Prognostic factors of recurrent intrahepatic cholangiocarcinoma after hepatectomy: A retrospective study

Table 1 Univariate analysis of prognostic factors after intrahepatic cholangiocarcinoma recurrence following hepatectomy

Factors	Cases, n (%)	Median survival after recurrence, mo (95%CI)	P value1
Sex			0.123
Male	34 (63.0)	4.0 (1.2-6.8)
Female	20 (37.0)	3.0 (1.1-4.9)
Age (yr)			0.031
< 65	42 (77.8)	4.0 (2.3-5.8)
≥ 65	12 (22.2)	3.0 (1.3-5.1)
Smoking			0.059
No	20 (37.0)	5.0 (2.0-8.0)
Yes	34 (63.0)	3.0 (1.0-4.1)
Alcohol consumption			0.004
No	10 (18.5)	10.0 (3.0-17.0)
Yes	44 (81.5)	3.0 (1.9-4.2)
Hypertension			0.309
No	38 (70.4)	4.0 (2.4-5.6)
Yes	16 (29.6)	4.0 (0.0-11.3)
Diabetes			0.193
No	45 (83.3)	4.0 (2.5-5.5)
Yes	9 (16.7)	8.0 (1.0-15.0)
Hepatitis B			0.904
Negative	30 (55.6)	3.0 (1.3-4.7)
Positive	24 (44.4)	5.0 (2.0-8.0)
Hepatitis C			0.175
Negative	45 (83.3)	4 .0 (2.2-5.8)
Positive	9 (16.7)	5.0 (2.1-7.9)
Anti-hepatitis-virus			0.969
No	29 (53.7)	4.0 (2.4-5.6)
Yes	25 (46.3)	5.0 (1.9-8.1)
Cholelithiasis			0.181
No	44 (81.5)	4.0 (2.1-5.9)
Yes	10 (18.5)	2.0 (0.0-4.8)
CA19-9 (U/mL) (initial)			0.002
< 200	33 (61.1)	5.0 (1.8-8.2)
≥ 200	21 (38.9)	2.0 (1.3-2.7)
CEA (ng/mL) (initial)			0.356
< 5	34 (63.0)	4.0 (2.1-5.9)
≥ 5	20 (37.0)	3.0 (0.8-5.2)
Hepatectomy			0.855
Limited	38 (70.4)	4.0 (2.1-5.9)
Extended	16 (29.6)	3 .0 (0.0-6.9)
Lymph node dissection			0.909
No	35 (64.8)	4.0 (2.2-5.8)
Yes	19 (35.2)	5.0 (2.1-7.9)
Adjuvant treatment			0.619
No	34 (63.0)	3 .0 (0.1-5.9)
Yes	20 (37.0)	4 .0 (2.7-5.3)
Tumor size (cm)			0.884
< 5	14 (25.9)	4.0 (0.4-7.6)
≥ 5	40 (74.1)	4 .0 (2.0-6.0)
Multiplicity			0.803
Solitary	46 (85.2)	4.0 (1.4-6.6)
Multiple	8 (14.8)	3.0 (1.3-4.7)
Satellite nodules			0.953
No	34 (63.0)	4.0 (2.1-5.9)
Yes	20 (37.0)	4.0 (2.4-5.6)
Histological grade			0.021
PD	22 (40.7)	2.0 (1.2-2.8)
WD or MD	32 (59.3)	5.0 (3.5-6.5)
Vascular invasion			0.705
No	49 (90.7)	4.0 (2.1-5.9)
Yes	5 (9.3)	5.0 (1.7-8.3)
Lymph node metastasis			0.531
No	29 (53.7)	3.0 (0.9-5.1)
Yes	25 (46.3)	5.0 (2.6-7.4)
Perineural invasion			0.428
No	45 (83.3)	4.0 (2.5-5.5)
Yes	9 (16.7)	2.0 (1.3-2.7)
Biliary invasion			0.003
No	35 (64.8)	5.0 (2.6-7.4)
Yes	19 (35.2)	2.0 (1.2-2.8)
Vascular tumour thrombi			0.002
No	42 (77.8)	5.0 (3.2-6.8)
Yes	12 (22.2)	2.0 (1.2-2.6)
AJCC T category			0.196
T1–2	14 (25.9)	4.0 (0.0-11.3)
T3–4	40 (74.1)	4.0 (2.1-5.9)
DFS			0.003
< 6 mo	27 (50.0)	2.0 (0.7-3.3)
≥ 6 mo	27 (50.0)	6.0 (2.3-9.7)
CA19-9 (U/mL) (recurrence)			0.002
< 200	35 (64.8)	4.0 (1.3-6.7)
≥ 200	19 (35.2)	2.0 (1.2-2.8)
CEA (ng/mL) (recurrence)			0.378
< 5	41 (75.9)	4.0 (2.3-5.7)
≥ 5	13 (24.1)	7.0 (1.7-12.3)
NLR (recurrence)			0.804
< 2	24 (44.4)	5.0 (2.8-7.2)
≥ 2	30 (55.6)	2.0 (0.9-3.1)
Recurrent site			0.334
Intrahepatic	24 (44.4)	4.0 (2.3-5.7)
Extrahepatic	6 (11.2)	3.0 (0.0-11.6)
Intrahepatic + extrahepatic	24 (44.4)	2.0 (0.4-3.6)
Treatment after recurrence			< 0.001
No	12 (22.2)	2.0 (1.0-2.8)
Yes	42 (77.8)	5.0 (2.9-7.1)

¹Data are based on log-rank test.

N: Number; CI: Confidence interval; CA19-9: Serum carbohydrate antigen 19-9; CEA: Carcinoembryonic antigen; PD: Poor-differentiated; WD: Well-differentiated; MD: Moderate differentiated; NLR: Neutrophil-to-lymphocyte ratio; AJCC: the American Joint Committee on Cancer; DFS: Disease free survival.

Table 2 Multivariate analysis of prognostic factors after intrahepatic cholangiocarcinoma recurrence following hepatectomy

Factors	Multivariate analysis
	HR	95%CI	P value1
Age (≥ 65 yr)	2.12	0.88-5.12	0.096
Alcohol consumption (Yes)	4.64	1.53-14.04	0.007
CA19-9 (≥ 200 U/mL) (initial)	2.63	0.94-7.35	0.065
Histological grade (PD)	1.18	0.59-2.35	0.646
Biliary invasion (Yes)	1.04	0.41-2.63	0.940
Vascular tumor thrombus (Yes)	1.80	0.70-4.65	0.222
DFS (< 6 mo)	3.47	1.59-7.60	0.002
CA19-9 (≥ 200 U/mL) (recurrence)	1.13	0.47-2.71	0.785
Treatment after recurrence (Yes)	0.21	0.08-0.55	0.001

¹Data are based on Cox regression model.

CI: Confidence interval; CA19-9: Serum carbohydrate antigen 19-9; PD: Poor-differentiated; DFS: Disease free survival.

Table 3 Treatment of recurrent intrahepatic cholangiocarcinoma

Treatment	n	Median DFS, mo (range)	MS after recurrence, mo (range)
Local therapy	14	6 (1-86)	3 (1-36)
Hepatectomy	2	10 (7-13)	25 (13-36)
TACE	8	3 (1-23)	2 (1-7)
RFA	4	7 (2-86)	3 (1-7)
Systemic therapy	22	5 (1-29)	4 (1-38)
Chemotherapy	3	11 (10-29)	4 (1-38)
Targeted therapy	12	3 (1-23)	4 (1-10)
Targeted + immunization therapy	7	4 (1-13)	7 (2-24)
Multimodality therapy	6	4 (2-11)	7 (4-24)
Best supportive care	12	6 (3-20)	1 (1-6)

N: Number; DFS: Disease-free survival; MS: Median survival; TACE: Transarterial chemoembolization; RFA: Radiofrequency ablation.

Table 4 Individual characteristics of patients receiving multimodality therapy for recurrent intrahepatic cholangiocarcinoma

Clinical features					Pathological characteristics				Recurrent		Survival
Case	Age (yr)	Sex	Hepatitis	Surgery	Lymph node metastasis	Tumour size (cm)	Tumour number	Histological grade	Recurrent site	Treatment	DFS (mo)	SAR (mo)	Outcome
1	62	M	HBV	ERH	Yes	12	1	MD	Liver + lymph node	TACE + GEMOX	4	3	Dead
2	48	M	HBV	ERH	None	8	1	MD	Liver	TACE + GEMOX	11	13	Dead
3	40	M	HBV	ERH	None	5	2	MD	Liver + lymph node + bone	TACE + GEMOX	2	5	Dead
4	53	M	None	LH	None	11	1	MD	Liver + lymph node	RFA + TACE + SOX	6	6	Alive
5	44	M	HBV	RH	None	14	1	MD	Liver + bone	RFA + FOLFOX-4	3	2	Dead
6	64	M	None	ERH	Yes	22	1	MD	Liver	RFA + PD-1 + TKI	4	1	Alive

DFS: Disease-free survival; SAR: Survival after recurrence; M: Male; HBV: Hepatitis B virus; ERH: Extended right hepatectomy; LH: Left hepatectomy; RH: Right hepatectomy; MD: Moderate differentiated; TACE: Transarterial chemoembolization; RFA: Radiofrequency ablation; GEMOX: Gemcitabine + oxaliplatin; FOLFOX-4: Fluorouracil + calcium folate + oxaliplatin; SOX: Tegafur + oxaliplatin; PD-1: Programmed death-1 inhibitor; TKI: Tyrosine kinase inhibitor.