Smoking, alcohol consumption, and the risk of extrahepatic cholangiocarcinoma: A meta-analysis

Table 1 Characteristics of the 12 studies that reported an association between smoking or alcohol consumption and the risk of extrahepatic cholangiocarcinoma

Author and year	Country	Design	Source	Number of cases	Number of controls	Risk factor assessment	ECC ascertainment	Smoking RR (95% CI)	Alcohol RR (95% CI)	Adjustments
Ghadirian et al[18] 1993	Canada	Case-control	Population	24	239	Questionnaire	NA	2.820 (1.010-7.860)	-	Age, sex, other smoking habits, alcohol consumption, schooling, respondent status
Chow et al[19] 1994	United States	Case-control	Population	64	255	Questionnaire	Pathological	1.630 (0.900-2.970)1	0.600 (0.290-1.220)1	Age, ethnic origin, smoking status (adjusted for alcohol consumption)
Khan et al[20] 1999	United States	Case-control	Hospital	31	138	Medical records	Pathological	0.630 (0.210-1.880)	-	Age, female gender, ethnicity, cholelithiasis, socioeconomic status
Zhang et al[21] 2004	China	Case-control	Population	99	373	Questionnaire	Cancer registry	1.490 (0.870-2.560)2	1.290 (0.780-2.170)2	Age, total energy, cholelithiasis, hypertension, history of salty food intake, smoking status (adjusted for alcohol consumption)
Welzel et al[11] 2007	United States	Case-control	Population	549	102782	Medical records	Cancer registry	1.700 (1.000-3.000)	-	Age, sex, race, geographic location, state buy-in status
Shaib et al[10] 2007	United States	Case-control	Hospital	163	236	Medical records	Pathological + imaging	1.300 (0.800-1.900)3	1.290 (0.190-8.910)1	Race, age, gender, HBV, HCV markers (adjusted for alcohol consumption)
El-Serag et al[22] 2009	United States	Cohort	-	-	-	Registry	Cancer registry	-	1.060 (0.600-1.870)	Age, sex, baseline visit date, type of visit, a preceding visit
Tao et al[23] 2010	China	Case-control	Hospital	129	380	Medical records	Pathological + imaging	0.900 (0.500-1.300)3	1.200 (0.800-1.900)3	-
Cai et al[24] 20114	China	Case-control	Hospital	313	608	Medical records	Pathological	0.900 (0.640-1.248)3	-	-
Onal et al[25] 2012	Turkey	Case-control	Hospital	89	48	Questionnaire	Pathological + imaging	1.900 (0.900-4.200)3	4.010 (0.480-33.62)3	-
Brandi et al[26] 2013	Italy	Case-control	Population	59	212	Questionnaire	Pathological	0.780 (0.400-1.500)	-	Age, sex, region of residence
Zhou et al[27] 2013	China	Case-control	Hospital	239	478	Medical records	Pathological + imaging	1.301 (0.863-1.962)	1.053 (0.670-1.655)	Age, sex, cirrhosis, cholelithiasis, cholecystectomy, DM, family history of other cancer

¹The summary RRs and 95%CI were derived by pooling the relative risks for each sex;

²Only males were included in the summary relative risks because of the rarity of smoking in females;

³Univariate OR was calculated because adjusted ORs were not available;

⁴Only hilar cholangiocarcinomas were included; ECC: Extrahepatic cholangiocarcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; DM: Diabetes mellitus; NA: Not available.

Table 2 Quality of the studies used in this analysis

Author and year	Quality indicators of Newcastle-Ottawa quality assessment scale									Score
	Selection				Comparability		Exposure/outcome
	Ia	Ib	Ic	Id	IIa	IIb	IIIa	IIIb	IIIc
Ghadirian et al[18] 1993	No	Yes	Yes	Yes	Yes	Yes	Yes	No	No	6
Chow et al[19] 1994	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	No	7
Khan et al[20] 1999	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	No	7
Zhang et al[21] 2004	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	No	7
Welzel et al[11] 2007	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	7
Shaib et al[10] 2007	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	7
El-Serag et al[22] 2009	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	8
Tao et al[23] 2010	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	No	7
Cai et al[24] 2011	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	No	7
Onal et al[25] 2012	Yes	Yes	No	Yes	Yes	No	Yes	Yes	No	7
Brandi et al[26] 2013	Yes	Yes	Yes	Yes	Yes	Yes	No	No	No	6
Zhou et al[27] 2013	Yes	Yes	No	Yes	Yes	No	Yes	Yes	No	7

For case-control studies; Ia: Indicates cases with independent validation; Ib: Indicates consecutive or representative cases; Ic: Indicates community controls; Id: Indicates controls with no history of ECC; IIa: Indicates that study controls were comparable for age and sex; IIb: Indicates that study controls were comparable on all additional factor(s) reported; IIIa: Indicates that the same method of ascertainment was used for cases and controls; IIIb: Indicates that assessment of exposure was from a secure record; IIIc: Indicates that the non-response rate was similar in both groups. For cohort studies; Ia: indicates that the exposed cohort was representative of the population; Ib: Indicates that the non-exposed cohort was drawn from the same population; Ic: Indicates that the exposure ascertainment was from secure records or a structured interview; Id: Indicates that ECC was not present at start of study; IIa: Indicates that the cohorts were comparable for age and sex; IIb: Indicates that the cohorts were comparable on all additional factor(s) reported; IIIa: Indicates that ECC was assessed from a secure record; IIIb: Indicates that follow-up was long enough for ECC to occur; IIIc: Indicates that follow-up was complete. ECC: Extrahepatic cholangiocarcinoma.

Table 3 Subgroup analyses of the association between smoking and extrahepatic cholangiocarcinoma and alcohol consumption and extrahepatic cholangiocarcinoma

	No. of studies	RR (95%CI)	Tests for heterogeneity
			Q	P	I2
Smoking
Geographical region
Non-Asia	7	1.39 (1.03-1.87)	8.280	0.218	27.5%
Asia	4	1.08 (0.85-1.38)	3.850	0.278	22.1%
Study design
Population-based	5	1.47 (1.06-2.05)	5.470	0.243	26.8%
Hospital-based	6	1.10 (0.88-1.37)	6.190	0.288	19.2%
Adjustment for cholelithiasis	3	1.28 (0.94-1.76)	1.917	0.383	0.0%
Alcohol drinking
Geographical region
Non-Asia	4	0.94 (0.56-1.56)	3.560	0.313	15.7%
Asia	3	1.17 (0.90-1.53)	0.360	0.835	0.0%
Study design
Population-based	2	0.92 (0.44-1.94)	2.890	0.089	65.4%
Hospital-based	4	1.16 (0.86-1.58)	1.520	0.678	0.0%
Case-control	6	1.10 (0.86-1.41)	4.750	0.447	0.0%
Cohort	1	1.06 (0.60-1.87)	-	-	-