Hepatocellular carcinogenesis, progression, and metastasis are closely related to multiple genetic mutations, intercellular messaging, and tumor vascular proliferation, and its pathogenesis is complex and contains multiple critical links that are also potential targets for molecularly targeted therapies.
Anti-cancer mechanism of sorafenib
Sorafenib (Nexavar, doxorubicin) is a multi-targeted therapeutic agent for hepatocellular carcinoma with the following mechanism of action:
- Inhibition of tumor growth enzymes and related receptors, such as the Vascular Endothelial Growth Factor Receptor (VEGFR), followed by inhibition of tumor cell growth;
- Inhibits enzymes and related receptors of tumor angiogenesis (e.g. platelet growth factor receptor), thereby significantly inhibiting tumor angiogenesis and cutting off the tumor blood supply.
In both cases, the two-pronged approach has the dual effect of antagonizing tumor angiogenesis and tumor cell growth.
Mapping the dose of sorafenib
After 2005, reports of the initial use of sorafenib in cancer patients were published, with studies aimed at balancing the drug toxicity and efficacy of sorafenib and finding the way to take the drug orally and the appropriate dose.
After 173 patients with advanced cancer were given different oral doses of the drug, the results of the trial determined that an oral dose of sorafenib of 400 mg orally twice daily, administered continuously by mouth, was the optimal dosing regimen.
Two of these patients achieved partial remission, including one with advanced hepatocellular carcinoma, and 38 patients with advanced cancer achieved stability for more than 6 months, including 5 for more than 1 year. The main adverse effects were diarrhea, fatigue, and skin irritation.
Sorafenib appears to exert some antitumor activity in patients with advanced tumors; how well would it work if applied solely to hepatocellular carcinoma?
A study in Japanese patients with advanced hepatocellular carcinoma showed that of 27 patients with hepatocellular carcinoma with a liver function Child score of A or B, 1 achieved partial remission, 20 achieved stable disease, and 3 experienced disease progression. This suggests that sorafenib can exert some antitumor activity when used in patients with advanced hepatocellular carcinoma.
Child grading is a commonly used grading scale for quantitative assessment of liver reserve function, which classifies liver reserve function into A, B, and C grades, predicting three different levels of severity of liver damage, with C and being the most severe.
Effectiveness of sorafenib for advanced hepatocellular carcinoma
The initial use of sorafenib offers a glimmer of hope for patients with liver cancer; is its treatment effect coincidental or does it really work? This brings us to two heavyweight studies, called the SHARP and Oriental studies.
The SHARP study confirmed that sorafenib showed a superior survival benefit compared to placebo in the European and American liver cancer populations, regardless of the presence of macrovascular invasion or extrahepatic metastases.
The subsequently published Oriental study confirmed that sorafenib significantly prolonged overall survival and time to disease progression in patients with advanced hepatocellular carcinoma in the Asia-Pacific region, and that all subgroups of patients showed a survival benefit.
| Study name | Method of administration | Results |
| SHARP Study (European and American populations) | Sorafenib vs. placebo |
Overall survival improvement with sorafenib: 44% Overall survival: 10.7 months vs. 7.9 months Time to disease progression: 5.5 months vs. 2.8 months Disease control rate: 43% vs 32% |
| Oriental study (Asia-Pacific population) | Sorafenib vs. placebo |
Overall survival improvement with sorafenib: 47% Overall survival: 6.5 months vs. 4.2 months Time to disease progression: 2.8 months vs. 1.4 months Disease control rate: 35% vs. 16% Time to symptom progression: no difference |
Together, the results of the two studies show that patients with hepatocellular carcinoma of different ethnicities and geographic regions show a favorable survival benefit with sorafenib, laying the foundation for sorafenib as a new treatment option for patients with advanced hepatocellular carcinoma.
Patients with hepatocellular carcinoma treated with sorafenib can experience some adverse effects, such as malaise, diarrhea, hypertension, and rash, but these adverse effects are often tolerated or controlled with some medications, and they seem to be minor compared to the survival benefit it provides.
Sorafenib becomes standard of care for patients with intermediate to advanced liver cancer
Sorafenib was approved by the European Union Drug Administration (October 2007), the US Food and Drug Administration (November 2007), and our own Food and Drug Administration (June 2008) for the treatment of hepatocellular carcinoma that cannot be surgically removed.
Sorafenib has opened up new horizons in the treatment of advanced hepatocellular carcinoma, becoming a milestone in molecularly targeted therapeutics for hepatocellular carcinoma and having a profound and dramatic impact on the treatment strategy for hepatocellular carcinoma.
The 2017 American Society of Clinical Oncology Annual Meeting also gave recognition to sorafenib, announcing a consensus that sorafenib remains the standard of care for intermediate-stage hepatocellular carcinoma! Through thick and thin, sorafenib shines in the arena of targeted therapy for advanced hepatocellular carcinoma!