29-Oct-2004

An insight into hepatocellular carcinoma

Summary

Hepatocellular carcinoma is the fifth commonest cancer worldwide with about one million new cases diagnosed annually. It is estimated that the incidence of hepatocellular carcinoma in the seven major pharma markets will continue to rise over the next decade. There is no gold standard therapy - the market is characterized by high levels of unmet need, large patient potential and high commercial potential. To mark the publication of its new feature "Hepatocellular Carcinoma" LeadDiscovery's analys

Last Updated: 27-Aug-2010

Hepatocellular carcinoma a difficult to treat cancer of increasing incidence

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. Similar trends have been observed in four other pharmaceutical markets: Italy, France, the UK and Canada.

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.

Cirrhosis resulting in hepatocellular carcinoma is associated with chronic hepatitis B and C infection, alcoholism and, in developing countries, Aflatoxin from Aspergillus moulds. The global distribution of hepatocellular carcinoma is predominantly influenced by geographic prevalence of hepatitis B and C carriers. The highest incidence is found where hepatitis B and C infection is endemic, such as South East Asia and Africa. The highest age standardized mortality is in China, where hepatocellular carcinoma is the second-biggest cause of cancer mortality, accounting for 53% of cancer deaths (3.47 million). Migration of people from areas where hepatitis B and hepatitis C is endemic and will continue to increase the incidence of hepatocellular carcinoma in the western world.

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.

Compromised liver function and increased drug resistance limit the efficacy of pharmaceutical approches to hepatocellular carcinoma

Liver cirrhosis severely compromises liver function, this is particularly problematic in hepatocellular carcinoma patients given the toxicity of anticancer agents and the pivotal role the liver plays in their detoxification and removal. Moreover, biochemical disturbances in proteins responsible for blood coagulation make hepatocellular carcinoma patients particularly vulnerable to bleeding disorders. Indeed, it is often the state of the remaining liver that dictates final treatment options. Thus, not only do hepatocellular carcinoma patients require effective agents to treat the tumor, there is also significant unmet need for drugs that will stabilize and treat the underlying liver disease.

Current pharmacotherapies are largely ineffective for hepatocellular carcinoma and medical oncologists face the challenge of gaining benefit from relatively ineffective drugs currently available for hepatocellular carcinoma. The anthracycline doxorubicin is frequently employed in patients with unresectable hepatocellular carcinoma, however, this achieves response rates of only 15-20%. A survey of opinion leaders produced the unaminous conclusion that current therapy for hepatocellular carcinoma is unsatisfactory but could offer no clear consensus as to what the future for hepatocellular carcinoma therapy would involve. Asked his opinion on the best pharmacotherapeutic approach to hepatocellular carcinoma, one US opinion leader concluded "platinum-based therapy, doxorubicin and maybe one or two other drugs. None of these are that good, but that's all we've got to offer right now."

In addition to the problems surrounding the limited capacity of the liver to deal with cytotoxics, hepatocellular carcinoma is a highly resistant tumor, thought to be because it is a malignancy of cells that confer protection to other cells from toxins. This protective role is thought to give hepatocytes additional mechanisms of resistance to various anticancer drugs.

Amgen's T67 and Eximias Pharmaceutical's Thymitaq offer a glimmer of light at the end of a dark tunnel

This has led to the development of novel interventions mainly local ablation techniques to try to halt progress of the disease, many of which are only effective in producing short-term remission. Moreover, local ablation techniques do not treat the cirrhotic liver, consequently there is a risk of hepatocellular carcinoma arising in the remaining diseased liver.

When asked if there are any pipeline drugs with the potential to change the way hepatocellular carcinoma is treated opinion leaders have responded "the answer is no; because there is not a lot of activity going on in hepatocellular carcinoma." Even the most optimistic believe that "there are a couple of drugs in clinical trials that may be marginally effective" although the impact of these is expected to be minimal.

Consequently, 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. One product, Amgen's T67 (formally owned by Tularik Inc; expected to launch in 2006), could potentially improve response and survival rates in hepatocellular carcinoma. T67 irreversibly binds to beta-tubulin, resulting in cell death. This concept is not new in anticancer agents however, T67 is not a substrate for P-Gp and appears to retain its anti-tumor activity in drug-resistant cell lines. T67 will undeniably benefit from Amgen's oncology experience and significant uptake is expected.

Eximias Pharmaceutical's Thymitaq is a thymidylate synthase (TS) inhibitor also in Phase III trials for hepatocellular carcinoma. The Phase II trials have demonstrated that Thymitaq confers some survival advantage over doxorubicin (19.8 weeks versus 14.8 weeks). If approved, Thymitaq will be the first agent to be specifically approved for hepatocellular carcinoma. This is highly likely given the lack of current treatment options available for hepatocellular carcinoma patients. However, uptake of Thymitaq may be a result of a lack of current treatment options rather than outstanding clinical activity. Furthermore, Thymitaq is Eximias's most advanced product and, as such, Eximias may lack the marketing strength or expertise to drive sales to their maximum potential.

With the expected launch of Eximias' Thymitaq in 2005 and and then the release of Tularik's T67 in 2006, analysts believe that the market value for hepatocellular carcinoma therapeutics wiil grow from the $70.1 million clocked in 2002 to $286 million in 2010.

Pharmaceutical companies with cytotoxic agents that have favorable or minimal metabolism by the liver should investigate their activity in hepatocellular carcinoma. One such agent, melphalan, is not metabolized by the liver and demonstrates anti-tumor activity in liver metastasis. Anti-tumor activity in hepatocellular carcinoma has been observed with isolated hepatic perfusion of melphalan thus reformulations of melphalan may have significant activity in hepatocellular carcinoma and further investigations may be warranted.

Novel intervention and pharmaceutical approaches may be the way forward

The lack of approved products for hepatocellular carcinoma may pave the way for innovative agents. Phase II trials are underway for targeted anti-angiogenesis agents such as Genentech's Avastin, AstraZeneca's Iressa and Onyx and Bayer's sorafenib. Opinion leaders are optimistic that these molecules may have a role to play in the future of hepatocellular carcinoma management. The Phase I trials of sorafenib comprised four hepatocellular carcinoma patients, a partial response was observed in one patient and disease stabilization was observed in another. These results are encouraging but need to be confirmed in a larger cohort before a role for sorafenib can be confirmed in hepatocellular carcinoma management.

Given the poor response rates of hepatocellular carcinoma to current cytotoxic therapy, agents that improve the quality of life of hepatocellular carcinoma patients may also gain approval. Furthermore, adjuvant therapy following local ablation techniques should be explored. In particular, a potential role for immunotherapy may exist following radiofrequency ablation. Patients appear to overcome immune intolerance following radiofrequency ablation and exhibit a significant increase in tumor-specific cytotoxic T-cells. This may be due to radiofrequency ablation inducing the exposure of altered or critical tumor-specific antigens, the numbers in this study were small, however, exploration into the role of immunotherapy following RFA may be warranted.

Progress into effective treatments for hepatocellular carcinoma has been hindered by the comorbid illnesses of hepatocellular carcinoma patients, underlying liver disease, the aggressiveness of the tumor, drug resistance and lack of tumor response to anticancer agents. Given the extent of liver dysfunction in hepatocellular carcinoma patients and the inability to detoxify current cytotoxic agents, the future of hepatocellular carcinoma and indeed other tumor indications will likely lie within targeted therapies. The advent of micro-array and genomic analysis means that specific gene mutations and disrupted biochemical pathways within hepatocellular carcinoma can be compared to normal or cirrhotic hepatic tissue and pharmaceutical intervention designed around these abnormalities.

As a final point, tumor response can be difficult to assess in hepatocellular carcinoma, as cirrhotic nodules can make interpretation of radiological responses difficult to determine. Pharmaceutical companies developing drugs for use in hepatocellular carcinoma must work closely with drug approval bodies to create mutually acceptable trial design and endpoints that will highlight the benefits of these drugs.

The data and conclusions in this feature are discusses in depth in our new feature on hepatocellular cancer - click here for further information