Extending Surgical Resection for Hepatocellular Carcinoma Beyond Barcelona Clinic for Liver Cancer (BCLC) Stage A: A Novel Application of the Modified BCLC Staging System

Figures & data

Table 1 Baseline Demographics and Clinical Variables Based on BCLC Status

Variable	BCLC Status				OverAll P – value⁎	Pairwise Comparisons^⁑
	A N = 473	B1 N = 132	B2 N = 189	Total N = 794		A vs B1	A vs B2	B1 vs B2
Age (years)
Mean (SD)^£	62.2 (10.0)	63.5 (11.4)	63.7 (14.0)	62.7 (11.3)	0.2030
Median (Min, Max)^€	62.7 (30, 85)	64.2 (25, 88)	66.6 (15, 88)	64.0 (15, 88)	0.0089	0.1965	0.0118	0.5952
Gender, n(%)					0.4533
Male	359 (75.9)	0102 (77.3)	0152 (80.4)	0613 (77.2)
Female	114 (24.1)	0030 (22.7)	0037 (19.6)	0181 (22.8)
Hepatitis B, n (%)	346 (73.2)	78 (59.1)	95 (50.3)	519 (65.4)	<0.0001	<0.0001	<0.0001	<0.0001
Hepatitis C, n (%)	48 (10.1)	23 (17.4)	14 (7.4)	85 (10.7)	0.0183	0.0312	0.3043	0.0074
Non Hepatitis B/C, n (%)	89 (18.8)	033 (25.0)	83 (43.9)	205 (25.8)	<0.0001	0.1404	<0.0001	0.0006
Child-Pugh Score, n (%)					<0.0001	0.2064	<0.0001	0.0496
5	366 (77.4)	96 (72.7)	113 (59.8)	575 (72.4)
6	88 (18.6)	33 (25.0)	68 (36.0)	189 (23.8)
7–9	19 (4.0)	3 (2.3)	8 (4.2)	30 (3.8)
Albumin-bilirubin (ALBI) score
Mean (SD)^£	−2.51 (0.434)	−2.48 (0.40)	−2.37 (0.43)	−2.47 (0.43)	0.0004	1.0000	0.0003	0.0468
Median (Min, Max)^€	−2.56 (−3.44, −0.76)	−2.52 (−3.71, −1.24)	−2.37 (−3.35, −1.16)	−2.52 (−3.71, −0.76)	<0.0001	0.4369	<0.0001	0.0573
Alpha-Fetoprotein (AFP) (ng/mL)
Mean (SD)^£	402.2 (1919)	1725.3 (7536.3)	8825.0 (21,889.6)	2627.1 (11,722)	<0.0001	0.6917	<0.0001	<0.0001
Median (Min, Max)^€	10.9 (1, 29,483)	13.1 (1, 70,700)	77.4 (1, 175,000)	13.15 (1, 175,000)	<0.0001	0.1240	<0.0001	0.0337
Tumour Capsule, n (%)					0.4600
Not encapsulated	147 (35.8)	36 (31.6)	47 (28.7)	230 (33.4)
Completely encapsulated	119 (29.0)	32 (28.1)	48 (29.3)	199 (28.9)
Partially encapsulated	145 (35.3)	46 (40.4)	69 (42.1)	260 (37.7)
Micro Vascular Invasion, n (%)	95 (21.1)	39 (31.0)	105 (56.8)	239 (31.4)	<0.0001	0.0234	<0.0001	<0.0001
Number of nodules, n(%)					<0.0001	<0.0001	<0.0001	0.0002
1	438 (92.6)	73 (55.3)	130 (68.8)	641 (80.7)
2	31 (6.6)	43 (32.6)	28 (14.8)	102 (12.8)
3–5	4 (0.8)	16 (12.1)	23 (12.2)	43 (5.4)
> 5	0	0	8 (4.2)	8 (1.0)
Maximum size nodules, n (%)					<0.0001	<0.0001	<0.0001	<0.0001
<3 cm	288 (60.9)	1 (0.8)	1 (0.5)	290 (36.5)
3–5 cm	185 (39.1)	52 (39.4)	4 (2.1)	241 (30.4)
>5 cm	0	79 (59.8)	184 (97.4)	263 (33.1)

Notes: ^⁑After adjusting for Bonferroni correction p-value <0.0167 is considered as statistical significance. *P-value <0.05 is considered as statistical significance. P-values for categorical and continuous data were based on Fisher’s exact test and ANOVA ^£Or Mann–Whitney U-test ^€Whichever appropriate, respectively.

Table 2 Baseline Demographics and Clinical Variables Based on Milan Criteria, Up-to-7 Criteria and Dispersion of Tumour

Variable	Milan Unilobar N = 448 (Grp 1)	Milan Bilobar N = 25 Grp 2	B1 - Out of Milan Within Upto 7 Unilobar N = 112 (Grp 3)	B1 - Out of Milan Within Upto 7 Bilobar N = 20 (Grp 4)	B2 - Out of Milan Out of Upto7 Unilobar N = 145 (Grp 5)	B2 - Out of Milan Out of Upto 7 Bilobar N = 44 (Grp 6)	Overall P - value^⁎	P – value to Compare^⁑
								Grp 1 vs Grp 2	Grp 3 vs Grp 4	Grp 5 vs Grp 6
Age (years)
Mean (SD)^£	62.0 (9.95)	64.9 (10.62)	63.5 (11.54)	63.2 (11.19)	63.7 (13.24)	63.7 (16.25)	0.2030
Median (Range)^€	65.43 (30, 85)	62.61 (39, 82)	64.3 (25, 88)	64.12 (41, 84)	68.08 (15, 85)	66.53 (15, 88)	0.0416	0.1427	0.8094	0.7305
Gender, n (%)							0.4533
Male	345 (77.0)	14 (56.0)	86 (76.8)	16 (80.0)	118 (81.4)	34 (77.3)
Female	103 (23.0)	11 (44.0)	26 (23.2)	4 (20.0)	27 (18.6)	10 (22.7)
Hepatitis B, n (%)	329 (73.4)	17 (68.0)	69 (61.6)	9 (45.0)	74 (51.0)	21 (47.7)	<0.0001	0.6427	0.2175	0.7332
Hepatitis C, n (%)	45 (10.0)	3 (12.0)	20 (17.9)	3 (15.0)	10 (6.9)	4 (9.1)	0.0183	0.7315	1.0000	0.7422
Non Hepatitis B/C, n (%)	84 (18.8)	5 (20.0)	25 (22.3)	8 (40.0)	63 (43.4)	20 (45.5)	0.0006	0.7968	0.1010	0.8632
Child-Pugh Score, n (%)							<0.0001	0.3992	0.2894	0.4373
5	348 (77.7)	18 (72.0)	80 (71.4)	16 (80.0)	83 (57.2)	30 (68.2)
6	81 (18.1)	7 (28.0)	30 (26.8)	3 (15.0)	55 (37.9)	13 (29.5)
7–9	19 (4.2)	0	2 (1.8)	1 (5.0)	7 (4.8)	1 (2.3)
Albumin-bilirubin (ALBI) score
Mean (SD)^£	−2.51 (0.44)	−2.50 (0.40)	−2.46 (0.39)	−2.59 (0.44)	−2.36 (0.45)	−2.40 (0.377)	0.0004	0.8982	0.2446	0.5561
Median (Range)^€	−2.59 (−3.44, −0.76)	−2.56 (−3.32, −1.72)	−2.73 (−3.71, −1.24)	−2.5 (−3.29, −1.56)	−2.35 (−3.35, −1.16)	−2.39 (−3.08, −1.16)	0.0006	0.7346	0.1042	0.5281
Alpha-Fetoprotein (AFP) (ng/mL)
Mean (SD)^£	395.2 (1929.0)	527.8 (1758.6)	1948.5 (8149.6)	474.9 (1279)	7572.6 (20,778.8)	12,952.2 (25,026.1)	<0.0001	0.7180	0.0752	0.1995
Median (Range)^€	010.5 (1, 29,483)	31.2 (2, 8739)	13.1 (1, 70,700)	16.1 (3, 4306)	77.4 (1, 175,000)	58.4 (1, 70,700)	<0.0001	0.0332	0.9975	0.5616
Tumour Capsule, n (%)							0.4600
Not encapsulated	139 (35.5)	008 (40.0)	0031 (32.0)	005 (29.4)	0031 (25.0)	00016 (40.0)
Completely encapsulated	115 (29.4)	004 (20.0)	0028 (28.9)	004 (23.5)	0039 (31.5)	00009 (22.5)
Partially encapsulated	137 (35.0)	008 (40.0)	0038 (39.2)	008 (47.1)	0054 (43.5)	00015 (37.5)
Micro Vascular Invasion, n (%)	090 (21.0)	005 (22.7)	0032 (30.2)	007 (35.0)	0083 (58.9)	00022 (50.0)	<0.0001	0.7921	0.7925	0.3837
Number of nodules, n(%)							<0.0001	<0.0001	0.0098	<0.0001
1	425 (94.9)	13 (52.0)	68 (60.7)	5 (25.0)	113 (77.9)	17 (38.6)
2	21 (4.7)	10 (40.0)	32 (28.6)	11 (55.0)	16 (11.0)	12 (27.3)
3–5	2 (0.4)	2 (8.0)	12 (10.7)	4 (20.0)	12 (8.3)	11 (25.0)
>5	0	0	0	0	4 (2.8)	4 (9.1)
Maximum size nodules, n (%)							<0.0001	0.8351	0.1359	0.0835
<3 cm	272 (60.7)	16 (64.0)	1 (0.9)	0	00	1 (2.3)
3–5 cm	176 (39.3)	9 (36.0)	40 (35.7)	12 (60.0)	2 (1.4)	2 (4.5)
>5 cm	0	0	71 (63.4)	8 (40.0)	143 (98.6)	41 (93.2)

Notes: ^⁑After adjusting for Bonferroni correction p-value <0.025 is considered as statistical significance. *P-value <0.05 is considered as statistical significance. P-values for categorical and continuous data were based on Fisher’s exact test and ANOVA ^£Or Mann–Whitney U-test, ^€Whichever appropriate, respectively.

Figure 1 CONSORT diagram.²⁸

Table 3 Summary of Overall Survival Analysis results

Group	HCC Stage, Location	BCLC Stage	5 Years Survival Rate (%) (95% CI)	Median Survival Time (Months) (95% CI)	P value (Log Rank)
A-u	Milan Unilobar	BCLC A	64.6 (59.5, 69.3)	100.43 (89.33, 132.73)	<0.0001
A-b	Milan Bilobar	BCLCA	58.4 (33.1, 77.1)	64.59 (23.72, 101.39)
B1-u	Out of Milan Within Upto7 Unilobar	BCLC B1	56.2 (44.9, 66.0)	74.84 (48.26, 98.46)
B1-b	Out of Milan Within Upto7 Bilobar	BCLC B1	45.5 (20.0, 68.0)	51.35 (18.83, 95.01)
B2-u	Out of Milan Out of Upto7 Unilobar	BCLC B2	44.0 (34.4, 53.0)	51.78 (35.94, 67.91)
B2-b	Out of Milan Out of Upto7 Bilobar	BCLC B2	38.2 (21.5, 54.8)	40.18 (21.19, NE)

Abbreviations: NE, Not estimable; CI, confidence interval; HCC, hepatocellular carcinoma; BCLC, Barcelona clinic liver cancer staging system.

Figure 2 Kaplan Meier curves depicting overall survival analysis of 6 subgroups.

Table 4 Summary of Survival Outcomes of Solitary Lesions Stratified by Size

Group	Solitary Lesions Stratified by Size	5 Years Survival Rate (%) (95% CI)	Median Survival Time (Months) (95% CI)	P value (Log Rank)
A-S	Within Milan	65.1 (59.9, 69.8)	100.44 (89.33, 129.48)	0.0003
B1-S	Out of Milan Within Upto7	56.0 (42.2, 67.7)	74.97 (46.52, 109.18)
B2-S	Out of Milan Out of Upto7	47.1 (37.0, 56.5)	53.29 (38.77, 86.05)

Abbreviation: CI, confidence interval.

Figure 3 Kaplan Meier curves depicting overall survival analysis of solitary HCC lesions.

Schulz KF, Altman DG, Moher D, for the CONSORT Group (2010) CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials. PLoS Med 7(3): e1000251

 Google Scholar