Postoperative adjuvant therapy for hepatocellular carcinoma with microvascular invasion

Table 1 Transcatheter arterial chemoembolization approved as an adjuvant therapy for hepatocellular carcinoma patients with microvascular invasion

Ref.	Study type	Adjuvant therapy	Number	2-yr DFS (%)	P value	2-yr OS (%)	P value	PMID
Li et al[17]	RCT	HAIC	63	58.7	0.023	97.7	0.037	32418078
		NAT	64	38.6		78.5
Sun et al[72]	Retrospective	TACE	137	55.5	0.012	78.8	0.006	26714945
		NAT	185	36.2		62.2
Wei et al[73]	RCT	TACE	125	44.7	0.02	64.3	0.029	30305149
		NAT	125	30.6		49.8
Ye et al[13]	Retrospective	TACE	86	58.3	0.002	86.5	0.019	29151695
		NAT	174	41.1		65.7
Liu et al[74]	Retrospective	TACE	24	26.9	0.03	NA	NA	27038790
		NAT	26	4.2		NA
Wang et al[75]	Retrospective	TACE	57	66	0.008	94	0.04	30249510
		NAT	57	50		83
Cai et al[76]	Retrospective	TACE	25	39.1	0.06	NA	NA	34926296
		TACE + T cell self	23	58.2		NA
Kim et al[27]	RCT	HAIC	31	9.1	0.324	87.1	0.561	22067673
		NAT	62	4.2		78.3
Nitta et al[77]	Retrospective	HAIC	38	33.1		56.2	0.318	23435678

DFS: Disease-free survival; OS: Overall survival; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic arterial infusion chemotherapy; NAT: No adjuvant therapy; NA: Not available; RCT: Randomized clinical trial.

Table 2 Tyrosine kinase inhibitor approved as an adjuvant therapy for hepatocellular carcinoma patients with microvascular invasion

NCT number	Title	Interventions	Characteristics	n	Date	Current status
NCT02678806	Radiotherapy in Hepatocellular Carcinomas After Hepatectomy With Narrow Margin (< 1 cm) and/or Microvascular Invasion (RHCC:BCLC-A)	Radiation: Postoperative radiotherapy. Drug: Postoperative TACE	Phase: Not applicable. Allocation: Randomized. Intervention model: Parallel. Outcome measures: Overall survival	620	November 1, 2017 to November 1, 2022	Recruiting
NCT04053972	The Impact on Recurrence Risk of Adjuvant Lenvatinib for Patients With Hepatocellular Carcinoma And Microvascular Invasion (MVI) After Hepatectomy: A Random, Controlled, Stage III Clinical Trial	Drug: Lenvatinib	Phase: 3. Allocation: Randomized. Intervention model: Parallel. Outcome measures: RFS and OS recurrence rate	377	January 31, 2018 to December 31, 2022	Recruiting
NCT02867280	Sorafenib Treatment in Patients With Hepatocellular Carcinoma With Microvascular Invasion After Radical Resection	Drug: Sorafenib	Phase: 3. Allocation: Non_x005f randomized. Outcome measures: Recurrence free survival; time to recurrence; recurrence rate; overall survival; incidence of treatment related; adverse events; incidence of dose modification of sorafenib due to adverse events	154	June 1, 2016 to January 31, 2020	Terminated
NCT03192618	The Impact on Recurrence Risk of Adjuvant Transarterial Chemoinfusion (TAI) for Patients With Hepatocellular Carcinoma And Microvascular Invasion (MVI) After Hepatectomy: A Random, Controlled, Stage III Clinical Trial	Procedure: Adjuvant transarterial chemoinfusion. Drug: mFOLFOX6 (oxaliplatin, calcium folinate, and 5-fluorouracil)	Phase: 3. Allocation: Randomized. Outcome measures: DFS; recurrence rate; OS	290	July 1, 2017 to December 31, 2024	Recruiting
NCT02436902	Adjuvant Therapies for Patients With HCC and MVI	Procedure: TACE. Drug: Sorafenib, TACE plus sorafenib and empty control	Phase: 3. Allocation: Non_x005f randomized. Outcome measures: Overall survivals; hospital mortality; recurrence rates	240	February 1, 2019 to August 30, 2022	Recruiting
NCT03732105	Radiotherapy/Apatinib for Adjuvant Treatment of HCC Patients receIved Curative resection With Microvascular Invasion	Radiotherapy. Drug: Apatinib and radiotherapy + apatinib	Phase: 2. Allocation: Randomized. Outcome measures: RFS; time to recurrence; overall survival; safety events; health related quality of life	160	November 1, 2018 to December 31, 2023	Not yet recruiting
NCT03575806	Combine TACE and Autologous Tcm Immunotherapy Versus TACE Alone for HCC With MVI After Radical Resection	Combination product: TACE plus autologous Tcm immunotherapy. Procedure: TACE	Phase: 2. Allocation: Non_x005f randomized. Outcome measures: RFS time; OS rate at 24 mo	52	January 9, 2017 to October 31, 2019	Completed
	Should we apply sorafenib in hepatocellular carcinoma patients with microvascular invasion after curative hepatectomy?	Drug: Sorafenib	Phase: Not applicable. Allocation: Retrospective study. Outcome measures: DFS; recurrence rate; OS	49	January, 2009 to December, 2016	Completed
	Microvascular Invasion as a Predictor of Response to Treatment with Sorafenib and Transarterial Chemoembolization for Recurrent Intermediate-Stage Hepatocellular Carcinoma	Procedure: TACE. Drug: Sorafenib, TACE plus sorafenib, and TACE	Phase: Not applicable. Allocation: Retrospective study. Outcome measures: DFS; recurrence rate; OS	127	January, 2010 to December, 2016	Completed
	Postoperative adjuvant sorafenib improves survival outcomes in hepatocellular carcinoma patients with microvascular invasion after R0 liver resection: a propensity score matching analysis	Drug: Sorafenib	Phase: Not applicable. Allocation: Retrospective study. Outcome measures: DFS; recurrence rate; OS	728	January, 2009 to December, 2016	Completed
NCT00692770	Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial	Drug: Sorafenib	Phase: 3. Allocation: Randomized. Outcome measures: DFS; recurrence rate; OS	1114	August 15, 2008 to November 17, 2010	Completed

TACE: Transcatheter arterial chemoembolization; DFS: Disease-free survival; OS: Overall survival; RFS: Recurrence-free survival; HCC: Hepatocellular carcinoma; MVI: Microvascular invasion.

Table 3 Immune checkpoint inhibitors as an adjuvant therapy for hepatocellular carcinoma patients with microvascular invasion

NCT number	Title	Interventions	Characteristics	n	Date	Current status
NCT04682210	Sintilimab Plus Bevacizumab as Adjuvant Therapy in HCC Patients at High Risk of Recurrence After Curative Resection	Drug: Sintilimab. Drug: Bevacizumab	Phase: 3. Allocation: Randomized. Intervention model: Parallel	246	December, 2020 to December, 2024	Not yet recruiting
NCT04981665	A Study to Evaluate TACE Sequential Tislelizumab as Adjuvant Therapy in Participants With HCC at High Risk of Recurrence After Curative Resection	Drug: Tislelizumab. Drug: TACE	Phase: 2. Allocation: N/A. Intervention model: Single group assignment	50	November 8, 2021 to December, 2024	Recruiting
NCT05407519	A Study to Evaluate Tislelizumab Combined With Sitravatinib as Adjuvant Therapy in Participants With HCC at High Risk of Recurrence After Curative Resection	Drug: Tislelizumab. Drug: Sitravatinib	Phase: 2. Allocation: N/A. Intervention model: Single group assignment	52	July 25, 2022 to June 30, 2026	Recruiting
NCT04639180	A Study to Evaluate Camrelizumab Plus Rivoceranib (Apatinib) as Adjuvant Therapy in Patients With Hepatocellular Carcinoma (HCC) at High Risk of Recurrence After Curative Resection or Ablation	Drug: Camrelizumab.Drug: Rivoceranib (apatinib)	Phase: 3. Allocation: Randomized. Intervention model: Crossover assignment	674	April 1, 2021 to July 31, 2024	Recruiting
NCT03839550	Combine Apatinib Mesylate With PD-1 Antibody SHR-1210 for HCC With High Risk of Recurrence After Radical Resection	Drug: Apatinib Mesylate. Drug: SHR-1210	Phase: 2. Allocation: Randomized. Intervention model: Parallel	200	February 15, 2019 to February 28, 2023	Not yet recruiting
NCT03847428	Assess Efficacy and Safety of Durvalumab Alone or Combined With Bevacizumab in High Risk of Recurrence HCC Patients After Curative Treatment (EMERALD-2)	Drug: Durvalumab. Drug: Bevacizumab. Other: Placebo	Phase: 3. Allocation: Randomized. Intervention model: Parallel	908	April 29, 2019 to May 31, 2024	Not yet recruiting
NCT04102098	A Study of Atezolizumab Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation (IMbrave050)	Drug: Atezolizumab. Drug: Bevacizumab	Phase: 3. Allocation: Randomized. Intervention model: Parallel	668	December 31, 2019 to July 16, 2027	Not yet recruiting

TACE: Transcatheter arterial chemoembolization; HCC: Hepatocellular carcinoma.

Table 4 Adjuvant therapy after liver transplantation

Ref.	Interventions	Characteristics	n	Result	PMID
Rodríguez-Perálvarez et al[53]	Drug: mTOR inhibitors	Multicenter retrospective study	219	Effective	23867318
Vivarelli et al[54]	Drug: Cyclosporine	Retrospective study	70	Effective	15838913
Vivarelli et al[55]	Drug: Tacrolimus	Retrospective study	139	Ineffective	18948815
Geissler et al[56]	Drug: Sirolimus	Phase: 3. Allocation: Randomized. Intervention model: Parallel	525	Ineffective	26555945
Friend et al[78]	Drug: Nivolumab	Retrospective study	2	Ineffective	28643391
Biondani et al[60]	Drug: Nivolumab	Case report	1	Ineffective	29293878
DeLeon et al[61]	Drug: PD-1/PD-L1 inhibitors	Retrospective study	7	Partly effective	30603124
Gassmann et al[63]	Drug: Nivolumab	Case report	1	Ineffective	30255136
Varkaris et al[65]	Drug: Pembrolizumab	Case report	1	Ineffective	29215617
Iavarone et al[79]	Drug: Sorafenib	Multicenter retrospective study	28	Ineffective	31365177

mTOR: Mammalian target of rapamycin; PD-1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1.