Review Article

Hepatocellular carcinoma: current management and recent advances Wan-Yee Lau and Eric C. H. Lai Hong Kong, China

BACKGROUND:  Hepatocellular carcinoma (HCC) is a major health problem worldwide. It is the fifth most common cancer in the world, and the third most common cause of cancer-related death. Without specific treatment, the prognosis is very poor. The goal of management is  "cancer control"    — a reduction in its incidence and mortality as well as an improvement in the quality of life of patients with HCC and their families. This article aims to review the current management of HCC and its recent advances. DATA SOURCES:  A MEDLINE database search was performed to identify relevant article using the    keywords  "hepatocellular carcinoma", "hepatectomy", "liver transplantation", and "local ablative therapy". Additional papers and book chapters were identified by a manual search of the references from the key articles. RESULTS:  Liver resection and liver transplantation remain the options that give the best chance of a cure. Recent evidence suggests that local ablative therapy may offer comparable survival results in patients with small HCC, and preserved liver function. Transarterial chemoembolization (TACE) is the most promising palliative modality for unresectable HCC, but other techniques, such as transarterial radioembolization (TARE), and local ablative therapy, have also shown comparable results. CONCLUSIONS: Early diagnosis of HCC remains a key goal in improving the prognosis of patients. During the last two decades, operative mortality and surgical outcome of liver resection and liver transplantation for HCC have improved. Progress also has been made in multi-modality therapy which can increase the chance of survival and improve the quality of life for patients with advanced HCC. (Hepatobiliary Pancreat Dis Int 2008; 7: 237-257)

Author Affiliations: Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China (Lau WY and Lai ECH) Corresponding Author:  Wan-Yee Lau, Professor of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China (Tel: 852-2632 2626; Fax: 852-2637 7974; Email: [email protected]) © 2008, Hepatobiliary Pancreat Dis Int. All rights reserved.

KEY WORDS: hepatocellular carcinoma; hepatectomy; liver transplantation; local ablative therapy

Introduction

H

epatocellular carcinoma (HCC) accounts for 80% to 90% of primary liver cancer. HCC is a major health problem worldwide, with an estimated incidence ranging between 500  000 and 1 000 000 new cases annually. It is the fifth most common cancer in the world, and the third most common cause of cancer-related death. The rates of HCC in men are 2 to 4 times higher than in women. It usually develops between 35 and 65 years of age, when people are most productive and have most family responsibilities.[1-5] HCC shows great geographical variation, with a very high incidence in Asia and subSaharan Africa. Although its incidence is far lower in the United States and Europe, those rates have been increasing in recent years. 80%-90% of cases of HCC develops in cirrhotic liver, and cirrhosis is the strongest predisposing factor for HCC. Overall, 80% of cases of HCC are attributable to chronic viral infections with either hepatitis B or hepatitis C virus. Hepatitis B infection is the main risk factor in Asia and Africa. Chronic carriers have a 100-fold relative risk for developing HCC, with an annual incidence rate of 2%-6% in cirrhotic patients. In Western countries and Japan, hepatitis C infection is the main risk factor. Other causes of HCC include alcoholic liver cirrhosis and aflatoxin B. Without specific treatment, the prognosis is very poor, and the median survivals for patients with early and advanced tumors are 6-9 months and 1-2 months, respectively. Therefore, HCC is a major global health problem. The goal of management is "cancer control"— a reduction in its incidence and mortality as well as an improvement in the quality of life of patients with HCC and their families. This article aims to discuss

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the current management of HCC and its recent advances.

Prevention and surveillance Prevention of infection with hepatitis B and C viruses is the key strategy to reduce the incidence of HCC. There are about 350 million carriers of hepatitis B virus worldwide. Hepatitis B vaccine has been proven to be safe and effective. The vaccine is 95% effective in preventing children and adults from developing chronic infection if they have not been infected. Since 1991, the World Health Organization (WHO) has called for all countries to add hepatitis B vaccine to their national immunization programmes.[4] By March 2000, 116 countries had included hepatitis B vaccine in their national programme, including most countries in Asia. In Taiwan area, the national vaccination of infants between 1984 and 1986 reduced the prevalence of hepatitis B virus carriers in childhood from 15% to 1% and that of HCC by 60% when compared with non-immunised children.[6] However, the mean age at diagnosis of hepatitis B-related HCC is 55-60 years, and three to four decades are needed to show the real impact of hepatitis B virus control on HCC incidence. Globally, an estimated 170 million persons are chronically infected with hepatitis C and 3 to 4 million persons are newly infected each year, but no vaccine is currently available. In the absence of an effective vaccine, all precautions to prevent infection must be taken including: screening of blood and organ donors, virus inactivation of plasma derived products, implementation and maintenance of infection control practice in the health care setting, promotion of healthy behavior change in the general public, such as prevention of sharing of needles for injection, and safe sexual practice. A surveillance program in cirrhotic patients has the potential advantage of detection of HCC at early stages, when the tumors are amenable to curative treatments. However, its cost-effectiveness is still debated. Surveillance of HCC in patients with recognized risk factors remains controversial. Two randomised controlled trials (RCTs) have been completed in China. Chen et al[7] investigated 5581 men aged 30-69 years, with chronic hepatitis B infection, in Qidong county, Jiangsu Province, China. Biannual screening with serum alpha-fetoprotein (AFP) resulted in earlier diagnosis of HCC but the gain in lead time did not result in any overall reduction in mortality. Another RCT confirmed that surveillance for HCC reduced disease-specific mortality. In the

study by Zhang et al,[8] 18816 people, aged 35-59 years, with HBV infection or a history of chronic hepatitis, were studied at the Liver Cancer Institute of Fudan University, Zhongshan Hospital, Shanghai, China. Screening group participants were invited to have an AFP test and abdominal ultrasonography (US) examination every 6 months. When the screening group was compared to the control group, biannual screening reduced HCC mortality by 37%. Although there is still no strong evidence that screening in HCC improves survival, many physicians advocate screening patients in high-risk groups with either serum AFP or US of the liver, or both. If surveillance is offered, it should be performed at 6-monthly intervals, based on tumor growth estimates. The natural history of HCC is variable. It has been estimated that the doubling time of tumor size ranges from 1 to 19 months, with a median of 4-6 months. Some investigators have suggested that, because of the unpredictable tumor growth rate, screening should be done more frequently (3-month intervals) in a highrisk population.[1-5]

Diagnosis of HCC The diagnosis of HCC is typically made by radiological liver imaging in combination with serum AFP. AFP is a tumor marker that is elevated in 60%-70% of patients with HCC. Normally, levels of AFP are below 10 ng/ml, but marginal elevations are common in patients with chronic hepatitis or cirrhosis. However, all patients with elevated AFP should be screened for HCC with imaging, especially if there has been an increasing trend from baseline level. The specificity of AFP is very high when the levels are above 400 ng/ ml in patients without testicular tumor. There is an agreement that biopsy proof of HCC is not required prior to surgery and that noninvasive diagnostic criteria can be applied. Seeding of tumor in the needle track occurs in 1%-3% of cases. US is usually the first line investigation within a surveillance plan or within the standard evaluation of patients with suspected or known liver disease. Upon US detection of a hepatic nodule, the next step is to characterize the nodule and establish its diagnosis. In the setting of a patient with known chronic hepatitis or cirrhosis of other aetiology, a liver mass found incidentally or on US screening has a high likelihood of being HCC. If AFP is normal, further dynamic imaging (contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) with gadolinium injection, or lipiodol angiography with

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Hepatocellular carcinoma: current management and recent advances

follow-up CT) usually allows a confident diagnosis to be made and the clinician can proceed to assessment of treatment without the need for biopsy. In the few cases where diagnostic doubt persists, biopsy may be indicated. However, difficulty still exists in recognizing very small (14% precludes major liver resection, as it indicates a significant reduction in the liver reserve. Many Japanese groups rely on the ICG retention test.[23] In Western countries, selection of surgical candidates for hepatectomy is usually based on the presence of portal hypertension and the bilirubin level.[5] Clinically relevant portal hypertension is defined as the presence of a hepatic vein pressure gradient higher than 10 mmHg, oesophageal varices, or splenomegaly with a platelet count lower than 100×109/L. Other tests that are used less commonly include Technetium-99m galactosyl serum albumin scintigraphy and hepatic galactose elimination rates. HCC recurrence after resection Recurrent HCC occurs in 50% to 80% of patients at 5 years after resection, the majority occurring within 2 years.[1-5] Following curative treatment for HCC, 50%-90% of postoperative death is due

to recurrent disease. HCC commonly arises from chronic viral or alcoholic liver diseases, which are likely to harbour multiple and independent clones of premalignant cells. When these clones are further exposed to continuous carcinogenic insults, a unicentric or multicentric carcinogenesis follows. Intra-hepatic recurrence can either represent de novo tumor formation in a cirrhotic liver, or intra-hepatic metastasis of a clonally identical neoplasm. No matter how the recurrence happens, it is generally believed that recurrences arise not because of inadequate resection but because of pre-existing microscopic tumor foci that are undetected by imaging modalities or because of malignant cells that have been disseminated during surgical manipulation.[24-27] In order to prevent tumor recurrence after curative treatments, eradication and/or inhibition of such clones of malignant cells is essential. Thus, any neoadjuvant or adjuvant therapy which can decrease or delay the incidence of intra-hepatic recurrence will improve the results of liver resection. Neoadjuvant treatment before resection With promising results in its palliative role, TACE was investigated as a form of neoadjuvant therapy. The place of neoadjuvant TACE in HCC remains controversial, and its effectiveness in preventing tumor recurrence and prolonging survival is not proven. The arguments against the use of preoperative TACE include: 1) the associated complications of preoperative TACE, such as perihepatic adhesions, rendering the liver resection more difficult; 2) the increased risk of liver failure; 3) a delay in definitive surgery; 4) an increased difficulty in future transarterial treatment for recurrent HCC as a result of the development of collateral neoplastic feeding vessels after embolisation of hepatic arterial branches; and 5) the partial tumor necrosis caused by preoperative TACE causes the remaining tumor cells to be less firmly attached and become more likely to be dislodged into the bloodstream during hepatic resection.[28-33] Non-randomised case-control studies show contradictory results.[28-32] In a recently published large case-control study involving 235 patients from Japan, the 5-year overall survival rate after partial hepatectomy was significantly lower in the preoperative TACE group (28.6%) than in the control group (50.6%), especially in patients without cirrhosis or with early HCC.[32] There are only two RCTs on TACE used in the form of neoadjuvant therapy before partial hepatectomy for HCC.[33,  34] Yamasaki et al selected 97 patients with small HCC

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(from 2 to 5 cm) and showed that neoadjuvant therapy had no impact on disease-free and overall survival.[34] Wu et al studied 52 patients with large but resectable HCC (>10 cm) and showed a decreased overall survival and a higher extrahepatic recurrence rate (57% vs. 23%) than in a control group.[33] Based on the currently available clinical evidence, preoperative TACE cannot be recommended for resectable HCC.

disease-free survival and overall survival, although the difference became statistically insignificant at 8 years after treatment.[37,  38] Subsequently, two French non-randomised studies also demonstrated favorable results with adjuvant 131I-lipiodol.[40, 41] Interferon has multiple therapeutic mechanisms, including a direct antiviral effect, an immunomodulatory effect, and direct and indirect antiproliferative effects. Ikeda et al assigned 20 Adjuvant treatment after resection patients either to an interferon-beta group (n=10) or a control group (n=10) after treatment with Many groups have studied adjuvant treatments surgery or PEI for hepatitis C virus-related HCC.[42] to minimize recurrent HCC after resection. RCT Seven patients in the control group developed tumor results suggested that adjuvant regional chemotherapy recurrence, while only 1 patient in the treatment with/without embolization or systemic chemotherapy group developed tumor recurrence during a median does not add benefit.[35, 36] Addition of systemic observation period of 25 months. Unfortunately, the chemotherapy to regional chemotherapy in the adjuvant setting also resulted in an adverse outcome. end-point of survival was not measured in this study. Kubo et al assigned 30 patients to an interferon-alpha At this moment, only adjuvant TARE with 131I-lipiodol treatment group (n=15) and a control group (n=15) and systemic interferon shows early promising after liver resection for hepatitis C virus-related results.[37-45] HCC.[43] Recurrent tumors were detected in 9 patients Adjuvant treatment with 131I-lipiodol delivered in the interferon-alpha group and in 13 patients in through the hepatic artery after curative liver the control group. The 5-year overall survival rate resection was first proposed by our group. The idea was significantly higher in the interferon group than is to use lipiodol to carry the radioactive 131I to the in the control group (78% vs. 48%). Unfortunately, residual tumor foci in the liver remnant after resection the number of patients in this study was too small. to kill the tumor cells. Lipiodol is the iodized ethyl Sun et al randomly assigned 236 patients into an esters of fatty acids of poppy seed oil containing interferon-alpha treatment (n=118) and a control 38% iodine by weight or 475 mg of iodine per ml. It group (n=118) after resection of hepatitis B-related has been used as a radiologic contrast medium for HCC.[44] They found that the median disease-free many years. The iodine moiety of lipiodol can be survival (31.2 months vs. 17.7 months) and the total changed to radioactive 131I through an atom-for-atom number of recurrences (n=67 vs. n=71) were not exchange reaction. 131I-lipiodol has a significantly statistically different. However, the overall survival longer half-life in the tumor than in normal tissue. It in the treatment group was significantly better than emits gamma radiation with energy of 364 keV, with a mean penetration of 0.4 mm. The physical half- that in the control group (median survival 63.8 months vs. 38.8 months). They suggested that this life is 8.04 days.[39] Between April 1992 and August difference was due to the delayed recurrence and the 1997, we studied 43 patients who underwent curative resection for HCC and recovered within 6 weeks. decreased severity of recurrence after interferonalpha treatment rendering secondary local ablative Twenty-one patients received one 1850 MBq dose 131 treatment and resection possible. In the recent RCT of of I-lipiodol and 22 patients received no adjuvant treatment. I-lipiodol had no significant toxic effects. Lo et al, patients with no residual disease after hepatic resection for HCC were randomly assigned with The actuarial 5-year disease-free survival in the treatment and control groups was 61.9% and 31.8%, stratification by pTNM stage to receive no treatment (control group), interferon alpha-2b 10 MIU/m (IFNrespectively. The actuarial 5-year overall survival in the treatment and control groups was 66.7% and Ⅰ group) or 30 MIU/m (IFN-Ⅱ group) thrice weekly 36.4%, respectively. The actuarial 10-year disease- for 16 weeks.[46] Enrollment to the IFN-Ⅱ group was terminated because adverse effects resulted in free survival in the treatment and control groups treatment discontinuation in the first 6 patients. Forty was 47.6% and 27.3%, respectively. The actuarial patients each had been enrolled in the control and 10-year overall survival in the treatment and control IFN-Ⅰ groups. The 1- and 5-year survival rates were groups was 52.4% and 27.3%, respectively. In patients 85% and 61%, respectively, for the control group, with HCC, adjuvant intra-arterial 131I-lipiodol after and 97% and 79%, respectively, for the IFN-Ⅰ group. curative liver resection provided benefit on the 242 • Hepatobiliary Pancreat Dis Int，Vol 7，No 3 • June 15，2008 • www.hbpdint.com

Hepatocellular carcinoma: current management and recent advances

Subgroup analysis showed that adjuvant interferon had no survival benefit for pTNM stage Ⅰ/Ⅱ tumors (5-year survival 90% in both groups), but it prevented early recurrence and significantly improved the 5-year survival of patients with stage Ⅲ/ⅣA tumors, from 24% to 68%. In summary, there is currently little evidence to suggest adjuvant treatment improves survival after HCC resection. Clinical trials assessing adjuvant therapies after curative resection are urgently needed, and they should constitute a priority area of investigation. Adjuvant TARE with 131I-lipiodol and systemic immunotherapy should also be studied in larger RCTs to confirm the favorable outcomes. Chemoprevention after resection Retinoid and its derivatives are collectively termed vitamin A (retinol). Polyprenoic acid is a synthetic acyclic retinoid that inhibits experimental hepatocarcinogenesis and induces differentiation and apoptosis of human HCC-derived cell lines. Muto et al randomly assigned patients who had curative resection or PEI for HCC to receive either polyprenoic acid or placebo for 12 months.[47] After a median follow-up of 38 months, only 12 patients (27%) treated with polyprenoic acid compared with 22 placebo-treated patients (49%) developed recurrence or new HCC. Vitamin K is fat-soluble and can be naturally produced (Vit. K1 and K2) or chemically synthesized (Vit. K3). Vit. K inhibits the proliferation of tumor cells in vitro at a decreasing potency from Vit. K3 to Vit. K1. The mechanism is not understood fully. Menatetrenone, a Vit. K2 analogue, was studied in a recent pilot RCT in 61 patients after curative liver resection or local ablative therapy, and the results suggested that menatetrenone may have a suppressive effect on the recurrence of HCC and a beneficial effect on survival.[48] The cumulative recurrence rates in the treatment group were 12.5% at 1-year, 39.0% at 2-year, and 64.3% at 3-year; and the corresponding recurrence rates in the control group were 55.2%, 83.2%, and 91.6%, respectively. The 1-, 2- and 3-year cumulative survival rates for the treatment group were 100%, 96.6% and 87%, respectively, while those for the control group were 96.4%, 80.9% and 64%, respectively. The beneficial role of vitamin A or K analogues in the chemoprevention of HCC require further and larger RCTs. Preoperative portal vein embolization

Because most patients with HCC have impaired hepatic functional reserves due to hepatitis B or C virus-associated cirrhosis, the amount of liver parenchyma that can safely be resected is very limited. In selected patients with small liver remnant, attempts have been made to improve on the safety of liver resection by embolising the portal vein supplying the part of liver containing the tumor. Preoperative portal vein embolisaton (PVE) can be used in patients with limited functional hepatic reserve to increase the resectability and safety of liver resection. PVE induces hepatocytes in the embolised lobe to go into apoptosis and hepatocytes in the unembolised lobe to enter into a highly active phase of proliferation, which results in hyperplasia of the unembolised lobe. PVE can be performed by one of three standard approaches: the intraoperative transileocolic venous approach, the transhepatic contralateral approach, and the transhepatic ipsilateral approach. These approaches are chosen on the basis of the type of resection planned, the location of the tumor, the extent of embolization, the type of embolic agent used, and the availability of the surgical and radiological facilities. PVE is generally performed in patients with a predicted functional liver remnant of