EASL Special Conference

Hepatocellular carcinoma from genomics to treatment

25-26 June 2010

Conference newsletter

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and as such represents a significant disease burden.  Under the auspices of the European Association for the Study of the Liver (EASL)[1] and Chairmanship of EASL Member Professor Josep Llovet, around 600 hepatologists and other specialists from around the world convened in Dubrovnik, Croatia for the EASL Special Conference to discuss the latest developments in screening, diagnosis, treatment and the vision for the future management of HCC. This newsletter reports the conference proceedings, highlighting the most pertinent discussions and expert conclusions.

Milestones in the management of HCC

In the past decade, the management of HCC has seen major breakthroughs in terms of diagnosis and treatment algorithms. Our understanding of the etiology and progression of HCC has evolved, enabling the development of evidence-based criteria to determine tumour staging. This has resulted in clear improvements in patient selection and better treatment outcomes.

The old perspective that HCC is a rare cancer with a very poor prognosis has now changed, as the prognosis of HCC patients has improved with early diagnosis and treatment. Indeed, surveillance of patients at risk has led to an increase in the detection of small, potentially curable tumours. This is in addition to major advances in surgical and ablative therapies, changing the landscape of HCC treatment and leading to a substantial improvement in survival.

This shift has occurred not only for patients with an early detected tumour, but also for those previously classified as having a non-resectable tumour, who are no longer left untreated to fight alone against the natural course of the disease. In the late nineties, the development of a standardized staging system for HCC (Barcelona Clinic Liver Cancer (BCLC) staging classification) that was constructed on evidence-based data made it possible to effectively stratify the HCC patients to receive appropriate treatments, resulting in substantial clinical benefits. Experts now agree that most treatment failures in the past were often due to faulty staging of the tumour.

The same was true for liver transplantation, where outcomes have clearly improved following the adoption of stringent criteria for patient selection based on the volume and number of tumour nodules and venous invasion – the Milan criteria. The systematic application of Milan criteria resulted in a fair balance between the risk of tumour recurrence and five year survival rate worldwide. This switch from an empirical to an evidence-based approach for patient selection also provides clinical benefit to patients undergoing local ablation therapies, such as radiofrequency, mainly owing to the identification of the ideal candidates.

Whilst patients with advanced HCC still face an overall poor prognosis, the recent availability of multikinase inhibitors has generated hopes for improved survival for those patients for whom treatment did not previously exist. In this sense, the identification of sorafenib as the first effective systemic treatment of advanced HCC has represented a breakthrough in the management of the disease, and has paved the path for new developments in the field of molecular targeted therapies for tumours. Similarly, major advancements in basic research on signalling pathways involved in the pathogenesis of HCC will not only improve our understanding of pathogenesis and the molecular classification of HCC, but also allow for a more personalised therapy approach.

Last but not least, primary prevention should be acknowledged as another major advance in the management of HCC, particularly in developing countries where this cancer is hyper-endemic and early detection remains a challenge, owing to limited financial resources in health infrastructure. In this case, primary prevention with hepatitis B vaccination is expected to lower the occurrence of HCC in countries across Asia and Africa.

Prevention of HCC

HCC is one of the most prevalent cancers worldwide, with an estimated 625,000 new cases each year.

The incidence of HCC appears to be on the rise in many countries in the developing western world. Worldwide, about 85% of cases appear to be linked with underlying chronic viral hepatitis, particularly hepatitis B infection. The focus on prevention of HCC is linked to the prevention and management of chronic viral hepatitis. It is now well established that vaccination of hepatitis B is an effective long term strategy for the prevention of HCC.

There is as yet no vaccine against hepatitis C virus, and is unlikely for some years to come. However, the incidence of new HCV infection cases has decreased due to greater awareness of the risks of blood-borne infections, mostly in the industrialised world. This lower incidence of new cases of hepatitis C can be expected to translate to fewer cases of HCC in the long-term.

Among patients already infected with chronic HBV or HCV it has been suggested that antiviral therapy may be effective as secondary prevention for HCC. Effective treatment of chronic hepatitis C with peginterferon-based therapy resulting in a sustained virologic response has been associated with a decreased incidence in HCC. Interestingly, long term maintenance therapy of hepatitis C with peginterferon does not appear to have a chemorepressive effect.

Long term antiviral therapy against hepatitis B however appears more effective in preventing HCC. Other logical strategies to prevent HCC in patients with chronic viral hepatitis include alcohol and smoking cessation and avoiding aflatoxin contamination.

Experts suggest that prevention of viral hepatitis by public health measures, such as large scale vaccination programmes, has the potential to substantially decrease the incidence of HCC, and that secondary prevention using antiviral therapy may be effective in some settings.

Molecular classification and diagnosis of HCC

Both benign and malignant hepatocellular tumours demonstrate a broad diversity at the genetic and epigenetic levels, leading to the need to establish a robust classification closely related to clinical features and carcinogenesis pathways.

Classifying tumours in homogeneous sub-groups using gene signature is a promising tool to construct rational protocols with targeted therapies and to enhance prognosis related to cancer progression, treatment response and overall clinical outcomes.

The current consensus clearly describes classification of dysplastic nodules and HCC, although confident pathological diagnosis of HCC especially for small nodules less than 2cm in diameter may be hazardous. Recent studies have shown that some protein markers that are differentially expressed in HCC can be used for molecular diagnosis of the disease.

In addition, recent studies have suggested that gene-expression profiling of cirrhotic liver tissue can provide prognostic information in patients with surgically resected HCC. Molecular monitoring in cirrhotic patients can help with disease prognosis, aiding the efficient clinical management of the patient in early stage liver cirrhosis.

With the challenges associated with cirrhotic patients where dysplastic nodules may develop and may progress to HCC, tissue molecular markers and surrogate non-invasive biomarkers may provide useful prognosis predictors in the development of the cancer.

Novel anti-proliferative vs. anti-angiogenic drugs

The concept of personalised medicine has permeated all aspects of modern patient care, perhaps to no greater extent than in oncology. The benefits seen with the use of cytotoxic chemotherapy appear to have stabilised, while at the same time there has been a rapid increase in our knowledge of the etiology of cancer. This has been accompanied by new technology that has allowed for the molecular characterization of human cancers at the genomic level. No longer is any one specific cancer (i.e. liver, breast, lungs) viewed as one disease entity, but rather as distinct molecular subtypes. This new understanding is rapidly being implemented in clinical trials that are moving away from the ‘one size fits all’ approach to treating the disease through drug development.

These advances in the understanding of cancer biology have given way to the development of novel targeted agents aimed at disrupting key signalling pathways in tumour development and progression. As these new agents progress through the discovery phase, the challenges are identifying which patients are most likely to respond and benefit from these molecular targeted drugs in clinical settings.

The results of the pivotal SHARP study[2] have ushered in a new era of drug development in HCC research. The hyper-vascular nature of HCC has made the development of anti-angiogenic drugs a rational choice and arguably is what has driven the significant results of the sorafenib studies. However, sorafenib, like other molecules in development is non-selective, with the ability to inhibit several different pathways involved in proliferartion and angiogenesis alike. Nonetheless off-target effects of sorafenib are currently explored.

Still, there are other molecules in development that are not primarily expected to inhibit angiogenic pathways but selectively select pathways involved in tumour growth and survival. These include inhibitors of the mTOR axis, fibroblast growth factor pathway, epidermal growth factor pathway and others. Critical to successful clinical development of these agents will be the identification of predictive markers of response (and/or resistance) so the right drugs can be prescribed to the right patient and appropriate clinical endpoints selected.

Conclusions

In terms of HCC classification, a shift is taking place from morphological to morpho-phenotypical characteristics of the tumours, allowing advancement in establishing tumour progression and likely treatment outcomes. The aim is to select an optimal therapeutic strategy for individual HCC profiles and patients (personalised healthcare) in clinical practice.

Incorporation of this new information into the current HCC classification for clinical use might improve the stratification of tumours according to available therapies and oncology protocols. More information is also expected to come from HCC genetic profiling and novel biomarkers, which are being tested as effective diagnostic tools or predictors of behaviour for the cancer.

Invitation to the International Liver Congress^TM 2011

Symposia and early morning workshops during the International Liver Congress^TM 2011, the 46th annual meeting of the European Association for the study of the Liver, will be dedicated to HCC. Join clinicians and scientists from all over the world in Berlin, Germany at the Internationales Congress Centrum (ICC Berlin) one of the biggest, most advanced and most successful congress venues in the world to learn more about liver disease and best medical practice. The International Liver Congress^TM provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

Mark your calendar: March 30-April 3, 2011.