Neoadjuvant therapy: Dawn of reducing the high post-surgery recurrence rate of hepatocellular carcinoma

Table 1 Summary of neoadjuvant locoregional therapy studies in hepatocellular carcinoma in the last five years

Disease	HCC stage/liver function	Treatment arms (n)	Neoadjuvant duration (weeks)	Preoperative stopping time (weeks)	Median follow-up (months)	Primary endpoints findings	Ref.
Resectable HCC	BCLC A/B exceeding the Milan criteria	Neoadjuvant TACE (82) vs direct surgery (82)	4-6	NA	36	1-year OS (97.2% vs 82.4%); 2-year OS (88.4% vs 60.4%); 3-year OS (71.6% vs 45.7%; P = 0.0011)	Fang et al[11]
Resectable HCC (> 5 cm)	NA	Neoadjuvant TACE (60) vs direct surgery (324)	NA	NA	24	DFS (P = 0.935); OS (P = 0.172)	Giannone et al[12]
Resectable HCC (> 5 cm)	Child-Pugh A/B	Neoadjuvant TACE (30) vs Direct surgery (30)	12	NA	24	2-year DFS (P = 0.7045)	Kobayashi et al[13]
Resectable HCC with PVTT	Child-Pugh A	Neoadjuvant HAIC (65) vs direct surgery (55)	9.6	NA	36	1-year OS (94.9% vs 84.6%); 3-year OS (78% vs 47.6%); 5-year OS (66.4% vs 37.2%; P < 0.001)	Hu et al[16]
Centrally located resectable HCC	Child-Pugh A	Neoadjuvant IMRT (41) vs direct surgery (121)	5-6	4-12	45	1-year OS (95% vs 82%); 3-year OS (70% vs 64%); 5-year OS (70% vs 54%; P = 0.0099); 1-year DFS (71% vs 52%); 3-year DFS (53% vs 38%); 5-year DFS (37% vs 34%; P = 0.034)	Wei et al[19]
A single and small (≤ 5 cm) HBV-related resectable HCC	BCLC A	Neoadjuvant IMRT (30) vs direct surgery (30)	NA	4	68	DFS (P = 0.448)	Salem et al[20]

TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; IMRT: Intensity modulated radiotherapy; HCC: Hepatocellular carcinoma; PVTT: Portal vein tumor thrombus; BCLC: Barcelona Clinic Liver Cancer; OS: Overall survival; DFS: Disease-free survival; NA: Not available.

Table 2 Summary of neoadjuvant systemic antitumor treatment studies in hepatocellular carcinoma in the last five years

Disease	HCC stage/liver function	Treatment arms (n)	Neoadjuvant duration (weeks)	Preoperative stopping time (weeks)	Median follow-up (months)	Primary endpoints findings	Ref.
Resectable HCC	AJCC stage Ib, II, and IIIb	Neoadjuvant cemiplimab (21)	6	4	NA	Significant tumor necrosis: 20% (4/20)	Marron et al[26]
Locally advanced resectable HCC	Child-Pugh A	Neoadjuvant cabozantinib + nivolumab (15)	8	4	12	AEs: 93.3% (14/15)	Ho et al[27]
Resectable HCC	CNLC IIb/IIIa	Neoadjuvant camrelizumab + apatinib (18)	6	7	12	MPR: 17.6% (3/18); pCR: 5.9% (1/18)	Xia et al[28]
Resectable HCC	Child-Pugh A	Neoadjuvant nivolumab + ipilimumab (14) vs nivolumab (13)	6	NA	24.6	Grade 3 AEs: 43% (6/14) vs 23% (3/13)	Kaseb et al[29]

HCC: Hepatocellular carcinoma; AJCC: American Joint Committee on Cancer; CNLC: China Liver Cancer Stage; AEs: Adverse events; MPR: Major pathological response; NA: Not available.

Table 3 Summary of neoadjuvant locoregional combined with systemic antitumor treatment studies in hepatocellular carcinoma in the last five years

Disease	HCC stage/liver function	Treatment arms (n)	Neoadjuvant duration (weeks)	Preoperative stopping time (weeks)	Median follow-up (months)	Primary endpoints findings	Ref.
Resectable HCC	BCLC 0-A/CNLC I	Neoadjuvant tislelizumab + SBRT (20)	4	4	60	Delay of surgery: 0; AEs: 100%; Grade 3 AEs: 40% (8/20); Grade 4 or 5 AEs: 0; ORR: 63.2% (12/19); DCR: 100%; pCR: 10.5% (2/19)	Li et al[34]
Resectable HCC	CNLC II	Neoadjuvant TACE + ICIs (20)	8-22	4	24	ORR: 75.0% (15/20); DCR: 100.0%; 1-year DFS: 86.6%; 1-year OS: 100.0%; 2-year OS: 76.4%	Zhu et al[35]
Resectable or borderline Resectable HCC	CNLC Ib/IIa/IIIa	Neoadjuvant TACE + tislelizumab (41) vs direct surgery (41)	6	4	24	AEs: 87.8% (36/41); pCR: 31.7% (13/41); MPR: 43.9% (18/41); incidence of MVI: 4.9%	Zhao et al[36]
Resectable HCC	CNLC Ib-IIIa	Neoadjuvant lenvatinib + ICIs + TACE (24) vs direct surgery (76)	9	3	24	1-year OS (100% vs 92.1%); 2-year OS (100% vs 48.7%; P = 0.003)	Wu et al[37]
Resectable HCC with Cheng’s type I/II PVTT	Child-Pugh A	Neoadjuvant TKIs + ICIs + TACE (33) vs direct surgery (105)	6	4	60	1-year RFS (75.0% vs 55.0%); 3-year RFS (61.3% vs 22.7%); 5-year RFS (61.3% vs 19.9%; P = 0.002)	Hou et al[38]
Resectable HCC with macrovascular invasion	CNLC IIIa	Neoadjuvant TKIs + ICIs + TACE/HAIC/RT (22) vs direct surgery (40)	16	4	24	RFS (P = 0.046)	Wu et al[39]

TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; SBRT: Stereotactic body radiotherapy; HCC: Hepatocellular carcinoma; PVTT: Portal vein tumor thrombus; BCLC: Barcelona Clinic Liver Cancer; CNLC: China Liver Cancer Staging; OS: Overall survival; AEs: Adverse events; DFS: Disease-free survival; ORR: Objective response rate; MPR: Major pathological response; pCR: Pathological complete response; RFS: Recurrence free survival; DCR: Disease control rate; MVI: Microvascular invasion; TKIs: Tyrosine kinase inhibitors; ICIs: Immune checkpoint inhibitors; RT: Radiotherapy.