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 expressed on the cell surface in HCC and not in normal liver. Approximately 50% of patients with HCC have detectable levels of circulating glypican-3.26 Glypican-3 has not been evaluated in a screening mode, but the fact that it is expressed in early lesions suggests that it may be a suitable marker, at least in those patients in whom it is positive. The most widely used screening test is periodic ultrasonography. Although improvements in ultrasonographic techniques, including contrast-enhanced ultrasound, are under development, these are unlikely to be used for screening, because one of the requirements of a screening test is that it should be simple to administer and should be widely available. Contrast-enhanced ultrasound does not meet this test. Clearly, however, ultrasound detection of small HCC has to be improved. The major weakness of ultrasound is the extent to which the findings are dependent on the care and skill of the operator. Methods to automate the examination and reduce the dependency on the operator will make ultrasound more reliable. The members of the workshop on screening and surveillance for HCC believed that, although designing and running a trial of screening for HCC would be difficult, considerable support existed for testing whether screening was effective by performing a randomized controlled trial of screening versus no screening. The group recommended that future studies of screening should bank serum to assess new screening tests as they develop. In addition, given the profusion of small serum banks, a registry of serum banks should be developed. Other issues discussed included the fact that currently no universally accepted "gold standard" exists for the diagnosis of HCC in screening studies. Authors have used biopsy or explant diagnosis, or have used combined clinical and radiological diagnoses. These diagnoses have not been standardized. The recall process includes the initial testing undertaken to evaluate an abnormal screening test and, in the case of negative investigations, includes all follow-up studies performed over time to confirm or refute the presence of HCC. Unresolved issues in recall include the value of liver biopsy, the sensitivity and specificity of radiological investigations, and the identification of false-positive screening tests. Once an ultrasound result suggests the possibility of a small HCC, the next step is usually a triphasic CT scan. The larger the lesion, the more confident one can be about the diagnosis.27, 28 However, when the lesion is smaller than approximately 2 cm, other vascular lesions such as small hemangiomas, peliosis, and cirrhotic and dysplastic nodules, mimic HCC vascular patterns on CT.29, 30 Contrast-enhanced magnetic resonance imaging (MRI) has the same problems, although with MRI other helpful features may be present. HCC and dysplastic nodules are different on T1 and T2 images; unfortunately, the sensitivity and specificity of these features are not sufficiently high that they can be relied on in isolation.31 The EASL single-topic conference on HCC13 suggested that lesions smaller than 1 cm should be monitored by repeat scanning over time. Enlarging lesions are likely to be HCC. Lesions larger than approximately 2 cm can be confidently diagnosed on the basis of radiological features of HCC in the setting of cirrhosis and do not need additional investigations. For lesions between 1 and 2 cm, biopsy was recommended. There is evidence for accepting that lesions larger than 2 cm in the correct clinical setting are HCC. However, no evidence exists that performing a biopsy for lesions between 1 and 2 cm is the best strategy. Newer imaging techniques, such as the multidimensional CT scanning devices currently found16 and planned for the future,32 will allow much smaller slices of liver to be analyzed.33 Together with new software to reconstruct three-dimensional images, the quality of images will likely improve dramatically. Improved quality will likely result in enhanced detection of small lesions, but whether it will also result in enhanced characterization of small lesions and better distinction between small HCC and nonmalignant lesions is not clear. Unlike most other medical fields, the radiological literature lags behind clinical practice by 1 to 2 years. Thus, radiological clinical practice is driven by the availability of technology, rather than by scientific evidence. The lack of technology makes setting up studies in this area difficult. Nonetheless, studies will still be necessary to determine the optimal use of newer and existing in the of HCC. Studies are required to determine the most effective and most cost-effective tests and of tests required to confirm or refute the presence of HCC in patients with small liver nodules on screening. The role of liver biopsy has still to be determined. The sensitivity and specificity of biopsy of small lesions are No accepted standard exists for from lesions by an international only were by all to HCC, to HCC. Even has been whether a is versus dysplastic is still a of because the natural history of these lesions In to the with biopsy diagnosis of HCC, reports of Most of these are in nodules larger than those found on screening. Whether the risk of is as high in small HCC has not been determined. studies are to reduce in the diagnosis of small The next step will be to determine whether the classification to clinical It will likely be to whether nodules diagnosed as as because these will be However, that those diagnosed as nonmalignant as nonmalignant lesions is Newer markers of HCC need to be These should be shown to highly with behavior with Finally, studies should whether confirmation of the diagnosis of HCC by is necessary in small HCC, or whether the lesions should be according to the they over time. major in comparing of different therapeutic for HCC. Patients included in different studies are not different are such as time to or time to The use of survival should be This is a which both and both of which are independent A therapy could cancer but not disease. a the survival would be or that fact that the may significant The participants generally that the use of survival as an was time to and survival should be presented as No evidence exists that resection of HCC reports include patients according to some staging system. a survival in patients with small lesions and liver is with that of patients with large lesions and liver is as liver transplantation for HCC in at least in the The role of therapy before or is not clear. use of interferon in patients with hepatitis HCC also to reduce However, most these studies are not of high in of total hepatectomy and liver transplantation as therapy for HCC. Liver transplantation may be for the lesion as well as the that might lead to future cancers. In patients with cirrhosis, the possibility for exists for patients who might not have that, although not randomized and not indicate that patients who undergo liver transplantation have a better survival than do patients the for donor however, the time from to transplantation has the of patients with HCC on the waiting list. In an to the of has for patients with HCC, which to the The model for liver disease score for patients with stage larger than 2 cm but smaller than cm or than 3 all smaller than 3 HCC is 24 points and points for stage HCC smaller than 2 disease. studies have suggested that these are and that, in the may be to to patients with larger tumor with of overall This and not all that the for transplantation in comparable the of time on the waiting is in whether a is suitable for transplantation, understanding the patterns of HCC is understanding of how and identification of different of or may in for transplantation. data to determine whether or therapy before or liver transplantation has any on and cell transplantation have been in small No reports of the of on the outcome of liver transplantation. donor transplantation could the for transplantation to patients who would not for a donor even under This was the subject of a at the The points for and this can be as The survival of patients transplantation for HCC under current that of patients for that these patients lack such high survival for patients with cancer is an example, liver transplantation for has approximately a HCC stage an risk for liver transplantation is Two groups of patients must be patients who initially meet of but because of tumor on the waiting and patients current at the time of Markov analysis of the of liver transplantation suggest that living donor transplantation by approximately years with liver This analysis is highly dependent on the on the waiting and on However, living donor transplantation is a that on The of living must not be at risk by the of a in for The for transplantation, whether the or the have not been of to any HCC staging A staging system has been developed for transplantation for but the can only be applied in the liver. staging the tumor and is not an accurate for explant staging. The of research in liver transplantation for HCC should be to develop better modeling for of to patients with HCC versus no HCC. Current for HCC have in too patients who do not have HCC being for HCC because biopsy is not controlled that therapy with no therapy are the should be versus no and versus Study should be overall and presence of cancer on of the These studies should include an assessment of whether of HCC makes patients suitable for liver transplantation, or whether still have the prognosis associated with the tumor the suggested were versus no Whether such should include some form of of to those who form the group has to be studies should include studies on the quality of of patients liver transplantation for HCC with patients transplantation for other diagnoses. The group suggested that the of should develop and a to information on transplantation for HCC. a data can be used for clinical decision on screening patients waiting for and as well as data for clinical staging. has been performed with different including of and and of the lesion with or or None of these has been with and none has been with each other in randomized prospective studies of in most the follow-up has been up to 2 years. The have a survival of approximately 50% to and a survival of to studies not include biopsy, the of these survival is prospective studies comparing different methods of are Studies of resection versus may be feasible. Most of suggest that at years the survival that of with a comparable However, studies of not include a biopsy of the lesions being up to 50% of vascular lesions smaller than 2 cm found on screening are not HCC, in the of biopsy a of the lesions by least in the must have been in studies of in which biopsy is not performed are Prospective randomized are The standard in which are based on in tumor may not be helpful in In in of tumor the lesion does not initially of tumor may months or more to the for a partial namely, a in diameter of CT either or may show that the is vascular and is CT scanning can be difficult to because of the presence of the which tumor The time to of disease might be a more appropriate for of HCC therapy. Contrast-enhanced ultrasound to be as and as specific as CT scanning in studies have shown that ultrasound tumor and This technique is also useful for Clearly, additional studies are MRI also has been used to assess tumor by changes in the to into the Studies have shown that the area of by MRI well with lesions in and also a significant difference between and However, use of MRI as a of does not the of whether can be used to assess the of screening and surveillance for HCC, most patients are still diagnosed at a stage at which therapy is not feasible. all the only and have been to randomized controlled of size and quality to be confident of the randomized controlled of and of of internal using and external therapy also exist. randomized controlled have been performed using or and a of the data from some of these studies has been No study has shown any for with no The of all randomized also that should be the standard of care for appropriate questions about including how the should be agents to and should be These questions have to be by randomized controlled trials. should for to and such trials. has also been studied as for patients with HCC who are liver transplantation, but and studies have small and yield study of this area was to be and would require studies to A large number of have been studied in phase and trials. Only one of these of therapy was presented and discussed at the This therapy the use of into the the No randomized controlled of this therapy exist. However, the outcome of phase studies was with but by For both 1 and survival was over This study However, until the use of is with no therapy or with a the value of this therapy uncertain. This namely the lack of phase randomized controlled to a large number of useful therapies. Thus, a need exists for to the and running of randomized controlled to explore the value of these A decision has to be made as to whether the group should be or whether should be used as a The group believed that was and and should not be The agents to be studied are those that have been used to the underlying liver disease, particularly that might be suitable for should be at high risk for HCC. Although identification of at-risk is still no exists to identify patients at imminent risk for HCC. in such might be effective with to larger at but not risk of HCC. Two might of of or the In only interferon therapy in chronic hepatitis has been identified as HCC. In chronic hepatitis the suggests that patients who have cirrhosis do 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 addition, 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 result 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 however, the is insufficiently advanced to be clinically The role of and in HCC research was discussed in a The group believed that of and banks would such studies and were However, all studies using would have to be validated in prospective studies.

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