Patterns and risk factors of early recurrence after radical resection for intrahepatic cholangiocarcinoma

Table 1 Baseline characteristics of patients, median (interquartile range)/n (%)

Characteristic	Total (n = 386)	Early recurrence (n = 178)	No early recurrence (n = 208)	P value
Demographics
Age, years	62 (54-69)	61 (53-68)	63 (55-70)	0.082
Male sex	218 (56.5)	102 (57.3)	116 (55.8)	0.764
BMI, kg/m2 (mean ± SD)	23.8 ± 3.4	23.6 ± 3.5	24.0 ± 3.3	0.248
Comorbidities
Diabetes mellitus	87 (22.5)	42 (23.6)	45 (21.6)	0.645
Hypertension	134 (34.7)	58 (32.6)	76 (36.5)	0.415
Hepatitis B	98 (25.4)	51 (28.7)	47 (22.6)	0.171
Hepatitis C	31 (8.0)	13 (7.3)	18 (8.7)	0.625
Cirrhosis	67 (17.4)	35 (19.7)	32 (15.4)	0.267
Laboratory values
CA19-9 > 200 U/mL	156 (40.4)	98 (55.1)	58 (27.9)	< 0.001
CEA > 5 ng/mL	112 (29.0)	67 (37.6)	45 (21.6)	< 0.001
NLR > 3.0	143 (37.0)	89 (50.0)	54 (26.0)	< 0.001
PLR > 150	128 (33.2)	75 (42.1)	53 (25.5)	< 0.001
Albumin < 3.5 g/dL	76 (19.7)	42 (23.6)	34 (16.3)	0.074
Total bilirubin > 1.2 mg/dL	89 (23.1)	45 (25.3)	44 (21.2)	0.339
Tumor characteristics
Tumor size, cm	5.8 (3.5-8.2)	7.2 (5.0-9.5)	4.5 (3.0-6.8)	< 0.001
Tumor size > 5 cm	213 (55.2)	132 (74.2)	81 (38.9)	< 0.001
Multiple tumors	89 (23.1)	62 (34.8)	27 (13.0)	< 0.001
Bilobar distribution	54 (14.0)	38 (21.3)	16 (7.7)	< 0.001
Pathological features
Poor differentiation	98 (25.4)	67 (37.6)	31 (14.9)	< 0.001
Lymph node metastasis	124 (32.1)	89 (50.0)	35 (16.8)	< 0.001
Microvascular invasion	168 (43.5)	112 (62.9)	56 (26.9)	< 0.001
Perineural invasion	145 (37.6)	91 (51.1)	54 (26.0)	< 0.001
Surgical factors
Major hepatectomy	245 (63.5)	125 (70.2)	120 (57.7)	0.011
R1 resection	88 (22.8)	67 (37.6)	21 (10.1)	< 0.001
Blood loss > 500 mL	167 (43.3)	89 (50.0)	78 (37.5)	0.013
Transfusion required	98 (25.4)	56 (31.5)	42 (20.2)	0.011
Postoperative course
Major complications	67 (17.4)	35 (19.7)	32 (15.4)	0.267
Adjuvant chemotherapy	268 (69.4)	112 (62.9)	156 (75.0)	0.010

BMI: Body mass index; CA19-9: Carbohydrate antigen 19-9; CEA: Carcinoembryonic antigen; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio.

Table 2 Patterns of recurrence according to timing, n (%)

Recurrence pattern	Total recurrence (n = 237)	Early recurrence (n = 178)	Late recurrence (n = 59)	P value
Site of first recurrence
Intrahepatic only	134 (56.5)	89 (50.0)	45 (76.3)	< 0.001
Solitary	74 (55.2)	42 (47.2)	32 (71.1)	0.007
Multiple	60 (44.8)	47 (52.8)	13 (28.9)	0.007
Extrahepatic only	79 (33.3)	64 (36.0)	15 (25.4)	0.135
Lymph nodes	43 (54.4)	35 (54.7)	8 (53.3)	0.923
Peritoneum	19 (24.1)	16 (25.0)	3 (20.0)	0.681
Lung	11 (13.9)	8 (12.5)	3 (20.0)	0.449
Bone	6 (7.6)	5 (7.8)	1 (6.7)	0.878
Combined	24 (10.1)	25 (14.0)	0 (0)	0.002
Number of recurrence sites
Single site	162 (68.4)	103 (57.9)	45 (76.3)	0.012
Multiple sites	75 (31.6)	75 (42.1)	14 (23.7)	0.012
Treatment of recurrence
Repeat resection	34 (14.3)	15 (8.4)	19 (32.2)	< 0.001
Locoregional therapy	67 (28.3)	38 (21.3)	29 (49.2)	< 0.001
Systemic chemotherapy	112 (47.3)	98 (55.1)	14 (23.7)	< 0.001
Best supportive care	24 (10.1)	27 (15.2)	0 (0)	0.001

Table 3 Univariate and multivariate analysis of risk factors for early recurrence

Variable	Univariate analysis, HR (95%CI)	P value	Multivariate analysis, HR (95%CI)	P value
Age > 65 years	0.89 (0.65-1.22)	0.467
Male sex	1.04 (0.76-1.42)	0.812
Hepatitis B/C	1.23 (0.88-1.72)	0.227
Cirrhosis	1.31 (0.89-1.93)	0.172
Tumor size > 5 cm	2.87 (2.06-3.99)	< 0.001	2.14 (1.52-3.01)	< 0.001
Multiple tumors	2.65 (1.91-3.68)	< 0.001	1.89 (1.34-2.67)	< 0.001
Bilobar distribution	2.34 (1.61-3.40)	< 0.001		NS
Poor differentiation	2.18 (1.57-3.03)	< 0.001		NS
Lymph node metastasis	3.42 (2.48-4.72)	< 0.001	2.43 (1.71-3.45)	< 0.001
Microvascular invasion	2.89 (2.09-4.00)	< 0.001	1.76 (1.25-2.48)	0.001
Perineural invasion	2.13 (1.55-2.93)	< 0.001		NS
R1 resection	3.21 (2.29-4.50)	< 0.001	2.01 (1.38-2.93)	< 0.001
CA19-9 > 200 U/mL	2.76 (2.00-3.81)	< 0.001	1.92 (1.37-2.69)	< 0.001
CEA > 5 ng/mL	1.89 (1.37-2.61)	< 0.001		NS
NLR > 3.0	2.03 (1.48-2.79)	< 0.001		NS
PLR > 150	1.78 (1.29-2.45)	< 0.001		NS
Major hepatectomy	1.42 (1.02-1.97)	0.038		NS
Blood loss > 500 mL	1.51 (1.10-2.07)	0.011		NS
Major complications	1.34 (0.91-1.97)	0.139
No adjuvant chemotherapy	1.67 (1.21-2.31)	0.002		NS

HR: Hazard ratio; CI: Confidence interval; CA19-9: Carbohydrate antigen 19-9; CEA: Carcinoembryonic antigen; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; NS: Not significant in multivariate analysis.

Table 4 Risk stratification model for early recurrence

Risk group	Score range	n (%)	12-month recurrence rate, %	RFS, median (95%CI), months	P value
Low risk	0-3 points	98 (25.4)	18.4	38.5 (32.1-44.9)	Reference
Intermediate risk	4-7 points	176 (45.6)	48.3	14.2 (11.8-16.6)	< 0.001
High risk	8-13 points	112 (29.0)	82.1	5.8 (4.7-6.9)	< 0.001

RFS: Recurrence-free survival; CI: Confidence interval.

Table 5 Survival outcomes according to recurrence status, %

Group	n	OS, median (95%CI), months	1-year OS	3-year OS	5-year OS	P value
Overall cohort	386	31.2 (27.8-34.6)	82.4	42.7	28.3
By recurrence status
No recurrence	149	58.7 (52.3-65.1)	96.6	71.8	54.2	Reference
Early recurrence	178	18.5 (16.2-20.8)	71.3	18.0	5.1	< 0.001
Late recurrence	59	42.3 (36.7-47.9)	100	52.5	23.7	< 0.001
Post-recurrence survival
Early recurrence	178	9.8 (8.4-11.2)	38.2	8.4	2.8	Reference
Late recurrence	59	18.6 (14.9-22.3)	71.2	25.4	10.2	< 0.001
By treatment of recurrence
Repeat resection/RFA	34	28.3 (21.7-34.9)	82.4	35.3	17.6	Reference
Locoregional therapy	67	19.2 (15.8-22.6)	71.6	19.4	7.5	0.012
Systemic chemotherapy	112	12.4 (10.1-14.7)	51.8	8.9	0	< 0.001
Best supportive care	24	3.1 (2.2-4.0)	4.2	0	0	< 0.001

RFA: Radiofrequency ablation; CI: Confidence interval; OS: Overall survival.