Preventive treatments for recurrence after curative resection of hepatocellular carcinoma - A literature review of randomized control trials

Table 1 The important issues related to evaluation of efficacy of prevention of recurrence

Authors	Average tumor size	Definition of curative resection			1 year RR	1 year DFS	1 year OS
		Complete removal in operation	Negative in histology on surgical margin	Negative in post-operative exams
Kubo	2.6 cm	Yes	No	Yes	25%a	NA	92%
Lau	3.8 cm	Yes	Yes	No	NA	59.1%	86.4%
Tang	< 5 cm, complete tumor	Yes	Yes	No	6.5%	NA	NA
	capsule, without portal
	vein involvement
Poon[12]	> 5 cma	Yes	No	No	46%	NA	55.5%
Izumi[6]	> 5 cma	Yes	No	No	51.7%	43.0%	81.0%
Lai[8]	10.4 cm	Yes	No	Yes	20%-30%	69.0%	75%*

RR: Recurrence rate; DFS: Disease free survival; OS: Overall survival; NA: Data not available.

^aestimated according to the authors’ paper.

Table 2 Summary of RCTs to evaluate the efficacy of pre- and post-operative TACE on prevention of recurrence

Authors	Tumor factors	Treatment protocol	Sample size (Tx/Ctl)	Observation time	DFS (Tx vs Ctl)	OS (Tx vs Ctl)	Conclusions
Wu[18]	> 10 cm; resectable	Pre-operative TACE	52 (24/28)	2-10 years	3-year	3-year	Harmful
					39% vs 46%a	31% vs 62%a
Yamasaki[19]	2-5 cm; Single	Pre-operative TACE	97 (50/47)	4-6.6 years	39.1% vs 31.1%	NA	Not effective
Izumi[6]	With vessel	Post-operative TACE,	50 (23/27)	28.7 Months	3-year	3-year	Postpone
	involvement or	once L 3 ml/m2 + A		(median)	32% vs 11.7%	56.6% vs 53.4%	recurrence, but
	intrahepatic spreading	20 mg/m2 + M					change over
		10 mg/m2 + G or:					all survival
		L 2 ml/m2 + A + M
Lai[8]	Negative in lipiodol	Post-operative TACE,	66 (30/36)	Median 28.3	3-year	3-year	Harmful
	CT, angiography and	3 times L 10 ml + C		months	18% vs 48%	65% vs 67%a
	ultrasound one month	10 mg + EA (40 mg/m2 iv × 8)
	after operation
Lau[7]	Surgical	Post-operative TACE	43 (21/22)	14.1-69.7	3-year	3-year	Beneficial
	margin ≥ 1 cm	I131 Lipiodol		months	74.5% vs 36%	84.4% vs 46.3%

L: Lipiodol; M: Mitomycin; A: Adriamycin, G: Gelfoam; C: Cis-platin; Tx: Treatment; Ctl: Control; DFS: Disease free survival; OS: Overall survival.

^aestimated according to the figure in authors’ paper.

Table 3 Summary of locoregional or systemic chemotherapy for prevention of recurrence

Authors	Entry criteria	Treatment protocol	Sample size (Tx/Crl)	Observation time	DFS (Tx vs Ctl)	OS (Tx vs Ctl)	Conclusions
Yamamoto[20]	Liver cacner study	HCFU	67 (32/35)	6-10 years	Stage Ib cirrhosis	Stage I cirrhosis	Beneficial only to
	group of japan for	200 mg, bid			62% vs 32%	79% vs 70%	patients with
	UICC stage II HCCa				Stage II cirrhosis	Stage II cirrhosis	Stage I liver
					0% vs 0%c	59% vs 57%c	dys function
Kohno[21]	NA	UFT 300 mg, qd vs	88 (40/48)	NA	3-year	NA	Not effective
		UFT 300 mg, qd + A			37% vs 32%
		(ia, 40 mg/m2, once)
Ono[22]	NA	A 40 mg/m2 ia and	56 (29/27)	24 months	NA	NA	Not effective,with
		40 mg/m2 iv every					poor tolerance
		3 months for 2 years,
		and HCFU 300 mg
		qd for 2 years
Ueno[23]	NA	CDDP 50-80 mg and	21 (11/10)	> 1 year	70% vs 20%c	NA	Beneficial
		MMC 10 mg ia, 2-3 times

NA: Not available; A: Adriamycin or Epirubicin; ia: Intraarterially; iv: Intravenously; DFS: Disease free survival; OS: Overall survival.

^acomplete excision of a solitary tumor, less than 5 cm in diameter, with a tumor capsule and no vascular invasion to the first or second branches of the portal vein, or for other stage II tumors, complete removal with a surgical margin from the tumor edge of more than 1 cm;

^bsee the original paper;

^cestimated according to the figure in authors’ paper.

Table 4 A summary of RCT results of adoptive immunotherapy to prevent recurrence

Authors	Entry criteria	Treatment protocol	Sample size	Observation	DFS	OS	Conclusions
			(Tx/Ctl)	time	Tx vs Ctl	Tx vs Ctl
Une[30]	NA	A ia vs A + LAK and IL2 ia	24 (12/12)	NA	50% vs 8.3%	NA	Beneficial
Kawata[31]	NA	A ia vs A + IL2 + LAK ia	24 (12/12)	NA	NS	NA	Not beneficial
Lygidakis[32]	NA	No Tx vs	40 (20/20)	NA	Recurrence:	NA	Beneficial
		Chemoimmunotherapy			0/18 vs 7/17
Takayama[1]	Completely remove;	LAK IV at the 2nd,	155 (76/79)	> 5 years	3-year	5-year	Beneficial
	histologically negative	3rd, 4th, 12th, 24th week			48% vs 33%	68% vs 62%
	in surgical margin	after operation			5 year 37% vs 22%

ia: Intra-arterially; iv: Intravenously; NA: Not available; NS: Not significant; DFS: Disease free survival; OS: Overall survival; Tx: Treatment; Ctl: Control; LAK: Lymphokine activated killer cells; NA: Not available.

Table 5 Summary of RCTs of Interferon treatment

Authors	Entry criteria	Tx protocol	Sample size	Observation time	DFS	OS	Conclusions
					Tx vs Ctl	Tx vs Ctl
Ikeda[35]	Complete remove by	IFNβ 6MU im	20 (10/10)	2-34.6 months	1 year	NA	Beneficial
	resection or PEI	biw × 36 months			0% vs 62.5%
Kubo[14,36]	Complete remove,	IFNα 6MU biw × 2	30 (15/15)	1817 days (Tx)	Recurrence	NA	Beneficial
	negative in CT scan 3-4	weeks then tiw × 14		and 1487 (Ctl)	9/15 vs 13/15
	weeks after operation	weeks then biw × 88 weeks			P = 0.041

Table 6 Summary of RCTs of acyclic retinoic acid

Authors	Entry criteria	Tx protocol	Sample size	Observation time	Recurrence	OS	Conclusions
					Tx vs Ctl	Tx. vs Ctl
Muto[37,38]	Complete removal by resection	ARA	89 (44/45)	62 months	27% vs 49%	6 year	Beneficial
	or PEI, negative in postoperative	300 mg, bid		(Median)	(P = 0.04)	74% vs 46%
	Ultrasound or CT

Tx: Treatment; Ctl: Control; OS: Overall survival.