Alternative treatment strategies to sorafenib in patients with advanced hepatocellular carcinoma: a meta-analysis of randomized Phase III trials

Figures & data

Table 1 Demographic and disease characteristics of studies included

Study	Regimen	Patients	Median age, years (range)	Asian (yes/no)	Male/female	Etiology (HBV/HCV)	CP (A/B)	PS (0/1)	BCLC (B/C)	MVI/EHS (yes/no)	Jadad score
Cheng et al^Citation8	Sunitinib	530	57 (18–85)	411/119	436/94	290/113	529/0	278/248	67/462	418/112	3
	Sorafenib	544	59 (18–84)	418/126	459/85	288/119	541/1	288/254	89/454	415/129
Johnson et al^Citation9	Brivanib	577	61 (19–87)	346/231	483/94	254/116	531/46	361/216	95/444	361/216	5
	Sorafenib	578	60 (25–89)	372/206	484/94	258/119	531/47	352/226	97/449	361/217
Cainap et al^Citation10	Linifanib	514	59 (21–84)	339/175	444/70	275/130	484/30	323/191	81/433	362/152	3
	Sorafenib	521	60 (23–87)	350/171	436/85	276/129	493/26	344/176	102/418	364/157
Kudo et al^Citation12	Lenvatinib	478	63 (20–88)	321/157	405/73	NA	475/3	304/174	104/374	329/149	5
	Sorafenib	476	62 (22–88)	319/157	401/75	NA	471/5	301/175	92/384	336/140
Vilgrain et al^Citation15	SIRT	237	66 (60–72)	0/237	212/25	13/55	196/39	145/92	66/162	149/88	3
	Sorafenib	222	65 (58–73)	0/222	202/20	15/49	187/35	139/83	61/149	128/94
Chow et al^Citation16	SIRT	182	60 (47–72)	182/0	147/35	93/26	165/14	135/47	93/88	56/126	3
	Sorafenib	178	58 (47–68)	178/0	151/27	104/19	160/16	141/37	97/80	54/124

Abbreviations: SIRT, selective internal radiotherapy; HBV, hepatitis B virus; HCV, hepatitis C virus; PS, performance status; BCLC, Barcelona Clinic Liver Cancer; CP, Child–Pugh; MVI, macrovascular invasion; EHS, extrahepatic spread; NA, not available.

Figure 1 Study-selection procedure.

Abbreviations: TKIs, tyrosine-kinase inhibitors; SIRT, selective internal radiotherapy.

Figure 2 Overall survival and pooled estimates of other TKIs vs sorafenib.

Abbreviations: TKIs, tyrosine-kinase inhibitors; IV, inverse variance.

Figure 3 Time to progression and pooled estimates of other TKIs vs sorafenib.

Abbreviations: TKIs, tyrosine-kinase inhibitors; IV, inverse variance. sorafenib vs other TKIs

Table 2 Results of subgroup analyses for OS in studies of sorafenib vs other TKIs

	HR(95% CI)	P-value
Region
Asia	1.04 (0.91–1.20)	0.55
No Asia	1.23 (0.97–1.58)	0.09
AFP
<200 ng/mL	1.03 (0.81–1.30)	0.83
≥200 ng/mL	0.91 (0.69–1.19)	0.48
ECOG PS
0	1.00 (0.90–1.11)	0.98
1	1.04 (0.91–1.19)	0.56
Etiology
HBV(+)	0.97 (0.88–1.07)	0.57
HCV(+)	1.23 (0.91–1.65)	0.18
Tumor burden
MVI/EHS	1.00 (0.91–1.11)	0.95
No MVI/EHS	1.04 (0.89–1.21)	0.63

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; MVI, macrovascular invasion; EHS, extrahepatic spread; OS, overall survival; TKIs, tyrosine-kinase inhibitors.

Table 3 Summary of the RRs of treatment response rates

	Other TKIs vs sorafenib		SIRT vs sorafenib
	RR (95% CI)	P-value	RR (95% CI)	P-value
ORR	1.67 (1.15–2.43)	0.008	2.60 (1.69–4.00)	<0.0001
DCR	1.11 (0.98–1.26)	0.11	0.91 (0.81–1.02)	0.11

Abbreviations: TKIs, tyrosine kinase inhibitors; SIRT, selective internal radiotherapy; RR, risk ratio; CI, confidence interval; vs, versus; ORR, objective response rate; DCR, disease control rate.

Table 4 Summary of the RRs of grade 3/4 adverse events incidences in trials of other TKIs vs sorafenib

Adverse events	RR	95% CI	P-value
Hypertension	1.99	1.67–2.39	<0.00001
Fatigue	1.79	1.42–2.26	<0.00001
Thrombocytopenia	4.18	1.66–10.56	0.002
Decreased appetite	2.21	1.62–3.01	<0.00001
Vomiting	3.15	1.88–5.26	<0.0001
Hand-foot syndrome	0.39	0.19–0.82	0.01
Rash	0.34	0.17–0.68	0.002

Abbreviations: TKIs, tyrosine kinase inhibitors; RR, risk ratio.

Figure 4 Overall survival (OS) and pooled estimates of SIRT vs sorafenib.

Abbreviations: IV, inverse variance; TKIs, tyrosine-kinase inhibitors; SIRT, selective internal radiotherapy.

Figure 5 Time to progression (TTP) and pooled estimates of SIRT vs sorafenib.

Abbreviations: IV, inverse variance; TKIs, tyrosine-kinase inhibitors; SIRT, selective internal radiotherapy.

Table 5 Summary of the RRs of grade 3/4 adverse events incidences in trials of SIRT vs sorafenib

Adverse events	RR	95% CI	P-value
Diarrhea	0.10	0.03–0.28	<0.0001
Fatigue	0.42	0.26–0.69	0.0006
Hand-foot syndrome	0.04	0.01–0.22	0.0002
Pyrexia	0.21	0.03–1.75	0.15
Nausea	0.66	0.04–11.68	0.78
Abdominal pain	0.61	0.27–1.36	0.23
Ascites	1.20	0.58–2.48	0.62
Gastric ulcer	3.13	0.50–19.68	0.22
Upper gastrointestinal hemorrhage	0.61	0.22–1.67	0.34

Abbreviations: SIRT, selective internal radiotherapy; RR, risk ratio.

ChengALKangYKLinDYSunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trialJ Clin Oncol201331324067407524081937

 PubMed Web of Science ®Google Scholar

JohnsonPJQinSParkJWBrivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL studyJ Clin Oncol201331283517352423980084

 PubMed Web of Science ®Google Scholar

CainapCQinSHuangWTLinifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trialJ Clin Oncol201533217217925488963

 PubMed Web of Science ®Google Scholar

KudoMFinnRSQinSLenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trialLancet2018391101261163117329433850

 PubMed Web of Science ®Google Scholar

VilgrainVPereiraHAssenatEEfficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trialLancet Oncol201718121624163629107679

 PubMed Web of Science ®Google Scholar

ChowPKGandhiMTanSBSIRVENIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinomaJ Clin Oncol201836191913192129498924

 PubMed Web of Science ®Google Scholar