Prolonged survival in patients with hand-foot skin reaction secondary to cooperative sorafenib treatment

Table 1 Baseline characteristics of patients in Groups A, B, and C

	Group A (n = 41)	Group B (n = 30)	Group C (n = 63)	P value
Age (yr)	70 (43–89)	67 (41–87)	69 (48–87)	0.233
Sex
Male, n (%)	33 (80.5)	22 (73.3)	44 (69.8)	0.481
Child-Pugh class, n (%)				0.288
A	33 (80.5)	27 (90.0)	57 (90.5)
B	8 (19.5)	3 (10.0)	6 (9.5)
Etiology, n (%)
HCV	22 (53.7)	11 (36.7)	44 (69.8)	0.235
HBV	9 (21.9)	10 (33.3)	11 (17.5)	0.417
Other	10 (24.4)	9 (30.0)	8 (12.7)	0.109
Portal vein thrombosis	14 (34.1)	10 (33.3)	11 (17.5)	0.099
Extrahepatic spread, n (%)	20 (48.8)	19 (63.3)	28 (44.4)	0.230
AFP (ng/mL), n (%)
> 400	17 (41.5)	17 (56.7)	29 (46.0)	0.437
BCLC staging, n (%)				0.333
Stage B	15 (36.6)	10 (33.3)	30 (47.6)
Stage C	26 (63.4)	20 (66.7%)	33 (52.4)
ECOG performance status, n (%)				0.955
0	30 (75.6)	22 (73.3)	46 (73.0)
1	10 (24.4)	8 (26.7)	17 (27.0)
Total bilirubin (mg/dL)	0.99 ± 0.36	0.91 ± 0.37	0.83 ± 0.33	0.052
Albumin (g/L)	3.61 ± 0.50	3.73 ± 0.54	3.82 ± 0.49	0.301
INR	1.14 ± 0.11	1.15 ± 0.16	1.14 ± 0.19	0.481
Pre-sorafenib TACE procedures, n (%)				0.531
0	13 (31.7)	9 (30.0)	20 (31.8)
1	3 (7.3)	6 (20.0)	13 (20.6)
2	6 (14.6)	1 (3.3)	4 (6.4)
3	4 (9.8)	2 (6.7)	8 (12.7)
4	5 (12.2)	3 (10.0)	12 (19.0)
> 5	10 (24.4)	9 (30.0)	6 (9.5)

AFP: Alpha-fetoprotein; BCLC: Barcelona Clinic Liver Cancer; HCV: Hepatitis C virus; HBV: Hepatitis B virus; INR: International normalized ratio; TACE: Transcatheter arterial chemoembolization; ECOG: Eastern Cooperative Oncology Group.

Table 2 Prevalence of adverse events after beginning sorafenib, according to CTCAE version 5.0, n (%)

	Group A (n = 41)				Group B (n = 30)				Group C (n = 63)
	All grades	Grade 1	Grade 2	Grade 3	All grades	Grade 1	Grade 2	Grade 3	All grades	Grade 1	Grade 2	Grade 3
Any adverse event	37 (90.2)	30 (73.2)	18 (43.9)	5 (12.2)	30 (100)	28 (93.3)	24 (80.0)	14 (46.6)	63 (100)	58 (92.1)	36 (57.1)	14 (22.2)
Hand-foot skin reaction	0 (0)	0 (0)	0 (0)	0 (0)	30 (100)	15 (50.0)	10 (33.3)	5 (16.7)	63 (100)	39 (61.9)	19 (30.2)	5 (7.9)
Anemia	17 (41.5)	8 (19.5)	8 (19.5)	1 (2.4)	20 (66.6)	13 (43.3)	4 (13.3)	3 (10.0)	23 (36.5)	14 (22.2)	7 (11.1)	2 (3.2)
Diarrhea	15 (36.6)	12 (29.3)	3 (7.3)	0 (0)	11 (36.6)	9 (30.0)	1 (3.3)	1 (3.3)	27 (42.8)	21 (33.3)	2 (3.2)	4 (6.3)
Fatigue	14 (34.1)	10 (26.8)	3 (7.3)	0 (0)	11 (36.6)	7 (23.3)	4 (13.3)	0 (0)	16 (25.4)	10 (15.9)	6 (9.5)	0 (0)
Anorexia	14 (34.1)	10 (24.4)	3 (7.3)	1 (2.4)	7 (23.3)	5 (16.7)	1 (3.3)	1 (3.3)	19 (30.1)	15 (23.8)	4 (6.3)	0 (0)
Hypertension	12 (29.3)	10 (24.4)	2 (4.9)	0 (0)	7 (23.3)	2 (6.6)	5 (16.7)	0 (0)	23 (36.5)	16 (25.4)	4 (6.3)	3 (4.8)
Thrombocytopenia	9 (22.0)	2 (4.9)	4 (9.7)	3 (7.3)	23 (76.7)	10 (33.3)	8 (26.7)	5 (16.7)	20 (31.7)	10 (15.9)	5 (7.9)	5 (7.9)
Alopecia	6 (14.6)	4 (9.7)	2 (4.9)	0 (0)	2 (6.6)	2 (6.6)	0 (0)	0 (0)	20 (31.7)	19 (30.2)	1 (1.6)	0 (0)
Hepatic encephalopathy	1 (2.4)	0 (0)	1 (2.4)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)

Table 3 Dose modification related to adverse events

	Group A (n = 41)	Group B (n = 30)	Group C (n = 63)	Group A vs Group B, P value	Group A vs Group C, P value	Group B vs Group C, P value
Dose reduction to initial dose of sorafenib	8/41 (19.5%)	2/30 (6.7%)	26/63 (41.3%)	0.700	0.108	0.005
Re-escalation to initial dose of sorafenib	2/8 (25.0%)	2/2 (100.0%)	2/26 (7.7%)	NA	NA	NA

NA: Not available.

Table 4 Radiological response according to the modified response evaluation criteria in solid tumors

	Group A (n = 41)	Group B (n = 30)	Group C (n = 63)
Complete response	0	1	1
Partial response	1	1	5
Stable disease	10	11	35
Progressive disease	30	17	22
Response rate	2.4%	6.7%	9.5%
Disease control rate	26.8%	43.3%	65.1%

Table 5 Reasons for permanent sorafenib discontinuation, n (%)

	Group A (n = 41)	Group B (n = 30)	Group C (n = 63)	Group A vs Group B, P value	Group A vs Group C, P value	Group B vs Group C, P value
Progression	26 (63.4)	7 (23.3)	33 (52.4)	0.006	1.000	0.046
Intolerance	7 (17.1)	18 (60.0)	13 (20.6)	0.002	1.000	0.001
Liver failure	6 (14.6)	3 (10.0)	8 (12.7)	1.000	1.000	1.000
Other	2 (4.9)	2 (6.7)	9 (14.3)	1.000	0.690	1.000

Table 6 Prognostic factors of overall survival by multivariable Cox regression analysis

	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Age (within 70 yr)	0.867	0.603–1.246	0.440	-	-	-
Male	1.216	0.802–1.842	0.357	-	-	-
Etiology (HBV)	1.313	0.809–2.133	0.271	-	-
BCLC stage B	0.667	0.459–0.969	0.033	0.601	0.405–0.891	0.011
Portal vein thrombosis	1.677	1.092–2.575	0.018	1.133	0.674–1.903	0.638
Extrahepatic spread	0.740	0.509–1.074	0.113	0.671	0.419–1.076	0.098
AFP (> 400 ng/mL)	1.282	0.893–1.839	0.178	1.370	0.936–2.006	0.105
ECOG Performance status 1	0.752	0.488–1.158	0.196	1.042	0.636–1.708	0.869
Group A vs Group B	0.703	0.431–1.147	0.159	0.658	0.398–1.088	0.103
Group A vs Group C	0.431	0.281–0.663	< 0.001	0.407	0.253–0.654	< 0.001
Sorafenib administration period (second half vs first half)	1.205	0.840–1.728	0.311	-	-	-

AFP: Alpha-fetoprotein; BCLC: Barcelona Clinic Liver Cancer; HBV: Hepatitis B virus; ECOG: Eastern Cooperative Oncology Group.

Table 7 Prognostic factors of time-to-treatment failure by multivariable Cox regression analysis

		Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Age (within 70 yr)	1.059	0.747–1.501	0.747	-	-	-
Male	0.926	0.625–1.372	0.703	-	-	-
Etiology (HBV)	1.208	0.768–1.901	0.413	-	-	-
BCLC stage C	1.311	0.921–1.866	0.132	-	-	-
Portal vein thrombosis	1.379	0.925–2.056	0.115	1.011	0.662–1.545	0.958
Diarrhea	0.675	0.473–0.965	0.031	0.654	0.449–0.952	0.027
Hypertension	1.070	0.735–1.556	0.725	-	-	-
ECOG Performance status 1	0.687	0.446–1.058	0.089	0.725	0.463–1.135	0.159
Group B vs Group A	1.670	1.034–2.698	0.036	1.694	1.044–2.748	0.033
Group C vs Group A	0.495	0.328–0.747	< 0.001	0.529	0.346–0.811	0.003
Sorafenib administration period (second half vs first half)	0.980	0.694–1.384	0.908	-	-	-

AFP: Alpha-fetoprotein; BCLC: Barcelona Clinic Liver Cancer; HBV: Hepatitis B virus; ECOG: Eastern Cooperative Oncology Group.

Table 8 Prognostic factors of proportion of days covered by logistic regression analyses

	Adjusted analyses
	OR	95%CI	P value
Male	0.352	0.141–0.877	0.025
Child-Pugh stage B	3.830	1.180–12.400	0.025
Diarrhea	0.472	0.198–1.120	0.089
Group B vs Group A	0.113	0.036–0.356	< 0.001
Group B vs Group C	0.091	0.031–0.266	< 0.001