Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: A multicenter study of 412 patients

Table 1 Clinical features of the study population

Age (yr)	52.7 ± 9.2
Sex (M/F), n (%)	339 (82.3)/73( 17.7)
Etiology: Alc./Vir./Metab./Miscel1, n (%)	136 (33.2)/236 (57.3)/ 8(2.0)/32 (7.5)
Cirrhosis (yes/no), n (%)	377 (91.5)/35 (8.5)
AFP (μg/L)	26.9 (ext: 0.5-245.240)
Number of nodules	1.8 ± 1.3 (median: 1, range: 1-11)
Maximum diameter (cm)	4.1 ± 3.1 (median: 3.4, range: 0.6-25)
Bilobar location (yes/no), n (%)	105 (25.5)/307 (74.5)
Portal or hepatic vein obstruction (yes/no) (n)	33 (8.1)/379 (91.9)
Milan Criteria (yes/no), n (%)	263 (63.8)/149(36.2)
Peri-operative treatment (yes/no), n (%)	275 (66.8)/137(33.2)
Transarterial chemoembolization (yes/no)	161 (39.2)/251 (60.8)
Pre-transplant surgery (yes/no)	42 (10.2)/370(89.8)
Pre-transplant ethanol injection (yes/no)	65 (15.8)/347 (84.2)
Post-transplant chemotherapy (yes/no)	57 (13.9)/355 (86.1)
Tumor differentiation (Well/moderate/poor), n (%)	248 (69.3)/90 (25.4)/20 (5.3)
Time on waiting list (mo)	4.4 ± 4.0 (median: 3.3, range: 0.1-32.3)
Initial immunosuppression Calcineurine inhibitors/ATG-OKT32, n (%)	357 (86.6)/55 (13.4)
Steroid-treated rejection episodes, n (%)	125 (30.5)
Maintenance immunosuppression
Cyclosporine A/tacrolimus, n (%)	284 (68.9)/128 (31.1)

¹Alc: alcohol; Vir: Viral; Metab: Metabolic; Miscel: Miscellaneous;

²ATG: anti-lymphocyte ab; OKT3: anti-CD3 ab.

Table 2 Factors associated with recurrence-free survival (Univariate analysis)

Variables (n)	5-yr recurrencefree survival (%)	P
Age < 50 (151)/> 50 (261)	58.2/56.4	0.58
Sex Male (339)/female(73)	56.8/58.3	0.46
Liver disease etiology
Alcohol (122)/virus (210)/ Alcohol+virus (41)/others (39)	64.8/55.1/58.1/40.2	0.03
Cirrhosis Present (377)/absent (35)	58.7/35.7	0.001
AFP (μg/L)
< 200 (281)/200-2000 (73)/> 2000 (33)	62.9/47.8/26.4	< 0.0001
ASAT
Normal (139)/N-2N (129)/> 2N (112)	59.2/60.5/51.1	0.3
ALAT
Normal (178)/N-2N (116)/> 2N (86)	56.4/63.5/60.6	0.3
Alkaline phosphatase
Normal (170)/high (200)	60.9/61.1	0.2
G-GT
Normal (107)/N-2N (113)/> 2N (145)	66.9/59.9/49.7	0.02
Child-Pugh classification
A (219)/B (125)/C (56)	58.7/49.6/71.1	0.07
Karnofsky index
> 80% (251)/< 80% (155)	58.2/55.7	0.78
Number of nodules, pre- transplant
1 (228)/2 or 3 (142)/> 4 (33)	58.4/58.4/48.5	0.02
Maximum diameter of the largest nodule, pre-transplant
< 3 cm (126)/3-5 cm (191)/> 5 cm (82)	69.3/61.4/32.9	< 0.0001
Sum of tumor diameter (cm)
< 3 cm (123)/3-5 cm (121)/ 5-10 cm (92)/> 10 cm (34)	72.1/61.1/50.3/19.5	< 0.0001
Tumor location, pre- transplant
Uni-lobar (303)/Bi-lobar (104)	60.4/48.3	0.01
Portal or hepatic vein obstruction, pre-transplant
Absent (373)/Present (33)	60.2/27.3	< 0.0001
Pre or post transplant adjuvant treatment
Present (274)/absent (136)	61.1/47.9	0.002
Pre LT arterial chemoembolization
Present (241)/absent (162)	62.3/53.0	0.03
Tumor differentiation
Well (248)/moderate (91)/poor (19)	58.3/47.1/42.1	0.01
Period of transplantation
< 91 (82)/91-93 (91)/94-96 (118)/97-98 (121)	26.8/56.0/61.6/73.3	< 0.0001
Waiting time
< 6 mo (318)/6-12 mo (71)/> 12 mo (23)	55.4/67.1/52.2	0.18
Maintenance immunosuppression
Cyclosporine A (264)/tacrolimus (119)	52.5/70.8	0.003
Steroid-treated rejection
Yes (125)/no (284)	48.5/60.8	0.003
Use of mono or polyclonal antilymphocyte antibodies
Present (55)/absent (356)	45.4/58.8	0.02

Table 3 Factors associated with recurrence-free survival (Multivariate analysis)

	Relative risk	95% CI	P
Use of anti-lymphocyte antibodies	1.8	1.2-2.6	0.005
Tumor differentiation	1.6	1.24-2.06	0.0006
Maximum diameter of the largest nodule	1.12	1.08-1.17	< 0.0001
Portal/hepatic vein obstruction	1.6	1.01-2.72	0.06
Number of nodules	1.13	1-1.28	0.06
Recent period of transplantation	0.66	0.54-0.82	0.0001