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REVIEW ARTICLE Table of Contents   
Year : 2005  |  Volume : 2  |  Issue : 1  |  Page : 154-185
Pathogenesis, prevention and treatment of hepatitis B associated hepatocellular carcinoma


Fox Chase Cancer Center, 333 Cottman Avenue Philadelphia, PA 19111, USA

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How to cite this article:
London W T, Mason WS, Nguyen M. Pathogenesis, prevention and treatment of hepatitis B associated hepatocellular carcinoma. Hep B Annual 2005;2:154-85

How to cite this URL:
London W T, Mason WS, Nguyen M. Pathogenesis, prevention and treatment of hepatitis B associated hepatocellular carcinoma. Hep B Annual [serial online] 2005 [cited 2019 Mar 22];2:154-85. Available from: http://www.hepatitisbannual.org/text.asp?2005/2/1/154/29379



   Introduction Top


Primary liver cancers, 85 to 90 percent of which are hepatocellular carcinomas (HCC), caused more than 600,000 deaths worldwide in 2002.[1] HCCs are malignant tumors of liver parenchymal cells (hepatocytes). They are the third most common cause of cancer deaths among men and sixth most common among women.[2] About 80% of HCCs and the resulting deaths occurred in the developing countries of Asia and Africa. Eighty to 95% of HCCs are associated with chronic infection of hepatocytes with either hepatitis B virus (HBV) or hepatitis C virus (HCV). Of these, HBV infections account for 75 to 80% of virus-associated HCCs, with HCV responsible for 10 to 20 percent.

In this chapter, we describe what is known and what is hypothesized about the pathogenesis of HBV associated HCC. Primary prevention of HBV associated HCC can be accomplished by vaccination against HBV. This will only be discussed briefly here. Treatment of chronic hepatitis B may reduce the risk of HCC, but this subject is covered by Lok and will be discussed minimally here. Therefore, our discussion of prevention will emphasize screening for early detection of HCC and chemoprevention. With respect to treatment, we would focus on surgical resection, ablation procedures, and transplantation.

Even though vaccination is not the main focus of this chapter, it should be understood that if immunization of newborns and infants against HBV became universal, HBV associated HCC would become a comparatively minor cause of cancer mortality in the not too distant future.[3],[4],[5]


   Prevention of HCC Top


Primaryprevention - Immunization against hepatitis B virus

Chronic HBV infection, which is the cause of the largest proportion of HCCs in the world, is 90 percent preventable with proper use of the hepatitis B vaccine.[6] The currently approved recombinant vaccines have remarkably few adverse effects. Studies from Taiwan, where universal immunization of newborns was introduced in 1984, have shown a 50 to 90 percent reduction in the incidence of HCC among adolescents.[3],[4],[5] It is likely that the failure to completely eradicate HBV associated HCC is related to the inability of vaccination to prevent mother to child transmission of HBV infection.[7] As the vaccinated population moves into their late teens and early 20s, it will be important to see whether the initial magnitude of protection is maintained. The challenge now is to expand hepatitis B vaccination coverage to the populations at greatest risk of HBV infection and HCC. In 1992, the WHO set a goal for all countries to integrate hepatitis B vaccination into their universal childhood vaccination programs by 1997. That goal was not achieved, but significant progress is being made. By 2001, 126 of the 191 WHO member states had universal infant or childhood hepatitis B vaccination programs.[8] Through the efforts of the Global Alliance for Vaccines and Immunization (GAVI), the cost of vaccine has been reduced from $100 to $1.00 per pediatric dose. The developed countries of the world can already afford universal vaccination of newborns and now vaccination programs are being introduced into the 72 poorest countries.[6] From studies done in several high risk countries, we can predict that vaccination programs will reduce the prevalence of chronic HBV infection from 8 to 20 percent to less than 2 percent.[7],[9] and this should lead to major decreases in the incidence of HCC in the coming decades.

Secondary prevention - Screening and early detection


Clinicians commonly screen patients who are chronically infected with HBV or HCV, with or without cirrhosis, with annual or semiannual serum alpha-fetoprotein (AFP) levels and ultrasonography (US) of the liver to detect small HCCs. Whether such screening confers a survival advantage is still uncertain. Randomized clinical trials are difficult to justify ethically and those that have been done have either not shown a reduction in mortality or have had methodological problems. There are several components to screening for HCC that currently limit its value including: (1) the sensitivity and specificity of AFP, (2) the quality and maintenance level of the US equipment, particularly in developing countries, (3) the skill of the US operator in identifying small tumors, (4) the ability to accurately distinguish nodular hyperplasia from HCC, (5) the availability of high quality surgery, and 6) cost.[10],[11]

As with all tests, the sensitivity of AFP can be increased to 100 percent if the cut-off level is set low enough, but at the price of loss of specificity. The most commonly used cut-off level for HBV carriers is 20 ng/ml, which yields a sensitivity between 50 and 75 percent and a specificity of 90 percent.[10] The sensitivity of US to detect HCCs less than 3 cm in diameter among HBV infected individuals has ranged from 68 to 87 percent, but the specificity has been 80 per cent or less.

Recently, Evans et al .[12] completed the analysis of a randomized trial of AFP screening followed by US of individuals chronically infected with HBV in Haimen City, China. Approximately 14,500 HBV infected adults were randomly assigned by village to Screening or Usual Care. The Screened group received semiannual AFP testing, and those with elevations (>20 ng/ml) were referred for ultrasound testing to detect tumors. Individuals in the usual care group were managed by their primary care physicians. Such patients generally received AFP tests and US only after they developed symptoms of liver disease. The screening program lasted four years from December 1993 to December 1997, and follow-up for HCC occurrence and mortality continued for six years thereafter. HCC mortality was not different between groups at any point during the screening program or follow-up. From the end of screening through the end of follow-up, more than 200 HCCs occurred in the study groups. The tumor size of HCCs at detection was somewhat smaller among the Screened group than the Usual Care group. Among those in the screened group developing HCC, 8% had HCCs < 2 cm and 26% 3-4 cm in diameter, but 66% had tumors > 5 cm or multifocal tumors. In the Usual Care group 2.5% were < 2 cm, 18% 3-4 cm, and 79% > 5 cm. Thus, periodic AFP and US screening may detect HCCs earlier, but not a great deal earlier than usual care. Furthermore, to impact mortality an effective screening program must be combined with effective therapy. Currently, periodic screening with AFP and US is the best available means for early detection, but it is of limited value particularly in developing countries.

Secondary prevention - Chemoprevention

A number of chemopreventive agents have been examined in HCC, though many have not moved beyond animal studies. In general, the aim of most chemoprevention interventions is to prevent cirrhosis because prevention of HCC in the presence of established cirrhosis has been essentially unachievable. Of the agents that have moved into clinical trials, a-interferon has been the most extensively investigated. Although a-interferon has reduced HCC risk among HCV-infected individuals,[13],[14],[15],[16] it has had little effect in diminishing HCC risk among HBV-infected persons.[17],[18] Whether therapy with antiviral nucleoside inhibitors like lamivudine, adefovir dipivoxil, and entecavir will reduce the risk of HCC among HBV-infected patients is unknown, but the improvement in liver histopathology with prolonged treatment with these drugs is encouraging.[19]

Glycyrrhizin, an aqueous extract of licorice root and an immune modulator, has been reported to decrease the risk of HCC in HCV-infected individuals.[20],[21],[22] Its effect on HBV infected patients has not been reported. Medicinal ginseng.[23] is being tested for HCC-preventive capability among HCV-infected Japanese patients. Chemopreventive agents that have not yet reached HCC clinical trials include cyclooxygenase-2 inhibitors,[24] S-adenosyl-L-methionine,[25] curcumin,[26] a 5a-reductase inhibitor,[27] vitamin E,[28] vitamin D,[29] green tea,[30] and selenium,[31] as well as a number of herbal extracts.

Vitamin A (retinol) or a synthetic retinoid may be a more promising approach to chemoprevention. A study in Taiwan of serum samples collected up to five years before the diagnosis of HCC showed significantly reduced levels of retinol among individuals who developed the disease.[32] Low levels of retinol were associated with chronic HBV infection, cigarette smoking and low vegetable intake. Muto et al[33] randomly assigned 89 HCC patients who were cancer free following resection or ablation to receive a placebo or polyprenoic acid, an acyclic retinoid. The recurrence rate was about 50% lower in the retinoid treated group. Polyprenoic acid is being tested for HCC-preventive capability among HCV-infected Japanese patients[34] and presumably, if successful, will be tried in persons chronically infected with HBV.

Aflatoxin is a mycotoxin produced by Aspergillus species. Storage of corn or peanuts in warm, humid environments may lead to overgrowth of Aspergillus and heavy contamination with aflatoxin. Experiments in fish, poultry, and rodents have shown that aflatoxin B 1 (AFB1) is a powerful hepatic carcinogen.[35],[36],[37] An interaction of AFB1 exposure with chronic HBV infection was revealed in short-term prospective studies in Shanghai, China. Urinary excretion of aflatoxin metabolites increased the risk of HCC 4-fold, HBV infection increased the risk 7-fold, but individuals who excreted AFB1 metabolites and were HBV carriers had a 60 times increased risk of HCC.[38],[39] By and large, in areas of the world where AFB1 exposure continues to be an environmental problem, chronic HBV infection is highly prevalent and this interaction merits intervention.

Prevention of exposure to aflatoxin is a more practical and cost effective approach to reducing risk of HCC from this co-carcinogen than chemoprevention. For example, in Africa, where contaminated peanuts (ground nuts) are the main source of aflatoxin, simple post-harvest drying procedures can greatly reduce exposure.[40] These include removal of mouldy nuts by hand sorting, drying nuts on fiber mats instead of the ground, sun drying nuts to completeness, storage in natural fiber bags instead of plastic bags, use of wooden palletes in storage facilities to keep bags of nuts off the ground, and application of insecticide in storage facilities to reduce spread of fungal spores. Nevertheless, chemoprevention is being developed for individuals chronically exposed to aflatoxin. Two agents targeted against aflatoxin-related liver damage, oltipraz and chlorophyllin are being investigated. Oltipraz works to alter phase I and II metabolism of aflatoxin, while chlorophyllin acts by forming complexes with aflatoxin which limit aflatoxin bioavailabilty.[41] Though both have demonstrated promising results in reducing the levels of aflatoxin adducts and metabolites, neither has yet been demonstrated to decrease the risk of HCC in aflatoxin-exposed populations.


   Pathogenesis of HCC Top


Pre-neoplastic changes in hepatocytes

Persistent HBV infection in neonatally infected humans typically results from perinatal transmission or exposure in early childhood. Though HCC may occur in the first decade of life, this is uncommon, and incidence typically doesn't peak until middle age.[42] In the first decade of life, there is a high level of virus production but little inflammation and only mild elevations in liver enzymes.[43] Lack of disease reflects the fact that infection per se is not cytopathic, and that liver disease results from the antiviral immune response. Often, however, the infection may progress after adolescence to include chronic recurrent inflammatory liver disease, cirrhosis, and a high risk of HCC. Cirrhosis results from the scarring associated with chronic injury and repair. The progression to HCC is less clear.

For at least three reasons, HCC is believed to originate from infected hepatocytes. First, HCCs often express low levels of serum albumin, a major product of normal hepatocytes.[44] Second, hepatocytes are the major target of infection in the liver and at least 70% of tumors contain integrated HBV DNA, though they don't normally contain replicating HBV. Integrated viral DNA is found at the same site in all cells in any given tumor, indicating that oncogenic transformation occurred after HBV infection. Third, histologic evidence suggests that HCCs arise in HBV carriers from foci of altered hepatocytes (FAH) that evolve into cirrhotic and dysplastic nodules and spawn progressively more transformed cells and, ultimately, tumors.[45],[46],[47],[48],[49],[50],[51],[52]

Based on studies of chemical carcinogenesis in rodents, it has also been speculated that HCC in HBV carriers may arise from facultative progenitor cells (oval cells) in the liver. Dying hepatocytes are usually replaced by proliferation of other hepatocytes. When hepatocyte proliferation is blocked by a carcinogen, progenitor cells can become an important source of hepatocyte replacement. However, while oval cell proliferation occurs during chronic infections, hepatocytes also continue to proliferate. One study reported that oval cells express HBsAg and HBcAg, indicating that these cells may become infected.[53] a necessary requisite for HCC precursors. So, despite histologic evidence which seems to support progression from hepatocytes, the possibility exists that oval cells are the true precursors, or than more that one pathway is involved. An additional confounding problem in defining progression from normal hepatocytes, or hepatocyte progenitors, to neoplasia is that HCC, although sometimes multicentric, is still a relatively rare occurrence compared to the frequency of "preneoplastic" hepatocytes observed histologically. For instance, foci of altered hepatocytes (FAH), presumed to reflect a stage in neoplastic progression, are readily found in random histologic specimens, indicating that there are hundreds of thousands of these in the entire liver, but obviously, very few if any, give rise to HCC. Thus, while it seems plausible that FAH ultimately give rise to HCCs, the frequency and mechanism by which this occurs remains obscure. Indeed, while these are often described as preneoplastic, the best evidence for neoplastic progression comes from analyses of very large foci (cirrhotic and dysplastic nodules) containing hundreds of thousands of cells[47],[49],[50],[51],[52] and not from the typically smaller and more abundant FAH. These larger foci have been shown to be clonal in humans, based upon Southern blot analyses of integrated HBV DNA and on assays for an active X chromosome in lesions in female patients.[54],[55],[56] Often, such foci over express putative oncogenes that are also found in HCC.

The reason for the appearance of both FAH and larger nodules is unclear. The simplest explanation is that they are clonal outgrowths of hepatocytes that have acquired a selective growth or survival advantage (e.g., an enhanced response to regenerative signals). In view of the duration of infection and the increase in liver regeneration, perhaps 10-100 times that in uninfected liver, even a slight advantage could lead over time to the generation of clones containing thousands of hepatocytes. One strong selective pressure in the liver is the adaptive immune response to viral antigens expressed by hepatocytes. Hepatocytes that have lost the ability to support virus reproduction, or expressed very low levels of virus, would presumably be killed by CTL at a lower rate than hepatocytes expressing high levels of viral antigen, and would therefore have a survival advantage leading to their clonal selection.

In a study in woodchucks chronically infected with woodchuck hepatitis virus (WHV), integrated viral DNA was used as a marker to identify clonally expanded hepatocytes.[57] It was determined that the livers contained at least 100,000 clones of >1000 cells, representing at least 0.2% of hepatocytes. Since the integration frequency in these livers was about 1-2%, it can be calculated that >10% of the liver may be comprised of clones of >1000 cells. The basis for this expansion was not determined, nor was it determined if the clones corresponded to FAH. However, it was shown that the integration sites did not occur near Nmyc2 or the win locus, which are sites of integration in most woodchuck HCCs. It is therefore plausible that clonal expansion and by inference FAH result in the first instance from immune selection of hepatocytes defective in the ability to express HBV (or WHV) and that this process coincidentally also selects in rare cases for outgrowth of cells with preneoplastic changes that eventually progress to HCC.

Molecular genetic characteristics.

As with the cellular progenitor of HCC in HBV carriers, the genetic changes leading to HCC remain obscure. Early studies in woodchucks infected with woodchuck hepatitis virus revealed activation of Nmyc2 due to WHV DNA integration in the vast majority of tumors, in association with elevated expression of insulin-like growth factor II (ILGF II).[46],[58],[59] These genes are also upregulated in large FAH in the woodchuck,[51],[52] particularly in more dysplastic regions within the foci, again suggesting a connection between larger foci (nodules) and HCC. However, while elevated transcription of ILGF II has been observed in large FAH and cirrhotic nodules, as well as tumors in HCC patients, a link to viral DNA integration was not established. In rare instances, HBV DNA was found integrated near a host oncogene in the HCC, for example, cyclin A and retinoic acid receptor b;[60],[61],[62],[63] but in the remaining tumors, sequencing of cellular DNA flanking intergration sites has not been informative. Most of these studies were carried out prior to the human genome project. It remains to be seen whether placement of integration sites on the genome would be informative. This is possible since integration of woodchuck hepatitis virus DNA in the win locus is believed to activate Nmyc2 transcription from a distance of 150-180 kb.[59] It has also been suggested that HBV DNA integration in HCCs may be located within nuclear matrix attachment regions,[64] which could alter transcription over long stretches of DNA.

Finally, there is the question of whether HBV proteins are able to transform hepatocytes. Transgenic mouse models have been used to show that the HBV X gene product, when overexpressed in the liver, can transform hepatocytes[65],[66] or contribute to hepatocyte transformation. However, in view of the slow progression to HCC, interpretation of these observations remains controversial.

In view of the fact that not all carriers develop HCC, there is the question of whether those that do have a genetic predisposition. While the idea seems plausible, evidence is still lacking. Aflatoxin exposure in HBV carriers is believed to increase the risk of HCC, and some studies have looked at genes involved in aflatoxin detoxification as possible risk factors. In general, these studies have been controversial. A recent study identified a polymorphism in the epoxide hydrolase family 2 locus as a risk factor (odds ratio ~ 2) in a population that was likely to have been exposed to aflatoxin. It will be important to see if such correlations are sustained in follow-up studies.

In summary, HCC probably arises due to mutations caused by persistent inflammation and by carcinogens in the food supply. However, the ultimate emergence of the tumor is probably the result of an elevated rate of cell turnover due to CTL killing of infected hepatocytes and their replacement by other hepatocytes, some of which carry mutations. Proliferation and clonal expansion of mutant hepatocytes may also be aided by selection for cells that are poor virus producers and therefore poor targets for antiviral CTLs. Aside from P53, which is mutated in about 50% of HCCs, perhaps due to the mutagenic effect of aflatoxin, no obvious candidate oncogene has been identified that might be a target for therapeutic intervention.


   Treatment of HBV-related hepatocellular carcinoma Top


Prognostic staging in liver cancer

Treatment outcome and prognosis of hepatocellular carcinoma (HCC) depend on the stage of the tumor and the patient's preserved hepatic function. Clinical staging systems have incorporated four conditions generally recognized as prognostic determinants in HCC: severity of underlying liver disease, size and number of tumor(s), local extent of the tumor and presence of metastases.[67]

Many staging systems are currently used including: Okuda, Cancer of the Liver Italian Program (CLIP), modified TNM [T = tumor extent, N = spread to lymph nodes, M = extrahepatic metastases], Barcelona Clinic Liver Cancer (BCLC), and the Japanese Integrated Staging system (JIS). Each of these staging systems has advantages and deficiencies. Some, like BCLC and JIS, combine features of other systems.[68],[69] The BCLC system also provides a complex algorithm for HCC therapy by linking each disease stage to a specific treatment strategy. For patients undergoing liver transplantation, the American Liver Tumor Study Group-modified TNM system showed enhanced prognostic prediction and transplant selection by incorporating the Milan criteria, which will be discussed further below.[70] Only three systems, CLIP, BCLC and JIS have been validated. Widely used in Japan, JIS needs further validation in western countries. For an in-depth discussion on these systems and their relative clinical performance, see Marrero et al .[71]

The importance of staging systems is that they not only select candidates for appropriate therapies, but also identify patients for whom only supportive care would be appropriate because of poor life expectancy. Since they are essential in both the study design and comparison of results of therapeutic trials, we urgently need to reach a consensus in prognostic staging for HCC.

Treatment options for hepatocellular carcinoma

For patients with early HCC and adequate hepatic function, there are three potentially curative options: orthotopic liver transplantation (OLT), partial hepatectomy, or local ablative therapies. The use of any of these therapies varies greatly according to the geography because of availability of resources, technical expertise and cost: 50-70% of cases in Japan, 25-40% in Europe and the United States, 10-20% in India, and less than 10% of cases in Africa. There are no randomized controlled trials comparing these therapies. The choice between them for patients with suitable stage depends on the patient's overall performance status and the resources and technical expertise available. Unfortunately, most patients with HCC present with advanced tumor stage and hepatic decompensation and should receive supportive care only. Chemotherapy and radiotherapy have limited efficacy.

Generally, there are no significant differences in therapeutic approach for HBV-related and non-HBV-related HCC. However, when liver transplantation or surgical resection is a therapeutic option, vigorous suppression of HBV viremia must be administered before and after these interventions to improve survival and reduce graft loss. In the following sections, we address therapies for HCC in decreasing order of curative potential.

Treatment for early-stage hepatocellular carcinoma

Orthotopic liver transplantation

In developed countries, OLT has increasingly become the treatment of choice for patients with early-stage HCC. It not only offers a potential cure for the disease, but also eliminates the risk of recurrence in the diseased liver and complications associated with cirrhosis.

The Milan criteria

In 1996, Mazzaferro et al[72] established the Milan criteria for transplantation. Transplant candidates must have a single tumor 5 cm or no more than 3 tumors, each 3 cm, on preoperative imaging studies. Selection of patients using these criteria yielded a 5-year survival rate of 75% and recurrence-free survival rates of 83-92%, which is similar to the expected post-transplant survival of non-HCC cases. These findings were reproduced by other centers.[73],[74] The Milan criteria have been widely adopted as the cornerstone of pre-transplant evaluation and officially incorporated into United Network of Organ Sharing (UNOS) policy in the United States.

Downstaging is the attempt to reduce tumor sizes outside the Milan criteria, by applying transarterial chemo-embolization (TACE) or other ablative modalities, to make patients suitable for OLT or to maintain their candidacy while on the waiting list. Although patients who had their tumors downstaged had somewhat better survival than those who did not,[75] pre-transplant adjuvant therapy does not modify HCC biology or its natural behavior sufficiently to improve outcome significantly.[76]

Waiting time for organs and the MELD system

In 1998, the United States Department of Health and Human Services required that waiting time be minimized and organ allocation based on medical urgency. For HCC patients on the transplant waiting list, the shortage of organs and consequent prolonged waiting time decreased overall survival rate as their disease progressed. The 2-year survival rate decreased from 84% to 54% when mean waiting time increased from 62 to 162 days.[77] The MELD score is based on prothrombin time (standardized to an international ratio, INR), bilirubin, and creatinine, and accurately predicts 3-month mortality of HCC patients on the waiting list.

The transplantation survival advantage

Analysis of outcomes of OLT of 985 HCC patients in the UNOS database, 1987-2001, showed that the five-year survival rates improved from 25% in the earliest to 61% in the latest 5-year time period, even though waiting time increased from 37 to 215 days.[78] This was still lower than the 71% 5-year survival of 30,000 patients transplanted for non-malignant diseases.

Although no randomized controlled trials have compared OLT to surgical resection or ablative therapies, one study of 533 patients with cirrhosis and HCC, stratified by OLT, surgical resection, TACE, percutaneous ethanol injection (PEI) or no therapy showed a survival advantage for OLT patients with a single tumor < 5 cm. Five-year survivals were 68% for OLT versus 44% for resection, 36% for PEI, and 22% for TACE.[79]

Living donor transplantation

Before the implementation of the MELD system for organ allocation, the use of adult-to-adult living donor transplantation (LDT) had risen steadily. In LDT, the right lobe or 60% of the donor liver is removed, and both separated liver portions usually grow to > 85% of the original volume within several months. After a few donor deaths and adoption of MELD, the demand for LDT has declined. Ethical issues related to LDT remain unresolved.

Need for biopsy-proven diagnosis of HCC

Current management guidelines for HCC do not require biopsy to confirm the diagnosis, provided that there is one imaging study showing a focal liver lesion greater than 2 cm in size with features of arterial hyper-vascularization and a serum a-fetoprotein level of greater than 400 ng/mL.[70] However, in general, guided biopsy of suspicious liver lesions is strongly recommended.

Special issues related to HBV-related HCC

Patients with hepatitis B-related HCC tend to be younger and have better hepatic functional reserve compared to those with HCV. Despite having better-differentiated tumors with less aggressive biology, and less vascular invasion, patients with HBV-related HCC treated with OLT had similar overall and disease-free survival compared to those with HCV.[80]

Other series reported poorer outcomes after OLT for HCC in HBV patients compared to Roayaie et al .[80],[81],[82] Reinfection of the graft rather than tumor recurrence was responsible for the high mortality in these studies. Mazzaferro et al[83] suggested that vigorous suppression of viremia with antiviral drugs prior to transplantation could result in an infection-free graft and enhanced disease-free survival in HBV patients with HCC. Currently, the combination of low-dose HBIG and lamivudine is the most effective prophylaxis to maintain viral suppression post-transplant.[84],[85] Studies with more potent HBV suppressors like adefovir and entecavir are underway.

Surgical resection

Persistent organ shortage, lack of resources and technical expertise, and certain cultural or religious beliefs have limited use of OLT. Surgical resection offers the next best hope for cure or long-term survival. In addition to adequate functional hepatic reserve, which plays an even more prominent role in surgical resection than in transplantation, intrahepatic location of the tumor and lack of vascular involvement determine resectability. According to the modified TNM staging system, tumors of stage IIIB or above (tumor nodules in both lobes, major vascular invasion, tumor extension to nearby organs, nodal and distant metastases) are unresectable. Only 15-30% of newly diagnosed cases are potentially resectable.[86]

Resected patients who met the Milan criteria with tumors < 5 cm had significantly higher overall survival rates at 3 and 5 years when compared to those with larger tumors (76% vs 50% and 58% vs 39% respectively).[87] Other series had lower 5-year survival rates. Philosophe et al[88] showed that recurrent HCC after resection accounted for 86% of deaths, whereas recurrent HBV infection was responsible for 42% of deaths after OLT. Predictors of poor survival were vascular invasion, advanced liver disease, multiple tumor nodules, high alpha-fetoprotein levels and positive histological margins.

Modifications in surgical techniques and tumor downstaging are often used to enlarge the pool of surgical candidates. In non-cirrhotic patients, up to two-thirds of functional hepatic parenchyma can be safely removed whereas in cirrhotic patients, less than one-fourth can be removed. Preoperative portal vein embolization (PVE) induces selective hypertrophy of the uninvolved portion of the liver and helps maintain adequate hepatic function post-resection in many otherwise unsuitable candidates.[89]

Postoperative adjuvant therapy in HCC is still a developing field. Systemic chemotherapy offered no improvement in overall or disease-free survival. Cirrhotic patients had a higher mortality rate with chemotherapy probably due to advanced liver disease.[90] Local radiotherapy with intra-arterial I(131) lipiodol,[91],[92] and polyprenoic acid[33] (see chemoprevention section), have been reported to decrease tumor recurrence and to increase disease-free and overall survival.

Treatment for unresectable hepatocellular carcinoma

Local ablative therapies

Percutaneous ethanol injection (PEI): Injection of 95% ethanol into the middle of a tumor nodule causes cell dehydration and subsequent tumor necrosis and shrinkage. Ethanol also induces thrombosis of tumor microvasculature leading to tissue ischemia. Local recurrence rates have been reported as high as 40% in tumors up to 3 cm diameter. Ideal candidates for PEI are patients with poor hepatic function (Child-Pugh class C) and early-stage HCC, preferably solitary tumors < 2 cm in diameter. PEI is contraindicated in patients with extrahepatic disease, portal vein thrombosis, severe coagulopathy or decompensated liver disease. Many patients require multiple sessions. One- and 3-year survival rates range from 73 to 98 and 42 to 79%, respectively, depending on Child-Pugh classification and tumor size.[93],[94]

Radiofrequency ablation (RFA): RFA delivers thermal energy to the tumor with a high frequency alternating current at the tip of an electrode. It causes cell death and tissue necrosis at temperatures over 60 degrees Celsius. Introduction of the electrode can be done percutaneously, laparoscopically or by laparotomy. Tumors >3 cm in size often require more than one deployment of the needle electrode. Ideally, the thermal zone should include the tumor and a 1 cm perimeter of uninvolved liver tissue.

Good candidates for RFA include cirrhotic patients with Child-Pugh class A or B, tumor size up to 6 cm, no evidence of extrahepatic disease, and tumor not near the liver capsule, stomach, and small or large intestines. Although it is generally well tolerated, potentially fatal complications have occurred including liver failure, intestinal perforation, portal vein thrombosis, liver abscess, biliary fistula, pneumothorax, hypoxia, acute renal failure and needle tract tumor seeding.[95] The benefit of RFA decreases with increasing tumor size, although in one series, complete or nearly complete ablation was noted in 79% of tumors from 3 cm to 9.5 cm in size.[96]

RFA is more effective than PEI. Fewer treatment sessions were required for RFA (1.2 vs 4.8) and RFA yielded better local recurrence-free survival at 1 and 2 years (98% vs 83%; 96% vs 62% respectively).[97],[98]

Cryoablation: Cryoablation uses a cryoprobe intra-operatively to cool tissues below 35oC, causing irreversible cell death by dehydration, rupture, and destruction of small vessels by hypoxia. This technique can be used in tumors > 5 cm in diameter. Exclusion criteria include extrahepatic disease and inability to undergo general anesthesia or laparotomy. Complications comprising hypothermia-associated coagulopathy, cardiac arrhythmias, biliary fistula, abscess, metabolic derangement and acute renal failure led to a procedure-related mortality of 4%.[99] Several trials have shown acceptable 3- and 5-year survival rates of 52% and 40% respectively.[100],[101]

Transarterial chemoembolization (TACE)

TACE involves injection of a chemotherapeutic agent, followed by an occlusion procedure using materials such as gelatin sponge, lipiodol or glass microspheres. Since the majority of the blood supply to HCC is derived from the hepatic artery, embolization of the involved branches of this artery results in better retention of chemotherapy inside the tumor and enhanced tumor destruction. No optimal regimen of chemotherapy and embolic materials has been established.

TACE has been effectively used as a primary treatment for large (>10 cm) unresectable HCC and as downstaging treatment for OLT and surgical resection. Contraindications to TACE include portal vein thrombosis, tumor burden > 50% of parenchyma, biliary obstruction, decompensated liver disease, severe coagulopathy and concomitant cardiac or renal disease. A meta-analysis of seven randomized controlled trials using TACE for unresectable HCC showed significant efficacy in improving 2-year survival;[102] two out of five large randomized clinical trials demonstrated survival benefits at 1 and 3 years.[103],[104] Chemoembolization was significantly better than embolization alone.[104]

The usefulness of TACE must be weighed against the risks of progressive (20%) and irreversible (3%) liver failure following treatment. TACE often causes a post-embolization syndrome consisting of abdominal pain, fever, nausea and elevated transaminases, and more rarely, pleural effusion and ischemic cholecystitis.[105]

Radiation therapy

HCC is a radiosensitive tumor, but it is located in an even more radiosensitive liver. Thus, radiotherapy requires special methods for targeting tumors and shielding normal tissues from damage. In one study, proton beam therapy for unresectable HCC was well tolerated and caused substantial tumor destruction.[106] Patients who had the least hepatic dysfunction and solitary tumors had a 5-year survival rate of 53.5%. Complications included worsening liver function and gastroduodenal ulcerations.

Selective internal radiation (SIR) delivers radiation locally by using radioactive isotopes I131 or Yttrium-90 (Y90), attached to delivery vehicles such as lipiodol (see above) or glass microspheres. Sirspheres are biocompatible, non-biodegradable radioactive microspheres of 20-40 m in diameter that contain Y90. Selective infusion of radioactive spheres into large, unresectable liver tumors induces measurable tumor responses in the majority of cases.[107] Longer follow-up and randomized controlled trials comparing sirspheres with other non-surgical therapies are needed to assess efficacy.

Combination therapies

The combination of PEI and TACE offered better local tumor control, but no survival advantage, when compared to PEI alone.[108] The combination of TACE followed by external radiation therapy showed acceptable, if not better, survival rates in patients with large HCC (mean tumor size 9 cm),[109] and was particularly effective for patients with portal vein tumor thrombosis.[110] In general, in patients with adequate hepatic function but heavy tumor burden, successive use of several non-surgical techniques is a reasonable approach.

Systemic chemotherapy

HCC is relatively resistant to systemic chemotherapy because the tumor often expresses drug resistance genes like glutathione-S-transferase, p-glycoprotein, dihydropyrimidine dehydrogenase and heat shock proteins, and frequently contains mutations in p53.[111],[112] The severity of the underlying liver disease often limits dosage and hence, efficacy of chemotherapy. Doxorubicin, 5-fluorouracil and leucovorin, capecitabine have acceptable toxicity and modest response rates (20-28%) in patients with advanced HCC.[113],[114],[115],[116] Combination chemotherapy regimens, e.g., doxorubicin and 5-FU, doxorubicin and cisplatin, gemcitabine and cisplatin have shown inconsistent responses and no survival advantage.[117],[118] New chemotherapeutic agents targeting several critical pathways responsible for liver carcinogenesis are being developed and tested in clinical trials. These include tyrosine kinase inhibitors and anti-angiogenic agents.[119],[120],[121],[122] As there is no clearly superior regimen, enrollment in clinical trials of patients with systemic disease should be strongly encouraged.


   Conclusions Top


Worldwide, chronic hepatitis B remains the most common cause of HCC. The mechanisms by which HCC develops in a liver that is chronically infected with HBV are gradually being unraveled, but much remains to be learned. In most of the high incidence countries of the world, the great majority of patients with HCC present with advanced disease for which available therapies are of limited benefit. If however, all countries of the world adopted and vigorously enforced universal hepatitis B vaccination of all newborns, HBV related HCC would become a minor problem for the future generations.

 
   References Top

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120.Schiffer E, Housset C, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C, et al . Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 2005;41:307-14.  Back to cited text no. 120    
121.Ramadori G, Fuzesi L, Grabbe E, Pieler T, Armbrust T. Successful treatment of hepatocellular carcinoma with the tyrosine kinase inhibitor imatinib in a patient with liver cirrhosis. Anticancer Drugs 2004;15:405-9.  Back to cited text no. 121    
122.Patt YZ, Hassan MM, Lozano RD, Nooka AK, Schnirer II, Zeldis JB, et al . Thalidomide in the treatment of patients with hepatocellular carcinoma: A phase II trial. Cancer 2005;103:749-55.  Back to cited text no. 122    

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Correspondence Address:
W Thomas London
Fox Chase Cancer Center, 333 Cottman Avenue Philadelphia, PA 19111
USA
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    Introduction
    Prevention of HCC
    Pathogenesis of HCC
    Treatment of HBV...
    Conclusions
    References

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