Hepatocellular carcinoma: prevention, detection and treatment … in the real world

Hepatocellular carcinoma (HCC) is an important cause of death worldwide and an increasing problem in Western countries.1–3 In Australia and the USA an increase in the incidence of HCC over the past three decades has been documented.2,3 This has been attributed both to immigration from areas endemic for hepatitis B and to a cohort of individuals with chronic hepatitis C originally infected 20–40 years ago and now progressing through cirrhosis to HCC. The future is no brighter: the hepatitis C epidemic shows no signs of abating whereas non-alcoholic fatty liver disease (NAFLD) related to diabetes and obesity looms as a potential second wave of cirrhosis and HCC in developed countries.4 HCC generally arises in patients with cirrhosis on a background of chronic viral hepatitis, alcohol excess or other chronic liver diseases (NAFLD or haemochromatosis, for example). These diseases are opportunities for intervention and, through this, prevention of HCC both at an individual and at a population level. Effective hepatitis B vaccination programmes can prevent vertical and horizontal transmission leading to a reduction in HCC incidence. This has been documented in Taiwan where the incidence of childhood HCC declined following implementation of targeted (1984) and then universal (1986) neonatal vaccination.5 In Australia, universal neonatal hepatitis B vaccination is recommended with catch-up vaccination of preadolescents (10–13 years of age) not immunized at birth.6 Effective immunization against hepatitis C is not yet available, but screening of blood products has minimized transmission by this route and harm reduction strategies, such as needle exchange programmes, may help to decrease transmission among i.v. drug users. Likewise, strategies to reduce alcohol abuse and obesity in the community, if effective, would be expected to reduce the future incidence of HCC. Worldwide, hepatitis B is the most important cause of HCC and, in some regions, dietary aflatoxin exposure is a key cofactor. Public health measures to reduce aflatoxin exposure and chemopreventative agents to counteract the effects of this toxin are currently being evaluated.7 Treatment options for chronic viral hepatitis have improved dramatically over the past decade and provide an opportunity for intervention at a second stage in the pathogenesis of HCC. The combination of pegylated interferon and ribavirin achieves sustained response rates of approximately 50–55% in chronic hepatitis C. Sustained response in non-cirrhotic patients should prevent progression to cirrhosis and HCC provided other causes of liver injury, such as alcohol abuse and coinfection with hepatitis B, are also eliminated. Treatment of cirrhotic patients with hepatitis C may also reduce subsequent progression to HCC presumably by reducing ongoing hepatocellular injury, regeneration and repair and possibly through a direct antiproliferative effect of interferon.8–12 In chronic hepatitis B, treatment with nucleoside analogues is effective in suppressing viraemia, reducing inflammatory activity and slowing the progression of fibrosis. The nucleoside analogues lamivudine, adefovir and entecavir are now available for treatment of hepatitis B in Australia. Long-term treatment with entecavir appears to reduce the development of HCC in the infected woodchuck model of hepatocarcinogenesis.13 In humans, a prospective randomized controlled study of lamivudine in advanced hepatitis B fibrosis or established cirrhosis has shown a reduction in HCC occurrence from 7.4% in the control group to 3.9% in the treated group (P = 0.047).14 Probably, such benefits will be seen in treatment regimes using other agents.15 Likewise, prevention of cirrhosis by venesection in patients with haemochromatosis and, hopefully, future interventions in NAFLD will further reduce the incidence of HCC in other groups at risk.4,16 Although elimination of HCC through prevention and treatment of chronic liver disease should be the goal, the full impact of such strategies may be decades away. Early detection of HCC remains an important focus in the management of patients with advanced liver disease. Surveillance for HCC, generally by 6-monthly hepatic ultrasound and monitoring of α-fetoprotein, identifies smaller lesions that are more amenable to treatment and may result in a survival advantage though further evidence for the latter is required.17,18 Despite uncertainties regarding the benefits, HCC surveillance has been widely adopted by gastroenterologists. Offered the choice and provided with appropriate information, most cirrhotic patients will opt for surveillance.19 Protocols for the investigation and management of small lesions identified through surveillance have been developed.20 There is a range of treatment options depending on the size, number and location of tumours within the liver, the severity of the underlying liver disease and the age and general health of the patient. In patients with HCC confined to one lobe, adequate hepatic reserve and without significant portal hypertension, 5-year survival rates greater than 50% have been reported following hepatic resection.21 Recurrent HCC, reflecting both true recurrence and new primaries in a premalignant liver, is a major problem following resection. Adjuvant intra-arterial 131I lipiodol appears to reduce recurrence and improve survival when given following apparently curative resection for HCC.22 For those with advanced liver disease or significant portal hypertension, liver transplantation can offer prolonged survival provided the tumours are small in size and number and there is no extrahepatic or vascular spread.23 Donor shortages and the resulting waiting times remain key issues in transplantation for HCC. Finally, there have been major advances in local ablative therapies for HCC. Imaging-guided radiofrequency ablation, in particular, is emerging as an important method for the treatment of small lesions.24 For larger lesions, transarterial chemoembolization appears to offer a modest survival benefit.25 In the future, as our understanding of the molecular basis of hepatocarcinogenesis increases, new strategies for the management of HCC are likely to emerge.26,27 It is against this background that Gellert et al.28 report their ‘real world’ experience of HCC in this issue and emphasize the difficulties of delivering optimal care to those at greatest risk for this disease. The authors describe 151 patients with HCC managed at two large public hospitals in Sydney South West Area Health Service between 1993 and 2003. The median survival was only 5.1 months. Most of the patients (75%) presented with symptomatic disease. Only 18% were detected through surveillance. It is difficult to know whether surveillance was of benefit in this group because of small numbers and the confounding effect of lead-time bias. Nevertheless, surveillance patients were more likely to have small tumours potentially suitable for resection or transplantation. At a population level, surveillance for HCC is only likely to have an influence if the target population is identifiable, accessible and willing to participate. In this study, cirrhosis was previously undiagnosed in a significant number of cases meaning that surveillance would not have been considered. In addition, only 7% of those with chronic viral hepatitis had ever received antiviral therapy. We can only speculate as to whether family members of the 63 hepatitis B patients had previously been offered vaccination, but it is clear that opportunities to intervene in the natural history of chronic liver disease and HCC are being missed. Education of the medical community and the public regarding the established and potential benefits of vaccination, treatment of chronic liver disease and surveillance for HCC, should help. Patients with chronic liver disease can be relatively isolated by virtue of language difficulties or socioeconomic circumstances so that strategies need to be well targeted and appropriately supported. The proportion of Asian-born HCC patients rose from 38 to 53% from the first to the second 5-year period in the series reported by Gellert et al.28 The number of patients requiring interpreters increased from 44 to 65% over the same period. Addressing the increasing incidence of HCC in Australia will not be easy. We will need to set aside funds for education and plan for an increasing demand over a range of services including interpreters, hepatitis nurse specialists and clinicians. The demand for specialized HCC services in hepatology, radiology, surgery and transplantation has already increased significantly. At the time of writing, more than a quarter of adult patients awaiting liver transplantation in New South Wales have HCC and waiting times for therapeutic radiological interventions in HCC patients are beginning to cause concern. In developing nations, where HCC is most prevalent, the problems in equitably delivering the recent advances in the management of chronic liver disease and HCC are even greater. The real world poses real challenges in the prevention, detection and treatment of HCC.