Neo-adjuvant therapy for hepatocellular carcinoma before liver transplantation: Where do we stand?

Table 1 Studies of external beam radiotherapy for hepatocellular carcinoma before liver transplant

Ref.	n	Medial dose (Gy)/fractions (n)	Tumor (n)	Size of tumor (cm)	Child C n (%)	Patients who failed previous LRT	Radiological CR/PR	Transplanted after EBRT	HCC recurrence after LT
Sandroussi et al[50]	10	33/6	2 (1-10)	6.3 (2.2-10.8)	1 (10)	5	0/7	5	0
Andolino et al[13]	60	48/3	1 (1-3)	3.1 (1.0-6.5)	0	23	18/24	23	2
Katz et al[14]	18	50/10	1 (1-2)	4.0 (1.2-6.5)	4 (22)	3	0/4	11	0
O'Connor et al[49]	10	51/3	1 (1-2)	3.4 (2.5-5.5)	1 (10)	4	NA	10	0

HCC: Hepatocellular carcinoma; LRT: Locoreginal therapy; CR: Complete response; PR: Partial response; EBRT: External beam radiotherapy; NA: Not available.

Table 2 Studies of neo-adjuvant therapy for down-staging hepatocellular carcinoma before liver transplant

Ref.	Year	n	LRT	Inclusion criteria for DS protocol	Successful DS criteria	Mandatory waiting time prior to LT (mo)	The role of AFP	DS rate	LT (patients)	Waiting time to LT (mo)	Patient survival after LT	Recurrence-free survival after LT
Transarterial therapy alone
Otto et al[25]	2006	62	TACE	Beyond MC	30% decrease in size	No	NA	55%	27	5.9	73%	68% at 5 yr
										(1.9-19.3)	at 5 yr
Chapman et al[28]	2008	76	TACE	Beyond MC	MC	3-4	NA	24%	17	5.8 ± 3.5	94%	100%, 50%
											at 5 yr	at 3, 5 yr
De Luna et al[32]	2009	27	TACI	Beyond MC	MC	No	Not significant	63%	15	10.9	79%	NA
										(0.7-114.1)	at 3 yr
Multimodal approach
Yao et al[6]	2008	61	TACE, RFA,	One lesion, 5-8 cm	MC for DDLT	3	AFP > 1000 ng/mL	71%	35	8.2 (3-25)	92%	92%
			Resection	2-3 lesions, 3-5 cm,	UCSF criteria for LDLT		Predicts DS failure				at 2 yr	at 2 yr
				total diameter ≤ 8 cm
				4-5 lesions, ≤ 3 cm,
				total diameter ≤ 8 cm
Ravaioli et al[8]	2008	48	TACE, RFA	One lesion, 5-6 cm	MC and AFP ≤ 400 ng/mL	3	AFP ≤ 400 ng/mL, listing criteria	67%	32	6	NA	78%, 71%
			PEI, resection	2 lesions 3-5 cm			AFP > 30 ng/mL, predictor of recurrence after LT					at 1, 3 yr
				3-5 lesions, ≤ 4 cm, total diameter ≤ 12 cm
Barakat et al[44]	2010	32	TACE, RFA,	Beyond MC	MC	No	Failed vs successful DS	56%	14	11.2	92%, 75%	2 patients
			TARE, resection				5670 ng/mL vs 799 ng/mL			(4.4-22.6)	at 1, 2 yr	Recurrence

HCC: Hepatocellular carcinoma; LRT: Locoreginal therapy; DS: Down-stage; LT: Liver transplant; AFP: Alpha-fetoprotein; TACE: Transarterial chemoembolization; MC: Milan criteria; TACI: Transarterial chemo-infusion; RFA: Radiofrequency ablation; UCSF: University of California at San Francisco; PEI: Percutaneous ethanol injection; NA: Not available.

Table 3 Studies of bridging therapy for hepatocellular carcinoma before liver transplant n (%)

Ref.	Treatment	Tumor stage (n)	Number of treatments	Exclusion for LT	Tumor progression	Waiting time to LT (mo)	Intention to treat survival	Transplanted patients	Patient survival after LT
Graziadei et al[9]	TACE	Within MC (48)	2.5 (1-8)	MC	0 (0)	6.0 (0.9-15)	94% at 5 yr	41 (85)	94% at 5 yr
Yao et al[69]	TACE, RFA, PEI, resection	Within MC (70)	3.1 (1-8)	UCSF	18 (26)	6.1	57% at 3 yr	38 (54)	NA
Hayashi et al[29]	TACE	Within MC (20)	?	MC	4 (20)	11.4 ± 9.8	61% at 5 yr	12 (60)	100% at 4 yr
Maddala et al[27]	TACE	Within MC (47),	3 (1-4)	MC	6 (11)	7.0 (1-36)	61% at 5 yr	46 (85)	74% at 5 yr
		Beyond MC (7)
Mazzaferro et al[33]	RFA	Within MC (40),	1	MC	0 (0)	9.5 (2-47)	NA	50 (100)	83% at 3 yr
		Beyond MC (10)
Lu et al[34]	RFA	Within MC (42),	1.5	MC	3 (6)	12.7	74% at 3 yr	41 (79)	76% at 3 yr
		Beyond MC (10)
Millonig et al[10]	TACE	Within MC (68)	2.7 ± 1.7	UCSF	2 (3)	9.0 (1.2-34)	70% at 5 yr	66 (97)	NA
De Luna et al[32]	TACI	Within MC (95)	1.8 ± 1.1	MC	6 (6)	11.4 (1.0-133)	85% at 3 yr	68 (72)	82.4% at 3 yr

HCC: Hepatocellular carcinoma; LT: Liver transplant; TACE: Transarterial chemoembolization; MC: Milan criteria; RFA: Radiofrequency ablation; PEI: Percutaneous ethanol injection; UCSF: University of California at San Francisco; TACI: Transarterial chemo-infusion; NA: Not available.