Hepatocellular Carcinoma: Molecular Biology and Therapy

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Advanced and metastatic hepatocellular carcinomas (HCC) are challenging to treat, and no cytotoxic agents have impacted survival. The underlying liver cirrhosis that commonly accompanies HCC provides an additional challenge; indeed, functional scoring of cirrhosis and HCC is a critical component of patient evaluation. Currently, the molecular biology and pathogenesis of HCC are being increasingly investigated, which may lead to better understanding of the evolution of the disease, especially differing etiologies and identification of survival genes that may affect outcome. Early studies of targeted therapies in HCC have shown disease stabilization, and an increased understanding of the mechanism(s) of these novel agents combined with correlative studies may lead to the identification of an active agent or combination of agents that impacts the natural history of HCC.

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Cirrhosis and Scoring Systems

The presence of cirrhosis is an important factor to assess when evaluating any patient with HCC. Historically, medical oncologists have used the Child’s-Pugh Scoring System3, 4 which consists of five parameters: albumin, bilirubin, prothrombin time, and encephalopathy. Each of those parameters is given one to three points based on severity, and the addition of those points will lead to a score system, A, B or C, which helps define a patient’s outcome (Table 1). A limitation of the Child’s-Pugh

Chemotherapy

Many chemotherapeutic agents have been tested in HCC, mainly in phase II studies evaluating response. Response rates ranging from 10% to 20%9, 10, 11 have been reported, but no clear impact on survival has been identified.

The most studied chemotherapeutic agent is doxorubicin (adriamycin), with a response rate of 11%.12 The regimen that has shown the highest response in HCC is the combination of cisplatin, interferon, doxorubicin, and 5-fluorouracil (PIAF), which showed a 26% response rate and

Molecular Concepts

In recent years, investigators have achieved a better understanding of the molecular events leading to oncogenesis of HCC. In parallel, multiple novel therapeutic agents are being assessed in HCC.

With regard to etiology, as an example, chronic hepatitis can lead to phenotypically altered hepatocytes and ultimately cirrhosis. Occasionally, chronic hepatitis B leads to HCC without the interval development of cirrhosis. Phenotypically altered hepatocytes have high epidermal growth factor receptor

Novel Therapeutics

Many novel therapeutic agents for HCC have been evaluated in phase I and II studies. Sorafenib (Nexavar; Bayer, West Haven, CT and Onyx, Bellevue, WA), erlotinib (Tarceva; OSI Oncology, Melville, NY), bevacizumab (Avastin; Genentech, San Francisco, CA), and flavopiridol will be discussed herein. Sorafenib is a Raf kinase inhibitor with anti-vascular endothelial growth factor and anti–platelet-derived growth factor activity.19 Vascular endothelial growth factor and platelet-derived growth factor

Conclusion

Management of advanced and metastatic HCC continues to be challenging because of high expression of drug resistance genes, underlying cirrhosis, and poor liver function in many patients. Functional scoring of the cirrhosis and the HCC is a critical part of evaluating a patient with HCC. The CLIP scoring system should be used for patients with a hepatitis C etiology, and the CUPI scoring system is optimal for patients with hepatitis B-related HCC.

Thus far, no cytotoxic agent has been shown to

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