Impact of biliary stent-related events in patients diagnosed with advanced pancreatobiliary tumours receiving palliative chemotherapy

Table 1 Demographic characteristics of patients included in the study

Variables		All patients (n = 96)	SRE group (n = 41; 43%)	no-SRE group (n = 55; 57%)	P-value for distribution within baseline parameter (χ2 test), SRE vs no-SRE groups
Gender	Female	42 (44)	20 (49)	22 (40)	0.391
	Male	54 (56)	21 (51)	33 (60)
Age1	Median (range)	66.6 (26-83.8)	64.9 (26-84)	67.6 (42.4-83.2)	0.88332
Primary tumour site	Ampulla	3 (3)	1 (2)	2 (4)	0.3803
	Bile duct (cholangiocarcinoma)	17 (18)	10 (24)	7 (13)
	Intrahepatic	5 (31)	3 (33)	2 (29)	1.0004
	Extrahepatic	11 (69)	6 (67)	5 (71)
	Gallbladder	1 (1)	0 (0)	1 (2)
	Pancreas	75 (78)	30 (73)	45 (82)
	Head	66 (89)	26 (90)	40 (89)	1.0005
	Body	8 (11)	3 (10)	5 (11)
Stage	Locally advanced	58 (60)	22 (54)	36 (65)	0.294
	Metastatic	38 (40)	19 (46)	19 (35)
ECOG-PS	0	17 (18)	9 (22)	8 (15)	0.547
	1	51 (53)	22 (54)	29 (53)
	≥ 2	28 (29)	10 (24)	18 (33)
Diabetic	No	68 (71)	29 (71)	39 (71)	1.000
	Yes	28 (29)	12 (29)	16 (29)
Comorbidities	None	31 (32)	14 (34)	17 (31)	0.428
	Mild	41 (43)	18 (44)	23 (42)
	Moderate	20 (21)	9 (22)	11 (20)
	Severe	4 (4)	0 (0)	4 (7)
Line of palliative chemotherapy	First	96 (100)	41 (100)	55 (100)	1.000
Type of chemotherapy	FOLFIRINOX	11 (11)	4 (10)	7 (13)	0.605
	Cisplatin Gemcitabine	13 (14)	8 (20)	5 (9)
	Gemcitabine Nab-paclitaxel	7 (7)	2 (5)	5 (9)
	Gemcitabine +/- TH302	2 (2)	0 (0)	2 (4)
	Gemcitabine Capecitabine	25 (26)	12 (29)	13 (24)
	Gemcitabine single agent	37 (39)	15 (37)	22 (40)
	FOLFOX	1 (1)	0 (0)	1 (2)
Time from first stent to starting chemotherapy1	Median (range)	1.8 (0.1-12.6)	1.6 (0.6-5.8)	1.9 (0.1-12.6)	0.18242
Time of chemotherapy duration1	Median (range)	3.2 (0.1-7.6)	3.8 (0.1-7.2)	3.1 (0.1-7.6)	0.45202

No differences were identified between SRE group and the no-SRE group.

¹Variables do not meet a normal distribution (as per Shapiro-Wilks test);

²Mann-Whitney P-value has been provided for variables not meeting normal distribution criteria;

³the P for χ² test for comparison of distribution of primary tumour [ampulla vs bile duct (cholangiocarcinoma) vs gallbladder vs pancreas] between SRE group and no-SRE group;

⁴the P for χ² test for comparison of distribution of primary tumour [type of bile duct tumour (cholangiocarcinoma): intrahepatic vs extrahepatic] between SRE group and no-SRE group;

⁵The P for χ² test for comparison of distribution of primary tumour (site of pancreatic cancer: head vs body) between SRE group and no-SRE group. SRE: Stent-related event; ECOG-PS: ECOG performance status; FOLFIRINOX: 5-fluorouracil, oxaliplatin and irinoetecan combination; FOLFOX: 5-fluorouracil and oxaliplatin combination.

Table 2 Characteristics of the baseline biliary stenting and stent-related event

Variables		All patients (n = 96)	SRE group (n = 41; 43%)	no-SRE group (n = 55; 57%)	P-value for distribution within baseline parameter (χ2 test), SRE vs no-SRE groups
Stents at baseline	1	70 (73)	24 (59)	46 (84)	0.008
	2	21 (22)	13 (32)	8 (14)
	3	3 (3)	3 (7)	0 (0)
	4	1 (1)	1 (2)	0 (0)
	Not specified	1 (1)	0 (0)	1 (2)
Number of stents/biliary interventions at baseline	1 previous stent/intervention	70 (73)	24 (59)	46 (84)	0.004
	≥ 2 previous stent/intervention	25 (26)	17 (41)	8 (15)
	Not specified	1 (1)	0 (0)	1 (1)
Type of stent (baseline)	Metal	85 (89)	37 (90)	48 (87)	0.170
	Plastic	7 (7)	4 (10)	3 (5)
	Not specified	4 (4)	0 (0)	4 (7)
Type of SRE (SRE group only)	Cholangitis	16 (17)	16 (39)	-	-
	Stent obstruction	12 (13)	12 (29)	-
	Both	13 (14)	13 (32)	-
Consequence of SRE (SRE group only)	None	15 (16)	15 (37)	-	-
	Chemotherapy delayed	10 (10)	10 (24)	-
	Chemotherapy stopped	7 (7)	7 (17)	-
	Death	9 (9)	9 (22)	-
Further SRE (SRE group only)	No	27 (28)	27 (66)	-	-
	Yes	14 (15)	14 (34)	-

Forty-three percent of patients developed a SRE during the follow-up. SRE: Stent-related event.

Table 3 Risk of development of stent-related event increased with longer follow-up period in the absence of competing event (death)

Time-point of follow-up since first biliary stenting	Estimated risk of development of SRE rate for all patients
3 mo	11.5% (95%CI: 6.5-19.7)
6 mo	32.0% (95%CI: 23.5-42.7)
12 mo	48.6% (95%CI: 37.5-61)
18 mo	59.9% (95%CI: 44-76.5)
24 mo	79.9% (95%CI: 48.03-98.1)

SRE: Stent-related event.

Table 4 Univariate and multivariable analysis looking for factors related with time-to-stent-related event

Time-to-SRE		Univariate analysis (Fine-Gray regression)		Multivariable analysis (Fine-Gray regression)
		HR (95%CI)	P-value	HR (95%CI)	P-value
Primary	BTC	Ref		X
	Pancreas	0.8 (0.4-1.5)	0.407
Stage	Locally advanced	Ref		X
	Metastatic	1.4 (0.8-2.6)	0.251
ECOG-PS	0/1	Ref		X
	≥ 2	0.8 (0.4-1.5)	0.435
Comorbidities	None	Ref		Ref
	Mild	0.8 (0.4-1.7)	0.605	1.1 (0.5-2.2)	0.844
	Moderate	0.9 (0.4-1.9)	0.734	1.1 (0.5-2.2)	0.986
	Severe	3.6 × 10-8 (1.2 × 10-8-1.1 × 10-7)	< 0.001	9.4 × 10-7 (2.9 × 10-7-3.1 × 10-6)	< 0.001
Number of stents/biliary interventions at baseline	1	Ref		Ref
	≥ 2	2.5 (1.4-4.6)	0.003	2.3 (1.2-4.44)	0.010
Type of the most recent stent	Metal	Ref		X
	Plastic	2.1 (0.7-6.5)	0.182

Fine-Gray Regression; competing event: Death. BTC: Biliary tract cancer; ECOG-PS: ECOG performance status.

Table 5 Univariate and multivariable analysis looking for factors related with overall survival (Cox Regression)

Overall survival		Univariate analysis (Cox regression)		Multivariable analysis (Cox regression)
		HR (95%CI)	P-value	HR (95%CI)	P-value
Primary site	BTC	Ref		Ref
	Pancreas	1.6 (0.8-2.9)	0.153	1.5 (0.8-2.8)	0.205
Stage	Locally advanced	Ref		Ref
	Metastatic	1.6 (0.99-2.9)	0.067	1.8 (1.06-2.9)	0.029
ECOG-PS	0/1	Ref		Ref
	≥ 2	0.9 (0.5-1.6)	0.748	0.9 (0.5-1.6)	0.716
Stent-related event	No-SRE group	Ref		Ref
	SRE group	0.7 (0.4-1.1)	0.098	0.6 (0.4-1.01)	0.205

For assessment of factors with an impact on OS, variables considered of interest [such as site of primary tumour, stage, ECOG-PS and development of SRE (yes/no)] and those variables which showed statistically significant P-value in the univariate analysis were included in multivariable analysis. BTC: Biliary tract cancer; ECOG-PS: ECOG performance status.

Table 6 Summary of the available literature exploring the role of prophylactic treatment for stent-related event

Disease	Ref.	Randomised	Type of stent	Total number of patients	Number of patients per arm	Treatment arm(s): Stent insertion plus….	Investigation and result
Benign	Sciumè et al[21], 2004	Yes	Plastic	90	49/41	Ursodeoxycholic acid and levofloxacin vs Ursodeoxycholic acid alone	Longer stent patency with lower cholangitis and admission rate.
		(not blinded)
	Katsinelos et al[22], 2008	Yes	Plastic	41	21/20	Ursodeoxycholic acid vs Placebo	Common bile duct stones. No reduction in the bile duct stone size.
		(blinded)
	Han et al[23], 2009	No	Plastic	28	28	Ursodeoxycholic acid and terpene	Gallstones in elderly patients. Size of gallstones was reduced.
	Lee et al[24], 2011	No	Plastic	51	51	Ursodeoxycholic acid	Gallstones in elderly patients. No benefit of adding Ursodeoxycholic acid.
	Nishizawa et al[25], 2013	No	Plastic	36 patients, 63 procedures	Non-randomised, two arms: 20/43 procedures	Ursodeoxycholic acid vs Observation	Bile duct stones. Longer patency time and reduction in gallstone size in the intervention cohort.
Malignant	Ghosh et al[26], 19941	Yes	Plastic	70	31/39	Ursodeoxycholic acid + antibiotic (ampicillin, metronidazole, ciprofloxacin) vs Observation	No differences in stent occlusion rate.
		(not blinded)
	Barrioz et al[27], 19941	Yes	Plastic	20	Not specified	Ursodeoxycholic acid and norfloxacin vs Observation	Longer stent patency, prolonged median survival and shorter mean hospital stay.
		(not blinded)
	Luman et al[28], 19991	Yes	Not specified	40	20/20	Ciprofloxacin and rowachol vs Observation	Similar rate of obstruction and time to event.
		(not blinded)
	Sung et al[29], 19991	Yes	Plastic	58	Not specified	Ursodeoxycholic acid vs Observation	Similar rate of obstruction and time to event.
		(not blinded)
	De Lédinghen et al[30], 20001	Yes	Plastic	62	33/29	Ursodeoxycholic acid and norfloxacin vs Observation	Stopped after the interim analysis. No differences in stent patency.
		(not blinded)
	Halm et al[31], 20012	Yes	Plastic	52	26/26	Ursodeoxycholic acid and ofloxacin vs Ursodeoxycholic acid alone	Similar rate of obstruction and times to stent obstruction.
		(not blinded)
	Chan et al[32], 20052	Yes	Plastic	94	50/44	Ciprofloxacin vs Placebo	No differences in stent patency. Lower rate of cholangitis, but there was improvement in quality of life.
		(double blinded)

Overall, studies are underpowered for reaching definitive conclusions.

¹These studies were included in The Cochrane review[33];

²These studies were not included in The Cochrane review[33].