Liver cancer: epidemiology

C. La Vecchia

Upward trends in incidence and mortality from hepatocellular carcinoma over the last two decades have been reported from Japan, Europe, and the USA. These rises were observed in men and women, in blacks and whites in the USA, in younger and elderly populations, suggesting that they cannot be accounted for totally by increased diagnosis and certification of the disease. It has also been suggested that the increased prevalence of hepatitis C viruses (HCV) may, at least in part, explain these upward trends. Liver cancer incidence and, even more, mortality rates have however to be interpreted with utmost caution, due to the substantial problems of reliability and validity of certification data for liver cancer, most notably the difficulty of distinguishing accurately primary from secondary liver cancers. With these cautions in mind, I have systematically reviewed the descriptive and analytical epidemiology of liver cancer.
Causes of increases in liver cancer in at least some European countries should be searched for in the two most important groups of risk factors for liver cancer in developed countries: hepatitis B (HBV) and HCV viruses and high alcohol consumption and/or their combination. Tobacco is another major risk factor for liver cancer, particularly in China where, together with hepatitis, it may be responsible for 50,000 liver cancer deaths per year. Diabetes, whose prevalence has substantially increased worldwide, has been associated to an approximately 2-fold excess liver cancer risk. Other risk factors such as aflatoxin, low intake of vegetables and fruit, or oral contraceptive use in females are likely to play a small, or minimal, role in liver cancer trends in Europe, but some of these factors may be relevant in developing countries.

C. La Vecchia
The “Mario Negri” Institute for the Pharmacological Research,
Milan and the Institute for Medical Statistics and Biometry,
State University of Milan, Italy.

Natural history and early diagnosis
of hepatocellular carcinoma (HCC).

M. Colombo

HCC is a multistep process associated with changes in host gene expression that affect the multiple, redundant, negative, growth-regulatory pathways protecting cells against transformation. In most patients, the tumor is the end-stage evolutionary step of compensated cirrhosis of any etiology. In the last decades, early diagnosis has emerged as a practical approach to improve the management of HCC, since early detected, small cancers can be successfully treated with radical therapies like hepatic resection, liver transplantation or local ablation. Hepatitis B and hepatitis C virus carriers with cirrhosis and non-cirrhotic Asian or African carriers of hepatitis B who are at high risk of liver cancer, have been identified for surveillance with abdominal ultrasounds (US).
In a cohort of 447 Italian patients with compensated cirrhosis of any etiology. HCC developed in 112 patients (3.4% per year) and was the prime cause of death. 46 patients (41%) had a single tumor with a mean size of 3.7 cm, 3.0 cm and 2.2 cm in 3 quinquennia of surveillance from 1986 to 2001 (1st vs 3rd: p=0.0147; 2nd vs 3rd: p=0.02) and 38 (44%) underwent radical therapies. Mortality rates in HCC patients fell from 45% in the 1st quinquennium to 10% in the third (p=0.0009) in parallel with a reduction in mortality of treated patients (34%, 28%, 5%) (1st vs 3rd: p=0.0024).
Thus, cirrhotic patients developing a HCC during the last 5 years of surveillance survived longer than previously, as a consequence of improved management of the tumor and complications of cirrhosis. Surveillance is worth to be pursued in the management of patients at risk of HCC.

M. Colombo
Department of Gastroenterology and Endocrinology,
IRCCS Maggiore Hospital, University of Milan,
Milan, Italy

Therapy for hepatocellular carcinoma

J. Bruix

Surgical resection should be limited to single asymptomatic HCC in patients with preserved liver function. Selection of Child-Pugh A patients is not efficient enough, as the optimal results are obtained in subjects with normal bilirubin and absence of portal hypertension. Resection is associated with a high recurrence rate (>70% at 5 years) that can be predicted by pathological characteristics, such as vascular invasion, satellites and poor differentiation degree. Several agents (retinoids, interferon, lipiodol coupled to 131-I, adoptive immunotherapy) have been evaluated, but their preventive value and survival impact need further investigation.
The optimal candidates for liver transplantation are patients with early HCC (single < 5 cm or up to 3 nodules < 3 cm). They achieve 70% 5-year survival with a recurrence rate below 15%. Transplantation is not available worldwide and there is a huge shortage of donors that deteriorates the results when analyzed according to intention to treat.
Living donor liver transplantation (LDLT) may partially solve this limitation but medium and long-term results are still not available.
Percutaneous ablation (ethanol injection or radiofrequency) under US guidance achieves complete necrosis in 70-80% of solitary tumors < 3 cm. Child-Pugh A patients achieve a 50% 5-year survival rate, which compares with the outcome of surgical patients that do not qualify for an optimal long-term outcome. By contrast, survival benefits of PEI in Child-Pugh B class patients are controversial.
More than 50% of the patients are diagnosed at an advanced stage when only palliative options can be applied.
Amongst these, only chemoembolization has been shown to provide survival benefits within randomized trials and meta-analytical assessment.
Tamoxifen has no positive impact on survival and there are no robust data to support a benefit from options such as systemic chemotherapy, octreotide, internal radiation with I-131, proton beam radiation, antiandrogens, Interferon and immunotherapy.

J. Bruix
Barcelona Clínic Liver Cancer (BCLC) Group. Liver Unit.
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).
Hospital Clínic. University of Barcelona.
Catalonia, Spain.

Prevention of hepatitis viruses
associated hepatocellular carcinoma.

A. Alberti

Chronic infection with the hepatitis B (HBV) and C (HCV) viruses is the leading cause of hepatocellular carcinoma world-wide with striking major impact of HBV in the Middle and far East Regions and a more relevant effect of HCV, either alone or with an overt or occult HBV coinfection, in the Western Countries. Hepatocellular carcinoma develops after decades of chronic HBV or HCV infection and usually, at least with HCV, after long-standing chronic liver disease leading to cirrhosis and intense nodular regeneration and hepatocellular dysplasia. Thus, prevention of the infection, or of its chronic evolution, or of the associated progressive liver damage, are all rational approaches for reducing the burden of Hepatocellular carcinoma in the different epidemiological and clinical settings at risk. Chronic HBV infection is mainly caused by infection in early childhood through mother-to-child transmission. Therefore, neonatal vaccination against HBV is an effective measure of primary prevention that has been already proven to result in a marked decrease in HCC incidence in Eastern Countries.
However, access to universal vaccination programs is still quite limited and needs to be strongly encouraged and facilitated. As a consequence of limited implementation of these vaccination programs, still a huge number of individuals are chronically infected with HBV worldwide. These HBV carries, estimated as more than 350-4000 millions, 75% in the East, have an increased risk of HCC, depending on the levels and duration of HBV replication.
Recent data indicate that chemoprevention with oral antiviral therapy can reduce the HCC risk in HBV carriers with advanced liver disease. At least two studies conducted with long-term lamivudine monotherapy concluded that this treatment reduces, but doesn’t abolish, the incidence of HCC in cirrhotic patients infected with replicating HBV.
The frequent development of drug resistant HBV mutants is a major limitation to this approach and new, more potent strategies able to achieve more profound and durable HBV suppression and eradication of cellular ccc HBV-DNA are urgently needed.
Other studies, mainly retrospective and often poorly controlled, have addressed the issue of chemoprevention of HCC with interferon therapy.
Circumstantial evidence suggests that the HCC risk is reduced in patients with chronic hepatitis c who have developed a sustained virological response to interferon, while the effect, if any, of this treatment in partial responders and in virological non responders is still much controversial and will be clarified by the ongoing International clinical trials.

A. Alberti, L. Benvegnù
Department of Clinical and
Experimental Medicine, University
of Padova, and Molecular Hepatology Unit,
Venetian Institute of Molecular Medicine,
Padova, Italy