Reverse time-dependent effect of alphafetoprotein and disease control on survival of patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma

Table 1 Clinical and tumor characteristics of patients included in the study

Variable	Overall (110)
Age (yr)	67.5 (41-80)
Gender
Male	91 (82.7)
Female	19 (17.3)
Etiology of liver disease
Viral (HBV/HCV/HBV and HCV)	70 (63.6)
Alcohol	17 (15.5)
NASH/NAFLD	14 (12.7)
Viral and alcohol	9 (8.2)
PS
0	33 (30)
1	64 (58.2)
2	13 (11.8)
Diabetes
No	87 (79.1)
Yes	23 (20.9)
Child-Pugh score
A	82 (74.5)
B	28 (25.5)
N nodules
Single	35 (31.8)
2-3	20 (18.2)
> 3 or infiltrating	55 (50)
Maximum size
≤ 5 cm	56 (50.9)
> 5 cm	54 (49.1)
Macrovascular invasion
No	60 (54.5)
Yes	50 (45.5)
Extrahepatic spread
No	91 (82.7)
Yes	19 (17.3)
Macrovascular invasion and/or extrahepatic spread
No	49 (44.5)
Yes	61 (55.5)
NIACE
≤ 3	84 (76.4)
> 3	26 (23.6)
AFP
≤ 200 ng/mL	74 (67.3)
> 200 ng/mL	36 (32.7)
Treatment before BCLC C diagnosis
No	53 (48.2)
Yes	57 (51.8)
Type of treatment before BCLC C diagnosis (one or more per patient)
TACE	35
Surgical resection	20
RFA	18
Sorafenib	13
PEI	11
TACE + RFA	8
TARE	4
DSM-TACE	1
Number of treatments after BCLC C diagnosis
None	22 (20)
Single	32 (29.1)
Multiple	56 (50.9)
Type of treatment after BCLC C diagnosis (one or more per patient)
Sorafenib	53
TACE	25
TARE	18
Second line systemic agent	15
PEI	12
DSM-TACE	5
LT	3
RFA	1
Best tumor response
CR	10 (9.1)
PR	21 (19.1)
SD	12 (10.9)
PD	67 (60.9)
DC
No	67 (60.9)
Yes	43 (39.1)

Continuous variables are reported as median value and range, categorical variables as frequencies and percentage. HBV: Hepatitis B virus; HCV: Hepatitis C virus; NASH: Nonalcoholic Steatohepatitis; NAFLD: Nonalcoholic fatty liver disease; PS: Performance status; AFP: Alphafetoprotein; DC: Disease control; TACE: Transarterial chemoembolization; TARE: Transarterial radioembolization; DSM-TACE: Degradable starch microspheres transarterial chemoembolization; PEI: Percutaneous ethanol injection; RFA: Radiofrequency ablation; LT: Liver transplant; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; DC: Disease control.

Table 2 Univariate (Kaplan-Meier) and multivariate (Cox proportional hazard regression) survival analysis of patients with Barcelona Clinic Liver Cancer C hepatocellular carcinoma according to clinical and tumor variables

Variable	Univariate analysis		Multivariate analysis
	Survival time (mo)	P value	Hazard ratio (95%CI)	P value
Age
< 65 yr	13.9	0.903	-	-
≥ 65 yr	13.8
Gender
Male	13	0.900	-	-
Female	14.2
PS
0	10.3	0.128	-	-
1/2	13.9
Diabetes
No	13	0.813	-	-
Yes	13.8
Child-Pugh score
A	13.4	0.957	-	-
B	12.8
N nodules
Single	13.8	0.776	-	-
2-3	13.4
Multinodular/infiltrating	13
Tumor size
≤ 5 cm	13.9	0.0221	1	0.275
> 5 cm	9.9		1.357 (0.784-2.349)
Macrovascular invasion
No	15.8	0.0141	1	0.866
Yes	9.5		1.095 (0.379-3.162)
Extrahepatic spread
No	11.2	0.274	-	-
Yes	6.7
Macrovascular invasion and/or extrahepatic spread
No	13.8	0.0081	1	0.429
Yes	6.3		1.547 (0.523-4.571)
AFP
≤ 200 ng/mL	15.8	0.00021	1	0.0061
> 200 ng/mL	6.3		2.194 (1.249-3.855)
DC
No	7.6	< 0.00011	1	< 0.00011
Yes	15.8		0.190 (0.098-0.367)
NIACE score
≤ 3	13.8	0.515	-	-
> 3	6.7

¹Statistically significant results. PS: Performance status; AFP: Alpha-fetoprotein; DC: Disease control.

Table 3 Multivariate Cox regression model including alphafetoprotein and disease control as time dependent covariates

Variable	Multivariate analysis
	Hazard ratio (95%CI)	P value
Macrovascular invasion
No	1	0.917
Yes	1.066 (0.412-2.762)
Macrovascular invasion and/or extrahepatic spread
No	1	0.366
Yes	1.552 (0.584-4.124)
Tumor size
≤ 5 cm	1	0.266
> 5 cm	1.369 (0.786-2.382)
AFP (> 200 ng/mL vs ≤ 200 ng/mL)
< 6 mo	5.073 (2.159-11.916)	0.00021
7-12 mo	0.948 (0.275-3.267)	0.932
> 12 mo	1.698 (0.620-4.648)	0.303
DC (Yes vs No)
< 6 mo	0.220 (0.075-0.650)	0.096
7-12 mo	0.463 (0.181-1.189)	0.109
> 12 mo	0.110 (0.038-0.314)	< 0.00011

For all other variables single hazard ratios were reported.

¹Statistically significant results. AFP: Alphafetoprotein; DC: Disease control.

Table 4 Characteristics of the 5 patients with long-survival (median 63.3 mo)

PT	Gender	Age	Etiology	PS	Child-Pugh	AFP > 200 ng/mL	No. of nodules	Maximum size	Macrovascular invasion	Extrahepatic spread	Diabetes	Pre-BCLC C treatments	Post-BCLC C treatments	Best response	DC	Survival (mo)	Status
PT3	M	65	HBV	1	A	No	Infiltrating	Infiltrating	Yes	No	No	None	Sorafenib	CR	Yes	79.4	Alive
PT10	M	73	HCV	1	A	No	> 3	18	No	No	No	TACE, resection, sorafenib	Second line systemic agent, DSM-TACE (2)	SD	Yes	63.3	Alive
PT27	M	58	HBV	2	B	No	2	19	No	No	No	RFA, TACE	LT	CR	Yes	67.1	Alive
PT53	M	63	Alcohol	1	B	No	> 3	50	No	No	No	None	TACE (4), TACE + RFA (1), LT	CR	Yes	58.9	AliVe
PT54	M	65	HCV	0	A	No	Single	40	Yes	No	Yes	None	TARE (2)	SD	Yes	38.1	Alive

HBV: Hepatitis B virus; HCV: Hepatitis C virus; PS: Performance status; BCLC: Barcelona Clinic Liver Cancer; AFP: Alphafetoprotein; TACE: Transarterial chemoembolization; RFA: Radiofrequency ablation; DSM-TACE: Degradable starch microspheres transarterial chemoembolization; LT: Liver transplant; TARE: Transarterial radioembolization; CR: Complete response; SD: Stable disease; DC: Disease control.

Table 5 Univariate (Fisher’s exact test) and multivariate (binomial logistic regression) analysis of factors associated with the achievement of disease control in patients with Barcelona Clinic Liver Cancer C hepatocellular carcinoma

Variable	DC (43)	No DC (67)	Univariate analysis	Multivariate analysis
			P value	Odds ratio (95%CI)	P value
Age
< 65 yr	15	27	0.229	-
≥ 65 yr	28	40
Gender
Male	35	56	0.471	-
Female	8	11
PS
0	37	60	0.06	-
1/2	6	7
Diabetes
No	34	53	0.653	-
Yes	9	14
Child-Pugh score
A	31	51	0.524	-
B	12	16
N nodules
Single	13	22	0.078
2-3	11	9		-
Multinodular/infiltrating	19	36
Tumor size
≤ 5 cm	30	26	0.0061	1	0.298
> 5 cm	13	41		0.617 (0.236-1.610)
Macrovascular invasion
No	32	28	0.00031	-	-
Yes	11	39
Extrahepatic spread
No	40	51	0.021	-	-
Yes	3	16
Macrovascular invasion and/or extrahepatic spread
No	29	20	< 0.00011	1	0.0021
Yes	14	47		0.263 (0.111-0.622)
AFP
≤ 200 ng/mL	35	39	0.0081	1	0.179
> 200 ng/mL	8	28		0.461 (0.169-1.258)
NIACE score
≤ 3	34	50	0.502	-
> 3	9	17
Treatment after BCLC C diagnosis
No	4	18	0.041	1	0.270
Yes	39	49		0.531 (0.147-1.917)

¹Statistically significant results. PS: Performance status; AFP: Alpha-fetoprotein; DC: Disease control.