Aasld Single–Topic Research Conference on Hepatocellular Carcinoma: Conference Proceedings

The goal of the American Association for the Study of Liver Disease (AASLD) single-topic conference on hepatocellular carcinoma (HCC) was to highlight areas of research necessary to further our understanding of the pathogenesis and management of this disease. Three major areas in which the necessity of extensive further research was identified include screening for HCC, staging of disease, and management, particularly studies on liver transplantation. The need for better disease models for decision analysis and better diagnostic methods was noted. For screening, better serological screening tests will be required, and, difficult though it may be, a randomized controlled study comparing screening with no screening is still a necessary study. Current staging systems are insufficiently validated and are not comparable in different areas of the world. A universal staging system is essential and would require international collaboration for it to be established. In the therapeutic area, studies are needed to improve identification of patients suitable for transplantation, and to improve management on the waiting list. Properly conducted phase 3 studies are required to establish the role of current improperly evaluated therapies. Newer agents should also be subject to randomized controlled trials. Finally, although progress is being made in the understanding of the pathogenesis of HCC, the sequential molecular changes in hepatocarcinogenesis remain obscure. Genomics and proteomic studies are likely to yield significant insights. The American Association for the Study of Liver Diseases sponsored a Single Topic Research Conference on Hepatocellular Carcinoma, which was held in Atlanta in September 2003. Topics were selected for presentation that reflected controversy, required additional research, or subjects that were currently under active research. The objective of this conference was to identify deficiencies in our knowledge of the pathogenesis, diagnosis, and management of hepatocellular carcinoma (HCC) and to identify areas of research and suggest study designs to explore these deficiencies in our knowledge. This document summarizes the information that was presented and the discussions that followed. HCC, hepatocellular carcinoma; CT, computed tomography; AFP, alpha-fetoprotein; MRI. Magnetic resonance imaging. A number of staging and prognostic scoring systems have been recently reported.1-5 Most cancer scoring systems and prognostic indices are developed by retrospectively identifying variables correlating with prognosis, using either chi-square or univariate analysis techniques. Whether these variables are independent of each other is then determined by multivariate analysis (usually using the Cox proportional hazards model). The independent variables are combined into a score. Kaplan-Meier survival curves are constructed for each variable and combinations of variables and the log rank test applied to show whether the curves are statistically different. Thus, the scores are combined into a staging system. The Barcelona Cancer of the Liver Clinics (BCLC) system1 started by classifying patients according to markers of disease severity previously used to determine the type of therapy to be applied. The Child-Turcotte-Pugh score was also incorporated into the BCLC staging. Other scores were developed using traditional methodology. The Cancer of the Liver Italian Program (CLIP)2 score incorporated the Child-Turcotte-Pugh Score, and the Chinese University Prognostic Index4 incorporated the standard TNM (tumor, node, metastasis) classification. None of these staging systems were felt to be ideal. Each system incorporates features of earlier prognostic scores, either the Child-Turcotte-Pugh score or the TNM score. The validity of using the Child-Turcotte-Pugh score for patients with HCC has never been established, and the TNM score does not include prognostic variables related to liver disease. The CLIP score does not differentiate tumor size until the tumor occupies 50% of the liver. In other systems, tumor size is important, although the diameter at which tumor size starts to make a difference to survival is uncertain. Only the CLIP score has had any external validation. However, not all reports find the CLIP score adequately predictive.4 A consensus panel struck by the American Hepatopancreaticobiliary Association (AHPBA) and the American Joint Committee on Cancer (AJCC) recommended that the CLIP system be applied initially. Patients who underwent resection (including transplantation) should undergo a secondary classification using either the AJCC or the international Hepatopancreaticobiliary Association (IHPBA) classification.6 The AHPBA/AJCC group also recommended that all future reports on diagnosis, therapy, and prognosis should stratify patients by at least one prognostic score. The participants in the workshop on HCC staging indicated that all current staging systems need refinement, and that none were sufficiently validated or widely applicable. In particular, a need exists to accurately stage small HCC. This should be achieved by international collaboration to prospectively validate one or more of the current staging systems, or to develop a new system that is representative of all the different risk factor groups across the world. Any system that claims to indicate prognosis must be based on a large clinical database, and may include laboratory data and radiology. The system must undergo extensive internal and external validation and must be generally applicable to HCC with different underlying etiologies. Finally, the staging system must eventually be a guide to therapy. Two types of models are in common use. Statistical models (e.g., Cox proportional hazards model) are used to determine how well an outcome correlates with explanatory variables. Decision analysis models (e.g., Markov model) are used to answer questions about the relationship between disease outcome and a number of different disease stages. The Cox proportional hazards model is the most appropriate statistical technique to model the natural history of disease. Cox models are used to identify factors either associated with, or predictive of, a disease. This is a form of regression analysis. A Markov model attempts to define health states found in the natural history of the disease (e.g., hepatocellular carcinoma) and to determine the probability of transitioning between the different health states. The model is used to determine how changes in transition probabilities might impact overall outcome (e.g., survival or mortality rates). Markov modeling has been used to evaluate several HCC-related questions, including the cost–utility of screening policies in patients with cirrhosis,7, 8 the value of partial hepatectomy or liver transplantation for early HCC,9 the value of liver resection and salvage transplantation for early HCC,10 and issues around living donor transplantation for HCC.11, 12 Decision analysis is useful for providing estimates where experimentation is lacking, or where experimentation is not feasible. For example, decision analysis has identified circumstances in which screening for HCC might be an effective strategy to reduce mortality from this disease.7, 8 However, the models are highly dependent on the quality of data used to populate the model, and on the basic assumptions about natural history. Markov modeling is commonly used in assessment of the efficacy of interventions (e.g., interferon therapy for hepatitis C). To date, no studies directly assess the question of whether HCC screening decreases the gold standard of disease-specific or all-cause mortality. The population that needs to undergo screening has only been defined in outline, namely, patients with cirrhosis, and among patients without cirrhosis, those with chronic hepatitis B. The European Association for Study of the Liver (EASL) consensus conference on HCC recommended that patients with hepatitis C and stage 3 fibrosis also undergo screening.13 The risk of HCC is not high, but screening is recommended because the transition to cirrhosis cannot be defined without repeated liver biopsies. The efficacy and cost-efficacy of this recommendation have not been determined. Studies are needed to better identify the at-risk population. These studies should define overall HCC incidence in specific groups and subgroups of the at-risk population (e.g., men vs. women, or at different ages). They should also identify markers of imminent HCC risk (e.g., within 3 years vs. lifetime risk). Modeling techniques could then be used to determine whether screening was effective or cost-effective in the specific subgroups. Most of the information we have about the behavior of HCC comes from observation of clinically detected cancer. However, screening detects lesions before they become clinically active. It cannot be assumed that the cancer behaves in a similar manner in the two situations. The sensitivity and specificity of a diagnostic test changes with cancer stage,14 and thus they are also likely to be different in preclinical cancers. The sensitivity and specificity of diagnostic or screening tests cannot be considered reliable when the disease in question has not been verified, such as when the diagnosis of small HCC is made without biopsy. Second, the sensitivity and specificity of a screening test cannot be considered accurate when confirmation of the disease depends on the screening test itself (such as when computed tomography [CT] scan is used for both screening and diagnosis). Lack of consideration of these points bedevils reports of HCC screening. Validation of a test as a screening test requires several steps.15 First, the test has to be shown to be positive in patients with known disease. The optimal cutoff has to be determined by receiver operating characteristic (ROC) curve analysis, and is not the usual laboratory normal range. The sensitivity, specificity, and positive and negative predictive values have to be determined at the optimal value. Separate values for the optimal cutoff and sensitivity and specificity have to be determined for the test, initially when used diagnostically and then when used for screening. The test then has to be evaluated in a prospective fashion in a screening rather than a diagnostic study. Finally, a randomized controlled trial comparing the test with standard screening tests, or with no testing, has to be done.16 Alpha-fetoprotein (AFP) has been well studied as a diagnostic test. Its performance characteristics as a screening test also have been documented.16-19 However, the sensitivity, specificity, and positive predictive value are too low for general use as a screening test. Even as a diagnostic test, at the optimal performance cutoff point determined by ROC curve analysis, the sensitivity is only 60%.16 AFP exists as a family of glycosylated molecules that can be separated electrophoretically. The relative concentration of the L3 subfraction is elevated in some patients with HCC, even when the total AFP concentration is normal.20 Prospective studies are underway of AFP–L3/total AFP ratio as a screening test, but most prior studies have been in a diagnostic setting. These have found that this marker has a sensitivity and specificity between 15% to 57% and 80% to 100%, respectively. The tests may be positive several months before the diagnosis of HCC, suggesting that it might be a valuable screening test.21 However, data also indicate that a high AFP-L3 to total AFP ratio is also a marker of more aggressive disease.22 Ideally, screening tests should detect early disease. Screening tests that identify late disease are unlikely to lead to improvements in disease-specific mortality. Serum levels of des-gamma-carboxy-prothrombin are widely used in Japan as a screening test.23, 24 However, its performance characteristics have been defined mainly as a diagnostic test. No prospective studies of DGCP as a screening test exist. Some data suggest that this test is a marker of more advanced disease, namely portal vein invasion.25 The most recent potential screening test is the glypican-3 assay.26 This is a protein on the in HCC and not in normal liver. 50% of patients with HCC have levels of has not been evaluated in a screening but the that it is in early lesions that it may be a suitable at least in those patients in it is The most widely used screening test is improvements in including are under these are unlikely to be used for screening, because one of the of a screening test is that it should be to and should be widely does not this test. of small HCC has to be The major of is the to which the are dependent on the and of the to the and reduce the on the will make more The of the workshop on screening and for HCC although and a trial of screening for HCC would be for whether screening was effective by a randomized controlled trial of screening no screening. The group recommended that future studies of screening should to assess new screening tests as they In the of small a of should be Other issues the that currently no exists for the diagnosis of HCC in screening have used or diagnosis, or have used combined clinical and These have not been The the to evaluate an screening test and, in the of negative all studies to or the of HCC. issues in include the value of liver the sensitivity and specificity of and the identification of screening an the of a small HCC, the is a The the the more one can be about the However, when the is than other lesions such as small and and HCC on resonance has the although with other features may be HCC and are different on and the sensitivity and specificity of these features are not sufficiently high that they can be on in The single-topic conference on that lesions than should be by lesions are likely to be HCC. than can be on the of features of HCC in the of cirrhosis and not need additional For lesions between and was is for that lesions than in the clinical are HCC. 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In patients with cirrhosis, the for exists for patients who might not have although not randomized and not indicate that patients who undergo liver transplantation have a better survival than patients the for donor the from to transplantation has the of patients with HCC on the waiting list. 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The of research in liver transplantation for HCC should be to develop better modeling for of to patients with HCC no HCC. 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Two might of of or the In only interferon therapy in chronic hepatitis has been identified as HCC. In chronic hepatitis the that patients who have cirrhosis have a risk of although the of the risk is Whether patients without cirrhosis have a similar or risk is because such studies are to In hepatitis the data are too to determine whether interferon or therapy HCC other agents that might a have not been adequately randomized controlled studies can determine whether of chronic hepatitis will reduce cancer but these are difficult to In recent a number of in the pathogenesis of HCC have been The agents have been and some of the molecular changes that the hepatitis have been In study of a large number of and of the changes that in HCC have been However, the is as and all this the molecular that in HCC are not well in and have the potential to identify characteristics of HCC that may be related to prognosis or to and these may be useful in HCC screening or the is insufficiently advanced to be clinically The role of and in HCC research was in a The group that of and would such studies and were However, all studies using would have to be validated in prospective

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