Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation

Table 1 Hepatocellular carcinoma patients’ pre-transplant α-fetoprotein level, outcome, and biological features according to some recent studies

Ref.	No. of patients	Static AFP cut-off (mg/L)	Dynamic AFP	Outcome for increasing AFP ranges	Pvalue	Other biological features
Berry et al[31] (2013)	8659	≤ 15, 16-66, 66-320, > 320	-	6 yr OS: from 70% to 60%, 57%, 51%	-	-
Toso et al[26] (2011)	6478	≤ 100, 100-500, > 500	-	3 yr OS: from 71% to 60%, 51%	< 0.001	-
Mailey et al[32] (2011)	2253	≤ 20, > 400	-	4 yr OS: from 76% to 54%	< 0.001	-
Duvoux et al[20] (2012)	1033	≤ 100, 100-1000, > 1000	-	5 yr OS: from 68% to 51%, 39%	< 0.001	VI, poor differentiation
Todo et al[30] (2007)	653	≤ 200, > 1000	-	5 yr OS: from 73% to 34%	< 0.001	-
Fujiki et al[41] (2009)	144	≤ 200, > 800	-	5 yr RFS: from 90% to 40%	0.003	VI, poor differentiation
Sotiropoulos et al[12]	100	≤ 20, 20-200, 200-1000, > 1000	-	5 yr RFS: from 97% to 60%, 57%, 51%	0.0003	-
Hameed et al[45]	211	≤ 1000, > 1000	-	5- yr RFS: from 80.3% to 52.7%	0.025	VI
Kondili et al[46]	32	-	grate increasing, low increasing	In 5 Patents with recurrence AFP increased at a greater magnitude than in 27 without recurrence	-	-
Han et al[28]	48	-	≤ 50 mg/L per month, > 50 mg/L per month	1 yr RFS: from 90% to 40%	< 0.001	VI
Vibert et al[29]	153	-	≤ 15 mg/L per month, > 15 mg/L per month	5 yr RFS: from 76% to 54%	0.01	VI
Merani et al[47]	6817	-	Stable, ≥ 400, downstaged to < 400	ITT survival: from 81% to 48%	< 0.001	-

OS: Overall survival rate; RFS: Recurrence-free survival rate; ITT: Intention-to-treat; VI: Vascular invasion.

Table 2 Integrated selection criteria schemes for liver transplantation in hepatocellular carcinoma patients

Ref.	Model	No. of Patients	Parameters	Cut-off (points)	Criteria	Endpoint	Criteria-in outcome	Criteria-out outcome	Validation
Toso et al[26]	TTV/AFP	6478	TTV	≤ 115 cm³, > 115 cm³	TTV ≤ 115 cm³ AND AFP ≤ 400 ng/mL	Corrected posttransplant 3-yr OS	> 65%	< 50%	Grat et al: 104 patients with similar results
			AFP	≤ 400 ng/mL, > 400 ng/mL
Duvoux et al[20]	The AFP Model	Training cohort: 597 Validation cohort: 435	Longest Diameter	< 3 cm (0), 3-6 cm (1), > 6 cm (4)	Sum of individual points ≤ 2	posttransplant 5-yr RFS	7.7 % (Milan-in) 14.4% (Milan-out)	53.3 % (Milan-in) 47.6 % (Milan-out)	Notarpaolo et al[44]: 560 patients with similar results
			No. of nodules	1-3 (0), ≥ 4 (2)
			AFP	< 100 ng/mL (0), 100-1000 (2), > 1000 (3)
Lai et al[211]	-	422	mRECIST	Progression vs No progression	No progression AND AFP solpe ≤ 15	5-yr RFS 5-yr OS	RFS: 90% (Milan-in), 87% (Milan-out) OS: 88% (Milan-in), 83.5% (Milan-out)	RFS: 67.7% (Milan-in) 47% (Milan-out) OS 67.3% (Milan-in) 55.4% (Milan-out)	Not yet validated
			AFP slope	≤ 15 ng/mL per mo, > 15 ng/mL per mo

AFP: Alpha-fetoprotein.

Table 3 Response to therapy: comparison of outcomes following different pre-transplant strategies

Ref.	Treatment	Response assessemnt	Transplant criteria	No. of patients		Outcome		Comparison between responders and non responders	Comparison between downstaged patient vs conventional criteria
Millonig et al[187]	TACE	RECIST	UCSF	Total	116	Total	-
				Downstaging (DS)	NA	DS responders	5-yr OS = 25%		NS1
				Bridging (B)	NA	B responders	5-yr OS = 85.7%	0.02
						B non responders	5-yr OS = 51.4%
Chapman et al[212]	Resection, ablation, TACE	RECIST	Milan	Total	136	Total	-
				DS	76	DS responders	5-yr RFS = 50%		NS
				B	60	B responders	5-y RFS = 62.6%	NA
						B non responders
Vitale et al[15]	Resection, ablation, TACE	RECIST	Milan	Total	147		5-yr ITT survival = 74%
				DS	NA	DS responders	-		NA
				B	NA	B responders	5-yr ITT survival = 83%	< 0.01
						B non responders	5-yr ITT survival = 63%
Cucchetti et al[199]	Resection, ablation, TACE	mRECIST	Milan	Total	315	Total	-
				DS	53	DS responders	5-yr RR = 19.2%		NS1
				B	240	B responders	5-yr RR = 5.5%	0.017
						B non responders	5-yr RR = 19.4%
Ravaioli et al[17]	Resection, ablation, TACE	RECIST	Milan	Total	177	Total	3-yr RFS = 82%
				DS	48	DS responders	3-yr RFS = 75%		NS
				B	NA	B responders	3-yr RFS = 83%	NA
						B non responders
Yao et al[214]	Resection, ablation, TACE	mRECIST	Milan	Total	606	Total	-
				DS	118	DS responders	5-yr RFS = 90.8%		NS
				B	NA	B responders	5-yr RFS = 88%	NA
						B non responders
De Luna et al[213]	TACI	NA	Milan	Total	122	Total	3-yr OS = 82.7%
				DS	27	DS responders	3-yr OS = 84.1%		NS
				B	NA	B responders	3-yr OS = 84.7%	NA
						B non responders
Graziadei et al[190]	TACE	NA	Milan	Total	63	Total	NA
				DS	15	DS responders	4-yr OS = 41%		NA
				B	48	B responders	5-yr OS = 94%	NA
						B non responders	na
Otto et al[195]	TACE	mRECIST	Milan	Total	136	Total	-
				DS	49	DS responders	5-yr RFS = 92%	< 0.0001	NA
				B	87	B responders
						B non responders	5-yr RFS = 22%
De Giorgio et al[198]	Resection, ablation, TACE	NA	Milan	Total	206	Total	NA
				DS	NA	DS responders			NA
				B	83	B responders		NA
						B non responders

¹Computed not stastically significant. NA: Not available; NS: Not statistically significant; OS: Overall Survival; RFS: Recurrence free survival or freedom from recurrence; RR: Recurrence rate; RECIST: Response Evaluation criteria in solid tumors; mRECIST: Modified response evaluation criteria in solid tumors; TACE: Trans arterial chemo-embolization; TACI: Trans Arterial chemo-infusion; UCSF: University of California San Francisco.