“Six-and-twelve” score for outcome prediction of hepatocellular carcinoma following transarterial chemoembolization. In-depth analysis from a multicenter French cohort

Table 1 Summary of points-based scores

CLIP (0 to 7 points)			MESH (0 to 6 points)		NIACE (0 to 7 points)
Portal vein thrombosis		1 point	Tumor extent: Beyond Milan criteria	1 point	Tumor nodules ≥ 3	1 point
AFP ≥ 400 ng/mL		1 point	Vascular invasion and/or Extrahepatic spread	1 point	Infiltrative HCC	1.5 points
					Nodular HCC	0 point
Child-Pugh grade	A	0 point	PS ≥ 2	1 point	AFP ≥ 200 ng/mL	1.5 points
	B	1 point	Child-Pugh grade ≥ A6	1 point
	C	2 points
Tumor extent	Unidolar and extension ≤ 50%	0 point	AFP ≥ 20 ng/mL	1 point	Child-Pugh grade A	0 point
	Multinodular and extension ≤ 50%	1 point	Alkaline phosphatase ≥ 200 IU/l	1 point	Child-Pugh grade B	1.5 points
	Massive or extension > 50%	2 points			PS ≥ 1	1.5 points

CLIP: Cancer of the Liver Italian Program; MESH: Model to Estimate Survival for Hepatocellular carcinoma; NIACE: Tumor nodularity, infiltrative nature of the tumor, alpha-fetoprotein, Child-Pugh class, and performance status.

Table 2 Baseline characteristics of hepatocellular carcinoma patients undergoing transarterial chemoembolization treatment, n (%)

Demographic variables	Marseille/Nancy cohort, n = 324	Marseille cohort1, n = 252
Age - Median [Q1-Q3], year	68 [62-74]	68 [60-73]
Gender Male/female	276 (85)/48 (15)	214 (85)/38 (15)
Liver disease HCV/HBV/Alcoholism/MS/other	129 (40)/14 (4)/122 (38)/42 (13)/17 (5)	109 (43)/12 (5)/84 (33)/37 (15)/10 (4)
ECOG (PS-0)	324 (100)	252 (100)
Cirrhosis	311 (96)	243 (96)
Tumor variables:
Tumor Size – mm - median [q1-q3]	35 [25-50]	32 [25-44]
Nodule (s): 1/2/3/4/≥ 5	95 (29)/72 (22)/80 (25)/38 (12)/39 (12)	83 (33)/67 (27)/34 (13)/31 (12)/37 (15)
Laboratory variables
AFP – ng/mL, median [q1-q3]	16.3 [6.0-120.3]	11.2 [5.0-77.7]
PT (%), median [q1-q3]	76 [64-88]	78 [68-88]
Albumin (g/L), median [q1-q3]	35 [28-38]	36.6 [32.7-41.0]
Total bilirubin (mcmol/L), median [q1-q3]	19.0 [13.7-28.7]	17 [11-27]
Child - Pugh grade A/B7	249 (77)/75 (23)	180 (71)/72 (29)
ALBI1 class	64 (20)/230 (71)/30 (9)	37 (15)/175 (73)/29 (12)
BCLC1 stage A/B	145 (45%)/179 (55%)	134 (56)/107 (44)
“6&12”1 score allocation n ≤ 6/> 6 - ≤ 12/> 12	154 (48)/163 (50)/7 (2)	130 (54)/106 (44)/5 (2)
NIACE score allocation ≤ 1/1.5 - 3/> 3	168 (52)/134 (41)/22 (7)
CLIP1 score allocation 0/1/2/≥ 3	-	55 (23)/135 (56)/45 (19)/ 6 (2)
MESH1 score allocation 0/1/2/3/4	-	41 (17)/77 (32)/78 (32)/37 (15)/8 (4)
Up-to-Seven model1 (In/Out)	-	176 (73)/65 (27)
HKLC1 stage 1/2a/2b/3a/3b	-	89 (37)/43 (17)/65 (27)/24 (10)/21 (9)

¹Available data for 241 patients for staging and scores calculation. The Albumin-Bilirubin (ALBI) score was calculated according to the . ALBI grades were defined as ALBI grade 1 (score ≤ -2.60), ALBI grade 2 (score > - 2.60 and ≤ - 1.39) and ALBI grade 3 (score > - 1.39). Bilirubin level in mcmol/L and albumin level in g/L; Up-to-seven criteria: With seven as the sum of the largest tumor size (in cm) + number of tumor(s). Barcelona Clinic Liver cancer (BCLC) classification: Current (BCLC) staging considers solitary tumor > 2 cm or no more than 3 tumors not exceeding 3 cm in diameter (Performance Status-0, Child-Pugh (CP) class A or B7 grade) as stage A. No tumor was classified at the very early stage of hepatocellular carcinoma (HCC) (BCLC 0) in this multicenter French cohort. BCLC stage B HCC encompassed patients with multiple tumors beyond 3 cm, PS-0, CP A or B7 grade. Hong Kong Liver Cancer classification: Early tumor: ≤ 5 cm, ≤ 3 tumor nodules; CP grade A (stage 1), CP grade B (stage 2a), -Intermediate tumor: ≤ 5 cm and > 3 tumor nodules or > 5 cm and ≤ 3 tumor nodules, CP grade A (stage 2b), CP grade B (stage 3a), - Locally-advanced tumor: > 5 cm, > 3 tumor nodules, CP grade A or B (stage 3b). HCC: Hepatocellular carcinoma; TACE: Transarterial chemoembolization; HCV: Hepatitis C virus; HBV: Hepatitis B virus; MS: Metabolic syndrome; ECOG (PS): Eastern Cooperative Oncology Group (Performance Status); AFP: Alpha-fetoprotein; PT: Prothrombin Time; ALBI: Albumin-Bilirubin; BCLC: Barcelona Clinic Liver Cancer; “6&12”: “Six-and-twelve”; NIACE: Tumor nodularity, infiltrative nature of the tumor, AFP, CP, PS; CLIP: Cancer of the Liver Italian Program; MESH: Model to Estimate Survival for Hepatocellular carcinoma; HKLC: Hong Kong Liver Cancer.

Table 3 Kaplan-Meier survival analysis according to “Six-and-twelve” score and other systems in the multicenter French cohort (n = 324)

Scoring/stage systems	OS [95%CI], mo	P value (log-rank)	Sidak1	Hazard ratio [95%CI]	P value
“6&12” score		< 0.0001
sum ≤ 6 (n = 154)	31 [27-35]		Ref	Ref
sum > 6 ≤ 12 (n = 163)	20 [17-24]		0.0009	1.55 [1.21-1.99]	0.0005
sum > 12 (n = 7)	15 [5-19]		< 0.0001	3.80 [1.76-8.21]	0.0007
BCLC staging		< 0.0001
A (n = 145)	35 [29-38]		NR	Ref
B (n = 179)	19 [17-23]		NR	1.88 [1.47-2.41]	< 0.0001
NIACE score		< 0.0001
≤ 1 (n = 168)	35 [28-36]		Ref	Ref
1.5 - 3 (n= 134)	20 [16-23]		< 0.0001	1.92 [1.49-2.48]	< 0.0001
> 3 (n = 22)	11 [5-16]		< 0.0001	6.23 [3.87-10.02]	< 0.0001
Child-Pugh class		0.0003
A (n = 249)	27 [25-31]		NR	Ref
B (n = 75)	21 [15-24]		NR	1.66 [1.26-2.19]	0.0003
ALBI grade		0.0029
Grade 1 (n = 64)	35 [25-43]		Ref	Ref
Grade 2 (n = 230)	26 [22-28]		0.1228	1.50 [1.06-2.11]	0.0216
Grade 3 (n = 30)	16 [12-24]		0.0016	2.30 [1.41-3.75]	0.0009

¹Sidak test for multiple comparisons. OS: Overall Survival; CI: Confidence Interval; “6&12”: “Six-and-twelve”; Ref: Reference; BCLC: Barcelona Clinic Liver Cancer; NIACE: Tumor nodularity, infiltrative nature of the tumor, alpha-fetoprotein, child-pugh class, performance status; ALBI: Albumin-Bilirubin.

Table 4 Comparison of predictive accuracy for overall survival between “Six-and-Twelve” score and staging/scoring systems (multicenter French cohort n = 324)

Scoring/stage systems	1-yr AUROC	P (vs ref)	2-yr AUROC	P (vs ref)	3-yr AUROC	P (vs ref)	C-index	P (vs ref)
“6&12” score	0.65 [0.57-0.74]	Ref	0.65 [0.59-0.71]	Ref	0.64 [0.58-0.71]	Ref	0.66 [0.58-0.74]
BCLC staging	0.61 [0.54-0.67]	0.1827	0.64 [0.59-0.70]	0.7079	0.61 [0.55-0.68]	0.2317	0.61 [0.54-0.68]	NS
NIACE score	0.75 [0.68-0.83]	0.0134	0.69 [0.64-0.75]	0.2368	0.69 [0.63-0.74]	0.2827	0.70 [0.64-0.77]	NS
Child-Pugh class	0.56 [0.49-0.63]	0.1057	0.56 [0.51-0.60]	0.0217	0.55 [0.50-0.59]	0.0304	0.59 [0.55-0.64]	NS
ALBI grade	0.63 [0.57-0.69]	0.6835	0.56 [0.51-0.61]	0.0479	0.55 [0.49-0.61]	0.1033	0.62 [0.55-0.68]	NS

“6&12”: “Six-and-twelve”; AUROC: Area under receiver operating characteristic curve; C-index: Concordance index; Ref: Reference; BCLC: Barcelona Clinic Liver Cancer; NS: Not significant; NIACE: Tumor nodularity, infiltrative nature of the tumor, alpha-fetoprotein, child-pugh class, performance status; ALBI: Albumin-Bilirubin.

Table 5 Kaplan-Meier survival analysis according to “Six-and-twelve” score and other systems in the main cohort from Marseille (available data for 241 hepatocellular carcinoma patients)

Scoring/stage systems	OS [95%CI], mo	P value (log-rank)	Sidak1	Hazard ratio [95%CI]	P value
“6&12” score		0.0004
sum ≤ 6 (n = 130)	32 [28-36]		Ref	Ref
sum > 6 ≤ 12 (n = 106)	20 [17-25]		0.0017	1.61 [1.21-2.14]	0.0010
sum > 12 (n = 5)	16 [5-34]		0.0003	3.34 [1.35-8.25]	0.0092
CLIP		< 0.0001
0 (n = 55)	35 [30-68]		Ref	Ref
1 (n = 135)	28 [25-32]		0.0724	1.81 [1.23-2.67]	0.0028
2 (n = 45)	18 [15-23]		< 0.0001	2.86 [1.81-4.54]	< 0.0001
3 (n = 6)	10 [1-27]		< 0.0001	8.12 [3.35-19.67]	< 0.0001
HKLC		< 0.0001
1 (n = 89)	36 [30-40]		Ref	Ref
2a (n = 42)	25 [19-35]		0.0024	1.79 [1.18-2.72]	0.0060
2b (n = 65)	26 [19-34]		0.0749	1.45 [1.01-2.10]	0.0450
3a (n = 24)	17 [11-23]		< 0.0001	3.30 [2.03-5.36]	< 0.0001
3b (n = 21)	14 [11-16]		< 0.0001	4.55 [2.73-7.58]	< 0.0001
Up-to-Seven		0.0001
In (n = 176)	30 [27-35]		NA	Ref
Out (n = 65)	18 [15-24]		NA	1.81 [1.34-2.46]	0.0001
MESH		< 0.0001
0 (n = 41)	43 [35-70]		Ref	Ref
1 (n = 77)	30 [25-35]		0.1291	2.16 [1.33-3.48]	0.0017
2 (n = 78)	26 [19-34]		0.0490	2.30 [1.41-3.74]	0.0008
3 (n = 37)	15 [10-21]		< 0.0001	6.02 [3.51-10.33]	< 0.0001
4 (n = 8)	13 [4-24]		< 0.0001	9.69 [3.86-24.36]	< 0.0001

¹Sidak test for multiple comparisons. “6&12”: “Six-and-twelve”; OS: Overall Survival; CI: Confidence Interval; Ref: Reference; CLIP: Cancer of the Liver Italian Program; HKLC: Hong Kong Liver Cancer; MESH: Model to Estimate Survival for Hepatocellular carcinoma.