Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation

Table 1 Advantages and disadvantages of the bridging and downstaging procedures for hepatocellular carcinoma in cirrhotic patients who are candidates for liver transplantation

	Advantages	Disadvantages
Resection	Higher complete effectiveness than non-surgical procedures	Unfeasible in patients with decompensated liver disease or severe portal hypertension
	More simple in cases with peripheral subglissonian nodules
TACE	More effective using the selective/superselective technique in well-vascularized nodules with large feeding arteries	Unfeasible in patients with severely reduced portal vein flow, intratumoral arteriovenous fistula, or renal failure (creatinine clearance < 30 mL/min)
TARE	Possible better effectiveness than TACE in cases with multiple nodules	Less experience with TARE than TACEHigh cost
RFA	More effective in nodules ≤ 3 cm	Potentially dangerous in patients with impaired clotting parameters or lesions located superficially or near the gallbladder, major bile ducts, or bowel loops
PEI	More effective in nodules ≤ 3 cmSuitable in patients with impaired clotting parameters or lesions located in dangerous sites for thermal ablation	Less effective than RFA for nodules > 2 cm
PLA	More effective in nodules ≤ 3 cmSuitable in patients with impaired clotting parameters	Less experience with PLA than RFATechnically complexPotentially dangerous in cases of lesions located superficially or near the gallbladder, major bile ducts, or bowel loops
MWA	Possible better effectiveness than RFA in nodules ≥ 3 cm or located near large vessels	Less experience with MWA than RFAPotentially dangerous in patients with impaired clotting parameters or withlesions located superficially or near the gallbladder, major bile ducts, or bowel loops

TACE: Transarterial chemoembolization; TARE: Transarterial radio embolization; RFA: Radiofrequency ablation; PEI: Percutaneous ethanol injection; PLA: Percutaneous laser ablation; MWA: Microwave ablation.

Table 2 Selected studies on non-surgical bridging therapy for hepatocellular carcinoma before liver transplantation n (%)

Ref.	Treatment	Patients	HCC stage	Dropout rate -Total -HCC progression	HCC recurrence after LT	Intention-to-treat survival	Survival after LT
Fontana et al[99]	RFA	33 (15 LT)	MC (30 pts)	NA	2 (13)	NA	85% at 3 yr
Graziadei et al[60]	TACE	48 (41 LT)	MC	0	1 (2.4)	94% at 5 yr	94% at 5 yr
Hayashi et al[61]	TACE	20 (12 LT)	MC	6 (35)	NA	61% at 3 yr	100% at 4 yr
Maddala et al[98]	TACE	54 (46 LT)	MC (47 pts)	8 (14.8)	5 (13.3)	61% at 5 yr	74% at 5 yr
				6 (11.1)
Mazzaferro et al[73]	RFA	50 (50 LT)	MC (40 pts)	0 (0)	2 (4)	NA	83% at 3 yr
Lu et al[74]	RFA	52 (41 LT)	MC (42 pts)	6 (12)	0 (0)	74% at 3 yr	76% at 3 yr
				3 (5.8)
Castrogaudin et al[81]	PEI	34 (23 LT)	UNOS T1-T2 (30 pts)	5 (14.7)	1 (4.3)	NA	19/23 (82.6%) alive (median FU 21 mo)
				2 (5.9)
Pompili et al[75]	RFA, PEI	40 (40 LT)	MC (37 pts)	NA	3 (7.5)	NA	85.4% at 3 yr
Porrett et al[79]	TACE, RFA, TARE	31 (31 LT)	UNOS T1-T2	NA	7 (22.6)	NA	84% at 3 yr
Brillet et al[76]	RFA	21 (16 LT)	MC	5 (23.8)	1 (6.3)	NA	11/16 (69%) alive (median FU 25 mo)
				3 (14.3)
Millonig et al[63]	TACE	68 (66 LT)	MC	2 (3)	5 (7.6)	70% at 5 yr	NA
Majno et al[69]	TACE	43 (43 LT)	MC	12 (27.9)	4 (9.3)	NA	NA
				4 (9.3)
Rodríguez-Sanjuán et al[77]	RFA	28 (28 LT)	MC (25 pts)	NA	2 (7.1)	NA	NA
Alba et al[64]	TACE	63 (56 LT)	MC	7 (11)	6 (10.7)	NA	60.4% at 5 yr
				3 (4.8)
Branco et al[82]	PEI	62 (59 LT)	MC	3 (4.8)	3 (5.1)	64.4% at 3 yr	67.7% at 3 yr
DuBay et al[78]	RFA	77 (51 LT)	MC	19 (25)	1 (2)	NA	> 80% at 3 yr
				16 (21)
Ashoori et al[96]	TACE + RFA	36 (16 LT)	MC	6 (16.7)	0 (0)	NA	11/16 alive (median FU 29.9 mo)
				4 (11.1)
Tsochatzis et al[67]	TACE, TAE	67 (67 LT)	MC	NA	4 (6)	NA	NA

HCC: Hepatocellular carcinoma; LT: Liver transplantation; RFA: Radiofrequency ablation; MC: Milan criteria; NA: Not available; TACE: Transarterial chemoembolization; PEI: Percutaneous ethanol injection; UNOS: United Network for Organ Sharing; TARE: Transarterial radio embolization; TAE: Transarterial embolization.

Table 3 Selected studies on downstaging therapy for hepatocellular carcinoma before liver transplantation n (%)

Ref.	Treatment	Pts	Inclusion criteria1	Successful downstage-Criteria-Rate	Transplanted pts	Recurrence free survival after LT	Intention to treat survival	Survival after LT
Graziadei et al[60]	TACE	36	HCC > 5 cm	Decreased size > 50%11/36 (31)	10	Recurrent HCC: 3 pts (30)	31% at 5 yr	41% at 4 yr
Otto et al[116]	TACE	62	Beyond MC	Decreased size ≥ 30%34/62 (55)	27	68% at 5 yr	NA	73.2% at 5 yr
Cillo et al[4]	TACE, RFA, PEI, Resection	40	Beyond MCWD or MD HCC	Maintenance of selection criteriaNA	31	Recurrent HCC: 0 pts	79% at 5 yr	> 90% at 3 yr
Chapman et al[108]	TACE	76	Beyond MC	MC18/76 (24)	17	50% at 5 yr	NA	93.8% at 5 yr
Yao et al[106]	TACE, RFA, Resection	61	1 HCC 5-8 cm2-3 HCCs 3-5 cm, total diameter ≤ 8 cm4-5 HCCs ≤ 3 cm total diameter ≤ 8 cm	UCSF43/61 (71)	35	92% at 2 yr	69% at 4 yr	92% at 2 yr
Ravaioli et al[115]	Multimodal (TACE, PEI, RFA, Resection)	48	1 HCC 5-8 cm2 HCCs 3-5 cm, total diameter ≤ 8 cm3-5 HCCs ≤ 4 cm total diameter ≤ 12 cm	MC and AFP < 400 ng/mL32/48 (67)	32	71% at 3 yr	62% at 3 yr	NA
Lewandowski et al[109]	TACE (43 patients)TARE (43 patients)	86	UNOS T3	MCTACE 11/35 (31)TARE 25/43 (58)	TACE 11TARE 9	TACE 73% at 1 yrTARE 89% at 1 yr	TACE 19% at 3 yrTARE 59% at 3 yr	NA
De Luna et al[107]	TACI	27	Beyond MC	MC17/27 (63)	15	NA	84.1% at 3 yr	78.8% at 3 yr
Jang et al[110]	TACE	386	Beyond MC	MC or complete tumor necrosis160/386 (41.5)	37	66.3% at 5 yr	NA	54.6% at 5 yr
Barakat et al[111]	TACE, TARE, RFA, Resection	32	Beyond UCSF (18 pts)Beyond MC (14 pts)	UNOS T218/32 (56.3)	13	Recurrent HCC: 2 pts (15.4%)	NA	75% at 2 yr
Bargellini et al[112]	TACE	33	Beyond MC	Complete or partial response, or stable disease according to mRECIST criteriaNA	33	74.4% at 5 yr	NA	72.5% at 5 yr
Bova et al[113]	TACE, TAE	48	Beyond MC	MCAFP < 100 ng/mL19/48 (39)	9	Recurrent HCC: 1 pt (11.1%)	NA	NA
Lei et al[114]	TACE, RFA, Resection, HIFU	58	Beyond MC Within UCSF	MCNA	58	63.8% at 5 yr	NA	74.1% at 5 yr

¹Patients with vascular invasion or extrahepatic tumor spread at baseline excluded in all series. HCC: Hepatocellular carcinoma; LT: Liver transplantation; TACE: Transarterial chemoembolization; MC: Milan criteria; NA: Not available; RFA: Radiofrequency ablation; PEI: Percutaneous ethanol injection; WD: Well differentiated; MD: Moderately differentiated; UCSF: University of California San Francisco; AFP: α-fetoprotein; TARE: Transarterial radio embolization; UNOS: United Network for Organ Sharing; TACI: Transarterial chemoinfusion; mRECIST: Modified Response Evaluation Criteria in Solid Tumors; TAE: Transarterial embolization; HIFU: High-intensity focused ultrasound; pts: Patients.