Sorafenib plus transarterial chemoembolization vs sorafenib alone for patients with advanced hepatocellular carcinoma: A systematic review and meta-analysis

Table 1 Baseline characteristics of patients with advanced hepatocellular carcinoma receiving sorafenib with or without add-on transcatheter arterial chemoembolization

Ref.	Study design	Group	Number of cases	Age1 (yr)	Male	ECOG-PS		BCLC stage			Child-Pugh class		AFP		PVTT
						0	1-2	A	B	C	A	B
Koch et al[19], 2021	Retrospective cohort study	Sorafenib + TACE	54	64 (34-77)	47 (87)	16 (30)	38 (70)	0 (0)	0 (0)	54 (100)	40 (74)	14 (26)	< 400 ng/mL; 36 (66)	≥ 400 ng/mL; 18 (34)	18 (33)
		Sorafenib alone	82	66 (28-85)	72 (88)	37 (45)	45 (55)	0 (0)	0 (0)	82 (100)	61 (74)	21 (26)	52 (64)	30 (36)	27 (33)
Park et al[20], 2019	Multi-center RCT phase III	Sorafenib + TACE	170	60 ± 10	136 (80)	136 (80)	34 (20)	3 (2)	39 (23)	128 (75)	148 (87)	22 (13)	< 200 ng/mL; 79 (47)	≥ 200 ng/mL; 91 (54)	68 (40)
		Sorafenib alone	169	61 ± 10	147 (87)	140 (83)	29 (17)	0 (0)	44 (26)	125 (74)	147 (87)	22 (13)	76 (45)	93 (55)	63 (37)
Kok et al[23], 2019	Retrospective cohort study	Sorafenib + TACE	426	60 (51-69)	355 (83)	NA		0 (0)	0 (0)	426 (100)	426 (100)	0 (0)	NA		NA
		Sorafenib alone	1686	60 (52-68)	1410 (84)	NA		0 (0)	0 (0)	1686(100)	1686 (100)	0 (0)	NA		NA
Wu et al[21], 2017	Retrospective study	Sorafenib + TACE	56	50 ± 12	48 (86)	NA		0 (0)	10 (18)	46 (82)	45 (80)	11 (20)	< 400 ng/mL; 33 (59)	≥ 400 ng/mL; 23 (41)	32 (57)
		Sorafenib alone	48	48 ± 13	46 (96)	NA		0 (0)	16 (33)	32 (67)	46 (96)	2 (4)	23 (49)	24 (51)	24 (50)
Zhang et al[22], 2015	Retrospective study	Sorafenib + TACE	45	50 ± 9	43 (96)		45 (100)	NA			34 (76)	11 (24)	< 200 ng/mL; 3 (7)	≥ 200 ng/mL; 42 (93)	45 (100)
		Sorafenib alone	44	54 ± 10	41 (93)		44 (100)	NA			34 (77)	10 (23)	9 (20)	35 (80)	44 (100)

¹Ages are expressed as the median (range) or mean ± SD.

Data are expressed as n (%) for categories. ECOG-PS: Eastern Cooperative Oncology Group performance status; BCLC: Barcelona Clinic Liver Cancer; AFP: Alpha-fetoprotein; PVTT: Portal vein tumor thrombus; TACE: Transcatheter arterial chemoembolization; NA: Not available.

Table 2 Intervention characteristics and outcome measures of the trials included in this meta-analysis

Ref.	Intervention	Patients	Follow-up (mo)	Sorafenib dose	Sorafenib duration (mo)	OS (mo)		TTP (mo)		PFS (mo)		DCR (%)
						Median	HR (95%CI)	Median	HR (95%CI)	Median	HR (95%CI)
Koch et al[19], 2021	TACE was usually initiated before sorafenib	54	NA	NA	NA	16.5	0.34 (0.23-0.53)	7.0	NA	NA	NA	28/53 (53)
	Sorafenib alone	82	NA		NA	8.4		4.1		NA		17/74 (23)
Park et al[20], 2019	Sorafenib initiated within 3 d of randomization, first TACE initiated between 7 and 21 d after randomization	170	14 (4-27)	200-400 mg twice daily, then 400 mg twice daily	5.5 (0.1-41.6)	12.8	0.91 (0.69-1.21)	5.3	0.67 (0.53-0.85)	5.2	0.73 (0.59-0.91)	103/170 (61)
	Sorafenib initiated within 3 d of randomization	169	19 (2-27)		4.3 (0.2-48.4)	10.8		3.5		3.6		80/169 (47)
Kok et al[23], 2019	Sorafenib prior to TACE	426	7.4 (4.7-11.5)	NA	4.7 (4.2-5.3)	12.5	0.74 (0.63-0.88)	4.7	0.76 (0.65-0.89)	NA	NA	NA
	Sorafenib alone	1686	4.4 (2.3-8.4)		2.8 (2.6-3.0)	6.7		2.8		NA
Wu et al[21], 2017	Sorafenib prior to TACE	56	NA	400 mg twice daily	NA	22	0.50 (0.28-0.89)	NA	NA	8	0.46 (0.27-0.78)	27/48 (56)1
	Sorafenib alone	48	NA		NA	18		NA		6		23/40 (58)
Zhang et al[22], 2015	Sorafenib started 1-3 d after TACE	45	7.3 (2-18)	NA	5.6 (1-18)	7	1.17 (0.52-1.81)	3	NA	NA	NA	24/43 (60)
	Sorafenib alone	44			5.4 (1-17)	6		3		NA		18/44 (51)

¹DCR was measured at the 6^th month.

Data are n (%) for categories, and median for continuous data. OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression; DCR: Disease control rate; TACE: Transarterial chemoembolization; HR: Hazard ratio; 95%CI: 95% confidence interval; NA: Not available.

Table 3 Quality assessment of included trials

Ref.	Newcastle-Ottawa scale
	Selection	Comparability	Outcome	Score	Quality
Koch et al[19], 2021	3	2	3	8	Good
Kok et al[23], 2019	3	2	3	8	Good
Wu et al[21], 2017	3	2	3	8	Good
Zhang et al[22], 2015	3	2	3	8	Good
Park et al[20], 2019	Jadad scale
	Randomization	Double blinding	Withdrawals and dropouts	Score	Quality
	2		1	3	Good

Table 4 Summary of adverse events occurring in either group of the trials included in this meta-analysis

Ref.	Group	Patients	AE
			Any	Grade ≥ 3	HFSR	Diarrhoea	Hypertension	Fatigue	Alopecia	Abdominal pain	Vomiting
Koch et al[19], 2021	Sorafenib + TACE	50	43 (86)	17 (34)	12 (24)	13 (26)	NA	3 (6)	NA	14 (41)	5 (14)
	Sorafenib alone	78	62 (80)	25 (32)	13 (17)	17 (22)	NA	6 (8)	NA	0 (0)	0 (0)
Park et al[20], 2019	Sorafenib + TACE	153	148 (97)	NA	74 (48)	60 (39)	27 (18)	24 (16)	23 (15)	82 (54)	31 (20)
	Sorafenib alone	167	151 (90)	NA	88 (53)	54 (32)	23 (14)	24 (14)	25 (15)	29 (17)	11 (7)
Kok et al[23], 2019	Sorafenib + TACE	NA
	Sorafenib alone	NA
Wu et al[21], 2017	Sorafenib + TACE	56	NA	13 (23)	30 (54)	25 (45)	13 (23)	12 (21)	4 (7)	NA	31 (55)
	Sorafenib alone	48	NA	14 (29)	36 (75)	27 (56)	22 (46)	12 (25)	3 (6)	NA	27 (56)
Zhang et al[22], 2015	Sorafenib + TACE	45	NA	12 (27)	29 (64)	20 (44)	1 (2)	11 (24)	25 (56)	26 (58)	21 (47)
	Sorafenib alone	44	NA	6 (14)	26 (59)	19 (43)	2 (5)	12 (27)	22 (50)	0 (0)	0 (0)

AE: Adverse event; HFSR: Hand-foot skin reaction; TACE: Transarterial chemoembolization; NA: Not available.