Where are we in the chemoprevention of hepatocellular carcinoma?
Authors: Shelly C. Lu
Journal: Hepatology (2009)

Chemoprevention uses chemical compounds, either natural or synthetic, to prevent the development of cancer. In the field of hepatocellular carcinoma (HCC), this vitally important topic remains in its infancy, particularly when human trials are concerned. Over the past decade, tremendous efforts have improved the understanding of the pathogenesis and treatments of HCC, but relatively little effort has been made to develop effective chemoprevention of HCC. Indeed, the keyword "HCC" on Medline and PubMed brings up 15,812 articles from 1995 to present; however, only 87 of these deal with chemoprevention of HCC. Given the magnitude of the problem worldwide and the fact that risk factors for HCC are fairly well-identified, chemoprevention of HCC should receive much more attention. COX-2, cyclooxygenase-2; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SAMe, S-adenosylmethionine. HCC is a global health problem, ranking as the fifth most common cancer and the third most frequent cause of cancer death worldwide.1 Eighty percent of newly developed HCC occurs in developing countries but the incidence of HCC has increased steadily, particularly in the Western countries.2, 3 Etiologies vary geographically, with chronic hepatitis B virus (HBV) infection and aflatoxin playing dominant roles in sub-Saharan Africa and China; chronic hepatitis C virus (HCV) infection accounting for 80% of the cases in Japan; and HCV, alcohol, and nonalcoholic steatohepatitis being responsible for most of the cases in the United States and Europe.2 The prognosis for HCC has remained poor because the majority of patients present when the disease is already advanced. Treatment options depend on the tumor size, number, and stage of cancer. Only 30% of patients are candidates for surgical resection, and the recurrence rate is about 50% at 3 years.4 In 2008, a major breakthrough in the treatment of advanced HCC was announced in the form of sorafenib, a multikinase inhibitor which was shown to increase the median overall survival from 7.9 to 10.7 months without severe side effects in a randomized, placebo-controlled phase III trial (SHARP [Sorafenib HCC Assessment Randomized Protocol).5 However, sorafenib did not delay time to symptomatic progression and it costs about $5400/month for treatment. This is prohibitively expensive for many patients in countries in sub-Saharan Africa and in China, where most of the deaths from HCC occur. The National Institute for Health and Clinical Excellence (NICE) (Britain's healthcare watchdog) recently appraised the use of sorafenib in advanced HCC and published on November 19, 2009, that it does not recommend sorafenib for the treatment of advanced HCC because the cost is too high for the limited benefit it offers. Although the survival benefit is limited, sorafenib is proof-of-principle that targeting the different signaling pathways deregulated in HCC can be effective. This approach is likely to improve outcomes either with more effective agents or in combination with other treatments. Targeting the underlying cause of chronic liver disease is the best strategy for primary prevention. However, although primary prevention strategies such as vaccination against HBV and public health improvement to reduce aflatoxin contamination will have major impact in reducing the future incidence of HCC, an estimated two billion people have already been exposed to HBV worldwide and 350 million people have chronic HBV infection.6 As of 1999, the prevalence of HCV was estimated to be 3% worldwide, which translates to 200 million people.7 The annual incidence of HCC reaches 3% in patients with cirrhosis infected with HBV and 7% in patients with cirrhosis infected with HCV.8 With so many people at risk, it is imperative to develop effective chemoprevention in high-risk individuals. Although many compounds have been tested in animal models of HCC, only a handful have been studied in patients at risk for HCC. Chemopreventive agents may act by blocking carcinogen activation, inducing carcinogen metabolism (such as the action of oltipraz on aflatoxin), altering intracellular signaling pathways to prevent progression of an initiated cell to a malignant cell, inhibiting angiogenesis, inducing apoptosis selectively in malignant cells, or inhibiting pathways linked to inflammation (such as inhibitors of nuclear factor κB and cyclooxygenase-2 [COX-2]).9 Numerous compounds in animal models exhibit chemopreventive effects, including phytochemicals (i.e., curcumin, resveratrol, epigallocatechin gallate, caffeine, silymarin, silibinin, genistein),9 gefitinib,10 retinoid and its derivatives,11 antifibrotic agents,11 COX-2 inhibitors,9 tamoxifen,12 and S-adenosylmethionine (SAMe).13 Notably in the case of SAMe, most patients with chronic liver disease have impaired hepatic SAMe biosynthesis, and chronic deficiency in hepatic SAMe in mice leads to spontaneous development of HCC.14 Despite a long list of agents shown to prevent HCC formation in animal models, very few have been tested in humans. Chemoprevention can be divided into primary (preventing development of HCC) and secondary chemoprevention (preventing recurrence of HCC). Tumor recurrences within 2 years of treatment are probably microscopic metastases from the primary tumors whereas recurrences more than 2 years later are probably second primary tumors induced by multicentric carcinogenesis.15 Treatment efficacy likely differs depending on the origin of the recurrent tumor. Primary chemopreventive agents studied in humans are oltipraz and chlorophyllin (targeting aflatoxin metabolism and disposition),16 lamivudine in HBV,17 and interferon alpha in HCV-infected patients.11 Oltipraz and chlorophyllin have been tested in randomized, placebo-controlled trials in Qidong, China, where aflatoxin contamination is thought to synergize with HBV infection and result in one of the highest HCC rates in the world. Even though a phase 2 trial16 showed oltipraz alters aflatoxin metabolite levels (biomarkers for detoxification), a follow-up study failed to show any change in a urinary marker for oxidative DNA damage.18 This coupled with the expense and toxicity of long-term use raised doubt about the practicality of oltipraz use. Chlorophyllin is much cheaper and safer and reduces urinary level of aflatoxin-N7-guanine adducts by 55%,16 making this a more attractive alternative. However, whether these agents can reduce the incidence of HCC in this high-risk population remains unknown. By contrast, a landmark study showed lamivudine delays disease progression and reduces the incidence of HCC by 50% in predominantly Asian patients with chronic HBV infection and advanced liver fibrosis.17 This study was stopped after a median follow-up of 32.4 months because of significant improvement in the treatment group, but YMDD (Tyr-Met-Asp-Asp motif) mutations were detected in 49% of the treatment group (versus 5% in the placebo group) and most of these patients had evidence of rebound HBV viremia.17 Newer antiviral agents that have lower resistance profiles than lamivudine deserve further study in this population. The other primary chemoprevention treatment that has received a lot of attention is interferon-alpha in patients with HCV infection.11, 15 Japanese investigators first reported that the risk of HCC was reduced significantly in patients with HCV who responded to interferon (both sustained and transient).11 Since then, other groups have also shown a protective effect against HCC in patients with HCV who responded to interferon.15 Japanese investigators also showed glycyrrhizin, an aqueous extract of licorice root with anti-inflammatory activity, reduces both cirrhosis and HCC risk in patients with chronic HCV infection.15 A few other chemopreventive agents have also been reported such as vitamins K1, K2, and K3, and coffee and tea, but these observations await prospective validation. Two secondary chemopreventive agents have been studied in patients. The first is interferon-alpha after liver resection in HCV-induced cirrhosis.19 Although there was no difference in HCC recurrence overall, there was a 50% reduction in late recurrence rate in the treatment arm in HCV-pure (no previous contact with HBV) patients who adhered to treatment. The other agent reported to have a beneficial effect in secondary chemoprevention is acyclic retinoic acid.20 In a prospective, randomized, controlled trial in Japan, acyclic retinoic acid was given for 12 months to patients treated with resection or local ablation of HCC. After 68 months of follow-up, survival rates were 74% in patients treated with acyclic retinoic acid versus 46% in the untreated group.15 However, the effectiveness of retinoid in secondary chemoprevention remains to be confirmed by another group. Up to now, the data are compelling that for patients infected with HBV and HCV, response to antiviral therapy correlates with reduced risk of HCC. However, for those nonresponders and for the patients with cirrhosis who are not infected with HBV or HCV, the options are unclear. Ideal chemopreventive agents would be safe to use chronically and affordable for the population at risk. Of the numerous agents studied in animal models, not many have been examined, even in small trials in humans. Currently, of 246 active clinical trials on adult HCC (searched at http://clinicaltrials.gov), three trials examine prevention of HCC recurrence after surgical resection or local ablative therapy, and only one study examines primary chemoprevention of HCC. This study seeks to determine whether 24 weeks of SAMe treatment in HCV-infected patients can reduce serum levels of des-gamma carboxyprothrombin and alpha-fetoprotein and is expected to end on December 31, 2010. Given the magnitude of the problem, more emphasis on and support for conducting these studies are sorely needed. Agents that have been shown in multiple animal models to be effective, safe, and affordable are ideal candidates for these studies. Because different etiologies are likely to have distinct mechanisms in the pathogenesis of HCC, it may also be important to test these agents in models designed for different etiologies, such as HCV and HBV transgenic mice. Biomarkers for response are essential. Finally, a global cooperative approach to tackle this major health issue should hopefully bring us closer to reduce the future burden of HCC.