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The evidence for this protocol comes from a randomised, multicenter, phase III, double blind, placebo-controlled trial conducted by the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) Investigators Study Group reported by Llovet et al.r
Between March 10 2005 and April 11 2006, a total of 602 patients were randomised to either the sorafenib group (299 patients) or the placebo group (303 patients).
The primary endpoints were overall survival and time to symptomatic progression and the secondary endpoints included time to radiologic progression, disease control rate and safety.
The efficacy and safety of sorafenib for hepatocellular in the Asia-Pacific population was studied in a multicentre, double-blind, placebo-controlled RCT involving 271 patients. Median overall survival was 6.5 vs 4.2 months (HR=0.68; 95% CI 0.50-0.93; p=0.014) and median time to treatment progression was 2.8 vs 1.4 months (HR=0.57; 95% CI 0.42-0.79;p=0.0005) in the sorafenib and placebo arms respectively. Sorafenib was generally well tolerated with hand-foot skin reaction (10.7%), diarrhoea (6%), and fatigue (3.4%) the most frequently reported adverse events.r
Efficacy
The median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; p<0.001).
There was no significant difference in the median time to symptomatic progression between the sorafenib group and the placebo group (4.1 months vs 4.9 months respectively; p=0.77).
The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (p<0.001). 7 patients in the sorafenib group and 2 patients in the placebo group had a partial response; no patient had a complete response.
Efficacyr |
Sorafenib (n=299) |
Placebo (n=303) |
p-value |
Overall Survival |
10.7 months |
7.9 months |
<0.001 |
Time to symptomatic progression |
4.1 months |
4.9 months |
0.77 |
Time to radiologic progression |
5.5 months |
2.8 months |
<0.001 |
Kaplan-Meier Analysis of Overall Survival and Time to Symptomatic Progressionr

© New England Journal of Medicine 2008
Toxicity
The overall incidence of treatment-related adverse events, predominantly grade 1 or 2, was 80% in the sorafenib group and 52% in the placebo group. Diarrhoea, weight loss, hand-foot skin reaction, alopecia, anorexia, voice changes, hypophosphataemia and thrombocytopenia occurred at a higher frequency in the sorafenib group than in the placebo group.
Rates of discontinuation of treatment were similar in the two groups (38% in the sorafenib and 37% in the placebo). Gastrointestinal events (6%), fatigue (5%), and liver dysfunction (5%) were the most frequent causes of discontinuation of sorafenib.
Toxicityr |
Sorafenib (%) |
Placebo (%) |
p-value |
Diarrhoea |
39 |
11 |
<0.001 |
Weight loss |
9 |
1 |
<0.001 |
Hand-foot skin reaction |
21 |
3 |
<0.001 |
Alopecia |
14 |
2 |
<0.001 |
Anorexia |
14 |
3 |
<0.001 |
Voice changes |
6 |
1 |
<0.001 |
Hypertension |
5 |
2 |
0.05 |
Bleeding |
7 |
4 |
0.07 |