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Hepatocellular carcinoma: new advances in diagnosis, staging and treatment all predicted to improve patient outcomes


Epidemiological, genetic and clinical data presented at the International Liver Congress 2014 are collectively focussed on different approaches designed to improve the diagnosis, staging and treatment of hepatocellular carcinoma ( HCC ).
Human hepatocellular carcinoma is one of the most prevalent cancers worldwide and the second most frequent cause of cancer-related death.
Hepatocellular carcinoma is an extremely diverse and heterogeneous disease; a number of existing therapeutic options have been subjected to rigorous study but have not shown any patient benefit.

In Japan, approximately 80% of hepatocellular carcinoma (HCC) cases are detected by screening. In marked contrast, the figures for the UK, Spain and Hong Kong data were significantly lower at 15%, 35% and less than 10% respectively.

There was also a dramatic difference in the stage of disease at diagnosis. In Japanese patients, 59% were within the Milan Criteria ( generally accepted set of parameters designed to assess the suitability of HCC patients for liver transplantation ) and 71% were suitable for potentially curative treatment.
Comparative figures for Spain were much lower at 26 and 32%, the UK 37 and 38% and Hong Kong, 8 and 16%, respectively.

Median HCC survival for Japan, Spain, UK and Hong Kong were 47, 26, 20 and 7 months respectively.
The wide geographical variation in survival among HCC patients had been attributed to intrinsic ethnic differences, different aetiologies, or disease stages at presentation. However, age, gender and Child-Pugh class distribution were all similar between the HCC patient populations from each of these four countries. Statistical analysis has shown that aetiology had little impact on survival.
It would appear that the marked difference in the intensity of screening programmes between different countries, and the consequent variation in curative therapeutic options goes a long way to explaining the wide geographical variation in HCC survival.

In this study, more than 5,000 patients were recruited from two high incidence areas, Japan ( n=2599; predominantly HCV ) and Hong Kong ( 1112; predominantly HBV ), from a medium-incidence area, Spain ( n=834; predominantly HCV & alcohol ) and the UK ( n=724; multiple aetiologies ).
Comprehensive demographic, aetiological and staging data along with treatment details were made available.

A) Staging HCC with Gadoxetic acid-enhanced MRI improves treatment outcomes in patients with early disease

Additional staging of HCC patients using Gadoxetic acid-enhanced MRI has been shown to be associated with lower recurrence and better survival in patients presumed to have a single nodular hepatocellular carcinoma on the basis of a dynamic CT scan. These were the exciting findings of a study presented at the International Liver Congress 2014.

Using multivariable analysis, the group of patients who were additionally evaluated with Gadoxetic acid-MRI ( CT+MR group ) was shown to be associated with a significantly lower risk of HCC recurrence ( hazard ratio [ HR ] 0.72, P=0.02 ) and overall mortality ( HR 0.67, P=0.04 ) compared with the CT alone group.

Early recurrence of hepatocellular carcinoma after curative treatment is frequent and thought to represent a metastasis from the primary tumour that was actually present before treatment was started.
Using Gadoxetic acid-enhanced MRI to more accurately stage HCC patients with early disease has the potential to significantly improve outcomes by ensuring each patient receives the optimum treatment.

Gadoxetic acid is a contrast agent for MRI that has combined perfusion and hepatocyte-specific properties. This technique has shown higher detection sensitivity for hepatocellular carcinoma compared to dynamic CT or MRI.

In this historical cohort study, a total of 700 consecutive patients presumed to have a single nodular hepatocellular carcinoma by dynamic CT scan were analysed. Out of this patient population with early disease, 323 were additionally evaluated with Gadoxetic acid-MRI ( CT+MR group ); 377 were not ( CT group ).

Results of the initial CT scanning using the Barcelona Clinic Liver Cancer ( BCLC ) staging system had identified 243 ( 34.7% ) patients at a very early stage ( 0 ) with a single lesion less than 2 cm; and 457 ( 65.3% ) at an early stage A with a single lesion less than 5 cm, or three lesions less than 3 cm. There was no statistical difference in the numbers of patients at stages 0 and A between the CT+MR and CT groups.

After evaluation of those HCC patients in the CT+MR group with Gadoxetic acid-MRI, a total of 74 HCC nodules were additionally detected in 53 ( 16.4% ) patients, escalating the BCLC staging in 34 ( 10.5% ) of the patients.

In the 298 propensity score-matched pairs ( a statistical matching technique that attempts to estimate the effect of treatment by accounting for the covariates that predict receiving the treatment ), the CT+MR group was again associated with a significantly lower risk of HCC recurrence ( hazard ratio, HR=0.74, P=0.047 ) and mortality ( HR=0.61, P=0.02 ).

B) Novel gene signature able to predict development of HCC in high-risk individuals

A 3-gene signature that can be identified from analysis of a blood sample was able to reliably identify hepatocellular carcinoma with a high degree of sensitivity and specificity.

Comprehensive gene expression profiling of purified RNA from peripheral blood mononuclear cells taken from patients with chronic hepatitis B ( CHB ) and cirrhosis has identified 3 genes namely AREG, TNFAIP3 and GIMAP5 that were differentially expressed.

Subsequent studies on an independent cohort of 206 HCC patients and 194 patients with chronic hepatitis B and cirrhosis validated that these 3 genes were able to identify hepatocellular carcinoma with an accuracy of 82.5%, 81.5% and 71.8%, respectively.

Using multivariate logistic regression, these 3 genes in combination accurately predicted the development of hepatocellular carcinoma, with an AUC of 0.929, and yielded a sensitivity of 82% and a specificity of 90.2%.

Timely and effective diagnosis of hepatocellular carcinoma is critically important because surgical resection in early disease remains the only cure. Hence, the identification of early stages of disease in high-risk individuals for the development of hepatocellular carcinoma would greatly improve clinical outcomes.

C ) Radiofrequency ablation effective in treating both small hepatocellular carcinoma and advanced disease

Percutaneous radiofrequency ablation ( RFA ) is an effective and safe treatment for small hepatocellular carcinoma.
The technique provides excellent overall survival and tumour-to-progression rates, according to the results of a 10 year follow-up study in a population of Chinese patients.

The development of local ablative therapy has been one of the major advances in the treatment of hepatocellular carcinoma. Percutaneous RFA, performed under radiological guidance, is a minimally invasive, repeatable procedure with few complications.

In the treatment of hepatocellular carcinoma, where less than 40% of patients are candidates for surgery, and the rate of recurrence after curative surgery is high, percutaneous techniques like RFA are very important.

During the period 2000-2012, a total of 1020 small tumour nodules in 837 patients were treated with percutaneous RFA.
Complete ablation was achieved in 98.8% ( 1008/1020 ) with major complications occurring in only 0.59% ( 5/837 ) of patients.
The estimated overall 1-, 3-, 5-, 10-year survival rates were 91%, 71%, 54%, and 33%, respectively. The 1-, 3-, 5-, and 10-year recurrence-free survival rates were 74%, 44%, 30% and 15%, respectively.

A second 7-year follow-up study has evaluated the efficacy of percutaneous RFA in hepatocellular carcinoma, but this time looking specifically at patients with advanced disease.
In this patient population, in whom there was accompanying main portal vein tumour thrombus ( MPVTT ) and compensated liver cirrhosis, percutaneous RFA significantly prolonged long-term survival compared with no treatment.

The one, three, five and seven year cumulative survival rates of treated patients were 62%, 29%, 18% and 5%, respectively, compared to a 12-month cumulative survival rate of 0% in untreated patients ( p less than 0.001 ). The disease free survival rates in the treated group was 52%, 38%, 35% and 23% at one, three, five and seven years, respectively.

During the period 2005-2012, among 3144 consecutive cirrhosis patients, 772 had hepatocellular carcinoma with MPVTT; of these, 70 patients had a single hepatocellular carcinoma with MPVTT and were therefore eligible for percutaneous RFA.
A total of 48 out of these 70 patients ( 38 men; mean age 69 years ) with 48 HCC nodules 3.7-5.0 cm in diameter invading the main portal trunk ( MPT ) underwent percutaneous RFA.
The remaining 22 matched patients ( 18 men; mean age 69 years ) with 22 HCC nodules 3.6-4.8 cm in diameter extending into the MPT, refused RFA and therefore made up the control group.

Efficacy of RFA was defined complete when both complete necrosis of the hepatocellular carcinoma and complete re-canalisation of the MPT and its branches were achieved.

"Based on these long-term efficacy data, percutaneous RFA could be considered an effective tool in the treatment of advanced hepatocellular carcinoma where a single hepatocellular carcinoma is associated with thrombosis of the main portal vein but these data do need confirmation in a prospective randomized trial. ( Xagena )

Source: European Association for the Study of the Liver ( EASL ), 2014

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