Combining local regional therapy and systemic therapy: Expected changes in the treatment landscape of recurrent hepatocellular carcinoma

Table 1 Clinical studies of systemic therapy in recurrent hepatocellular carcinoma after liver transplantation

Ref.	Medication regimen	Study type	Number of patients	OS (mo)	PFS (mo)	1-yr OS
Iavarone et al[125]	Regorafenib	Retrospective	28	12.9
Li et al[126]	Sorafenib 79%; lenvatinib 2.3%; chemotherapy 4.7%; chemotherapy plus bevacizumab 7.0%; pembrolizumab 2.3%	Retrospective	41	17.0
Li et al[127]	Sorafenib	Retrospective	10	10.0
de'Angelis et al[128]	Sorafenib	Retrospective	15			60%
Gomez-Martin et al[129]	Sorafenib	Retrospective	31	19.3	6.77
Zavaglia et al[130]	Sorafenib	Retrospective	11	5.0
Staufer et al[131]	Sorafenib	Retrospective	13	7.0
López Ortega et al[132]	Sorafenib	Retrospective	17			62%
Weinmann et al[133]	Sorafenib	Retrospective	11	20.1
Piñero et al[134]	Lenvatinib	Case	1	84.0
Sotiropoulos et al[135]	Sorafenib	Retrospective	14	25.0

OS: Overall survival; PFS: Progression-free survival.

Table 2 Clinical studies of systemic therapy combined with local regional therapy in recurrent hepatocellular carcinoma

Ref.	Interventions	Study type	Disease	Outcome
Wang et al[160]	Anti-PD-1 + RFA (n = 40) vs RFA (n = 40)	Retrospective	Recurrent HCC after resection	RFS 39.1 wk vs 19.3 wk, P = 0.002
Gu et al[161]	Apatinib + TACE (n = 40) vs TACE (n = 40)	Prospective	Intrahepatic recurrence after resection	RFS 17.2 mo vs 12.5 mo, P = 0.041
Peng et al[162]	Sorafenib + TACE (n = 128) vs TACE (132)	Retrospective	Intermediate-stage recurrent HCC	5-yr OS: 38.9% vs 20.5%, P = 0.01; 5-yr PFS, 37.5% vs 18.7%, P = 0.003
Wan et al[163]	Sorafenib + TACE (n = 127) vs TACE (n = 127)	Retrospective	Unresectable recurrent HCC	OS 30.7 mo vs 18.2 mo, P = 0.003
Zhou et al[164]	Sorafenib + RFA (n = 174) vs RFA (n = 174)	Retrospective (multicenter)	Recurrent HCC after curative resection	1-, 3-, 5-yr OS: 97.7%, 83.7%, 54.7% vs 93.1%, 61.3%, 30.9%, P < 0.001
Guo et al[165]	Camrelizumab + TACE (n = 20) vs TACE (n = 59)	Retrospective	Recurrent HCC after curative resection	ORR 40.0% vs 56.9% NS; PFS 6 mo vs 9 mo NS
Iwata et al[166]	Sorafenib + HAIC	Case	Recurrent HCC after resection	OS 24 mo
Chen et al[167]	Toripalimab + TKI + Radiation (n = 17)	Prospective	Advanced recurrent HCC	1-, 2-yr OS: 60%, 24%
Wei et al[168]	Sorafenib + RFA (n = 103) vs RFA (n = 108)	Retrospective (multicenter)	Early-stage recurrent HCC with MVI	RFS: 17.7 mo vs 13.1 mo, P < 0.001; OS: 32.0 mo vs 25.0 mo, P = 0.002
Feng et al[169]	Sorafenib + RFA (n = 48) vs RFA (n = 40)	Retrospective (multicenter)	BCLC Stage 0-B1 recurrent HCC	1-, 2-, 3-, and 4-yr OS: 85.6%, 64.0%, 58.7%, 50.3% vs 80.7%, 47.2%, 30.9%, 30.9%, P = 0.036
Mahn et al[170]	Resection, RFA; Sorafenib, Cabozantinib	Case	Recurrent HCC after LT	OS longer than 10 yr

HAIC: Hepatic artery infusion chemotherapy; HCC: Hepatocellular carcinoma; LT: Liver transplantation; MVI: Microvascular invasion; NS: Not significant; ORR: Objective response rates; OS: Overall survival; PD-1: Programmed death-1; PFS: Progression-free survival; RFA: Radiofrequency ablation; RFS: Relapse-free survival; TACE: Transhepatic arterial chemoembolization; TKI: Tyrosine kinase inhibitor.

Table 3 Ongoing clinical trials investigating systemic therapy and/or local regional therapy against hepatocellular carcinoma

Clinical trials number	Study type	Agent(s)	Local regional therapy	Estimated enrollment	Primary endpoint
chiCTR2100044057	Phase II	Camrelizumab + Bevacizumab	Microwave Ablation	30	PFS
chiCTR2100046533	Prospective	Apatinib + Camrelizumab	TACE	37	PFS
NCT05162898	Prospective	Toripalimab + Lenvatinib	Radiofrequency Ablation	90	PFS
NCT05010434	Phase II	Sintilimab + Bevacizumab	Radiofrequency Ablation		ORR
NCT05444478	Prospective	Lenavatinib	Microwave Ablation	274	3-yr PFS%
NCT05277675	Prospective	Tislelizumab/Sintilimab + Lenvatinib/Bevacizumab	Radiofrequency Ablation	160	1-yr PFS%
NCT05162898	Prospective	Toripalimab + Lenvatinib	Radiofrequency ablation	90	RFS
NCT04663035	Phase II	Tislelizumab	Ablation	120	1-yr PFS%
NCT05355155	Phase II	Bevacizumab + Biosimilar IBI305	-	15	ORR
NCT05103904	Phase II	Lenvatinib	-	19	ORR
NCT04615143	Prospective	Tislelizumab/Tislelizumab + Levatinib	-	80	PFS
NCT04564313	Phase I	Camrelizumab	-	20	ORR
NCT04237740	Phase III	Relenvatinib	-	40	3-yr PFS%
NCT04204850	Phase II	Cabozantinib		20	DCR

DCR: Disease control rates; ORR: Objective response rates; PFS: Progression-free survival; RFA: Radiofrequency ablation; RFS: Relapse-free survival; TACE: Transhepatic arterial chemoembolization.