Therapeutic strategies for post-transplant recurrence of hepatocellular carcinoma

Table 1 Studies evaluating the prognostic factors and outcome of treatment for hepatocellular carcinoma relapse after liver transplantation

Ref.	No. of patients	Type of study	Site of recurrence	Treatment	mTTR	mOS	Negative outcome predictors
Sapisochin et al[39], 2015	121 (15.5%)	Retrospective multicenter	18.4% liver, 47.4% extrahepatic, 34.2% liver + extra	31.4% surgery/ablation, 42.1% palliative, 26.4% BSC	14 mo	12.2 mo (1 yr 54%; 3 yr 19%; 5 yr 14%)	No curative treatment. RFS < 1 yr. AFP > 100 ng/mL
Ho et al[96], 2020	349 (16.4%)	National registry	≥ 38.1% liver, ≥ 20.3% extrahepatic/(liver + extra)	4.6% surgery, 6.3% ablation, 32.1% RT, 27.2% TACE, 20.3% Sorafenib, 20.3% BSC	17.8 mo	11.2 mo (1 yr 57%; 3 yr 24.7%; 4 yr 19%)	LT era > 2008 (due to listing of downstaged patients). No curative treatment. Sorafenib/RT
Hong et al[93], 2019	92 (17.3%) (LDLT)	Retrospective multicenter	37% liver, 34.8% lung, 28.3% bone, 16.3% lymph nodes	38% surgery, 51.1% TACE, 38% RT, 45.7% Sorafenib	11.3 mo	11.7 mo (1 yr 59.5%; 3 yr 23%; 5 yr 11.9%)	TTR < 6 mo. No curative treatment. Multiorgan involvement. Explant tumor size > 5 cm. mTORi (late)
Toso et al[92], 2013	30 (12.8%)	Retrospective multicenter	46.6% liver, 43.3% lung, 23.3% bone, 13.3% other	20% surgery, 10% TACE/RF/PEI, 70% CT/BSC	14.2 mo	33 mo	Graft rejection 0-6 mo. TTR
Bodzin et al[40], 2017	106 (12.4%)	Retrospective multicenter	37.8% liver, 55.7% lung, 25.5% bone, 3.8% brain	23.3% surgery, 3.9% RFA, 13.6% RT, 73.5% CT, 17% BSC	15.8 mo	10.6 mo	MELD at LT > 23. TTR. > 3 recurrent nodules. Size of recurrence. Bone recurrence. AFP at recurrence. Donor Na. Pre-LT NLR
Fernandez-Sevilla et al[41], 2017	70 (14.2%)	Retrospective single center	2.8% liver, 72.9% extrahepatic, 24.3% liver + extra	31.4% surgery, 8.6% TACE, 28.6% Sorafenib	17 mo	19 mo (1 yr 65%; 3 yr 26%; 5 yr 5%)	AFP > 100 ng/mL. Intrahepatic. Multifocal. No surgical treatment
Maccali et al[94], 2021	105 (16.6%)	Retrospective multicenter	23.8% liver, 21% liver + extra, 55.2% extrahepatic	9.5% surgery, 2.9% TACE, 4.8% RT, 44.8% CT/Sorafenib	13 mo	6.2 mo	RFS < 1 yr. No surgical, loco-regional or systemic treatment
Ekpanyapong et al[95], 2020	96 (13.5%)	Retrospective single center	21.9% liver, 78.1% extrahepatic/(liver + extra)	27.1% surgery. 5.2% RFA. 1% TACE. 10.4% RT. 39.6% Sorafenib. 16.7% BSC	17.1 mo	10.1 mo (1 yr 48%; 3 yr 16%)	AFP > 1000 ng/mL. Poorly differentiated HCC. Bilirubin ≥ 1.2 mg/dL and albumin < 3.5 mg/dL at recurrence. Peritoneal disease
Regalia et al[45], 1998	21 (15.9%)	Retrospective multicenter	19% liver, 19% lung, 14% bone, 38% multiple sites	33.3% surgery, 19% CT, 14.3% RT/CT-RT, 23.8% BSC	7.8 mo	1 yr 62%; 3 yr 29%; 4 yr 23%	Related to early recurrence: Explant tumor size > 3 cm; outside Milan Criteria; absence of capsule
Kornberg et al[38], 2010	16 (26.7%)	Retrospective single center	25% liver, 25% bone, 31.2% lung,6.2% brain, 6.2% peritoneum, 6.2% adrenal gland	43.7% surgery, 18.7% RT, 6.2% TACE, 6.2 Sorafenib, 31.2 %BSC	23 mo	10.5 mo	No surgical treatment. Early recurrence (< 24 mo)
Alshahrani et al[57], 2018	232 (15.6%)	Retrospective single center	31% liver, 57.8% extrahepatic, 13.4% multiple sites	-	-	1 yr 60.2%; 3 yr 28.3%; 5 yr 20.5%; 10 yr 7%	Early recurrence
Taketomi et al[100], 2010	17 (16.8%) (LDLT)	Retrospective single center	-	53% surgery, 47% other	12.9 mo	1 yr 76.5%; 3 yr 51.3%; 5 yr 34.2%	No surgical treatment. Early recurrence
Roh et al[90], 2014	63 (13.8%)	Retrospective single center	22% liver, 16% lung, 52% multiple sites, 10% other	6% surgery, 38% local treatment, 16% systemic treatment, 33% combined treatment, 13% BSC	12.9 mo	12.2 mo	Bone involvement. Early recurrence (< 6 mo). Multi-organ
Valdivieso et al[36], 2010	23 (12.6%)	Retrospective single center	8.7% liver, 21.7% liver + extra, 69.5% extrahepatic	47.8% surgery, 17.4 systemic treatment, 34.8% BSC	23.4 mo	R0 33.2 mo, other 11.9 mo	R0 surgical treatment
Mehta et al[101], 2020	84 (11.6%)	Retrospective multicenter	26.2% liver, 48.8% extrahepatic, 25% multiple sites	-	13 mo	-	-
Sharma et al[102], 2012	17 (18%)	Retrospective single center	35.3% liver, 64.7% multiple sites	-	25.2 mo	-	-
Shin et al[91], 2010	28 (20.3%) (LDLT)	Retrospective single center	50% liver, 25% extrahepatic, 25% multiple sites	Liver: TACE. Extrahepatic: Systemic therapy/RT	7.9 mo	11.7 mo (1 yr 52.8%; 3 yr 15.8%)	Major vascular invasion. Poorly differentiated HCC. No surgical treatment. Bone metastases
Schlitt et al[103], 1999	39 (56.5%)	Retrospective single center	23.1% liver, 38.5 liver + extra, 38.5% extrahepatic	38.4% surgery, 41% BSC, 12.8% systemic treatment, 2.5% TACE, 5.1% RT	14.5 mo	8 mo (non-surgical treatment)	-
Escartin et al[104], 2007	28 (15.2%)	Retrospective single center	14.3% liver, 46.4% extrahepatic, 39.3% multiple sites	-	-	7 mo	-
Cescon et al[105], 2010	34 (12%)	Retrospective single center	8.8% liver, 20.6% extrahepatic, 70.6% multiple sites	100% systemic treatment (in combination with: 5.9% surgery, 3% RT, 3% RFA, 3% IA CT)	12 mo	-	-
Roayaie et al[37], 2004	57 (18.3%)	Retrospective single center	15.8 % liver, 52.6% extrahepatic, 31.6% multiple sites	31.6% surgery, 5.2% TACE, 26.3% systemic treatment, 7% RT, 29.8% BSC	12.2 mo	8.7 mo	Bone metastases. No surgical treatment. Early recurrence

RFS: Relapse free survival; OS: Overall survival; RT: Radiotherapy; BSC: Best supportive care; IA CT: Intra-arterial chemotherapy. RFA: Radiofrequency ablation; LT: Liver transplant; mTTR: Median time to recurrence; mOS: Median overall survival; TACE: Transarterial chemoembolization; HCC: Hepatocellular carcinoma; PEI: Percutaneous ethanol injection; LDLT: Living donor liver transplantation.