National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

Table 1 Level of evidence based on the Oxford Centre for Evidence-based Medicine (adapted from the Oxford 2011 Levels of Evidence)

Level	Criteria	Simple model for high, intermediate, and low evidence
1	SR (with homogeneity) of RCT	Further research is unlikely to change our confidence in the estimate of benefit and risk
2	RCT or observational studies with dramatic effects; SR of lower quality studies (i.e. non-randomised, retrospective)
3	Non-randomised controlled cohort/follow-up study/control arm of randomised trial (SR is generally better than an individual study)	Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate
4	Case-series, case-control, or historically controlled studies (SR is generally better than an individual study)
5	Expert opinion (mechanism-based reasoning)	Any estimate of effect is uncertain

RCT: Randomised controlled trials; SR: Systematic reviews.

Table 2 Grades of recommendation

Grade	Wording	Criteria
Strong	Shall, should, is recommended. Shall not, should not, is not recommended	Evidence, consistency of studies, risk-benefit ratio, patient preferences, ethical obligations, feasibility
Weak or open	Can, may, is suggested. May not, is not suggested

Table 3 Risk factors for hilar cholangiocarcinoma

Established	Less established	Potential (inconclusive data)
PSC	IBD likely via PSC	Obesity
Choledochal cysts	Cirrhosis	Tobacco smoking
Parasitic infections	Hepatitis B and C viruses	Genetic polymorphisms
Hepatolithiasis	Diabetes
Choledocholithiasis	Heavy alcohol use
Toxins (Thorotrast contrast agent)	IgG4 related cholangitis
	Abnormal junction between the common bile duct and pancreatic duct
	Helicobacter bilis
	Chronic typhoid infection

IBD: Inflammatory bowel disease; PSC: Primary sclerosing cholangitis.

Table 4 Clinical trials of adjuvant treatment in hilar cholangiocarcinoma

Study	Design	Sample size	Treatment	Control	Key findings
JCOG1202, ASCOT	Phase 3	Total: 440; CCA: 180	S-11	Observation	3-yr OS: 77.1% vs 67.6% (95%CI: 61.0%-73.3%); 3-yr RFS: 62.4% vs 50.9% (95%CI: 44.1%-57.2%)
BILCAP	Phase 3	Total: 447; CCA: 284	Capecitabine, duration: 6 months	Observation	OS (month): 51.1 vs 36.4 (95%CI: 34.6%-59.1%); RFS (month): 24.4 vs 17.5 (95%CI: 18.6%-35.9%)
SWOG S0809	Phase 2	Total: 79; CCA: 53	gemcitabine and capecitabine followed by CRRT	None	Median OS: 35 months (R0, 34 months, R1, 35 months)

¹S-1 is available only in Japan.

95%CI: 95% Confidence interval; CCA: Cholangiocarcinoma; CRRT: Concomitant chemoradiation therapy; OS: Overall survival; RFS: Recurrence-free survival.