Impact of guideline adherence on the prognosis of Barcelona clinic liver cancer stage B hepatocellular carcinoma

Table 1 Modified Bolondi or Kinki subclassification system

Subclassification	B1	B2	B3
Child-Pugh score	5-7	5-7	8, 9
‘Beyond Milan’ and within ‘up to 7 criteria’	In	Out	Any
			In	Out
Concept of treatment strategy	Curative	Non-curative	Curative intent if within up-to-7 criteria	Palliative, no treatment
Treatment option	Resection	TACE with DC beads	Transplantation	HAIC
	RFA	HAIC	RFA	Superselective TACE with DC beads
	Superselective cTACE	Sorafenib	Superselective cTACE

RFA: Radiofrequency ablation; cTACE: Conventional transarterial chemoembolization; TACE: Transarterial chemoembolization; DC: Drug-eluting; HAIC: Hepatic arterial infusion chemotherapy.

Table 2 Baseline characteristics of patients with hepatocellular carcinoma between 2008 and 2016 according to the 2000 and 2012 European Association for the Study of the Liver guidelines

Variables	2000 EASL guidelines (HCC patients, 2008-2012)			2012 EASL guidelines (HCC patients, 2013-2016)
	Guideline-adherent	Upward treatment	P value	Guideline-adherent	Upward treatment	Downward treatment	P value
No. of patients	269.0	77.0		168.0	82.0	47.0
Age (yr)	60.7 ± 10.4	57.5 ± 10.2	0.017	62.6 ± 10.5	60.9 ± 9.7	64.8 ± 9.0	0.100
Male sex (n, %)	226 (84.0)	68 (88.3)	0.469	146 (86.9)	70 (85.4)	40 (85.1)	0.921
BMI (kg/m2)	24.5 ± 4.3	24.6 ± 3.1	0.919	23.8 ± 3.3	23.6 ± 4.2	23.2 ± 3.4	0.626
DM (n, %)	79 (29.4)	10 (13.0)	0.004	51 (30.4)	24 (29.3)	14 (29.8)	0.984
Hypertension (n, %)	98 (36.4)	28 (38.4)	0.991	58 (34.5)	40 (48.8)	19 (40.4)	0.095
Etiology
Hepatitis B (n, %)	166 (61.7)	51 (66.2)	0.469	99 (58.9)	51 (62.2)	27 (57.4)	0.729
Hepatitis C (n, %)	36 (13.4)	8 (10.4)	0.487	26 (15.5)	5 (6.1)	4 (8.5)	0.014
Alcohol (n, %)	98 (36.4)	30 (39.0)	0.685	72 (42.9)	41 (50.0)	21 (44.7)	0.566
Ascites (n, %)	23 (8.6)	1 (1.3)	0.085	19 (11.3)	9 (11.0)	7 (14.9)	0.522
Creatinine (mg/dL)	1.0 ± 0.6	0.9 ± 0.2	0.160	0.9 ± 0.5	1.0 ± 0.6	0.9 ± 0.3	0.624
Sodium (mmol/L)	139.4 ± 3.2	140.3 ± 2.9	0.021	138.7 ± 2.9	139.1 ± 3.8	137.8 ± 2.7	0.074
Alanine aminotransferase (IU/L)	49.2 ± 35.8	43.5 ± 32.8	0.206	50.7 ± 44.0	43.7 ± 26.3	43.9 ± 30.9	0.297
Platelet count (109/L)	143.8 ± 71.5	172.8 ± 68.1	0.002	146.4 ± 69.6	175.8 ± 74.4	173.6 ± 91.6	0.005
Serum albumin (g/dL)	3.8 ± 0.5	4.1 ± 0.6	< 0.001	3.8 ± 0.5	4.1 ± 0.5	3.6 ± 0.6	< 0.001
Total bilirubin (mg/dL)	1.1 ± 1.2	1.0 ± 0.6	0.475	1.0 ± 0.9	0.9 ± 0.8	1.1 ± 0.7	0.173
INR	1.1 ± 0.1	1.1 ± 0.2	0.017	1.1 ± 0.2	1.1 ± 0.1	1.1 ± 0.1	0.064
Child-Pugh score	5.5 ± 0.7	5.2 ± 0.5	0.025	5.5 ± 0.9	5.3 ± 0.7	5.8 ± 1.0	0.021
MELD score	8.8 ± 2.5	7.8 ± 2.2	0.002	8.7 ± 2.7	8.0 ± 2.5	8.8 ± 2.4	0.164
Alpha-fetoprotein (ng/mL)	1772.6 ± 7218.6	1826.7 ± 5996.8	0.952	3757.3 ± 19911.7	3186.6 ± 20583.6	2553.0 ± 9928.3	0.918
Numbers of tumor	3.7 ± 1.3	2.8 ± 1.2	< 0.001	3.7 ± 1.3	3.0 ± 1.3	4.0 ± 1.4	< 0.001
Maximum tumor diameter (cm)	4.8 ± 3.0	4.8 ± 2.2	0.989	5.1 ± 3.1	5.9 ± 3.4	6.0 ± 3.7	0.070

Data are presented as mean ± SD or number (%). BMI: body mass index; DM: Diabetes mellitus; EASL: European Association for the Study of the Liver; HCC: Hepatocellular carcinoma; INR: International normalized ratio; MELD: Mayo End-Stage Liver Disease.

Table 3 Baseline characteristics of patients with hepatocellular carcinoma between 2008 and 2016 according to the 2005 and 2010 American Association for the Study of Liver Diseases guidelines

Variables	2005 AASLD guidelines (HCC patients, 2008-2010)			2010 AASLD guidelines (HCC patients, 2011-2016)
	Guideline-adherent	Upward treatment	P value	Guideline-adherent	Upward treatment	P value
No. of patients	130	46		287	154
Age (yr)	60.8 ± 8.9	58.3 ± 10.2	0.286	62.6 ± 10.8	59.6 ± 10.0	0.005
Male sex (n, %)	106 (81.5)	40 (87)	0.498	252 (87.8)	130 (84.4)	0.319
BMI (kg/m2)	24.6 ± 4.5	24.2 ± 2.6	0.533	24.1 ± 3.4	24.0 ± 3.9	0.811
DM (n, %)	32.3	19.6	0.131	87 (30.3)	33 (21.4)	0.046
Hypertension (n, %)	40.8	30.4	0.289	107 (37.3)	63 (40.9)	0.456
Etiology
Hepatitis B (n, %)	86 (66.2)	30 (34.8)	0.908	164 (57.1)	93 (60.4)	0.656
Hepatitis C (n, %)	14 (10.8)	5 (10.9)	0.985	43 (15.0)	16 (10.4)	0.087
Alcohol (n, %)	47 (36.2)	19 (41.3)	0.596	117 (40.8)	68 (44.2)	0.492
Ascites (n, %)	4 (3.1)	4 (9.5)	0.156	14 (4.9)	36 (23.4)	< 0.001
Creatinine (mg/dL)	1.0 ± 0.7	0.9 ± 0.2	0.345	0.9 ± 0.4	0.9 ± 0.7	0.786
Sodium (mmol/L)	140.0 ± 3.0	139.8 ± 4.0	0.736	139.1 ± 2.8	138.6 ± 3.6	0.092
Alanine aminotransferase (IU/L)	51.3 ± 36.6	42.6 ± 25.3	0.138	48.5 ± 40.7	42.7 ± 27.0	0.112
Platelet count (109/L)	146.1 ± 70.3	151.3 ± 74.1	0.669	151.2 ± 67.8	158.3 ± 79.1	0.326
Serum albumin (g/dL)	3.9 ± 0.4	3.8 ± 0.7	0.063	3.9 ± 0.5	3.8 ± 0.7	0.146
Total bilirubin (mg/dL)	0.9 ± 0.4	1.6 ± 2.5	0.005	0.9 ± 0.4	1.2 ± 1.2	< 0.001
INR	1.1 ± 0.1	1.2 ± 0.2	0.074	1.1 ± 0.1	1.1 ± 0.2	< 0.001
Child-Pugh score	5.3 ± 0.5	5.8 ± 1.2	< 0.001	5.3 ± 0.5	5.8 ± 1.1	< 0.001
MELD score	8.6 ± 2.0	9.2 ± 3.5	0.186	8.2 ± 2.1	9.1 ± 3.3	< 0.001
Alpha-fetoprotein (ng/mL)	1516.5 ± 5731.8	440.0 ± 1635.9	0.212	2442.3 ± 10522.8	3862.8 ± 23036.1	0.379
Numbers of tumor	3.7 ± 1.3	3.0 ± 1.3	0.001	3.7 ± 1.3	3.1 ± 1.3	< 0.001
Maximum tumor diameter (cm)	4.3 ± 1.9	4.1 ± 1.9	0.579	5.1 ± 3.0	5.5 ± 3.5	0.169

Data are presented as mean ± SD or number (%). AASLD: American Association for the Study of Liver Diseases; BMI: Body mass index; DM: Diabetes mellitus; HCC: Hepatocellular carcinoma; INR: International normalized ratio; MELD: Mayo End-Stage Liver Disease.

Table 4 Distribution of treatment strategies according to each hepatocellular carcinoma guideline

Treatment strategy	2000 EASL		2012 EASL			2005 AASLD		2010 AASLD		2010 APASL
	Adherence	Upward	Adherence	Upward	Downward	Adherence	Upward	Adherence	Upward	Adherence	Upward	Downward
Total, n (%)	269 (76.2)	77 (21.8)	168 (56.6)	82 (27.6)	47 (15.8)	130 (71.8)	46 (15.5)	287 (61.2)	154 (32.8)	486 (91.7)	22 (4.7)	22 (4.7)
Liver resection	0	56 (72.7)	0	57 (63.4)	0	0	26 (56.5)	0	87 (56.5)	94 (19.3)	0	0
Liver transplantation	0	11 (14.3)	0	4 (4.9)	0	0	6 (13.0)	0	9 (5.8)	0	11 (50)	0
Radiofrequency ablation	0	6 (7.8)	0	7 (8.5)	0	0	4 (8.7)	0	10 (6.5)	0	11 (50)	0
TACE	261 (97)	0	168 (100)	0	0	130 (100)	10 (21.7)	269 (93.7)	45 (28.2)	6	0	0
TACE with drug-eluting beads	0	4 (5.2)	0	10 (12.2)	0	0	0	12 (4.2)	2 (1.3)	14 (2.9)	0	0
Radioembolization (Yttrium-90)	0	0	0	4 (4.9)	0	0	0	0	1 (0.6)	4 (0.8)	0	0
Chemotherapy	8 (1.9)	0	0	0	13 (27.7)	0	0	3 (0.9)	0	0	0	20 (90.7)
Radiation therapy	0	0	0	0	2 (4.3)	0	0	0	0	0	0	0
No treatment	0	0	0	0	0	0	0	0	0	0	0	2 (9.1)

Data are presented as number (%). AASLD: American Association for the Study of Liver Diseases; APASL: Asian Pacific Association for the Study of the Liver; EASL: European Association for the Study of the Liver; HCC: Hepatocellular carcinoma; TACE: Transarterial chemoembolization.

Table 5 Univariate and multivariate Cox regression analysis for hepatocellular carcinoma -related death according to 2000 and 2012 European Association for the Study of the Liver guidelines

Variables	2000 EASL guidelines (HCC patients, 2008-2012)				2012 EASL guidelines (HCC patients, 2013-2016)
	Univariate analysis		Multivariate analysis		Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
Age (≥ 70 yr)	1.339 (1.004-1.783)	0.046	1.300 (0.961-1.758)	0.089	1.838 (1.336-2.529)	< 0.001	1.765 (1.269-2.687)	0.001
Male sex	1.239 (0.875-1.754)	0.227			0.592 (0.401-0.874)	0.008	0.610 (0.409-0.910)	0.153
BMI (≥ 25kg/m2)	0.890 (0.695-1.140)	0.356			0.829 (0.606-1.135)	0.242
DM	1.153 (0.880-1.510)	0.301			1.027 (0.740-1.424)	0.875
Hypertension	1.072 (0.836-1.375)	0.583			1.026 (0.757-1.391)	0.867
Etiology
Hepatitis B	0.902 (0.704-1.156)	0.415			0.852 (0.624-1.165)	0.316
Hepatitis C	1.056 (0.743-1.501)	0.763			1.270 (0.822-1.962)	0.282
Alcohol	1.109 (0.866-1.420)	0.393			0.960 (0.711-1.295)	0.787
Ascites
Mild	2.499 (1.543-4.048)	< 0.001			1.552 (0.962-2.503)	0.072
Moderate to severe	1.302 (0.486-3.509)	0.597			1.736 (0.767-3.929)	0.186
Creatinine (> 1 mg/dL)	1.283 (0.975-1.689)	0.076			1.123 (0.786-1.605)	0.524
Sodium (> 135 mmol/L)	0.620 (0.411-0.937)	0.024			0.615 (0.408-0.929)	0.021
Alanine aminotransferase (> 80 IU/L)	1.166 (0.813-1.672)	0.403			0.886 (0.556-1.412)	0.610
Platelet count (> 105/μL)	0.685 (0.529-0.886)	0.004	0.672 (0.507-0.890)	0.006	0.735 (0.526-1.025)	0.07
Serum albumin (≥ 3.5 g/dL)	0.694 (0.523-0.921)	0.011			0.605 (0.428-0.855)	0.004
Total bilirubin (> 1.2 mg/dL)	1.529 (1.153-2.027)	0.003			1.510 (1.096-2.081)	0.012	1.391 (0.998-1.938)	0.051
INR (> 1.2)	1.303 (0.982-1.729)	0.067			1.333 (0.904-1.967)	0.147
Child-Pugh score (≥ 7)	1.808 (1.187-2.754)	0.006			1.586 (0.994-2.530)	0.053
MELD score (> 9)	1.463 (1.112-1.926)	0.007			1.438 (1.035-1.998)	0.030
Alpha-fetoprotein (≥ 200 ng/mL)	1.287 (0.993-1.668)	0.056			1.626 (1.196-2.211)	0.002	1.392 (1.001-1.936)	0.049
Numbers of tumor (> 3)	1.810 (1.419-2.309)	< 0.001	1.685 (1.293-2.196)	< 0.001	1.654 (1.219-2.244)	0.001	1.673 (1.178-2.275)	0.003
Maximum tumor diameter (cm)
< 2	Ref				Ref
2-5	0.642 (0.409-1.008)	0.054	0.969 (0.608-1.545)	0.894	1.489 (0.807-2.750)	0.203	1.725 (0.908-3.276)	0.096
5-10	1.061 (0.666-1.689)	0.803	1.862 (1.136-3.055)	0.0138	1.694 (0.912-3.148)	0.095	2.378 (1.228-4.603)	0.010
> 10	2.511 (1.328-4.748)	0.005	4.377 (2.268-8.448)	< 0.001	4.023 (2.051-7.892)	< 0.001	4.358 (2.120-8.956)	< 0.001
Treatment
Guideline adherence	Ref				Ref
Upward	0.372 (0.263-0.525)	< 0.001	0.448 (0.310-0.647)	< 0.001	0.631 (0.426-0.935)	0.022	0.720 (0.478-1.086)	0.117
Downward					1.974 (1.362-2.859)	< 0.001	1.838 (1.257-2.687)	0.002

95%CI: 95%confidence interval; BMI: Body mass index; DM: Diabetes mellitus; EASL: European Association for the Study of the Liver; HCC: Hepatocellular carcinoma; HR: Hazard ratio; INR: International normalized ratio; MELD: Mayo End-Stage Liver Disease.

Table 6 Univariate and multivariate Cox regression analysis for hepatocellular carcinoma-related death according to 2005 and 2010 American Association for the Study of Liver Diseases guidelines

Variables	2005 AASLD guidelines (HCC patients, 2008-2010)				2010 AASLD guidelines (HCC patients, 2011-2016)
	Univariate analysis		Multivariate analysis		Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
Age (≥ 70 yr)	1.229 (0.809-1.865)	0.334	1.210 (0.896-1.635)	0.214	1.775 (1.376-2.289)	< 0.001	1.587 (1.206-2.089)	0.001
Male sex	1.237 (0.776-1.972)	0.371			0.832 (0.602-1.152)	0.268
BMI (≥ 25 kg/m2)	1.164 (0.819-1.654)	0.397			0.827 (0.650-1.053)	0.123
DM	0.990 (0.681-1.438)	0.958			1.236 (0.954-1.600)	0.109
Hypertension	1.129 (0.798-1.596)	0.493			1.101 (0.868-1.398)	0.428
Etiology
Hepatitis B	0.867 (0.608-1.235)	0.429			0.828 (0.652-1.051)	0.121
Hepatitis C	1.068 (0.633-1.801)	0.807			1.225 (0.884-1.698)	0.223
Alcohol	1.155 (0.815-1.637)	0.417			0.994 (0.785-1.259)	0.961
Ascites
Mild	1.984 (0.872-4.516)	0.102			1.907 (1.303-2.791)	0.001
Creatinine (> 1 mg/dL)	1.322 (0.901-1.940)	0.153			1.206 (0.919-1.582)	0.176
Sodium (≥ 135 mmol/L)	0.876 (0.445-1.724)	0.702			0.573 (0.407-0.807)	0.002
Alanine aminotransferase (> 80 IU/L)	1.021 (0.614-1.699)	0.937			0.968 (0.670-1.400)	0.865
Platelet count (> 105/μL)	0.590 (0.414-0.839)	0.003	0.684 (0.518-0.904)	0.008	0.736 (0.568-0.952)	0.020
Serum albumin (≥ 3.5 g/dL)	0.865 (0.573-1.306)	0.491			0.533 (0.408-0.696)	< 0.001	0.596 (0.416-0.855)	0.005
Total bilirubin (> 1.2 mg/dL)	1.619 (1.102-2.378)	0.014			1.509 (1.162-1.959)	0.002
INR (> 1.2)	1.229 (0.838-1.802)	0.291			1.421 (1.054-1.915)	0.021
Child-Pugh score (≥ 7)	1.430 (0.667-3.065)	0.358			1.822 (1.288-2.577)	0.001	2.429 (1.434-4.114)	0.001
MELD score (> 9)	1.465 (1.018-2.108)	0.040			1.521 (1.163-1.988)	0.002
Alpha-fetoprotein (≥ 200 ng/mL)	1.436 (1.004-2.055)	0.048			1.319 (1.029-1.692)	0.029
Numbers of tumor (> 3)	1.458 (1.036-2.051)	0.030	1.570 (1.208-2.040)	0.001	1.830 (1.443-2.320)	< 0.001	1.870 (1.426-2.452)	< 0.001
Maximum tumor diameter
< 2	Ref				Ref
2-5	0.767 (0.408-1.442)	0.411	0.967 (0.606-1.543)	0.889	0.974 (0.623-1.522)	0.908	1.294 (0.794-2.107)	0.310
5-10	0.925 (0.475-1.800)	0.818	1.792 (1.093-2.939)	0.021	1.459 (0.929-2.291)	0.101	2.210 (1.338-3.650)	0.002
> 10	4.267 (0.918-19.839)	0.064	3.437 (1.784-6.623)	< 0.001	2.692 (1.578-4.594)	< 0.001	3.261 (1.834-5.797)	< 0.001
Treatment
Guideline adherence	Ref				Ref
Upward	0.442 (0.283-0.691)	< 0.001	0.465 (0.322-0.670)	< 0.001	0.678 (0.524-0.879)	0.003	0.478 (0.333-0.685)	< 0.001

95%CI: 95% confidence interval; AASLD: American Association for the Study of Liver Diseases; BMI: body mass index; DM: diabetes mellitus; HCC: Hepatocellular carcinoma; HR: Hazard ratio; INR: International normalized ratio; MELD: Mayo End-Stage Liver Disease.