Multidisciplinary approach for post-liver transplant recurrence of hepatocellular carcinoma: A proposed management algorithm

Table 1 Mammalian target of rapamycin inhibitors for patients engrafted for hepatocellular carcinoma

	No. (SRL/non-SRL)	5-year OS (%)	5-year DFS (%)	HAT (%)	ACR (%)	Discontinuation for toxicity (%)
Prospective controlled trial
Geissler et al[21], 2016	261/264	79.4/70.33	72.6/68.4	-	23.4/17.0	-
Meta-analysis
Liang et al[22], 2012	332/2615	OR: 2.473	1 yr: OR 2.413	OR: 1.32	-	-
Zhang et al[23], 2018	7695	OR: 1.683	1 yr: OR 2.133	-	-	-
Case-control
Vivarelli et al[24],2010	31/31	-	3 yr 86/563	0/0	3.2/3.2	-
Retrospective cohort
Zimmerman et al[25],2007	45/52	80/62	78.8/54	2.4/1.9	20/19.6	-
Zhou et al[28], 20081	27/46	19.8 ± 1.2/16.0 ± 1.423	17.3 ± 1.4/15.9 ± 1.62	0/0	30.4/19.6	8.3
Chinnakotla et al[26], 2009	121/106	80/503	-	1.9/2	62.8/54.7	0
Toso et al[27], 2010	109/2382	83.1/68.73	-	-	-	-

¹All tumours were beyond Milan criteria;

²Median survival in months;

³Statistically significant. SRL: Sirolimus; OS: Overall survival; DFS: Disease-free survival; HAT: Hepatic artery thrombosis; ACR: Acute cellular rejection.

Table 2 Sorafenib for recurrent hepatocellular carcinoma after liver transplantation

	No. (SFN/BSC)	Duration after LT (mo)	mTOR inhibitor (yes/no)	Response rate (% complete/partial/stable)	Median OS (mo)	Time to progression (mo)	Drug toxicity leading to
							Dose reduction (% patient)	Discontinuation (% patient)
Meta-analysis
Mancuso et al[42],2015	113	13.6	-	0/4.8/44.4	10.5	5.6	42.8	31.9
Retrospective cohort
Sposito et al[43], 2013	15/24	38.1/15.72	7/8	-	21.3/11.82	8.8/10.2	53.3	4.1
De'Angelis et al[45], 2016	15/18	18	7/8	0/26.6/46.8	41.4/19.12	-	53.3	13.3
Pinero et al[46], 2016	10/10	-	7/3	-	20/12.5	5/32	90	20
Case series
Yoon et al[47], 2010	13	12.3	1/12	0/0/46	5.4	2.9	30.7	0
Kim et al[48],2010	9	12.4	7/2	11/0/44	-1	-	-	0
Vitale et al[49], 2012	10	7	10/0	0/20/60	18	8	40	30
Gomez-Martin et al[50], 2012	31	22.6	31/0	0/3.8/50	19.3	6.77	25.8	-
Weinmann et al[51], 2012	11	37.5	9/2	0/0/36	20.1	4.1	73	18
Sotiropoulos et al[52], 2012	14	8	14/0	-	25	-	33	17
Zavaglia et al[44], 2013	11	12	7/4	0/18/9	5	17	90	-

¹Median survival not reached;

²Statistically significant. SFN: Sorafenib; BSC: Best supportive care; LT: Liver transplant; mTOR: Mammalian target of rapamycin; OS: Overall survival.

Table 3 Immunotherapy for recurrent hepatocellular carcinoma after liver transplantation

Patient	Age	Ref.	Tumour	Agent	Years after LT	Immunosuppression	Prior sorafenib	Response	OS (mo)	Rejection
1	41	De Toni et al[63], 2017	HCC	Nivolumab	1	Low dose tacrolimus	Yes	No	-	No
21	20	Friend et al[64], 2017	HCC	Nivolumab	4	Sirolimus	-	-	1	Yes
31	14	Friend et al[64], 2017	HCC	Nivolumab	3	Tacrolimus	-	-	1	Yes
4	70	Varkaris et al[65], 2017	HCC	Pembrolizumab	8	Low dose tacrolimus	Yes	No	3	No
5	57	DeLeon et al[66], 2018	HCC	Nivolumab	2.7	Tacrolimus	Yes	No	1.2	No
6	56	DeLeon et al[66], 2018	HCC	Nivolumab	7.8	MMF/sirolimus	Yes	No	1.1	No
7	35	DeLeon et al[66], 2018	HCC	Nivolumab	3.7	Tacrolimus	Yes	No	1.3	No
8	64	DeLeon et al[66], 2018	HCC	Nivolumab	1.2	Tacrolimus	Yes	-2	0.3	No
9	68	DeLeon et al[66], 2018	HCC	Nivolumab	1.1	Sirolimus	Yes	-	0.7	Yes
10	70	Varkaris et al[65], 2017	HCC	Pembrolizumab	6	Low dose tacrolimus	Yes	No	3	No
11	59	Ranganath et al[69], 2015	Melanoma	Ipilimumab	8	Tacrolimus	-	-	-	No
12	67	Morales et al[70], 2015	Melanoma	Ipilimumab	8	Sirolimus	-	-	-	No
13	55	DeLeon et al[66], 2018	Melanoma	Pembrolizumab	5.5	MMF/everolimus	-	-	-	No
14	63	DeLeon et al[66], 2018	Melanoma	Pembrolizumab	3.1	MMF/prednisolone	-	-	-	Yes
15	62	Kuo et al[71], 2018	Melanoma	Ipilimumab and pembrolizumab	6	Sirolimus	-	-	-	Yes

¹Fibrolamella hepatocellular carcinoma;

²Multiorgan failure, unrelated to immunotherapy. HCC: Hepatocellular carcinoma; LT: Liver transplant; OS: Overall survival.

Table 4 Surgery for recurrent hepatocellular carcinoma after liver transplantation

	No. resection/total (%)	Site of resection	Median OS in months		Selection criteria	Resection: Independent predictor of survival
			Overall	Resection/no resection
Comparative study
Roayaie et al[4], 2004	18/57 (31.6)	Liver (n = 8), lung (n = 7), adrenal (n = 2), chest wall (n = 1)1	8.7	-	Technical feasibility	Yes
Kornberg et al[76], 2010	7/16 (43.8)	Liver (n = 2), lung (n = 2), others (n = 3)	10.5	65/55	-	Yes
Valdivieso et al[39], 2010	11/23 (47.8)	Liver (n = 2), lung (n = 2), adrenal (n = 2), abdominal lymph node (n = 2)	-	32.3 ± 21.5/11.9 ± 6.925	Technical feasibility	-
Sapisochin et al[77], 2015	38/121 (31.4)	-	-	31/12/535	Technical feasibility	Yes
Bodzin et al[78], 2017	25/106 (23.6)	lung (n = 8), bone (n = 6), intra-abdominal (n = 4), liver (n = 3), brain (n = 2)	10.6	27.8/10.6/3.735	-	-
Fernandez-Sevilla et al[79], 2017	22/70 (31.4)4	-	19	35/155	Technical feasibility. No progression with systemic treatment	Yes

¹Include radiofrequency ablation of liver lesion (n = 2);

²R0 resection vs no R0 resection;

³Resection vs non-surgical treatment vs best supportive care;

⁴R0/1 resection vs no R0/1 resection;

⁵Statistically significant. OS: Overall survival.

Table 5 Graft resection for recurrent hepatocellular carcinoma after liver transplantation

	No.	Morbidity (%)	Mortality (%)	3-yr OS (%)
Case series
Marangoni et al[83], 2008	111	812	0	-
Sommacale et al[81], 2013	83	624	0	-
Chok[82], 2015	3	-	0	66.7

¹Hepatocellular carcinoma (HCC) (n = 4), ischaemic cholangiopathy (n = 2), segmental hepatic artery thrombosis (HAT) (n = 2), others (n = 5);

²Small bowel perforation (n = 1), bile leak (n = 1), intra-abdominal collection (n = 1), wound infection (n = 1), sepsis (n = 5);

³HCC (n = 3), bile leak (n = 1), recurrent segmental cholangitis (n = 1), hydatid cyst (n = 1), segmental HAT (n = 1), biliary cyst (n = 1);

⁴Statistically significant. OS: Overall survival.