Early α-fetoprotein response predicts survival in patients with advanced hepatocellular carcinoma treated with sorafenib

Figures & data

Table 1 Baseline characteristics of patients (n=126)

Variables	Values
Demographic variables
Age, years	58 (34–85)
Male sex, n	101 (80.2)
Viral etiology, n	90 (71.4)
ECOG, 0–1/2, n	120 (95.2)/6 (4.8)
Child-Pugh class, A/B, n	96 (76.2)/30 (23.8)
Previous treatment history, n	92 (73.0)
Tumor variables
Tumor size, cm	7.8 (2.0–18.0)
Multiple tumors, ≥4	57 (45.2)
Infiltrative type	50 (39.7)
Portal vein invasion	48 (38.1)
Presence of EHS and/or RNI	87 (69.0)
Laboratory variables
Alanine aminotransferase, IU/dL	28 (3–433)
Prothrombin time, INR	1.1 (0.9–2.2)
Total bilirubin, mg/dL	0.8 (0.3–3.6)
Serum albumin, mg/dL	3.9 (2.6–5.2)
Tumor markers
AFP, mg/dL	291.6 (22–120,000)
PIVKA-II, mAU/mL	491.5 (50–75,000)

Note: Values are expressed as median (range) or number (%).

Abbreviations: ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; RNI, regional nodal involvement; INR, international normalized ratio; AFP, α-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II.

Table 2 Comparison between patients with and without AFP response

Variables	Patients with AFP response (n=43; 34.1%)	Patients without AFP response (n=83; 65.9%)	P-value
Demographic variables
Age, years	56 (39–78)	59 (34–85)	NS
Male sex	38 (88.4)	68 (76.4)	NS
Viral etiology	34 (89.5)	61 (83.6)	NS
ECOG, 0–1	42 (97.7)	84 (94.4)	NS
Child-Pugh class A	33 (76.7)	67 (75.3)	NS
Previous treatment history	30 (69.8)	64 (71.9)	NS
Tumor variables
Tumor size, cm	4.0 (2.0–13.0)	3.2 (2.0–18.0)	NS
Multiple tumors, ≥4	27 (62.8)	47 (52.8)	NS
Infiltrative type	20 (46.5)	34 (38.2)	NS
Portal vein invasion	14 (32.6)	37 (41.6)	NS
Presence of EHS and/or RNI	30 (69.8)	62 (69.7)	NS
Laboratory variables
Alanine aminotransferase, IU/dL	25 (3.0–315.0)	30.0 (9.0–433.0)	NS
Prothrombin time, INR	1.1 (0.9–2.2)	1.1 (0.9–1.7)	NS
Total bilirubin, mg/dL	0.7 (0.3–2.1)	0.8 (0.3–3.6)	NS
Serum albumin, mg/dL	3.8 (2.6–4.6)	3.9 (2.6–5.0)	NS
Tumor markers
AFP, mg/dL	450.9 (22–120,000)	343.2 (22.5–120,000)	NS
PIVKA-II, mAU/mL	365.0 (9.0–20,000)	529.0 (9.0–75,000)	NS
Disease control rate	31 (72.1)	39 (47.0)	0.007

Note: Values are expressed as median (range) or number (%).

Abbreviations: ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; RNI, regional nodal involvement; INR, international normalized ratio; AFP, α-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; NS, not significant.

Table 3 Independent predictors of overall survival

Variables	Univariate	Multivariate
	P-value	P-value	Hazard ratio (95% CI)
Demographic variables
Age	NS
Male sex	NS
Viral etiology	NS
ECOG 0–1, vs 2	0.006	0.210	1.3 (0.8–2.1)
Child-Pugh class B, vs A	0.012	0.017	1.8 (1.1–3.1)
Tumor variables
Tumor size, ≥10 cm	0.001	0.001	2.7 (1.6–4.7)
Multiple tumors, ≥4	NS
Infiltrative tumor type, vs nodular	0.058
Portal vein invasion	<0.001	<0.001	2.4 (1.5–3.8)
Presence of EHS and/or RNI	NS
Tumor markers
AFP non-response	<0.001	0.001	2.6 (1.5–4.3)
PIVKA-II non-response	NS

Abbreviations: NS, not significant; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; RNI, regional nodal involvement; AFP, α-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; vs, versus.

Figure 1 Kaplan–Meier curves of overall survival (OS) (A) and progression-free survival (PFS) (B) according to α-fetoprotein (AFP) response. Patients with an AFP response had significantly longer OS and PFS than patients without an AFP response (median 10.9 versus 5.2 months, log-rank test P=0.001 for OS and 5.3 versus 2.9 months, log-rank test P<0.001 for PFS).

Abbreviation: vs, versus.

Table 4 Independent predictors of progression-free survival

Variables	Univariate	Multivariate
	P-value	P-value	Hazard ratio (95% CI)
Demographic variables
Age	NS
Male sex	NS
Viral etiology	NS
ECOG 0–1, vs 2	NS
Child-Pugh class A, vs B	NS
Tumor variables
Tumor size, ≥10 cm	0.019	0.042	1.6 (1.1–2.5)
Multiple tumors, ≥4	NS
Infiltrative tumor type, vs nodular	NS
Portal vein invasion	0.006	0.007	1.5 (1.1–2.6)
Presence of EHS and/or RNI	NS
Tumor markers
AFP non-response	0.001	0.001	2.1 (1.3–3.3)
PIVKA-II non-response	NS

Abbreviations: NS, not significant; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; RNI, regional nodal involvement; AFP, α-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; vs, versus.

Figure 2 curves of overall survival (OS) (A) and progression-free survival (PFS) (B) according to α-fetoprotein (AFP) response among patients with stable disease at the first radiological response evaluation. Patients with an AFP response had significantly longer OS and PFS than patients without an AFP response (median 12.7 versus 5.8 months, log-rank test P=0.027 for OS and 9.1 versus 3.7 months, log-rank test P=0.019 for PFS).

Abbreviation: vs, versus.

Table 5 Adverse events

Adverse events	Total	Grade ≥2
HFSR	52 (41.2)	15 (11.9)
Diarrhea	40 (30.4)	12 (9.5)
Alopecia	15 (11.9)	2 (1.6)
Anorexia	15 (11.9)	8 (6.3)
Abdominal pain	25 (19.8)	9 (7.1)
Fatigue	29 (23.0)	19 (15.1)

Note: Variables are expressed as n (%).

Abbreviations: HFSR, hand–foot skin reaction; n, number.

Figure S1 Kaplan–Meier analysis according to log relative hazard ratio (LRHR) which was established using four independent risk factors: LRHR = exp[0.63 × Child-Pugh class (A=0, B=1) + 1.0 × tumor size (<10 cm=0, ≥10 cm=1) + 0.9 × portal vein invasion (absence =0, presence =1) + 0.9 × AFP response (presence =0, absence =1)]. When the study population was stratified according to the mean LRHR value, patients with LRHR <4 showed significantly better OS compared to those with LRHR ≥4 [median 6.2 months (95% CI, 3.8–8.5) versus 2.9 months (95% CI, 1.7–4.0), P<0.001 by log-rank test).

Abbreviations: OS, overall survival; AFP, α-fetoprotein; CI, confidence interval.