Adjuvant Therapy of Hepatocellular Carcinoma: Molecular Mechanisms and Clinical Practice

Dear Colleagues,

Hepatocellular carcinoma (HCC) represents a major health problem. Radiofrequency ablation (RFA) and surgery are considered effective radical treatments; however, these therapies are still accompanied by high recurrence rates, which range from 60% to 80% at 4 years. As a consequence, new adjuvant agents designed to improve the prognosis of these patients are continually an object of research. Clinically available drugs, such as interferon or sorafenib, have not been definitively proven to be effective as adjuvant treatment against HCC recurrence; in addition, long-term administration to cirrhotic patients frequently leads to severe side effects and, consequently, to suspension of the therapy.

This, in addition to the high costs and lack of evidence for a survival advantage of their long-term administration, explains why data on the efficacy of adjuvant treatments tested so far have been found to be unsatisfactory.

An alternative approach to prevent HCC recurrence may be to find clinically available compounds that are inexpensive, easily manageable, and non-toxic, with a proven safety profile on long-term administration. Promising preliminary data have recently been published on the use of angiotensin-converting enzyme inhibitors (ACE-I) in the setting of adjuvant therapies for HCC, as a consequence of their well-known anti-angiogenic and anti-fibrogenic activity.

In fact, angiotensin II induces the release of vascular endothelial growth factor (VEGF) and enhances hepatic fibrosis through production of transforming growth factor-beta 1 (TGF-β1) by Kuppfer and activate stellate cells. Particularly of interest is the role of angiotensin II type 1 receptor blockers (sartans), which remain poorly understood. In fact, most of the biological properties of angiotensin II, including pro-fibrogenic and pro-angiogenic activity, are mediated by receptor 1. Only in the last few years has angiotensin II receptor 2 been known to have contrary effects to those of receptor 1, by inhibiting cell proliferation and stimulating apoptosis in a variety of cell lines. While ACE-I blocks the activation cascade of the renin-angiotensin aldosterone system (RAAS) upstream, thus preventing the binding of angiotensin II to both receptors, sartans selectively inhibit the activation of receptor 1.

Other interesting results are being collected on the beneficial and anti-oncogenic effects of statins. In vitro and animal studies have shown that statins exert antineoplastic effects through both HMG-CoA reductase-dependent and HMG-CoA reductase-independent pathways. By blocking the conversion of HMG-CoA into mevalonate, statins can inhibit several downstream products of the mevalonate pathway, including the generation of isoprenoids. This prevents posttranslational prenylation of small signaling G proteins of the Ras/Rho superfamily, which are important mediators of cell growth, differentiation, and survival.

Data on the chemoprevention effect against HCC recurrence of several drugs are still scanty and partially discording. Preclinical studies seem to provide promising results, but clinical confirmation is still yet to come.

The aim of this Special Issue is to provide an overview on the current state-of-the-art and to collect new laboratory and clinical data which can be of help to define the ideal adjuvant approach in HCC patients.

Dr. Antonio Facciorusso
Guest Editor

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• HCC
• survival
• recurrence
• progression
• radiofrequency ablation