Long-term outcomes of hepatocellular carcinoma that underwent chemoembolization for bridging or downstaging

Table 1 Downstaging and bridging protocol

Downstaging and bridging protocol
Inclusion Criteria
Bridging
	Patients who were within MC or UNOS T2
Downstaging subgroups (HCC exceeding MC)
	Group 1 = 1 lesion > 5 and ≤ 8 cm
	Group 2 = 2 or 3 lesions at least one > 3 and ≤ 5 cm with the sum of the maximal tumor diameters ≤ 8 cm
	Group 3 = 4 or 5 lesions each ≤ 3 cm with the sum of the maximal tumor diameters ≤ 8 cm
	Group 4 = 2 or 3 lesions at least one > 5cm with the sum of the maximal tumor diameters ≤ 8 cm
	Group 5 = total tumor diameter > 8 cm
	Absence of vascular invasion based on cross-sectional MRI or CT
Criteria for successful downstaging
	Residual tumor(s) within MC for deceased donor liver transplant
	In patients with 4 or 5 tumors, successful downstaging requires complete necrosis (based on cross-sectional MRI or CT) of at least 1 to 2 tumor(s), respectively, so that there will be no more than 3 lesions with viable tumor each ≤ 3 cm to meet MC
Criteria for downstaging failure and exclusion from liver transplant
	Progression of tumor(s) to beyond inclusion criteria for downstaging and bridging based on tumor size and number
	Vascular invasion based on cross-sectional MRI or CT
	Lymph node involvement by tumor or extra-hepatic spread of tumor

MC: Milan criteria; UNOS: United Network for Organs Sharing; HCC: Hepatocellular carcinoma; MRI: Magnetic resonance imaging; CT: Computed tomography.

Table 2 Patients demographics

Variable	Group		Total (n = 200)	P value
	Downstaging (n = 64)	Bridging (n = 136)
Gender (Male), n (%)	53 (82.8)	112 (82.4)	165 (82.5)	0.936
Age (yr) (mean ± SD, range)	57.6 ± 6.9 (41-71)	58.2 ± 8.8 (27-77)	58.0 ± 8.2 (27-77)	0.6261
Etiology, n (%)				0.0692
Hepatitis B	7 (10.9)	5 (3.7)	12 (6.0)
Hepatitis C	43 (67.2)	78 (57.4)	121 (60.5)
Hepatitis B/C	1 (1.6)	6 (4.4)	7 (3.5)
Alcohol	6 (9.4)	26 (19.1)	32 (16.0)
Alcohol/Hepatitis	2 (3.1)	2 (1.5)	4 (2.0)
Other	5 (7.8)	19 (14.0)	24 (12.0)
Child-Pugh score, n (%)				0.2442
A (5-6)	24 (41.4)	72 (53.7)	96 (50.0)
B (7-9)	30 (51.7)	52 (38.8)	82 (42.7)
C (10-15)	4 (6.9)	10 (7.5)	14 (7.3)
MELD, mean ± SD	13 (7-28)	11 (6-23)	12 (6-28)	0.0553
AFP (ng/dL) (mean ± SD, range)	12.3 (0.9-22.411)	10.1 (0.6-12.784)	11.0 (0.6-22.411)	0.3353
Coagulopathy, n (%)				0.095
No	41 (64.1)	70 (51.5)	111 (55.5)
Yes	23 (35.9)	66 (48.5)	89 (44.5)
Thrombocytopenia, n (%)				0.297
No	27 (42.2)	47 (34.6)	74 (37.0)
Yes	37 (57.8)	89 (65.4)	126 (63.0)
HCC multifocal, n (%)				< 0.001
Single tumor	14 (21.9)	89 (65.4)	103 (51.5)
Multinodular	50 (78.1)	47 (34.6)	97 (48.5)
Number of nodules (mean ± SD, range)	2 (1-9)	1 (1-3)	1 (1-9)	< 0.0013
Maximal tumor diameter (mean ± SD, range)	8.09 ± 2.75 (4.6-17.2)	3.75 ± 1.20 (1.4-7.5)	5.14 ± 2.74 (1.4-17.2)	< 0.0011
Pseudocapsule, n (%)				0.118
No	9 (17.0)	30 (28.3)	39 (24.5)
Yes	44 (83)	76 (71.7)	120 (75.5)
Vascular lake phenomenon, n (%)				< 0.001
No	42 (65.6)	119 (87.5)	161 (80.5)
Yes	22 (34.4)	17 (12.5)	39 (19.5)

Chi-squared test.

¹Student’s t test;

²Likelihood ratio test;

³Mann-Whitney test. AFP: Alpha-fetoprotein; HCC: Hepatocellular carcinoma; MELD: Model for End-Stage Liver Disease.

Table 3 Bivariate analysis of liver transplant predictors

Variable	Liver transplant		P value
	No	Yes
Gender (Male), n (%)	70 (42.9)	93 (57.1)	0.451
Age (yr), (mean, ± SD, range)	58.1 ± 8.7 (27-77)	57.9 ± 7.8 (32-73)	0.8861
Child-Pugh score, n (%)			0.644
A (5-6)	43 (44.8)	53 (55.2)
B (7-9)	33 (40.7)	48 (59.3)
C (10-15)	7 (53.8)	6 (46.2)
MELD, mean ± SD, range	11 (6-28)	12 (7-23)	0.0552
AFP (ng/dL), (mean, ± SD, range)	12.75 (0.6-22,411)	8.8 (1.1-8,216)	0.3352
Coagulopathy, n (%)			0.001
No	60 (55.0)	49 (45.0)
Yes	27 (30.7)	61 (69.3)
Trombocytopenia, n (%)			0.002
No	42 (58.3)	30 (41.7)
Yes	45 (36.0)	80 (64.0)
Group, n (%)			< 0.001
Downstaging	41 (66.1)	21 (33.9)
Bridging	46 (34.1)	89 (65.9)
Vascular lake phenomenon, n (%)			0.776
No	71 (44.7)	88 (55.3)
Yes	16 (42.1)	22 (57.9)
Total	87 (44.2)	110 (55.8)

Chi-squared test.

¹Student’s t test;

²Mann-Whitney test. AFP: Alpha-fetoprotein; HCC: Hepatocellular carcinoma; MELD: Model for End-Stage Liver Disease.

Table 4 Subgroup analysis

All patients before LT			Eligibility for LT, n (%)	Patients who received LT
HCC	Number of patients	Total tumor diameter mean ± SD (cm), range		Number of sessions of DEB-TACE until LT (mean)	Deaths < 30 d (n)	Deaths > 30 d (n)	Recurrence (n, %)
Bridging	135		89 (65.9)		8	14	5 (5.81)
Group 1	90	3.22 ± 0.90 (2-5)	55 (61.1)	1.74	5	8	1
Group 2	27	4.16 ± 0.64 (3.2-5.7)	19 (70.3)	1.63	3	2	1
Group 3	18	5.70 ± 0.81 (4.7-7.5)	15 (83.3)	1.6	0	4	3
Downstaging	62		21 (33.9)		0	3	5 (25)
Group 1	11	6.52 ± 0.70 (5.7-8)	3 (27.3)	1.33	0	0	0
Group 2	19	6.53 ± 0.95 (4.6-7.9)	11 (57.9)	1.54	0	2	3
Group 3	5	6.56 ± 0.56 (5.9-7.2)	2 (40)	2.5	0	1	1
Group 4	5	7.2 ± 0.34 (6.9-7.7)	3 (60)	3	0	0	0
Group 5	22	10.92 ± 2.92 (8.2-17.2)	2 (9.1)	4	0	0	1

Cause of deaths: Bridging < 30 d: 3 Severe graft disfunction; 2 Sepsis; 2 Hemorrhagic shock; 1 Cardiogenic shock. Downstaging < 30 d: 0. Bridging > 30 d: 5 Sepsis; 4 Hepatocellular carcinoma recurrence; 1 Graft rejection; 1 Severe graft disfunction; 1 Pulmonary metastasis; 1 Stroke after brain biopsy; 1 not found. Downstaging > 30 d: 2 Hepatocellular carcinoma recurrence; 1 Pulmonary metastasis. HCC: Hepatocellular carcinoma; LT: Liver transplant.

Table 5 Overall survival and recurrence-free survival

Variable	Group		Total	P value
	Downstaging	Bridging
Overall survival (yr), (mean ± SD, range)	n = 20	n = 87	n = 107	> 0.05
	3.15 ± 1.33 (0.52-5.07)	2.97 ± 1.66 (0-5.77)	3.00 ± 1.60 (0-5.77)
Recurrence-free survival, (mean ± SD, range)	n = 20	n = 86	n = 106	> 0.05
	3.02 ± 1.37 (0.34-5.07)	2.93 ± 1.69 (0-5.77)	2.95 ± 1.63 (0-5.77)
Time of the waiting list until OLT (mo), (median, range)	n = 21	n = 89	n = 110	< 0.051
	10.6 (1.70-20.1)	6.6 (0.60-30.47)	7.0 (0.60-30.47)

¹Mann-Whitney test. OLT: Orthotopic liver transplantation.

Table 6 Target lesion response

	Downstaging		Bridging		Total		P value
mRECIST	n	%	n	%	n	%	< 0.011
CR	8	14.3	41	31.8	49	26.5
PR	39	69.6	53	41.1	92	49.7
SD	8	14.3	31	24	39	21.1
DP	1	1.8	4	3.1	5	2.7
Objective response							> 0.05
OR (CR + PR)	47	83.9	94	72.9	141	76.2
Non-OR (SD + PD)	9	16.1	35	27.1	44	23.8

Chi-squared test.

¹Likelihood ratio test. OR: Objective response; CR: Complete response; PR: Partial response; SD: Stable disease; DP: Disease progression.

Table 7 Influence of baseline characteristics on overall survival after liver transplant

Variável	HR (not adjusted)	95%CI		P value	HR (adjusted)	95%CI		P value
		Inferior	Superior			Inferior	Superior
Age (yr)	1.02	0.97	1.07	0.469	1.01	0.96	1.06	> 0.05
Gender (male)	0.46	0.19	1.09	0.078	0.51	0.16	1.63	> 0.05
Etiology
Hepatitis B	1.00				1.00
Hepatitis C	1.92	0.25	14.61	0.529	1.31	0.14	12.29	> 0.05
Hepatitis B/C	1.50	0.09	23.93	0.776	1.14	0.06	22.88	> 0.05
Alcohol	2.92	0.34	25.16	0.330	2.58	0.24	27.33	> 0.05
Alcohol/Hepatitis	4.96	0.31	79.60	0.258	0.00	0.00		> 0.05
Other	1.73	0.18	16.66	0.636	1.60	0.14	18.40	> 0.05
Child-Pugh score
A	1.00				1.00
B	0.97	0.43	2.17	0.940	0.84	0.31	2.25	> 0.05
C	0.00	0.00		0.983	NA			> 0.05
MELD	0.99	0.86	1.14	0.875	1.07	0.90	1.27	> 0.05
Alpha-fetoprotein
< 10	1.00				1.00
10-100	1.47	0.62	3.49	0.383	1.37	0.47	3.97	> 0.05
100-1000	2.02	0.65	6.26	0.225	1.94	0.54	6.97	> 0.05
> 1000	NA			0.983	NA			> 0.05
Number of nodules	1.08	0.68	1.70	0.747	1.05	0.47	2.37	> 0.05
Maximal tumor diameter (cm)	0.96	0.76	1.21	0.733	1.10	0.66	1.86	> 0.05
Group (Bridging)	1.83	0.55	6.13	0.325	1.53	0.23	10.18	> 0.05

HR: Hazard ratio; CI: Confidence interval; NA: Not available.

Table 8 Influence of baseline characteristics on recurrence-free survival after liver transplant

Variável	HR (not adjusted)	95%CI		P value	HR (adjusted)	95%CI		P value
		Inferior	Superior			Inferior	Superior
Age (yr)	1.03	0.98	1.09	0.285	1.01	0.96	1.08	> 0.05
Gender (male)	0.53	0.21	1.32	0.174	0.69	0.20	2.41	> 0.05
Etiology
Hepatitis B	1.00				1.00
Hepatitis C	2.00	0.26	15.21	0.504	1.46	0.16	13.70	> 0.05
Hepatitis B/C	1.54	0.10	24.58	0.761	1.49	0.07	30.71	> 0.05
Alcohol	2.82	0.33	24.30	0.345	2.53	0.23	27.36	> 0.05
Alcohol/Hepatitis	10.15	0.91	112.71	0.059	6.07	0.26	142.70	> 0.05
Other	1.78	0.19	17.20	0.617	1.90	0.16	22.79	> 0.05
Child-Pugh score
A	1.00				1.00
B	1.21	0.55	2.64	0.642	1.01	0.36	2.81	> 0.05
C	NA			0.982	#			> 0.05
MELD	1.01	0.88	1.15	0.917	1.04	0.87	1.25	> 0.05
Alpha-fetoprotein
< 10	1.00				1,00
10-100	1.36	0.58	3.17	0.483	1.43	0.50	4.12	> 0.05
100-1000	2.15	0.70	6.61	0.182	2.38	0.65	8.70	> 0.05
> 1000	NA			0.982	NA			> 0.05
Number of nodules	1.28	0.83	1.98	0.261	1.34	0.61	2.94	> 0.05
Maximal tumor diameter (cm)	1.06	0.85	1.31	0.619	1.04	0.63	1.72	> 0.05
Group (Bridging)	1.04	0.39	2.76	0.935	1.15	0.20	6.78	> 0.05

HR: Hazard ratio; CI: Confidence interval; NA: Not available.