Predictors of survival in patients with established cirrhosis and hepatocellular carcinoma treated with sorafenib

Table 1 Clinical characteristics of the patients with cirrhosis and hepatocellular carcinoma enrolled in the study n (%)

Characteristics	n = 44
Age (yr)
mean (SD)	67.7 (10.1)
median (min-max)	70 (44-83)
Males	38 (86.4)
Recruiting unit
Hepatology	29 (65.9)
Medical Oncology	15 (34.1)
Etiology of cirrhosis
HCV	19 (43.2)
HBV	9 (20.5)
Alcohol	7 (15.9)
Multifactorial	4 (9.1)
Cryptogenic	4 (9.1)
Primary biliary cirrhosis	1 (2.3)
ECOG performance status
0	24 (54.5)
1	18 (40.9)
2	2 (4.5)
BCLC
B	15 (34.1)
C	29 (65.9)
Child-Pugh class
A	29 (65.9)
B	15 (34.1)
Extrahepatic spread	9 (20.5)
Portal vein thrombosis	8 (18.2)
Varices	15 (34.1)
Macroscopic category
Extrahepatic only	1 (2.3)
Uninodular	3 (6.8)
≤ 3 nodules	34 (77.3)
> 3 nodules	6 (13.6)
Previous therapies
TACE1	20 (45.5)
Locoregional ablation	3 (6.8)
Surgical resection	2 (4.5)
None	19 (43.2)

¹Includes 7 patients in whom trans arterial chemio-embolization (TACE) was performed in combination with other treatment modalities, and 2 patients treated with ⁹⁰Y radio-embolization. HCV: Hepatitis C virus; HBV: Hepatitis B virus; ECOG: Eastern Cooperative Oncology Group; BCLC: Barcelona clinic liver cancer.

Table 2 Incidence of adverse events in 44 patients with cirrhosis and hepatocellular carcinoma undergoing treatment with sorafenib n (%)

Adverse events	Statistics
Fatigue	29 (65.9)
Grade 1	11 (25.0)
Grade 2	11 (25.0)
Grade 3	7 (15.9)
Bleeding	7 (15.9)
Grade 1	3 (6.8)
Grade 2	1 (2.3)
Grade 3	3 (6.8)
Hand-foot syndrome	14 (31.8)
Grade 1	7 (15.9)
Grade 2	7 (15.9)
Grade 3	0 (0.0)
Diarrhea	15 (34.1)
Grade 1	6 (13.6)
Grade 2	8 (18.2)
Grade 3	1 (2.3)
Hepatic grade 31AEs	8 (18.2)
Other AEs2	20 (45.5)

¹An increase in aminotranspherase and bilirubin after starting sorafenib was observed in all patients;

²Including rash, hypertension, alopecia, diabetes, mucositis, abdominal pain, voice changes. All grades were evaluated according to Common Terminology Criteria for Adverse Event version 3.0. AEs: Adverse events.

Table 3 Changes in laboratory parameters at the beginning and the end of sorafenib treatment according to the reason of treatment interruption

			Bilirubin (mg/dL)	gGT (U/L)	ALP (U/L)	Platelets/mm3	INR	AST (U/L)	AFP (ng/mL)
Patients with treatment suspension due to progressive disease (n = 25; median treatment duration 19 wk)	Baseline	mean (SD) med (min-max)	1.3 (0.8)	192.5 (187.5)	173.8 (92.5)	143160 (83075.6)	1.18 (0.25)	66.5 (35.7)	3668.6 (8533.3)
			1.2 (0.2-3.5)	114 (41-648)	142 (64-436)	125000 (50000-337000)	1.10 (0.9-2.2)	66 (3.6-191)	18.8 (2.7-28136)
	End of treatment	mean (SD) median (min-max)	2.3 (1.7)	256.4 (276.8)	225.4 (196.3)	151360 (93196.4)	1.17 (0.26)	106.4 (97.8)	11060.4 (21903)
			1.6 (0.3-6.4)	165 (20-1249)	182 (75-1048)	114000 (42000-426000)	1.1 (0.9-2.2)	71 (2-472)	83.4 (3.0-73434.5)
	Mann-Whitney test	P value	0.003	0.008	0.163	0.391	0.724	0.012	0.013
Patients with treatment suspension due to AEs (n = 19; median treatment duration 5 wk)	Baseline	mean (SD) med (min-max)	1.6 (0.7)	144.4 (107.4)	170 (83)	122125 (67280.4)	1.14 (0.92)	76.0 (38.6)	1739.0 (2841.1)
			1.4 (0.6-3.1)	123 (40-416)	159.5 (65-345)	102000 (35000-254000)	1.1 (1.0-1.3)	66.5 (27-188)	70.6 (1.6-6836.9)
	End of treatment	mean (SD) median (min-max)	2.9 (2.8)	168.3 (147.1)	218.8 (142.8)	135500 (75371.1)	1.14 (0.17)	91.1 (41.5)	2204.4 (4406.1)
			2.3 (0.7-12.2)	121.5 (40-525)	183 (75-515)	123000 (37000-277000)	1.05 (1.0-1.4)	83.5 (27-153)	124.1 (2.1-14000)
	Mann-Whitney test	P value	0.029	0.441	0.051	0.147	0.891	0.125	0.333

gGT: Gamma-glutamyltranspeptidase; ALP: Alkaline phosphatase; AST: Aspartate transaminase; AFP: Alpha-fetoprotein; INR: International normalized ratio.

Table 4 Univariate and multivariate analysis of the factors associated with a 16-week “clinical benefit” as defined by the presence of partial response or stable disease at imaging, according to modified Response Evaluation Criteria in Solid Tumors criteria

Variable	Univariate analysis		Multivariate analysis
	OR (95%CI)	P value	OR (95%CI)	P value
ECOG
0	1 (ref.)	0.013	2	2
1-2	0.18 (0.05-0.70)
Cirrhosis etiology
Non-viral	1 (ref.)	0.040	1 (ref.)	0.043
HCV or HBV1	0.23 (0.06-0.94)		0.21 (0.05-0.95)
HCV infection
Absent	1 (ref.)	0.032	2	2
Present	0.24 (0.07-0.88)
BCLC class
B	1 (ref.)	0.003	1 (ref.)	0.004
C	0.12 (0.03-0.48)		0.10 (0.02-0.49)
Previous therapy
No	1 (ref.)	0.172	2	2
Yes	0.42 (0.12-1.45)
AFP (ng/mL)
≤ 400	1 (ref.)	0.069	2	2
> 400	0.28 (0.07-1.10)

¹Including patients with other concurrent etiologies;

²Removed during the stepwise variable selection, not included in the final multivariate model. AFP: Alpha-fetoprotein; HCV: Hepatitis C virus; HBV: Hepatitis B virus; ECOG: Eastern Cooperative Oncology Group; BCLC: Barcelona clinic liver cancer.

Table 5 Univariate analysis of factors associated with overall survival in 44 patients with hepatocellular carcinoma and cirrhosis treated with sorafenib

Variable	n	Overall survival
		HR (95%CI)	P value
Gender
Male	38	1 (ref.)	0.437
Female	6	1.52(0.53-4.38)
ECOG
0	24	1 (ref.)	0.049
1-2	20	2.01(1.01-4.05)
Age, yr
< 70	22	1 (ref.)	0.297
≥ 70	22	1.43 (0.73-2.78)
Cirrhosis etiology
Non-viral	12	1 (ref.)	0.832
HCV or HBV1	32	1.09 (0.51-2.34)
Extrahepatic spread
Absent	35	1 (ref.)	0.049
Present	9	2.26 (1.01-5.10)
Portal thrombosis
Absent	36	1 (ref.)	0.043
Present	8	2.52 (1.03-6.16)
HBV infection
Absent	32	1 (ref.)	0.279
Present	12	0.64 (0.29-1.43)
HCV infection
Absent	23	1 (ref.)	0.423
Present	21	1.32 (0.67-2.57)
Esophageal varices
Absent	28	1 (ref.)	0.883
Present	16	1.06 (0.52-2.14)
Child Pugh score
A	29	1 (ref.)	0.085
B	15	1.98 (0.91-4.29)
BCLC class
B	15	1 (ref.)	0.007
C	29	2.89 (1.34-6.25)
Previous therapy
No	19	1 (ref.)	0.526
Yes	25	1.25 (0.63-2.49)
Bilirubin (mg/dL)
≤ 1.5	27	1 (ref.)	0.124
>1.5	17	1.76 (0.86-3.60)
gGT (U/L)
≤ 48	5	1 (ref.)	0.483
> 48	39	1.54 (0.46-5.14)
ALP (U/L)
≤ 120	13	1 (ref.)	0.013
>120	31	3.20 (1.28-7.98)
Platelets/mm3
≤ 150000	28	1 (ref.)	0.317
> 150000	16	0.69 (0.33-1.43)
AST (U/L)
≤ 40	9	1 (ref.)	0.388
> 40	35	1.52 (0.59-3.94)
AFP (ng/mL)
≤ 40	22	1 (ref.)	0.016
> 40	22	2.38 (1.18-4.80)
AFP (ng/mL)
≤ 400	27	1 (ref.)	0.017
> 400	17	2.38 (1.17-4.86)
Interruption due to disease progression
No	19	1 (ref.)	0.238
Yes	25	0.67 (0.34 - 1.31)

¹Including patients with other concurrent etiologies. gGT: Gamma-glutamyltranspeptidase; ALP: Alkaline phosphatase; AST: Aspartate transaminase; AFP: Alpha-fetoprotein; HCV: Hepatitis C virus; HBV: Hepatitis B virus; ECOG: Eastern Cooperative Oncology Group; BCLC: Barcelona clinic liver cancer.

Table 6 Multivariate analysis of overall survival in 44 patients with hepatocellular carcinoma and cirrhosis treated with sorafenib

Variable	OS
	HR (95%CI)	Median OS in weeks (range)	P value
ECOG
0	1 (ref.)	50.2 (9.3-153.1)	0.031
1-2	2.36 (1.08-5.16)	29.0 (2.9-92.6)
Extrahepatic spread
Absent	1 (ref.)	45.9 (8.1-153.1)	0.059
Present	2.41 (0.97-6.01)	19.1 (2.9-83)
Portal thrombosis
Absent	1 (ref.)	45.8 (2.9-153.1)	0.015
Present	3.33 (1.27-8.72)	29.9 (8.1-50)
ALP (U/L)
≤ 120	1 (ref.)	45.9 (16.6-153.1)	0.017
> 120	3.13 (1.23-8.00)	33.2 (2.9-115.4)
AFP (ng/mL)
≤ 40	1 (ref.)	52.5 (10.7-153.1)	0.021
> 40	2.33 (1.13-4.78)	31.0 (2.9-87.4)

OS: Overall survival; ECOG: Eastern Cooperative Oncology Grou; ALP: Alkaline phosphatase; AFP: Alpha-fetoprotein.