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Clinical Developments in Hepatocellular Carcinoma
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Alex S. Befeler, MD
http://www.medscape.com
Introduction
Hepatocellular carcinoma (HCC) is usually diagnosed in the setting of chronic liver disease with cirrhosis and has been estimated to result in between 500,000 and 1,000,000 deaths per year.[1,2] In the West, HCC is becoming the first complication, and the most frequent cause of death, in patients with viral-associated cirrhosis.[3] The incidence and mortality associated with HCC, unlike most other cancers, are increasing in the United States.
In the United States, population-based studies show that the incidence of HCC increased 114% between 1975 and 1998.[4] Even more concerning is the finding that young patients, aged 45 to 55 years, are the fastest growing group.[4] The most recent estimates from the American Cancer Society predict that in 2004 there will be 18,920 new cases and 14,270 deaths from liver cancer in the United States.[5] An analysis of the Surveillance, Epidemiology, and End Results (SEER) database shows that hepatitis C virus (HCV) infection is a major contributor to the recent increase in the incidence and mortality due to HCC.[6] In the United States, it is estimated that 2.7 million persons are actively infected with HCV, and 186,000 of these individuals could develop HCC over the next 20 years.[1]
Median survival after diagnosis of HCC is less than 1 year. Survival is associated with a combination of tumor characteristics -- size and number of tumor lesions, vascular invasion, and the underlying hepatic function. In theory, orthotopic liver transplantation is an ideal therapy because it achieves the widest possible resection margins -- it removes the entire liver, which is at high risk of de novo tumor, and replaces the poorly functioning cirrhotic liver. If Milan criteria (no evidence of extrahepatic tumor and unifocal tumor mass < 5 cm in diameter or multifocal tumors up to 3 in number, each < 3 cm in diameter) are followed, survival post liver transplantation is comparable to other indications for liver transplant.[7] Unfortunately, only a small proportion of patients diagnosed with HCC in the United States are candidates for curative treatments such as liver transplantation or hepatic resection because of either tumor size or lack of hepatic reserve. Therefore, prevention of HCC or at least early detection that can enhance the chance for curative treatment may provide the best opportunity to reduce the predicted increases in mortality. These strategies depend on a better knowledge of the epidemiology and pathogenesis of HCC. New information presented during this year's meeting of the American Association for the Study of Liver Diseases (AASLD) may help achieve the goal of improved survival from HCC. This report focuses on the most important data presented during these meeting proceedings, as related to epidemiology, early detection markers, therapeutic intervention, and prevention of HCC.
Issues in Epidemiology
An understanding of the epidemiologic risk factors associated with HCC may allow the medical community to better target its limited resources to those individuals at highest risk for disease. Currently, hepatitis B- and C-related cirrhosis are believed to be the most important risk factors for this malignancy. This was confirmed by a preliminary report from the Liver Cancer Network, a new consortium of 8 centers across the United States that treat patients with HCC.[8] In addition, the network found that alcohol, often in combination with viral hepatitis, contributed almost 40% of the total number of patients with HCC. This study may have limited generalizability because it is not strictly population-based -- but it probably does capture the general type of patient who receives specific treatment for HCC.
Cryptogenic cirrhosis has been shown to be the cause of the underlying liver disease in up to 29% of US patients with HCC.[9] This consecutive case series suggested a strong association between diabetes mellitus, nonalcoholic steatohepatitis, and HCC, with half of patients with cryptogenic cirrhosis having diabetes mellitus. Specifically, Mohanty and colleagues[10] found that 18% of the cases of HCC in their single-center series were related to cryptogenic cirrhosis, and one third of these had evidence of nonalcoholic fatty liver disease. Davila and colleagues[11] analyzed a newly created population-based database that linked SEER data to Medicare data and showed that a diagnosis of diabetes mellitus conferred a 3-fold increased risk of developing HCC among individuals 65 years of age and older. Presence of hepatitis C and diabetes increased the risk for HCC 37 times, whereas hepatitis C alone increased the risk for development of HCC 24 times. Alcoholic liver disease had the highest risk, with an odds ratio of 70. This study is primarily limited by its investigation of only patients 65 years of age or older; thus, it may not be applicable to all patients with HCC. These studies all add to the growing evidence that cirrhosis associated with nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis, is a major risk factor for HCC.
Fattovich and colleagues[12] performed a systematic review of the literature to examine the risk factors for, as well as the incidence of, HCC. They found that cirrhosis conferred the highest risk -- 3- to 100-fold higher risk -- for HCC. The 5-year cumulative incidence of HCC in patients with cirrhosis was 17% for HCV, 21% for hereditary hemochromatosis, 10% for hepatitis B virus (HBV)-related cirrhosis, 8% for alcohol-related cirrhosis, and 4% for cirrhotics with primary biliary cirrhosis. Coinfection of HCV with HBV added a 2- to 6-fold increased risk, and alcohol abuse with viral-associated cirrhosis added a 2- to 4-fold increased risk of HCC.
Serum Markers and Screening for HCC
Screening and surveillance for HCC is commonly performed in patients with cirrhosis in the United States. Unfortunately, there remains considerable controversy regarding who to screen, what tests to use, and how often to use these tests. Alpha-fetoprotein (AFP) is commonly used as a marker in surveillance for HCC, but its utility for screening as opposed to diagnosis is limited. Therefore, new serum markers for early HCC detection need to be evaluated.
During this year's AASLD meeting, a group from New Zealand presented results of a study comparing the outcomes of chronic hepatitis B carriers with HCC who were identified in a new HCC screening program, using every-6-month AFP measurement and ultrasound exam.[13] They found marked improvements in identifying early-stage cancers that were treatable among this population with endemic HBV infection, as well as overall improved survival in the screened group compared with unscreened patients. Even with a 3-year lead time bias correction, screened patients had a superior outcome. The main criticism of this study is that it was not randomized and there was limited information about why patients were in the unscreened group.
Marrero and colleagues[14] assessed the utility of Des-gamma-carboxyprothrombin (DCP), GP-73, and AFP as markers for identifying patients with early-stage HCC. DCP is an abnormal prothrombin used in Asia as a marker for HCC, and GP-73 is a recently discovered golgi protein that is increased in cirrhosis and HCC. These investigators showed that DCP and GP-73 had superior positive and negative predictive values for early HCC compared with AFP. These findings suggest that these markers may eventually replace AFP as a screening study for HCC. However, results of a planned, multicenter trial of markers for early HCC and an easier assay for measuring serum GP-73 are needed before these tools can be adapted to clinical practice.
Although screening for HCC in high-risk cirrhotic patients is the de facto standard of care, what serum marker, if any, which imaging technique, and at what frequency to screen all remain to be determined. Clearly, a better understanding of the epidemiologic risk factors associated with HCC and identification of better serum markers for this malignancy are needed.
Staging for HCC
Disease staging in HCC should help the clinician decide on the appropriate treatment options as well as help predict patient survival. There are multiple competing staging systems for HCC, including tumor-based systems (American Joint Committee on Cancer [AJCC; used by oncologists and tumor registries] system, and the United Network for Organ Sharing [UNOS]-modified Tumor-Node-Metastasis [TNM] system [used for liver transplant allocation]), and combined tumor and liver function systems (Okuda, Cancer of the Liver Italian Program [CLIP; adapted by the American Hepatico-Pancreatico-Biliary Association] staging, Barcelona Liver Clinic [BCLC] classification, and others). During this year's meeting proceedings, several groups presented their analyses of the various staging systems.
The Liver Cancer Network, a US-based group, showed that UNOS-modified TNM staging performed better than the AJCC and CLIP classifications, both of which performed poorly.[8] The study authors also showed that candidacy for orthotopic liver transplantation and asymptomatic presentation were predictors of better survival. This study was criticized because of the short follow-up time and the large numbers of transplant patients (19%).
An Australian group[15] compared multiple different staging systems in nontransplant patients and concluded that CLIP was the most useful in predicting survival. These investigators were criticized because their sophisticated statistical testing failed to show any differences between the systems. An Italian group[16] compared the CLIP and BCLC systems and found that BCLC and Child-Pugh class were the only independent predictors of survival by multivariate Cox analysis. These conclusions are limited, however, because Child-Pugh class is already contained in both the CLIP and BCLC classifications, and thus, assumptions of the Cox model may be violated.
As can be gleaned from these studies, the controversy regarding staging in HCC continues, and perhaps application of 1 system for all types of patients may not be possible.
Liver Transplantation
There continues to be new information offered regarding the relationship between liver transplantation and HCC. For those patients who meet Milan criteria, orthotopic liver transplantation is recognized as the most effective treatment for HCC. Because it has been previously shown that many patients with HCC placed on the waiting list for liver transplantation can have progressive disease, fail to meet Milan criteria, and thus, become "untransplantable," efforts were made to change organ allocation policy in the United States.
Changes in MELD Allocation Policy
During this year's AASLD postgraduate course, Dr. Wiesner[17] reviewed the recent history of liver transplant organ allocation policies as they relate to HCC. In February of 2002, allocation of organs for orthotopic liver transplantation in the United States changed to the MELD (Model for End-Stage Liver Disease) system and granted special exception points to patients with HCC. T1 lesions (solitary HCC < 2 cm) received 24 MELD points, which is equivalent to a 15% 3-month waitlist mortality, and T2 (solitary lesion 2-5 cm or 2 to 3 lesions each < 3 cm) received 29 MELD points, equivalent to a 30% 3-month mortality. The end result was that HCC became a major indication for orthotopic liver transplantation, representing 22% of all adult deceased donor liver transplants. This system may have "overfavored" HCC patients because < 7% of potential candidates with HCC were removed from the waiting list for tumor progression or other causes. A review of the explant pathology reports from this first period of MELD transplant allocation showed that at least 23% of the patients transplanted for HCC had no evidence of HCC on further evaluation, including 31% of all patients with a T1 lesion. Additionally, during this period, removal from the transplant waiting list due to a patient becoming too sick, dying, or developing an advanced HCC for those wait-listed with T1 tumors was only 4%. Subsequently, UNOS changed organ allocation policy, with patients with T1 lesions receiving 20 points and those with T2 lesions receiving 24 points. HCC now represents about 14% of all adult orthotopic liver transplantations in the United States.
Sharma and colleagues[18] assessed the impact of the reduction in the MELD exception points (ie, priority MELD score) for HCC. These investigators showed that there were no differences in 12-month dropout rate on the transplant waiting list, no differences in survival while waiting for orthotopic liver transplantation, and no differences in postorthotopic liver transplant survival. Thus, reducing MELD score for HCC candidates did not adversely affect patient outcomes. More recently, exception points were eliminated for all patients with T1 lesions because their short-term survival is good. Continued assessment and refinement of this allocation policy is ongoing, and, clearly, the changes are far superior to the former scoring period.
Expansion of Conventional Criteria of Liver Transplantation for HCC
In 2001, Yao and colleagues[19] proposed that the Milan criteria could potentially be expanded (for determining eligibility for liver transplantation in patients with HCC) to either a unifocal tumor mass < 6.5 cm in diameter or multifocal tumors < 4 in number, each < 4.5 cm in diameter with total tumor diameter < 8 cm (now designated T3A), and demonstrated a 75% 5-year survival. Their proposal is often criticized because it was based on tumor size and number identified by review of transplant explants rather than what is clinically available -- the preoperative radiologic evaluation.
During this year's AASLD meeting, Yao and colleagues[20] presented their results of a new analysis comparing the outcomes after transplant of 17 T3A patients vs 53 T1 and T2 patients, all staged by radiologic evaluation before transplant. These investigators found similar 3-year survival between the groups. Understaging at radiologic evaluation to beyond T3A criteria occurred in 17% of T1 and T2 patients, and in 35% of T3A patients, but 23% of T3A-staged patients were overstaged and had only T2 on pathology.
A French group also assessed expanded Milan criteria for orthotopic liver transplantation in patients with HCC and confirmed Yao and colleagues' original study findings showing good 5-year survival based on tumor explant data.[21] These study authors also evaluated 44 patients who exceeded Milan criteria but were within expanded criteria, and compared them with 272 patients meeting Milan criteria -- all based on preoperative radiologic evaluation. They found a worse outcome in the expanded patients (48% 5-year survival). This study could be criticized because it included patients from the mid 1980s when imaging was inferior and more likely to improperly stage patients.
Overall, these studies provide evidence that a large multicenter trial should be conducted to determine whether a modest expansion in tumor size limits may be possible, but cautions that many patients will be under- and overstaged by radiology.
Liver Transplantation in Cirrhotic Patients With a History of Resection for HCC
Because of the organ donor shortage, many clinicians have suggested that orthotopic liver transplantation cannot be advocated as the primary modality for treatment of HCC without overwhelming the transplant system. During last year's AASLD meeting, a group from Clichy, France, presented a study examining outcomes among patients who had undergone hepatic resection for HCC prior to liver transplantation for HCC.[22] They found no differences in survival between the patients with prior resection and those without, after a median follow-up period of 32 months. Although these findings suggest that resection with salvage orthotopic liver transplantation for disease recurrence can be an effective strategy, the study was severely limited by their not presenting data regarding the number of patients who did not reach transplant as a result of the resection.
This year, the same group of investigators assessed 47 patients with HCV-associated HCC who fit Milan criteria and underwent resection.[23] They found that 5-year survival was low at 49% compared with an expected survival of 74% with orthotopic liver transplantation. Additionally, 61% of the tumor recurrences were outside of Milan criteria at presentation and prevented "rescue orthotopic liver transplantation." Thus, these study authors suggested that using resection as a bridge to transplant is a better strategy than resection with salvage transplant. What they really have shown is that salvage transplantation after resection is rarely possible, but they have no reason to conclude that surgery is a better bridge to transplantation than local ablative therapies.
Practice Patterns
A group from Loyola University performed a survey of Midwestern community gastroenterologists and oncologists regarding their practice patterns for HCC and showed that gastroenterologists were more likely to refer patients for orthotopic liver transplantation for early-stage HCC.[24] Oncologists generated more referrals for surgical resection and gave more chemotherapy to early-stage patients.
This finding is concerning because liver transplantation is clearly the most effective treatment for early HCC, and chemotherapy has little role in these patients.
Systemic Chemotherapy
Systemic chemotherapy is sometimes used as palliation for patients with HCC not amenable to surgery or local therapies. Success is variable and often limited by underlying cirrhosis. No agent is accepted as the standard of care. New less toxic agents are actively being investigated. It warrants mention that there were several small phase 1/2 chemotherapy studies presented during this year's meeting, but no findings were particularly striking clinically, and there were no reports from ongoing phase 3 studies.
Issues in Prevention
Given the limited availability of treatment options for patients with HCC, and the poor overall survival, prevention offers the best opportunity to change outcomes. Hepatitis B vaccination and eradication of HCV infection with interferon-based regimens before the onset of advanced fibrosis are the only currently available means of preventing HCC.
Lamivudine Therapy
During last year's AASLD meeting, Liaw and colleagues[25] showed that patients with hepatitis B-associated cirrhosis treated with the nucleoside analogue lamivudine had a significant reduction in the rate of HCC development (hazard ratio = 0.49). These investigators also showed dramatic reduction in the progression to decompensated liver disease.
During this year's meeting proceedings, an Italian group presented 4-year follow-up data on 84 cirrhotic patients with precore mutant hepatitis B who were treated with lamivudine.[26] These study authors found a marked decrease in clinical decompensation of liver disease (24% vs 0%), but no differences in HCC rates (27% vs 30%) among lamivudine-resistant vs responder patients. This study differed from the study conducted by Liaw and colleagues in that it included only precore mutant hepatitis B patients, Western (vs Asian) patients, and had a much higher baseline risk of HCC. Both studies, however, showed that for patients receiving nucleoside treatment for HBV infection, there is no difference in the rates of HCC for those with (immune elimination) escape mutants and those without. We probably will not have another large study to address the issue of whether nucleoside analogues prevent HCC in cirrhotic patients because randomization to placebo is unethical given the proven reduction in liver decompensation.
Interferon-Based Treatment
There have been many retrospective studies suggesting that interferon may prevent HCC in patients with chronic hepatitis. An interim analysis from the COPILOT (Colchicine vs Peg-Intron Long-Term) trial, a randomized trial comparing colchicine* with 0.5 mcg/kg/week subcutaneous pegylated interferon alfa-2b* for treatment of patients with HCV and advanced fibrosis, showed about a 50% reduction in a combined end point of death, orthotopic liver transplantation, rise in Child-Pugh class, and variceal bleeding for the interferon-treated group.[27] Disappointingly, there were no differences in the 2% annual risk of HCC between the 2 groups. Many of the patients in both treatment groups had received multiple courses of interferon before entry into the trial, which may dilute out the potential benefits of interferon-based therapy for HCC. We eagerly await the final results from the COPILOT trial and 2 other trials of long-term low-dose interferon, HALT-C (Hepatitis C Long-term Treatment against Cirrhosis) and EPIC (Early viral response with Peg-intron/rebetol weight-based dosing in previous Interferon/ribavirin HCV treatment failures), to address the question of whether interferon-based therapy can prevent HCC.
Role of Genetics
A better understanding of the pathogenesis underlying HCC may enable more directed chemoprevention strategies. Although there are several animal models that have been used to study the multistep genetic and cellular processes leading to HCC, the quality of these models and their relationship to human HCC are limited.
A group from the National Cancer Institute compared global gene expression profiles of HCC among mouse models and human HCC.[28] They were able to show that certain mouse models had similar expression profiles to human HCC expression clustering. Having a good mouse model of HCC will enable a better understanding of the pathogenesis underlying this malignancy and permit testing of potential chemopreventive agents. There were several presentations during these meeting proceedings that evaluated single nucleotide polymorphisms that may be linked to fibrosis progression and HCC. In the future, this class of studies may help identify those patients with an increased genetic risk for developing HCC so that screening and prevention strategies can be better directed.
Concluding Remarks
Viral hepatitis and alcoholism associated with cirrhosis remain the major risk factors for HCC. Diabetes mellitus and the associated fatty liver disease may be a new risk factor for development of this cancer that is particularly worrisome, given the current epidemic of obesity and type-2 diabetes in the United States. New and better serum markers for HCC appear to be on the horizon. Liver transplantation is the major mode of curative treatment for HCC in the United States. Recent changes in organ allocation policies for HCC have led to more timely transplants, lower dropout rates, and continuing improvement in allocation policies. New developments indicate that the size of acceptable tumors may also be able to be modestly expanded. There were no new developments in local ablative, regional, and systemic chemotherapy presented during this year's meeting. Thus, prevention and early diagnosis of HCC remain attractive, if difficult, goals to achieve. Clues from epidemiology, understanding hepatocarcinogenesis, and effective treatments for viral hepatitis will lead the way to effective strategies in the setting of HCC.
*The US Food and Drug Administration has not approved this medication for this use.
Supported by an independent educational grant from Gilead.
References
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