Are we SHARP enough? The importance of adequate patient selection in sorafenib treatment for hepatocellular carcinoma

Figures & data

Figure 1. Study flowchart.

Table 1. Baseline characteristics of all, SHARP eligible and non-eligible patients.

Variable	All patients, N = 257	Eligible, N = 193	Non-eligible, N = 64	p value^a
Age, median (range) (years)	65 (26–84)	66 (26–84)	63 (27–79)	.040
Male, n (%)	208 (81)	161 (83)	47 (73)	.098
Etiology, n (%)
Alcohol	87 (34)	67 (35)	20 (31)	.650
HBV	40 (16)	30 (15)	10 (16)	.998
HCV	41 (16)	31 (16)	10 (16)	.934
NAFLD/NASH	20 (8)	17 (9)	3 (5)	.420
Other/unknown	15 (6)	9 (5)	6 (9)	.215
Cirrhosis, n (%)	203 (79)	148 (77)	55 (86)	.081
Child–Pugh class, n (%)^b				<.001
A	218 (85)	193 (100)	25 (39)
B	35 (14)	NA (0)	35 (55)
ECOG performance status, n (%)				.558
0	81 (32)	64 (33)	17 (27)
1	153 (60)	113 (59)	40 (63)
2	23 (9)	16 (8)	7 (11)
BCLC stage prior to start sorafenib, n (%)				.300
B (intermediate)	69 (27)	55 (29)	14 (22)
C (advanced)	188 (73)	138 (72)	50 (78)
Number of nodes, n (%)				.097
1 node	53 (21)	41 (21)	12 (19)
2–3 nodes	60 (23)	66 (34)	14 (22)
>3 nodes or diffuse infiltrating	20 (8)	86 (45)	38 (59)
Size of largest node, mm (range)	72 (10–230)	70 (12–225)	77 (10–230)	.143
Macroscopic vascular invasion, n (%)	107 (42)	79 (41)	28 (44)	.692
Extend of disease				.085
Confined to liver	108 (42)	87 (45)	21 (33)
Extrahepatic spread	149 (58)	106 (55)	43 (67)
Laboratory analysis
AFP, ng/ml, median (range)	179 (2–1201500)	158 (2–1201500)	244 (3–688200)	.137
AFP ≥400 ng/ml, n (%)	109 (42)	81 (42)	28 (44)	.727
Hemoglobin (mmol/L), median (range)	8.2 (4.9–10.8)	8.3 (5.6–10.8)	7.8 (4.9–10.5)	.001
Thrombocytes (×10^9), median (range)	187 (52–846)	188 (62–672)	175 (52–846)	.761
PT (sec), median (range)	12.5 (9.8–17.5)	12.3 (9.8–16.4)	13.0 (10.7–17.5)	<.001
Creatinine (µmol/L), median (range)	72 (41–247)	74 (41–151)	68 (41–247)	.227
Albumin (g/dl), median (range)	40 (23–50)	40 (30–50)	35 (23–47)	<.001
Bilirubin (µmol/L), median (range)	14 (3–75)	13 (3–40)	22 (3–75)	<.001
AST (U/L), median (range)	69 (17–697)	64 (17–198)	126 (29–697)	<.001
ALT (U/L), median (range)	47 (9–493)	45 (9–224)	51 (20–493)	.012
Received prior treatment, n (%)	93 (36)	75 (39)	18 (28)	.121
Liver transplantation	5 (2)	5 (3)	0 (0)	.336
Surgical resection	26 (10)	23 (12)	3 (5)	.149
RFA	36 (14)	28 (15)	8 (13)	.836
TACE	53 (21)	41 (21)	12 (19)	.669
SIRT	1 (<1)	1 (<1)	0 (0)	1.00
Systemic therapy	4 (2)	NA	4 (6)	.004

^a p value applies to the ‘meeting’ versus ‘not meeting’ groups. p values <0.05 are highlighted in bold.

^b Missing in four patients.

AFP: α-fetoprotein; ALT: alanine transaminase; AST: aspartate transaminase; BCLC: Barcelona Clinic Liver Cancer classification; ECOG: Eastern Cooperative Oncology Group; HBV: hepatitis virus B; HCV: hepatitis virus C; NA: non-applicable; NAFLD/NASH: non-alcoholic fatty liver disease/non-alcoholic steatohepatitis; PT: prothrombin time; RFA: radiofrequent ablation; SHARP: Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol; SIRT: selective internal radiation therapy; TACE: transcatheter arterial chemoembolization.

Figure 2. (a) Overall survival and (b) time to progression in SHARP eligible and SHARP non-eligible subgroups. Thirty-three patients were not evaluable for TTP analysis.

Table 2. Treatment details and adverse events of SHARP eligible and non-eligible patients.

Variable	All patients, N = 257	Eligible, N = 193	Non-eligible, N = 64	p value^a
Weeks of treatment, median (range)	13 (0–225)	13 (0–209)	9 (0–225)	.052
Total tolerated daily dose, median (range)	400 (200–1400)	400 (200–1400)	400 (200–1000)	.203
Treatment emergent adverse events
Any, all grades	203 (79)	150 (78)	53 (83)	.082
Any, grade 3/4	140 (55)	104 (54)	36 (56)	.742
Asthenia, all grades	76 (30)	56 (29)	20 (31)	.734
Asthenia, grade 3/4	14 (5)	12 (6)	2 (3)	.528
Dermatological, all grades	88 (34)	72 (37)	16 (25)	.072
Dermatological, grade 3/4	29 (11)	24 (12)	5(8)	.370
Gastrointestinal, all grades	94 (37)	69 (36)	25 (39)	.634
Gastrointestinal, grade 3/4	32 (13)	27 (14)	5 (8)	.274
Hematological, all grades	26 (10)	21 (11)	5 (8)	.634
Hematological, grade 3/4	8 (3)	6 (3)	2 (3)	1.000
Hypertension, all grades	16 (6)	15 (8)	1 (2)	.130
Hypertension, grade 3/4	5 (2)	5 (3)	0 (0)	.336
Liver dysfunction, all grades	90 (35)	54 (28)	36 (56)	<.001
Liver dysfunction, grade 3/4	72 (28)	44 (23)	28 (44)	.001
Other, all grades	28 (11)	20 (10)	8 (13)	.634
Other, grade 3/4	14 (5)	9 (5)	5 (8)	.347
Treatment interruptions				.998
None	172 (67)	129 (67)	43 (67)
1–2 interruptions	77 (30)	58 (30)	19 (30)
≥3 interruptions	8 (3)	6 (3)	2 (3)
Reason termination				.030
Ongoing	6 (2)	6 (3)	0 (0)
Progression	127 (49)	104 (54)	23 (36)
Toxicity	34 (13)	25 (13)	9 (14)
Progression and adverse event	66 (26)	42 (22)	24 (38)
Other/unknown	24 (9)	16 (8)	5 (16)
Best radiological response (RECIST 1.1)				.373
Complete response	0 (0)	0 (0)	0 (0)
Partial response	20 (8)	13 (7)	7 (11)
Stable disease	98 (38)	79 (41)	19 (30)
Progressive disease	106 (41)	77 (40)	29 (45)
Not evaluable	33 (13)	9 (9)	6 (19)

^ap value applies to the ‘meeting’ versus ‘not meeting’ groups. p values <.05 are highlighted in bold.

RECIST: Response Evaluation Criteria in Solid Tumors; SHARP: Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol.

Table 3. Hazard ratios for overall survival in univariable and multivariable analysis.

Variable name, n (%)	Univariable analysis			Multivariable analysis
	HR	95% CI	p value^a	HR	95% CI	p value^a
Not meeting SHARP inclusion criteria	1.81	1.35–2.44	<.001	1.78	1.32–2.41	<.001
Female sex	1.27	0.92–1.75	.152
Age >65 years	0.96	0.74–1.24	.729
HBV	1.02	0.71–1.47	.929
HCV	0.87	0.60–1.25	.437
Alcohol abuse	0.96	0.73–1.26	.747
Cirrhosis	1.11	0.81–1.53	.520
ECOG PS 2 (ref = ECOG 0-1)	1.57	1.01–2.44	.045	1.36	0.86–2.15	.191
BCLC stage C (ref: B)	1.23	0.91–1.65	.180
Number of nodes (ref =1 node)			.087
2–3 nodes	0.86	0.60–1.24
>3 nodes/diffuse infiltrating	1.20	0.86–1.68
Tumor size >72 mm	1.53	1.17–1.98	.002	1.27	0.95–1.70	.111
Macroscopic vascular invasion	1.44	1.11–1.88	.006	1.34	1.02–1.76	.036
Extrahepatic spread (ref = liver confined)	1.11	0.85–1.44	.456
AFP ≥400	1.76	1.35–2.30	<.001	1.60	1.22–2.11	.001
Received previous treatments	0.67	0.51–0.88	.004	0.84	0.61–1.15	.264

^ap values <.05 are highlighted in bold.

AFP: α-fetoprotein; BCLC: Barcelona Clinic Liver Cancer classification; ECOG PS: Eastern Cooperative Oncology Group Performance status; HBV: hepatitis virus B; HCV: hepatitis virus C; NAFLD/NASH: non-alcoholic fatty liver disease/non-alcoholic steatohepatitis; SHARP: Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol.

Table 4. Studies comparing sorafenib outcomes in Child–Pugh A and B subgroups in advanced HCC.

First author	Year	Design	No. of patients (% Child–Pugh B)	Overall survival Child A versus B (mo.)	Conclusion on Child–Pugh B
Pinter [14]	2009	Retrospective	59 (39%)	8.3 versus 4.3	More data needed
Wörns [16]	2009	Prospective	34 (44%)	7.2 versus 3.3	Treat with caution
Abou-Alfa [7]	2011	Retrospective	127 (30%)	9.5 versus 3.2	More data needed
Hollebecque [9]	2011	Prospective	120 (17%)	13 versus 4.5	Treat with caution
Iavarone [10]	2011	Prospective	296 (12%)	12.7 versus 7.7	–
Pressiani [15]	2012	Prospective	297 (21%)	10.0 versus 3.8	Treat with caution
Da Fonseca [11]	2015	Retrospective	120 (17%)	9.7 versus 2.5	More data needed
Ogasawara [13]	2015	Prospective	89 (34%)	11.1–14.5 versus 4.6–8.7	Child–Pugh B7 is eligible
Marrero [12]	2016	Prospective	2717 (25%)	13.6 versus 5.2	Treat with caution
Edeline [8]	2016	Retrospective	905 (20%	7.0–10.2 versus 3.6	Limit indication to Child–Pugh A

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