Transarterial Chemoembolization Combined with Atezolizumab Plus Bevacizumab versus Transarterial Chemoembolization Alone in Intermediate‐stage Hepatocellular Carcinoma: A Multicenter Retrospective Study

Figures & data

Table 1 Baseline Characteristics of the Patients

Variable	Before PSM				After PSM
	TACE + Atez/Bev (n=46)	TACE-Alone (n=109)	P value	SMD	TACE + Atez/Bev (n=42)	TACE-Alone (n=42)	P value	SMD
Sex			0.785	0.049			0.405	0.095
Male	38(82.6)	88 (80.7)			36(85.7)	32(76.2)
Female	8(17.4)	21(19.3)			6(14.3)	10(23.8)
Age			0.311	0.177			0.825	−0.024
<65 years	26(56.5)	71(65.1)			25(59.5)	24(57.1)
≥65 years	20(43.5)	38(34.9)			17(40.5)	18(42.9)
HBsAg			0.969	0.007			0.801	0.024
Seropositive	36(78.3)	85(78.0)			32(76.2)	31(73.8)
Seronegative	10(21.7)	24(22.0)			10(23.8)	11(26.2)
Child-Pugh			0.637	0.074			0.771	0.048
A	38(82.6)	93(85.3)			34(81.0)	36(85.7)
B7	8(17.4)	16(14.7)			8(19.0)	6(14.3)
AFP			0.989	0.002			1.000	−0.024
<400 ng/mL	24(52.2)	57(52.3)			22(52.4)	21(50.0)
≥400 ng/mL	22(47.8)	52(47.7)			20(47.6)	21(50.0)
PIVKA-II			0.594	−0.107			1.000	0.000
<400 mAU/mL	29(63.0)	63(57.8)			26(61.9)	26(61.9)
≥400 mAU/mL	17(37.0)	46(42.2)			16(38.1)	16(38.1)
ALT			0.906	0.021			0.662	0.048
<40 U/L	24(52.2)	58(53.2)			21(50.0)	23(54.8)
≥40 U/L	22(47.8)	51(46.8)			21(50.0)	19(45.2)
AST			0.676	0.074			0.825	−0.024
<40 U/L	19(41.3)	49(45.0)			18(42.9)	17(40.5)
≥40 U/L	27(58.7)	60(55.0)			24(57.1)	25(59.5)
ALB			0.429	−0.056			0.405	−0.095
<35 g/L	11(23.9)	20(18.3)			10(23.8)	6(14.3)
≥35 g/L	35(76.1)	89(81.7)			32(76.2)	36(85.7)
Tbil			0.477	−0.126			0.362	0.095
<17.1 umol/L	29(63.0)	62(56.9)			25(59.5)	29(69.0)
≥17.1 umol/L	17(37.0)	47(43.1)			17(40.5)	13(31.0)
ALBI grade			0.432	−0.137			1.000	0.000
1	23 (50.0)	47(43.1)			20(47.6)	20(47.6)
2	23(50.0)	62(56.9)			22(52.4)	22(52.4)
Liver cirrhosis			0.538	−0.108			0.821	−0.024
Yes	28(60.9)	72(66.1)			26(61.9)	27(64.3)
No	18(39.1)	37(33.9)			16(38.1)	15(35.7)
Number of nodules			0.959	0.009			0.450	0.071
2–3	34(73.9)	81(74.3)			30(71.4)	33(78.6)
>3	12(26.1)	28(25.7)			12(28.6)	9(21.4)
Largest tumor size			0.428	−0.139			0.659	0.048
≤5cm	20 (43.5)	40(36.7)			17(40.5)	19(45.2)
>5cm	26(56.5)	69(63.3)			25(59.5)	23(54.8)
Up-to-7 criteria			0.295	−0.182			0.821	0.024
Within	17(37.0)	31(28.4)			15(35.7)	16(38.1)
Beyond	29(63.0)	78(71.6)			27(64.3)	26(61.9)

Notes: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab.

Abbreviations: PSM, propensity score matching; SMD, Standardized Mean Difference; TACE, transarterial chemoembolization; HBsAg, hepatitis B surface antigen; AFP, alpha‐fetoprotein concentration; PIVKA-II, Protein Induced by Vitamin K Absence or Antagonist II; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; Tbil, total bilirubin; ALBI, Albumin-bilirubin grade.

Figure 1 Diagram of patient screening.

Notes: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab.

Abbreviations: TACE, transarterial chemoembolization; HCC, hepatocellular carcinoma.

Figure 2 Kaplan-Meier curves for OS in patients with intermediate-stage HCC treated with TACE + Atez/Bev or TACE-alone before and after PSM. (2A) before PSM; (2B) after PSM.

Notes: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab.

Abbreviations: TACE, transarterial chemoembolization; OS, overall survival; HCC, hepatocellular carcinoma; PSM, propensity score matching.

Figure 3 Kaplan-Meier curves for PFS in patients with intermediate-stage HCC treated with TACE + Atez/Bev or TACE-alone before and after PSM. (3A) before PSM; (3B) after PSM.

Notes: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab.

Abbreviations: TACE, transarterial chemoembolization; PFS, progression‐free survival; HCC, hepatocellular carcinoma; PSM, propensity score matching.

Table 2 Univariate and Multivariate Cox Proportional Hazards Regression Model Analysis of OS and PFS After PSM

Variable	OS				PFS
	Univariate Analysis HR (95% CI)	P value	Multivariate Analysis HR (95% CI)	P value	Univariate Analysis HR (95% CI)	P value	Multivariate Analysis HR (95% CI)	P value
Sex
Male / Female	1.19(0.45–3.12)	0.723			0.94(0.47–1.89)	0.870
Age (year)
≥65 / <65	0.75(0.35–1.61)	0.459			0.70(0.39–1.26)	0.234
HBsAg
Seropositive /Seronegative	1.77(0.68–4.65)	0.245		–	1.21(0.63–2.31)	0.576
Child-Pugh
B7 / A	1.72(0.73–4.04)	0.212			1.45(0.72–2.91)	0.298
AFP (ng/mL)
≥400 / <400	1.08(0.52–2.24)	0.837			1.62(0.92–2.86)	0.094^a	1.36(0.73–2.53)	0.327
PIVKA-II (mAU/mL)
≥400 /<400	1.80(0.87–3.73)	0.116^a	1.07 (0.50–2.32	0.857	1.61(0.92–2.84)	0.096^a	1.13(0.60–2.11)	0.708
ALT (U/L)
≥40 /<40	1.15(0.55–2.40)	0.708			1.03(0.58–1.80)	0.932
AST (U/L)
≥40 /<40	1.80(0.82–3.95)	0.145^a	1.33(0.58–3.04)	0.503	1.45(0.81–2.60)	0.214
ALB g/L
≥35 /<35	0.89(0.36–2.18)	0.796		-	0.93(0.45–1.93)	0.854
Tbil (umol/L)
≥17.1 / <17.1	1.40(0.67–2.91)	0.369			1.30(0.74–2.31)	0.362
ALBI grade
2 / 1	1.54(0.73–3.27)	0.260			1.31(0.74–2.31)	0.351
Liver cirrhosis
Yes / No	2.27(0.97–5.32)	0.060^a	1.92(0.77–4.75)	0.160	1.65(0.90–3.03)	0.107^a	1.39(0.73–2.65)	0.315
Number of nodules
>3/2-3	2.56(1.18–5.55)	0.018^a	1.29(0.56–2.93)	0.552	1.45(0.76–2.75)	0.259
Largest tumor size
>5cm /≤5cm	3.59(1.46–8.84)	0.005^a	0.81(0.24–2.71)	0.729	2.02(1.11–3.67)	0.022^a	0.79(0.31–2.02)	0.624
Up-to-7 criteria
Beyond/Within	7.28(2.20–24.15)	0.001^a	7.55(1.53–37.34)	0.013^b	2.69(1.40–5.17)	0.003^a	3.01(1.11–8.19)	0.031^b
Treatment method
TACE+Atez/Bev / TACE alone	0.36(0.17–0.79)	0.010^a	-	-	0.47(0.26–0.84)	0.011^a	-	-

Note: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab. a, P value < 0.2 in univariate analysis; b, P value <0.05 in multivariate analysis.

Abbreviations: OS, Overall survival; PFS, progression-free survival; PSM, propensity score matching; HBsAg, hepatitis B surface antigen; AFP, alpha‐fetoprotein concentration; PIVKA-II, Protein Induced by Vitamin K Absence or Antagonist II; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; Tbil, total bilirubin; ALBI, Albumin-bilirubin grade; TACE, transarterial chemoembolization;

Table 3 Best Tumor Response According to mRECIST After PSM

Tumor response	TACE + Atez/Bev (n=42)	TACE-Alone (n=42)	P value
CR	12(28.6)	5(11.9)
PR	16(38.1)	11(26.2)
SD	11(26.2)	8(19.0)
PD	3(7.1)	18(42.9)
ORR	28(66.7)	16(38.1)	0.009^a
DCR	39(92.9)	24(57.1)	<0.001^a

Notes: TACE + Ate/Bev, TACE plus atezolizumab plus bevacizumab. a, P value < 0.05.

Abbreviations: PSM, propensity score matching; TACE, transarterial chemoembolization; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.

Figure 4 Forest plot of OS in subgroup analysis after PSM.

Notes: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab.

Abbreviations: OS, overall survival; PSM, propensity score matching; TACE, transarterial chemoembolization; HBsAg, hepatitis B surface antigen; AFP, alpha‐fetoprotein concentration; PIVKA-II, protein induced by vitamin K absence or antagonist II; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; Tbil, total bilirubin; ALBI, albumin-bilirubin grade.

Figure 5 Forest plot of PFS in subgroup analysis after PSM.

Notes: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab.

Abbreviations: PFS, progression‐free survival; PSM, propensity score matching; TACE, transarterial chemoembolization; HBsAg, hepatitis B surface antigen; AFP, alpha‐fetoprotein concentration; PIVKA-II, protein induced by vitamin K absence or antagonist II; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; Tbil, total bilirubin; ALBI, albumin-bilirubin grade.

Table 4 Treatment Emergent Adverse Events

AEs	Any Grade, n (%)			Grade ≥3, n (%)
	TACE+Atez/Bev (n=46)	TACE Alone (n=109)	P value	TACE+Atez/Bev (n=46)	TACE Alone (n=109)	P value
Fatigue	11(23.9)	14(12.8)	0.087	2(4.3)	0	0.087
Fever	12(26.1)	23(21.1)	0.498	0	0	–
Abnormal pain	10(21.7)	17(15.6)	0.357	0	2(1.8)	1.000
Diarrhea	9(19.6)	0	–	2(4.3)	0	–
Hand-foot skin reaction	4(8.7)	0	-	0	0	-
Nausea	11(23.9)	25(22.9)	0.895	0	1(0.9)	1.000
Decreased weight	5(10.9)	10(9.2)	0.770	0	0	-
Decreased appetite	11(23.9)	17 (15.6)	0.219	0	2(1.8)	1.000
Abdominal distention	10(21.7)	11(10.1)	0.053	1(2.2)	0	0.297
Hypothyroidism	4(8.7)	0	-	0	0	-
Hypertension	16(34.8)	32(29.4)	0.505	5(10.9)	3(2.8)	0.051
Peripheral edema	4(8.7)	0	-	0	0
Gastrointestinal hemorrhage	3(6.5)	1(0.9)	0.079	2(4.3)	1(0.9)	0.210
Constipation	5(10.9)	0	-	0	0	-
Elevated ALT	20(43.5)	33(30.3)	0.113	5(10.9)	11(10.1)	1.000
Elevated AST	19(41.3)	30(27.5)	0.092	3(6.5)	7(6.4)	1.000
Decreased albumin	17(37.0)	13(11.9)	<0.001^a	3(6.5)	0	0.025^a
Elevated Tbil	13(28.3)	25(22.9)	0.481	0	2(1.8)	1.000
Proteinuria	13(28.3)	0	-	2(4.3)	0	-
Platelet count decreased	8(17.4)	5(4.6)	0.021^a	0	0	-

Notes: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab. a, P value <0.05.

Abbreviations: AEs, adverse events; TACE, transarterial chemoembolization; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Tbil, total bilirubin.

Table 5 Alternative Treatment Approaches Adopted by Patients After Disease Progression

	TACE + Atez/Bev (n=46)	TACE-Alone (n=109)
Progression of HCC	24(52.2%)	71(65.1%)
Repeat TACE	21	58
Accepted other subsequent treatments	24	69
Atez +Lenvatinib	5	0
Ablation	3	11
HAIC	3	3
HAIC+ Lenvatinib	2	3
Lenvatinib	8	23
Sorafenib	0	4
Regorafenib	2	3
Radiotherapy	0	4
PD-1+Lenvatinib	0	8
FOLFOX4	0	1
PD-1+ Bevacizumab	0	4
Ablation + Lenvatinib	2	5
Refused treatment	0	2

Notes: TACE + Atez/Bev, TACE plus atezolizumab plus bevacizumab.

Abbreviations: Atez, atezolizumab; HAIC, Hepatic arterial infusion chemotherapy; PD-1, programmed cell death-1 inhibitor.

Data Sharing Statement

Data for this study can be reasonably obtained by contacting the corresponding authors.