Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma

Table 1 Selected studies on the use of adjuvant antiviral therapy

Ref.	Study type	Arms and Intervention	Number of patients	Main outcomes	Comments
Outcomes of adjuvant interferon-based therapy for HCV-related hepatocellular carcinoma.
Ikeda et al (2000)[167]	RCT	36 mo of Interferon (IFN) with 2-yr follow-up	20 (8 per arm)	IFN treatment decreased tumor recurrence.	Included 4 patients treated with PEI.
Kubo et al (2001,[75] 2002,[77] 2005[76])	RCT	88 weeks of IFN versus no therapy. Median follow up of 1087 days.	30 (15 per arm)	IFN decreased the recurrence and survival after resection	All male patients with high viral loads.
Hsu et al (2013)[78]	Retrospective Cohort	PEG-IFN + Ribavirin for > 16 weeks versus no therapy.	1065 (213 treatment and 852 controls)	PEG-IFN + Ribavirin associated with decrease 1‐, 3‐ and 5‐yr recurrence rate of HCC and 1‐, 3‐ and 5‐yr mortality.	The NNT for one fewer recurrent HCC at 5 yr = 8. Risk attenuation higher in younger patients.
Lee et al (2013)[79]	Prospective Cohort	PEG-IFN for 12 mo versus no therapy. Median follow up of 24 mo.	93 (31 treatment and 62 controls)	PEG-IFN associated with decrease 1‐and 2‐year recurrence and higher 1‐ and 2‐year survival.	All patients had MTA1‐positive HCC and high viral levels.
Wu et al (2018)[80]	Meta-analysis	PEG-IFN versus no therapy	4 cohort studies, 1280 patients. 3 studies had 5-year survival data with 276 PEG-IFN and 911 control total.	PEG-IFN improved the 3- and 5-yr RFS and 5-yr OS.	Included data from Hsu et al, and Lee et al
Outcomes of nucleoside analog treatment for HBV related HCC
Wu et al (2012)[90]	Retrospective Cohort	Nucleoside analog for at least 90 days vs no therapy	4569 (518 treated and 4051 controls)	Nucleoside analog treatment was associated with a lower risk of HCC recurrence.	Nucleoside analogues included lamivudine, entecavir, and telbivudine
Yang et al (2012)[91]	Prospective Cohort	Antiviral therapy vs no treatment.	330 patients (142 treated vs 188 untreated). All high viral loads.	Antiviral therapy was associated with RFS and OS. High associated with poor OS and RFS	High viral load (≥ 10000 copies/mL) and low viral load (< 10000 copies/mL). Antiviral included lamivudine, adefovir dipivoxil, or entecavir.
Yin et al (2013)[88]	Two-stage longitudinal clinical study (RCT and non-RCT)	Nucleoside analog (NA) vs no therapy.	617 in non-RCT (215 treatment and 402 controls)	NA treatment improved postop liver function, decreased HCC recurrence, and improved postoperative survival	Lamivudine, adefovir dipivoxil, or entecavir.
			163 in RCT (81 treatment and 82 controls)
Chong et al (2015)[168]	Retrospective cohort	Antiviral therapy vs no therapy	404 (254 antiviral and 150 controls)	Antiviral therapy improves long‐term survival post‐hepatectomy. No difference in early or late recurrence.
Zhang et al (2015)[74]	Retrospective cohort	Entecavir antiviral therapy vs no therapy	112 (72 antiviral and 40 controls)	Antiviral treatment improves morbidity and improved postoperative liver function.	Patients with preop HBV DNA > 104 copies/mL received antiviral therapy as well.
Huang et al (2015)[72]	RCT	adefovir antiviral therapy vs no therapy	200 (100 antiviral and 100 controls)	adefovir antiviral therapy reduced late HCC recurrence and improved OS	Patients had high preoperative HBV DNA (> 2000 IU/mL)
Huang et al (2018)[92]	RCT	Telbivudine antiviral therapy vs no therapy	200 (100 antiviral and 100 controls)	Telbivudine HCC resulted in better 5-year OS and RFS, as well as a lower rate of HBV reactivation	Patient with low (< 2000 IU/mL) HBV DNA titer.

HCV: Hepatitis C virus; RCT: Randomized controlled trial; IFN: Interferon; PEI: Percutaneous ethanol injection; PEG-IFN: Pegylated interferon; HCC: Hepatocellular carcinoma; NNT: Number needed to treat; OS: Overall survival; RFS: Recurrence-free survival; NA: Nucleos(t)ide analog; HBV: Hepatitis B virus.

Table 2 Selected studies on the use of adjuvant transarterial chemotherapy

Ref.	Study type	Arms and intervention	Number of patients	Main outcomes	Comments
Peng et al (2009)[169]	Retrospective cohort	LR vs LR+TACE	53 control vs 51 treatment (TACE)	Improved 1-, 3- and 5-yr survival with TACE	HCC< 3 cm + portal vein thrombosis
Liu et al (2016)[118]	Retrospective cohort	LR vs LR+TACE	55 Control vs 62 Treatment	Overall: Improved 1-year OS with TACE, but no difference in 2- and 3-yr DFS rates.	For tumor size > 5 cm: improve 1-, 2- and 3-yr DFS. For tumor size ≤ 5 cm: no difference in 1-, 2- and 3-yr DFS
Li et al (2017)[117]	Retrospective cohort	LR vs LR+TACE	459 control vs 295 treatment	LR + TACE improved postoperative recurrence and long-term survival.	Patients with HCC beyond Milan Criteria.
Ye et al (2017)[170]	Retrospective cohort	LR vs LR+TACE	260 microvascular invasion (86 in LR +TACE) resection; 259 w/o microvascular invasion (72 in LR+TACE) arm	LR + TACE improved OS and DFS in patients with microvascular invasion but not in patients without microvascular invasion.	All patients had BCLC Stage A or B
Qi et al (2018)[171]	Retrospective cohort	LR vs LR+TACE	200 patients with microvascular invasion (91 LR +TACE vs 109 LR only)	Similar 1-, 2- and 3-yr DFS between groups. Subgroup with tumor size > 5 cm had better DFS and OS with LR+TACE.	All patients had microvascular invasion and were BCLC A or B stage.
Liao et al (2017)[123]	Meta-analysis	LR vs LR+TACE	8 RCTs and 12 retrospective studies, totaling 3191 patients (1193 treatment vs 1952 control).	Significantly higher RFS and OS benefit with postoperative adjuvant TACE compared to surgery alone	Good consistency in findings between RCTs and non-RCTs, however, chemotherapy regimens differed between centers/trials.

LR: Liver resection; LR+TACE: Liver resection plus adjuvant transarterial chemoembolization; HCC: Hepatocellular carcinoma; DFS: Disease-free survival; OS: Overall survival; BCLC: Barcelona Clinic Liver Cancer; RCT: Randomized controlled trial; RFS: Recurrence-free survival.