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Hepatocellular Carcinoma

New Strategies to Improve Prognosis

  • Review Article
  • Published:
American Journal of Cancer

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Most patients still present late in the course of the disease so that curative therapy is rarely possible. Strategies developed to improve the prognosis include primary prevention, directed at the underlying liver diseases, secondary prevention by cancer surveillance and early intervention, and more effective therapies. Only childhood vaccination against hepatitis B (HBV) infection has been clearly documented to reduce the incidence of HCC. Eradication of the hepatitis B and C viruses by interferon in noncirrhotic patients may reduce the incidence of HCC. Removal of iron by phlebotomy in noncirrhotic patients with genetic hemochromatosis will largely prevent HCC. Many physicians offer secondary prevention by surveillance and early intervention involving repeated abdominal ultrasound and serial serum α-fetoprotein estimations in order to identify early malignant lesions, but such strategies have yet to be proven to reduce mortality from HCC. Nonetheless, early detection would seem to offer a greater chance for application of potentially curative therapy. Different surveillance strategies may be necessary in different patient groups. For example, in chronic hepatitis C the increased risk of HCC seems to be confined to patients with established cirrhosis, whereas even noncirrhotic patients with HBV have a substantially increased risk of HCC.

In high-risk patients, such as those with cirrhosis following chronic viral hepatitis, several factors can be identified which appear to confer additional risk. Examples are hepatocyte dysplasia found on biopsy, or non-neoplastic vascular nodules on computed tomography scanning. The management of such patients needs urgent resolution.

Potentially curative treatment options include resection, liver transplantation, and alcohol injection or radiofrequency ablation. Resection in ideal candidates may provide up to 60% survival at 5 years. Liver transplantation may result in a 5-year survival of up to 70%. However, the shortage of organ donors means that tumor progression while on the waiting list will disqualify some patients, while others will die before an organ becomes available. Local ablation has been reported to be as effective as resection and is applicable to a larger proportion of patients.

Of the palliative forms of therapy only chemoembolization has been shown to provide a significant improvement in life-span, although other forms of adjuvant and palliative therapy are under investigation.

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Acknowledgment

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Sakler School of Medicine, Institute of Gastroenterology, Sourasky-Tel Aviv Medical Center, University of Tel Aviv, Tel Aviv, Israel

    Laurie Blendis

  2. Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

    Morris Sherman

  3. Institute of Gastroenterology Sourasky-Tel Aviv Medical Center, 6 Welzmann St, Tel Aviv, Israel, 64239

    Laurie Blendis

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Addendum

Addendum

Since this article was written a number of further advances have been reported. We have selected a few of these that fit into the theme of this review.

Firstly, the incidence of HCC in US continues to increase.[214]Acquisition of HCV 2–4 decades previously explains 50% of the increase.[215]Although cirrhosis is a major cause of HCC, HCV cirrhosis is associated with the highest incidence of HCC in the cirrhotic population. Furthermore, it now seems clear that the coexistence of HBV and HCV, or HBV and hepatitis D virus can increase the risk two to six times.[216]In Japan the incidence of HCC has risen five times since the 1970s due mainly to the increase in HCV disease.[217]

At the same time, it is becoming increasingly clear of the importance of the metabolic syndrome and its components in the pathogenesis of HCC. These include the association of HCC with obesity,[218]diabetes,[219]nonalcoholic steatohepatitis,[220]and cryptogenic cirrhosis.[221]In one recent study of 105 patients with HCC in the US, HCV was the commonest associated condition, in 50% of cases, with cryptogenic cirrhosis the second most common in 30% of cases.[222]This was even more so in elderly men.[223]

In terms of less common causes of HCC, another study has demonstrated the synergy between nongenetic, noncirrhotic iron overload and viral liver disease in patients with thalassemia.[224]The role of aflatoxin B has been further clarified by studies from Singapore, where vast improvements in the economic prosperity of the country have led to decreased exposure to aflatoxins associated with a rapid decrease in the incidence of HCC.[225]Furthermore, there is now evidence that genetically determined differences in aflatoxin metabolism can effect the risk of HCC development in exposed subjects.[226]

Several attempts have been made in the last 2 years to identify patients with a very high risk of developing HCC. Most authors agree that men between the ages of 40 and 60 years or more with HCV cirrhosis may have a risk as high as 10% per year of developing HCC.[227]If the patient is Asian or African-American then the risk can increase by four or two times, respectively.[228]In addition, the presence of alcohol consumption, abnormal liver function tests, such as bilirubin or prothrombin levels, the doubling of or the elevation of serum AFP levels to >60–75 ug/L, and the presence of dysplasia on liver biopsy can all increase the risk of developing HCC to 24% per year. Therefore, surveillance of such high-risk groups would seem to be a worthwhile endeavour[229]and cost effective.[230]Identification and surveillance of such a group appears to have led to an increased survival,[231]but lead time bias was not adequately controlled.

Secondly, in terms of therapy, longer retrospective follow-up studies in patients with ‘early’ HCC have revealed overall 10-year cumulative survival rates of 15% for PEI versus 49% for orthotopic liver transplantation.[232]The increase in survival following liver transplantation using the Milan criteria for allocation of livers was emphasized by the results from a single unit.[233]These authors found that the 5-year survival rate improved from 42% to 83% (p < 0.005) following the application of the Milan criteria. These encouraging results have been followed by attempts to further liberalize the criteria in an effort to make them less restrictive, thereby allowing more patients the possibility of benefiting from this treatment without sacrificing the survival rates.

The most successful of these originated from The University of California in San Francisco, known as the UCSF criteria, which allowed patients with tumors of <6.5cm, three lesions <4.5cm, with up to a total tumor diameter of 8cm, to be included as candidates for transplantation.[234]A recent retrospective analysis found that in contrast to the period prior to 1998 allocation of livers using first the Milan and then the UCSF criteria resulted in similar survivals rates between patients with malignant and nonmalignant disease.[235]In addition to these impressive results, the introduction of the MELD (Model for Endstage Liver Disease) scoring system,[236]which gives added priority to patients with HCC for liver transplant allocation, has increased the percentage of HCC patients now being transplanted from 7% to 20% in the first year of application.[237]With the critical shortage of livers, and the importance of reducing waiting times for transplantation, it has been shown that the use of living related donors in patients waiting more than 7 months will result in a gain in life expectancy that is cost effective.[238]Although there are no controlled trials for pretransplant ablative therapy for HCC, a study using Markoff modeling suggested that ablative treatment by chemoembolization would be cost effective in patients having to wait for more than 1 year for a transplant.[239]

In conclusion, in this addendum, we have focused on two areas of the further advances in the last 2–3 years: first, the importance of defining very high-risk groups of patients likely to develop HCC for screening and surveillance purposes in order to diagnose early HCC, providing an opportunity for more successful therapy; and second, the continued improved results of liver transplantation for early HCC.

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Blendis, L., Sherman, M. Hepatocellular Carcinoma. Am J Cancer 3, 349–368 (2004). https://doi.org/10.2165/00024669-200403060-00003

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