Hepatocellular carcinoma is the fifth most common cancer worldwide with a global incidence of approximately one million cases a year. The US has witnessed a three-fold increase in the incidence of hepatocellular carcinoma over the past decade and 20,000 new cases are now diagnosed with approximately 18,700 deaths annually. Surgery and transplantation remain the only curative option for hepatocellular carcinoma patients. However, these modalities are confined to only 5-10% of presenting patients and for the remaining 90% there is no gold-standard therapy; currently used cytotoxics offer unsatisfactory response rates of 15-20%. Due to the paucity of effective treatments, any new therapy for hepatocellular carcinoma will gain rapid uptake if it shows even the slightest increase in efficacy or reduction in toxicity over doxorubicin-based regimes. AstraZeneca's Iressa has recently been shown to prevent proliferation and induce apoptosis in human hepatocellular cancer cell lines. Results from ongoing clinical studies designed to investigate the efficacy of this EGFR inhibitor in humans with this cancer are eagerly awaited; perhaps even more exciting considering recent disappointments with Iressa in non-small cell lung cancer would be studies investigating other EGFR1 inhibitors such as Tarceva

Hepatocellular carcinoma is the fifth most common cancer worldwide with a global incidence of approximately one million cases a year. The US has witnessed a three-fold increase in the incidence of this disease over the past decade; each year 20,000 new cases are now diagnosed while 18,700 patients die. Similar trends have been observed in other pharmaceutical markets (for a full evaluation of hepatocellular carcinoma and its emerging treatments click here).

Hepatocellular carcinoma is a complex heterogeneous neoplasm and is frequently described as two diseases in one - an aggressive malignant disorder arising in the setting of chronic liver disease. Around 70-90% of hepatocellular carcinoma patients will have liver cirrhosis at the point of diagnosis commonly resulting from chronic hepatitis B and C infection or alcoholism.

Surgery and transplantation remain the only curative option for hepatocellular carcinoma patients. However, complications due to underlying cirrhosis mean that these modalities are confined to only 5-10% of presenting patients. For the remaining 90% of patients there is no gold-standard therapy and currently used cytotoxics offer unsatisfactory response rates of 15-20%. As such, the hepatocellular carcinoma market has high patient potential and, consequently, high commercial value expected to grow from the $70.1 million clocked in 2002 to $286 million in 2010.

Due to the paucity of effective treatments, any new therapy for hepatocellular carcinoma will gain rapid uptake if it shows even the slightest increase in efficacy or reduction in toxicity over doxorubicin-based regimes. The issue of toxicity is important given the extent of liver dysfunction in hepatocellular carcinoma patients and the inability to detoxify current cytotoxic agents; likewise hepatocellular carcinoma appear particularly susceptible to drug resistance. One product, Amgen's T67 could potentially improve response and survival rates in hepatocellular carcinoma. Eximias Pharmaceutical's Thymitaq is a thymidylate synthase inhibitor also in Phase III trials for hepatocellular carcinoma. Eximias' Thymitaq is expected to launch in 2005 followed by Tularik's T67 in 2006.

One anti-cancer agent that has received considerable attention is AstraZeneca's Iressa (Gefitinib, ZD1839), a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. The side effect profile of gefitinib is good with the most common side effects being are low-grade rash or diarrhea. Based on data from pivotal phase II trials, IDEAL 1 and 2, which showed Iressa to shrink tumors and to improve symptoms, gefitinib received accelerated approval on May 5, 2003 by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Disappointingly however, in a press release on December 17th, 2004, AstraZeneca announced that the initial analysis of the IRESSA Survival Evaluation in Lung cancer (ISEL) showed that IRESSA failed to significantly prolong survival in comparison to placebo in the overall population or in patients with adenocarcinoma.

While the data from ISEL is being further evaluated, the clinical benefit of gefitinib in other cancer including those of the head and neck, colon, breast, and prostate is being investigated. Human hepatocellular carcinoma is associated with increased activation of EGFR, offering proof of concept to support the phase II trial of gefitinib currently underway in patients with this cancer. The evaluation of gefitinib in patients with hepatocellular carcinoma is based on a small number of animal and cellular studies. In 2003 Matsuo et al reported that gefitinib produced antiproliferative and apoptotic activity in murine hepatocellular carcinoma cells and reduced the size of xenografts; the metastatic properties of these cells were also blocked. More recently Hopner et al (2004) studied the antineoplastic potency of gefitinib in human hepatocellular carcinoma cells. Gefitinib induced a time- and dose-dependent growth inhibition of the human hepatocellular carcinoma cell lines Huh-7 and HepG2. Gefitinib-treatment also induced both mitochondria-dependent and -independent apoptosis. Changes in mitochondrial membrane potential and caspase-8 activation, followed by caspase-3 activation and nuclear degradation, were detected. Moreover, gefitinib induced cell cycle arrest at the G1/S checkpoint and decreased the phosphorylation of mitogen-activated protein kinase ERK1/2. Finally, gefitinib suppressed the expression of antiapoptotic Bcl-2 and Bcl-X(L), further rendering hepatocellular carcinoma cells prone to apoptosis.

These in vitro studies further support the evaluation of gefitinib in patients with hepatocellular carcinoma especially given that the human cell lines investigated are drug resistant and therefore show the characteristics of human disease. This positive data must however be countered by the lack of survival advantage in non-small cell lung cancer patients treated with gefitinib. This lack of effect may simply reflect differing efficacy in patient sub-populations and identifying those patients that may particularly benefit from gefitinib as well as prognostic markers of efficacy may allow benefits of this therapeutic to be more readily identified, not only in non-small cell lung cancer patients but also those with hepatocellular carcinoma.

Entry date Sunday, January 23, 2005

Adapted from Hopner et al, J Hepatol. 2004 Dec;41(6):1008-16.