Benefit of neoadjuvant concurrent chemoradiotherapy for locally advanced perihilar cholangiocarcinoma

Table 1 Patient characteristics n (%)

	Neoadjuvant chemoradiotherapy(n = 12)1	Non-neoadjuvant chemoradiotherapy (n = 45)1	P value2
Demographic variables
Age (yr)	59.0 (48.25, 62.75)	67.0 (60.00, 69.00)	0.02
Age ≥ 60	6 (50.0)	35 (77.8)	0.08
Sex (Male)	8 (66.7)	24 (53.3)	0.41
Follow-up duration (mo)	31.9 (19.8, 53.8)	26.4 (14.5, 42.1)	0.27
Laboratory variables
Albumin (g/dL)	3.75 (3.450, 4.075)	3.60 (3.200, 3.850)	0.32
Total bilirubin (mg/dL)	2.3 (0.60, 8.45)	6.4 (2.35, 11.40)	< 0.05
CA 19-9 (U/mL)	181.8 (27.08, 1452.50)	210.0 (71.35, 976.00)	0.74
Cancer-related variables
Bismuth classification
IIIA	2 (16.7)	21 (46.7)	0.10
IIIB	3 (25.0)	2 (4.4)	0.06
IV	7 (58.3)	22 (48.9)	0.56
Pre-op AJCC 7th stage
IIIA (T3N0M0)	8 (66.7)	23 (51.1)	0.34
IIIB (T1-3N1M0)	2 (16.7)	17 (37.8)	0.30
IVA (T4N0-1M0)	1 (8.3)	3 (6.7)	> 0.99
IVB (T1-4N2M0)	1 (8.3)	2 (4.4)	0.52
Tumor differentiation			< 0.01
Well	0 (0)	11 (24.4)
Moderately	7 (58.3)	29 (64.4)
Poorly	0 (0)	5 (11.1)
Undetermined	5 (41.7)	0 (0)
Post-operative adjuvant treatment	5 (41.7)	27 (60.0)	0.26
Recurrence	10 (83.3)	31 (68.9)	0.48
OP site	3 (30.0)	11 (35.5)
Liver	2 (20.0)	3 (9.7)
Distant organ	3 (30.0)	9 (29.0)
Carcinomatosis	2 (20.0)	8 (25.8)

¹Continuous variables were denoted median (Q1, Q3) and categorical variables were denoted number (%);

²P values were determined using a Mann-Whitney test for continuous variables and a χ² test (Fisher’s exact test, Pearson and Mantel-Haenszel χ² test) for categorical variables. CA19-9: Carbohydrate antigen 19-9; AJCC: American Joint Committee on Cancer.

Table 2 Summary of neoadjuvant chemoradiotherapy n (%)

	Neoadjuvant chemoradiotherapy (n = 12)
Regimen of chemotherapy
5-fluorouracil + leucovorin	5 (41.7)
Gemcitabine	5 (41.7)
Gemcitabine + cisplatin	1 (8.3)
Tegfur/Uracil (UFT)	1 (8.3)
Total dose of radiotherapy (cGy)	5040 (4545, 5040)1
Response in follow-up image
Partial response	7 (58.3)
Stable disease	5 (41.7)
Complete response in pathology	2 (16.7)
Downstaging of TNM stage	4 (33.3)
Toxicity
≥ Grade II	2 (16.7)

¹Continuous variables were denoted median (Q1, Q3) and categorical variables were denoted number (%).

Table 3 Efficacy of neoadjuvant chemoradiotherapy n (%)

	Neoadjuvant chemoradiotherapy (n = 12)	Non-neoadjuvant chemoradiotherapy (n = 45)	P value1
Alteration of TNM stage before and after surgery			0.01
Upstaging	0 (0)	11 (24.4)
No change	1 (8.3)	11 (24.4)
Downstaging	11 (91.7)	23 (51.1)
R0 resection	10 (83.3)	30 (66.7)	0.32
Surgical pathology
Microvascular invasion	6 (50.0)	29 (64.4)	0.51
Perineural invasion	7 (58.3)	44 (97.8)	< 0.01
Lymph node metastasis	3 (25.0)	25 (55.6)	0.06
Perioperative complications	2 (16.7)	11 (24.4)	0.71

¹P values were determined using a Mann-Whitney test for continuous variables and a χ² test (Fisher’s exact test, Pearson and Mantel-Haenszel χ² test) for categorical variables.

Table 4 Univariate analysis for identifying the risk factor for disease free survival and overall survival

	Disease-free survival		Overall survival
	HR(95%CI)	P value1	HR (95%CI)	P value1
Male	> 1.00 (0.54-1.87)	< 1.00	1.34 (0.75-2.41)	0.33
Age < 60	1.20 (0.61-2.36)	0.59	0.86 (0.46-1.61)	0.63
Bismuth type
IIIA	1.00		1.00
IIIB	1.95 (0.70-5.42)	0.20	1.07 (0.31-3.63)	0.92
IV	> 1.00 (0.52-1.95)	0.99	0.84 (0.47-1.51)	0.56
Pre-op AJCC 7th stage
IIIA	1.00		1.00
IIIB	0.86 (0.44-1.66)	0.64	0.88 (0.46-1.68)	0.70
IVA	0.55 (0.13-2.37)	0.42	0.70 (0.21-2.34)	0.57
IVB	2.51 (0.56-11.19)	0.23	2.43 (0.71-8.25)	0.16
Serum total bilirubin	0.76 (0.95-1.04)	0.76	1.01 (0.97-1.06)	0.66
Serum total bilirubin ≥ 3	1.21 (0.64-2.28)	0.56	1.40 (0.77-2.53)	0.27
Serum CA19-9	1.01 (> 1.00-1.01)	< 0.01	> 1.00 (1.00-1.01)	0.13
Serum CA19-9 ≥ 300	3.28 (1.68-6.41)	< 0.01	2.58 (1.39-4.78)	< 0.01
Variation of CA19-9 after NACCRT	1.07 (0.98-1.15)	0.12	1.02 (0.95-1.10)	0.61
Received NACCRT	1.05 (0.51-2.15)	0.91	0.65 (0.30-1.39)	0.27
Performed R0 resection	1.01 (0.50-2.04)	0.98	0.61 (0.33-1.15)	0.12
Tumor differentiation
Well	1.00		1.00
Moderately	2.30 (0.95-5.55)	0.06	1.34 (0.63-2.83)	0.45
Poorly	1.25 (0.15-10.47)	0.84	3.66 (1.08-12.33)	0.04
Indeterminate	3.30 (0.92-11.88)	0.07	1.21 (0.37-3.97)	0.75
Microvascular invasion	1.37 (0.73-2.56)	0.33	1.89 (1.02-3.51)	0.04
Perineural invasion	0.58 (0.22-1.49)	0.25	1.35 (0.53-3.45)	0.53
Lymph node metastasis	1.01 (0.54-1.86)	0.98	> 1.00 (0.56-1.78)	0.99
Received adjuvant treatment	0.78 (0.42-1.45)	0.43	0.77 (0.43-1.36)	0.36

¹P values were determined with a univariate Cox proportional hazards regression test. AJCC: American Joint Committee on Cancer; CA19-9: Carbohydrate antigen 19-9; NACCRT: Neoadjuvant concurrent chemoradiotherapy.

Table 5 Multivariate analysis for identifying the risk factor for disease-free survival and overall survival

	Disease-free survival		Overall survival
	HR (95%CI)	P value1	HR (95%CI)	P value1
Serum CA19-9 ≥ 300	3.28 (1.68-6.41)	< 0.01	2.66 (1.40-5.06)	< 0.01
R0 resection			0.47 (0.24-0.90)	0.02

¹P values were determined using a multivariate Cox proportional hazards regression test. CA19-9: Carbohydrate antigen 19-9.