Systemic treatment for hepatocellular carcinoma: Still unmet expectations

Abstract

Many patients with hepatocellular carcinoma (HCC) are diagnosed in an advanced stage, so they cannot be offered the option of curative treatments. The results of systemic chemotherapy are unsatisfactory and this has led to molecular targeted approaches. HCC develops in chronically damaged tissue due to cirrhosis in most patients. Several different cell types and molecules constitute a unique microenvironment in the liver, which has significant implications in tumor development and invasion. This, together with genome instability, contributes to a significant heterogeneity which is further enhanced by the molecular differences of the underlying causes. New classifications based on genetic characteristics of the tissue microenvironment have been proposed and key carcinogenic signaling pathways have been described. Tumor and adjacent tissue profiling seem biologically promising, but have not yet been translated into clinical settings. The encouraging first results with molecular - genetic signatures should be validated and clinically applicable. A more personalized approach to modern management of HCC is urgently needed.

Keywords: Chemotherapy; Hepatocellular carcinoma; Prognosis; Systemic.

Figure 1

Serial computed tomography scans of a hepatocellular carcinoma patient with multiple co-morbidities precluding radical treatment, surviving 7 years with sequential approach in systemic treatment (Octreotide long acting release, followed by sorafenib). Despite an increase in tumor size, it is evident the central necrosis related to Sorafenib treatment (which was commenced when it became available).

Figure 2

Interplay between genetic and non-genetic factors in the pathogenesis of hepatocellular carcinoma. Potential treatment targets. Hepatocellular carcinoma (HCC) is a complex entity with multifactorial pathogenesis. Control of non-genetic factors (A) (e.g., viral elimination, inhibition of CD133 positive cancer cell overexpression) may lead to alteration of the progress from cirrhosis to HCC. On the other hand, the various genetic irregularities (B) may lead to different HCC profiles with respect to invasiveness (miR-494) or response to treatment. New targeted treatments are also directed against Wnt/β-katenin. HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIF-1α: Hypoxia-inducible factor 1 alpha; TNF: Tumor necrosis factor; IL-6: Interleukin-6; NFκΒ: Nuclear factor-kappa B.