Hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis

Table 1 Baseline patient characteristics

Patient characteristics	Statistic
Age (yr)	54 (37-74)
Gender (male/female)	39/11
Etiology
HBV/HCV/non-viral	39/6/5
Child-Pugh classification
A5/A6/B7	17/25/8
Staging
BCLC staging C	50
Modified UICC (III/IVa/IVb)	9/31/10
Tumor type
Nodular/massive/infiltrative	3/4/43
Portal vein thrombosis
Vp2/Vp3/Vp4	7/13/30
Maximal tumor size (cm)
< 10/≥ 10	26/24
Tumor volume (cm3)1	492.7 (26.1-2746.6)
Extrahepatic metastases	16
Previous treatment
TACL/TACL + RFA/TACL + ERT	19/3/2
Total bilirubin (mg/dL)1	0.87 (0.34-1.99)
PT (INR)1	1.14 (0.94-1.38)
ALT (IU/L)1	37 (15-345)
Platelet count (× 103/mL)1	133 (50-326)
AFP (ng/mL)1	3084.15 (7.94-426100)
PIVKA-II (mAU/mL)1	1190 (16-12000)

¹Expressed as the median (range). AFP: Alpha-fetoprotein; AJCC: American Joint Committee on Cancer; ALT: Alanine aminotransferase; BCLC: Barcelona Clinic Liver Cancer; ERT: External radiation therapy; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PIVKA: Protein induced by vitamin K absence or antagonist; PT: Prothrombin time; RFA: Radiofrequency ablation; TACL: Transarterial chemolipiodolization; UICC: Union for International Cancer Control.

Table 2 Tumor responses to hepatic arterial infusion chemotherapy treatment

	Response after two cycles	Best response during HAIC	Overall response after HAIC	Intra-hepatic tumor response
CR	2%	6%	6%	6%
PR	20%	26%	10%	26%
SD	52%	44%	12%	52%
PD	26%	24%	72%	16%
Objective response	22%	32%	16%	32%
Disease control rate	74%	76%	28%	84%

HAIC: Hepatic arterial infusion chemotherapy; CR: Complete response; PD: Progressive disease; PR: Partial response; SD: Stable disease.

Table 3 Pre-treatment prognostic factors for survival in hepatic arterial infusion chemotherapy treatment

Variables	Univariate	Multivariate1
	HR (95%CI)	HR (95%CI)	P-value
Age (< 60/≥ 60 yr)	0.991 (0.514-1.912)
Gender (male/female)	1.453 (0.687-3.076)
Maximal tumor size (< 10/≥ 10 cm)	1.693 (0.894-3.204)
Tumor volume (< 400/≥ 400 cm3)	2.509 (1.289-4.885)	2.520 (1.252-5.072)	0.01
Child-Pugh score (5/> 5)	2.099 (1.038-4.244)	1.812 (0.878-3.738)	0.108
Stage
mUICC stage (III/IV)	1.198 (0.502-2.863)
AJCC (III/IV)	2.133 (1.085-4.193)	1.803 (0.895-3.634)	0.099
Extrahepatic metastases	1.508 (0.772-2.948)
Pre-HAIC treatment	0.939 (0.503-1.755)
Portal vein thrombosis (Vp4 vs non-Vp4)	1.603 (0.829-3.100)
AFP level (< 200/≥ 200 ng/mL)	1.707 (0.845-3.448)
PIVKA-II (< 40/≥ 40 mAU/mL)	2.860 (1.110-7.368)	3.121 (1.177-8.274)	0.022

¹Those variables with P < 0.05 in univariate analysis were included. AFP: Alpha-fetoprotein; AJCC: American Joint Committee on Cancer; HAIC: Hepatic arterial infusion chemotherapy; PIVKA: Protein induced by vitamin K absence or antagonist; mUICC: Modified Union for International Cancer Control.

Table 4 Post-treatment prognostic factors for survival in hepatic arterial infusion chemotherapy treatment

Variables		Univariate	Multivariate1
		HR (95%CI)	Adjusted HR (95%CI)	P-value2
After 2nd HAIC cycle	Objective response
	Responder	1
	Non-responder	2.382 (0.995-5.704)
	Disease control
	Control group	1
	Progressive group	3.708 (1.801-7.634)	3.850 (1.768-8.381)	0.001
	PVTT response
	Response	1
	Non-response	2.531 (1.164-5.505)	3.398 (1.529-7.552)	0.003
	AFP reduction
	≥ 50%	1
	< 50%	3.242 (1.297-8.102)	3.031 (1.194-7.691)	0.02
	PIVKA-II reduction
	≥ 50%	1
	< 50%	3.164 (1.469-6.818)	2.254 (0.989-5.137)	0.053
Response during HAIC	Best tumor response
	Objective response
	Responder	1
	Non-responder	4.747 (2.111-10.672)	4.445 (1.893-10.439)	0.001
	Tumor control
	Control group	1
	Progressive group	3.274 (1.594-6.724)	3.137 (1.494-6.591)	0.003
	Intra-hepatic tumor response
	Objective response
	Responder	1
	Non-responder	4.747 (2.111-10.672)	4.445 (1.893-10.439)	0.001
	Tumor control
	Control group	1
	Progressive group	3.032 (1.348-6.821)	3.009 (1.302-6.958)	0.01
	PVTT response
	Response	1
	Non-response	9.587 (2.879-31.927)	8.188 (2.403-27.898)	0.001
	Combination therapy
	Yes	1
	No	2.367 (1.218-4.601)	2.164 (1.082-4.328)	0.029

¹Adjusted for tumor volume and pre-treatment PIVKA-II level;

²P value for adjusted hazard ratio. AFP: Alpha-fetoprotein; HAIC: Hepatic arterial infusion chemotherapy; PIVKA: Protein induced by vitamin K absence or antagonist; PVTT: Portal vein tumor thrombosis.

Table 5 Adverse events related to treatment

	Grade 1	Grade 2	Grade 3	Grade 4
Hematological
Leukopenia	26%	38%	8%	0%
Neutropenia	10%	26%	30%	12%
Anemia	26%	48%	26%	0%
Thrombocytopenia	30%	18%	44%	0%
Non-hematological
Total bilirubin	30%	28%	10%	0%
AST	20%	36%	38%	6%
ALT	48%	12%	16%	2%

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Table 6 Causes of death

	Patient number (n = 37)
Disease progression	21
Hepatic dysfunction	6
Variceal bleeding	5
Infection	3
Unknown	2