversible
PRN1371	FGFR1-4	Early phase trials	Irreversible
H3B-6527	FGFR4 selective	FGFR4 focus (HCC)	Irreversible
Ponatinib	Multitarget (BCR-ABL, FGFR)	Not specific for CCA	Multitarget
Lucitanib	Multitarget (VEGFR, FGFR)	Exploratory	Multitarget
Nintedanib	Multitarget (VEGFR, FGFR, PDGFR)	Exploratory	Multitarget

FGFR: Fibroblast growth factor receptor; VEGFR: Vascular endothelial growth factor receptor; BCR-ABL: Breakpoint cluster region-Abelson; PDGFR: Platelet-derived growth factor receptor; CA: Cancer; CCA: Cholangiocarcinoma; ORR: Objective response rate; HCC: Hepatocellular carcinoma.