Efficacy Of Apatinib In Transcatheter Arterial Chemoembolization (TACE) Refractory Intermediate And Advanced-Stage Hepatocellular carcinoma：A Propensity Score Matching Analysis

Figures & data

Table 1 Comparison Of Two Treatment Groups Of Patients With Baseline Characteristics (Before And After PSM)

Characteristics	Before Matching			After Matching
n, (%)	TACE-Apatinib Group(n=42)	TACE-Alone Group(n=83)	P value	TACE-Apatinib Group(n=29)	TACE-Alone Group(n=29)	P value
Sex			0.142			1.000
Male	41(97.6)	73(88.0)		28(96.6)	27(93.1)
Female	1(2.4)	10(12.0)		1(3.4)	2(6.9)
Age (years)			0.343			1.000
<56	23(54.8)	38(45.8)		14(48.3)	14(48.3)
56	19(45.2)	45(54.2)		15(51.7)	15(51.7)
AFP (ng/mL)			0.952#			0.602#
<400	20(47.6)	40(48.2)		14(48.3)	16(55.2)
≥400	22(52.4)	43(51.8)		15(51.7)	13(44.8)
HBV			0.590			1.000
Infected	39(92.9)	73(88.0)		27(93.1)	28(96.6)
Uninfected	3(7.1)	10(12.0)		2(6.9)	1(3.4)
Child-Pugh			0.633			1.000
Class A	36(85.7)	75(90.4)		25(86.2)	26(89.7)
Class B	6(14.3)	8(9.6)		4(13.8)	3(10.3)
Tumor Size (cm)			0.938			0.597
<5	17(40.5)	33(39.8)		12(41.4)	14(48.3)
≥5	25(59.5)	50(60.2)		17(58.6)	15(51.7)
Number of lesions			0.206			0.703
Single	8(19.0)	9(10.8)		5(17.2)	3(10.3)
Multiple	34(81.0)	74(89.2)		24(82.8)	26(89.7)
PVTT			<0.001			0.788
Present	23(54.8)	17(20.5)		11(37.9)	12(41.4)
Absent	19(45.2)	66(79.5)		18(62.1)	17(58.6)
Metastasis			0.229			0.189
Present	27(64.3)	44(53.0)		17(58.6)	12(41.4)
Absent	15(35.7)	39(47.0)		12(41.4)	17(58.6)
BCLC			0.121			0.256
Stage B	9(21.4)	29(34.9)		7(24.1)	11(37.9)
Stage C	33(78.6)	54(65.1)		22(75.9)	18(62.1)
Number of Previous TACE			0.144			0.780
≤2	29(69.0)	67(80.7)		20(69.0)	19(65.5)
>2	13(31.0)	16(19.3)		9(31.0)	10(34.5)

Notes: ^#Rank sum test. Before PSM, there was a significant difference in the presence of PVTT between the two groups. After PSM, no statistical significance was found in any of the characteristics and compositions of the two groups became more similar.

Abbreviations: PSM, propensity score matching; TACE, transcatheter arterial chemoembolization; AFP, alpha-fetoprotein; HBV, Hepatitis B Virus; PVTT, portal vein tumor thrombus; BCLC, Barcelona Clinic Liver Cancer.

Figure 1 The flow diagram of this study.

Abbreviations: HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Cancer; JSH, Japan Society of hepatology; LCSGJ, Liver Cancer Study Group of Japan; TACE, transcatheter arterial chemoembolization.

Table 2 The Comparison Of AEs Between Two Treatment Groups

AEs	TACE-Apatinib (n=42)	TACE-Alone(n=83)	P-value
Fever	19(45.2%)	51(61.4%)	0.085
Hand-foot syndrome	20(47.6%)	0(0%)	<0.001*
Fatigue	12(28.6%)	21(25.3%)	0.695
Hypertension	13(31.0%)	2(2.4%)	<0.001
Nausea and vomiting	9(21.4%)	13(15.7%)	0.424
Diarrhea	11(26.2%)	6(7.2%)	0.003
Abdominal pain	8(19.0%)	19(22.9%)	0.622
Hoarseness	4(9.5%)	0(0%)	0.012*
Epistaxis	3(7.1%)	0(0%)	0.036*
Oral or anal ulcer	8(19.0%)	0(0%)	<0.001*
Proteinuria	1(2.4%)	0(0%)	0.336*
Hepatic failure	0(0%)	0(0%)	-

Notes: *Fisher’s exact test. Compared with the TACE-alone group, the incidences of apatinib-related AEs (hand-foot syndrome, hypertension, diarrhea, hoarseness, oral or anal ulcer) were significantly higher in the TACE-apatinib group.

Abbreviations: AEs, adverse events; TACE, transcatheter arterial chemoembolization.

Figure 2 Kaplan–Meier curves of OS for TACE+apatinib and TACE groups before (A) and after PSM (B).

Notes: The significant increase of OS can be both observed in the TACE-apatinib group compared with the TACE-alone group before (A) and after PSM (B).Abbreviations: OS, overall survival; TACE, transcatheter arterial chemoembolization; PSM, propensity score matching.

Figure 3 Kaplan–Meier curves of PFS for TACE+apatinib and TACE groups before (A) and after PSM (B).

Notes: The significant increase of PFS can be observed in the TACE-apatinib group compared with the TACE-alone group, especially after PSM.

Abbreviations: PFS, progression-free survival; TACE, transcatheter arterial chemoembolization; PSM, propensity score matching.

Table 3 Univariate And Multivariate Analysis Of Prognostics Factors Affecting OS For Two Treatment Cohorts

Variables	Univariate Analysis				Multivariate Analysis
Numbers	HR	P value		HR	P value
Sex (Male vs Female)	114/11	0.645(0.322–1.293)	0.217		–	–
Age (≥56 vs <56)	64/61	0.759(0.491–1.173)	0.214		–	–
AFP level (≥400 ng/mL vs <400 ng/mL)	65/60	1.644(1.050–2.572)	0.030		–	–
HBV (Present vs Absent)	112/13	1.231(0.592–2.561)	0.578		–	–
Child Pugh Class (B vs A)	14/111	0.805(0.398–1.626)	0.545		–	–
Tumor size (≥5 cm vs <5 cm)	75/50	1.794(1.135–2.837)	0.012		1.732(1.086–2.760)	0.021
Number of lesions (Multiple vs Single)	108/17	1.676(0.807–3.481)	0.166		–	–
PVTT (Present vs Absent)	40/85	1.591(1.001–2.528)	0.050		2.297(1.379–3.827)	0.001
Distant metastasis (Present vs Absent)	71/54	1.580(1.005–2.485)	0.048		1.962(1.223–3.148)	0.005
Number of Previous TACE (>2 VS ≤2)	29/96	0.709(0.413–1.214)	0.210		–	–
Treatments (TACE-apatinib vs TACE)	42/83	0.459(0.274–0.770)	0.003		0.280(0.158–0.499)	<0.001

Notes: Tumor size, PVTT, distant metastasis and treatments in this study were independent prognostic factors of OS.

Abbreviations: OS, overall survival; AFP, alpha-fetoprotein; HBV, Hepatitis B Virus; PVTT, portal vein tumor thrombus; BCLC, Barcelona Clinic Liver Cancer; TACE, transcatheter arterial chemoembolization.

Table 4 Univariate And Multivariate Analysis Of Prognostics Factors Affecting PFS For Two Treatment Cohorts

Variables	Univariate Analysis				Multivariate Analysis
Numbers	HR	P value		HR	P value
Sex (Male vs Female)	114/11	0.864(0.449–1.662)	0.661		–	–
Age (≥56 vs <56)	64/61	0.780(0.529–1.148)	0.208		–	–
AFP level (≥400 ng/mL vs <400 ng/mL)	65/60	0.986(0.669–1.455)	0.945		–	–
HBV (Present vs Absent)	112/13	1.013(0.542–1.895)	0.968		–	–
Child Pugh Class (B vs A)	14/111	1.112(0.607–2.038)	0.731		–	–
Tumor size (≥5 cm vs <5 cm)	75/50	1.408(0.941–2.106)	0.096		–	–
Number of lesions (Multiple vs Single)	108/17	2.038(1.083–3.834)	0.027		–	–
PVTT (Present vs Absent)	40/85	0.971(0.637–1.482)	0.892		–	–
Distant metastasis (Present vs Absent)	71/54	0.945(0.639–1.398)	0.776		–	–
Number of Previous TACE (>2 VS ≤2)	29/96	0.714(0.444–1.146)	0.163
Treatments (TACE-apatinib vs TACE)	42/83	0.348(0.223–0.544)	<0.001		0.348(0.223–0.544)	<0.001

Notes: The treatment was the only independent prognostic factor of PFS in this study.

Abbreviations: PFS, progression-free survival; AFP, alpha-fetoprotein; HBV, Hepatitis B Virus; PVTT, portal vein tumor thrombus; BCLC, Barcelona Clinic Liver Cancer; TACE, transcatheter arterial chemoembolization.

Table 5 The Comparison Of Post-Treatments Between Two Groups After PSM

Post Treatments	TACE-Apatinib (n=29)	TACE-Alone(n=29)	P-value
New targeted drugs	1(3.4%)	0(0%)	1.000*
Surgical resection	1(3.4%)	1(3.4%)	1.000
Ablative therapies	10(34.5%)	9(31.0%)	0.780
Intra-arterial infusion	5(17.2%)	2(6.9%)	0.420
Radiotherapy	1(3.4%)	0(0%)	1.000*
Immunotherapy	2(6.9%)	3(10.3%)	1.000
Radioactive seed implanting	1(3.4%)	0(0%)	1.000*

Notes: *Fisher’s exact test. No significant difference in post-treatments between the TACE-apatinib group and the TACE-alone group (after PSM) was found.

Abbreviations: TACE, transcatheter arterial chemoembolization. PSM, propensity score matching.