AASLD肝细胞肝癌指南update2010

AASLD PRACTICE GUIDELINE Management of Hepatocellular Carcinoma: An Update Jordi Bruix,1 and Morris Sherman2 Since the publication of the American Association for the Study of Liver Diseases (AASLD) practice guide- lines on the management of hepatocellular carcinoma (HCC) in 2005, new information has emerged that requires that the guidelines be updated. The full ver- sion of the new guidelines is available on the AASLD Web site at http://www.aasld.org/practiceguidelines/ Documents/Bookmarked%20Practice%20Guidelines/ HCCUpdate2010.pdf. Here, we briefly describe only new or changed recommendations. Surveillance and Diagnosis In the previous guideline, groups were specified for which surveillance was likely to be cost-effective because the hepatocellular carcinoma (HCC) incidence was high enough. New data on defining HCC risk have emerged for hepatitis B virus,1,2 hepatitis C vi- rus,3 and autoimmune hepatitis.4 Surveillance is deemed cost-effective if the expected HCC risk exceeds 1.5% per year in patients with hepatitis C and 0.2% per year in patients with hepatitis B. Analysis of recent studies show that alpha-fetoprotein determination lacks adequate sensitivity and specificity for effective surveil- lance (and for diagnosis).5,6 Thus, surveillance has to be based on ultrasound examination. The recom- mended screening interval is 6 months. Diagnosis of HCC should be based on imaging techniques and/or biopsy.The 2005 diagnostic algorithm has been vali- dated and the diagnostic accuracy of a single dynamic technique showing intense arterial uptake followed by ‘‘washout’’ of contrast in the venous-delayed phases has been demonstrated.7-9 Contrast-enhanced US may offer false positive HCC diagnosis in patients with cholangiocarcinoma and thus, has been dropped from the diagnostic techniques. The diagnostic algorithm is shown in Fig. 1. The application of dynamic imaging criteria should be applied only to patients with cirrho- sis of any etiology and to patients with chronic hepati- tis B who may not have fully developed cirrhosis or have regressed cirrhosis. Interpretation of biopsies and distinction between high-grade dysplatic nodules and HCC is challenging. Expert pathology diagnosis is re- inforced by staining for glypican 3, heat shock protein 70, and glutamine synthetase, because positivity for two of these three stains confirms HCC.10 Staging and Treatment of HCC The BCLC staging system (Fig. 2)11 has come to be widely accepted in clinical practice and is also being used for many clinical trials of new drugs to treat HCC. There- fore, it has become the de facto staging system that is used. The recommendations for liver transplantation have not changed. No new data have emerged that can be used to define a new limit for expanding the patient selection criteria. The usefulness of portal pressure mea- surement to predict the outcome of patients and define optimal candidates for resection has been validated in Japan.12 Thus, resection should remain the first option for patients who have the optimal profile, as defined by the BCLC staging system. Although resection can be performed in some of these patients with advanced liver disease, the mortality is higher and they might be better served by liver transplantation or ablation. A cohort study of radiofrequency ablation demonstrated that complete ablation of lesions smaller than 2 cm is possi- ble in more than 90% of cases, with a local recurrence rate of less than 1%.13 These data should be confirmed by other groups before positioning ablation as the first- line approach for very early HCC. The recommendations regarding patient selection and method of administration of chemoembolization are unchanged. Radioembolization, i.e., the intra-arte- rial injection of yttrium-90 bound to glass beads or to resin, has been shown to induce tumor necrosis, but Abbreviations: AASLD, American Association for the Study of Liver Diseases; BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma. From the 1Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clı´nic, University of Barcelona, Institut d’Investigacions Biome`diques August Pi i Sunyer, Barcelona, Spain; and 2University of Toronto and University Health Network, Toronto, Canada. Received January 3, 2011; accepted January 8, 2011. Address reprint requests to: Jordi Bruix, M.D., Hospital Clinic, University of Barcelona, IDIPAPS, CIBERehd, c/Villarroel 170, Barcelona 08036, Catalonia, Spain. E-mail: bruix@ub.edu; fax: (34) 93-227-9803. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24199 Potential conflict of interest: Dr. Bruix advises, consults for, serves on the speaker’s bureau of, and received grants from Bayer. Dr. Bruix consults for Biocompatibles, GlaxoSmithKline, Kowa, Novartis, and Arqule. Dr. Bruix also advises and consults for Bristol-Myers Squibb. Dr. Sherman serves on the speakers’ bureau of Bayer 1020 bh 下划线 there are no data comparing its efficacy to transarterial chemoembolization or to sorafenib treatment for those with portal vein invasion. However, for patients who have either failed transarterial chemoembolization or who present with more advanced HCC, new data indicates the efficacy of sorafenib (a multikinase inhib- itor with activity against Raf-1, B-Raf, vascular endo- thelial growth factor receptor 2, platelet-derived growth factor receptor, c-Kit receptors, among other kinases) in prolonging life.14,15 Sorafenib induces a clinically relevant improvement in time to progression and in survival The magnitude of the improvement in survival compares with other established molecular tar- geted therapies for other advanced cancers, and the Fig. 1. Diagnostic algorithm for sus- pected HCC. CT, computed tomography; MDCT, multidetector CT; MRI, magnetic resonance imaging; US, ultrasound. Fig. 2. The BCLC staging system for HCC. M, metastasis classification; N, node classification; PS, performance status; RFA, radiofrequency ablation; TACE, transarterial chemoembolization. HEPATOLOGY, Vol. 53, No. 3, 2011 BRUIX AND SHERMAN 1021 associated toxicity is easily managed without treat- ment-related mortality. The most frequent adverse events were diarrhea (sorafenib versus placebo: 11% versus 2%) and hand–foot skin reaction (sorafenib ver- sus placebo: 8% versus <1%), fatigue, and weight loss. Sorafenib is now considered first-line treatment in patients with HCC who can no longer be treated with potentially more effective therapies. In summary, in the past decade HCC has gone from being an almost universal death sentence to a cancer that can be prevented, detected at an early stage, and effectively treated. Physicians caring for patients at risk need to provide high-quality screening, proper management of screen-detected lesions, and provision of therapy that is most appropriate for the stage of disease. References 1. Yuen MF, Tanaka Y, Fong DY, Fung J, Wong DK, Yuen JC, et al. Inde- pendent risk factors and predictive score for the development of hepatocel- lular carcinoma in chronic hepatitis B. J Hepatol 2009;50:80-88. 2. Yang HI, Sherman M, Su J, Chen PJ, Liaw YF, Iloeje UH, et al. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Clin Oncol 2010;28:2437-2444. 3. Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK, Curto TM, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 2009;136:138-148. 4. Yeoman AD, Al-Chalabi T, Karani JB, Quaglia A, Devlin J, Mieli-Ver- gani G, et al. Evaluation of risk factors in the development of hepato- cellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening. HEPATOLOGY 2008;48:863-870. 5. Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009;30: 37-47. 6. Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, et al.; HALT-C Trial Group. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepato- cellular carcinoma. Gastroenterology 2010;138:493-502. 7. Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, et al. Di- agnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carci- noma. HEPATOLOGY 2008;47:97-104. 8. Sangiovanni A, Manini MA, Iavarone M, Romeo R, Forzenigo LV, Fra- quelli M, et al. The diagnostic and economic impact of contrast imag- ing techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59:638-644. 9. Khalili K, Kim TY, Jang HJ, Haider MA, Guindi M, Sherman M. Implementation of AASLD hepatocellular carcinoma practice guidelines in North America: two years of experience [Abstract]. HEPATOLOGY 2008;48(Suppl 1):362A. 10. International Working Party. Pathologic diagnosis of early hepatocellu- lar carcinoma: a report of the international consensus group for hepato- cellular neoplasia. HEPATOLOGY 2009;49:658-664. 11. Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 2010;30:61-74. 12. Ishizawa T, Hasegawa K, Aoki T, Takahashi M, Inoue Y, Sano K, et al. Neither multiple tumors nor portal hypertension are surgical contrain- dications for hepatocellular carcinoma. Gastroenterology 2008;134: 1908-1916. 13. Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, et al. Sustained complete response and complications rates after radiofre- quency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? HEPATOLOGY 2008;47:82-89. 14. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359:378-390. 15. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double- blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34. 1022 BRUIX AND SHERMAN HEPATOLOGY, March 2011 AASLD PRACTICE GUIDELINE Management of Hepatocellular Carcinoma: An Update Jordi Bruix1 and Morris Sherman2 Preamble The recommendations provided in this document pro- vide a data-supported approach to the diagnosis, staging and treatment of patients diagnosed with hepatocellular carcinoma (HCC). They are based on the following: (a) formal review and analysis of the recently-published world literature on the topic (Medline search through early 2010); (b) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (c) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterology Associa- tion Policy Statement on Guidelines2; (d) the experience of the authors. These recommendations suggest pre- ferred approaches to the diagnostic, therapeutic, and preventive aspects of care. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the American Association for Study of Liver Disease (AASLD) requires a category to be assigned and reported with each recommendation (Table 1). These recommenda- tions are fully endorsed by the American Association for the Study of Liver Diseases. Introduction The incidence of hepatocellular carcinoma is rising in many countries,3-8, but in a few areas such as Japan and Singapore, the incidence of HCC seems to have stabilized or even fallen slightly.9,10 Care of the patient with HCC involves physicians from different disci- plines, including hepatologists, surgeons, liver trans- plant teams, oncologists, interventional radiologists, and to some extent radiation oncologists. In most set- tings, the role of the hepatologist or gastroenterologist in these multi-specialty groups (usually organized as Tumor Boards) is not based on specific expertise in the application of a given intervention, but rather in assessing the degree of liver function impairment prior to, during and after therapy. This specific expertise is important since HCC usually appears in the setting of underlying liver disease. This results in a degree of complexity that is not present in other cancer types that seldom compromise vital organ function. All this suggests that patients with HCC should be managed in multidisciplinary settings, with all legitimate treat- ment options available. Under these circumstances, the hepatologist is to be a focal point around whom the process revolves. At all times, the hepatologist should assess liver function and suitability of various therapies. The hepatologist should also be responsible for man- agement of the liver disease before, during, and after cancer therapy. He/she must ensure that only treat- ments of proven value are administered, rather than treatments that are technically feasible but which have not been shown to enhance survival. Surveillance for Hepatocellular Carcinoma Definitions of the terms used in this section are given in Table 2. Surveillance for HCC involves more than simply applying a screening test or tests. Surveil- lance should be offered in the setting of a program or a process in which screening tests and recall procedures have been standardized and in which quality control procedures are in place. The process of surveillance also involves deciding what level of risk of HCC is high enough to trigger surveillance, what screening tests to apply and how frequently (surveillance inter- val), and how abnormal results should be dealt with (diagnosis and/or recall). Surveillance for HCC has become widely applied despite, until recently, the absence of evidence of bene- fit. There is now a single randomized controlled trial of surveillance versus no surveillance that has shown a survival benefit to a strategy of 6-monthly surveillance with alphafetoprotein (AFP) and ultrasound.11 This study, which was performed in China, recruited 18,816 patients who had markers of current or prior hepatitis B infection. Adherence to surveillance was suboptimal (less than 60%) but in the subjects in the From the 1BCLC Group. Liver Unit. Hospital Clı´nic, University of Barcelona, Institut d’Investigacions Biome’diques August Pi i Sunyer, Barcelona, Spain; 2University of Toronto and University Health Network, Toronto Canada. Both authors contributed equally to this work. Copyright VC 2010 by the American Association for the Study of Liver Diseases and published online at www.aasld.org. This version was updated July 2010. Previous version published 2005 online in Wiley InterScience (www.interscience.wiley.com). Potential conflict of interest: Jordi Bruix has received research support and consulting and lecture fees from Bayer; and Morris Sherman has received lecture fees from Bayer. 1 adavisowino Typewritten Text adavisowino Typewritten Text adavisowino Typewritten Text adavisowino Typewritten Text surveillance arm the HCC related mortality was reduced by 37%. Because of poor compliance these results probably represent the minimum benefit that can be expected from surveillance. Ideally, these results should be validated in other geographical areas and therefore, additional randomized controlled trials (RCT) assessing the benefits of surveillance are still considered necessary. However, in the West it is unlikely that such trials will ever be conducted. The objective of HCC surveillance must be to decrease mortality from the disease. Fewer people should die from HCC, or if this is not possible, sur- veillance should at a minimum provide a meaningful improvement in survival duration. Other endpoints, such as stage migration (detecting earlier stage disease) and 5-year mortality rates are not appropriate surro- gate endpoints. This has clearly been shown by analy- sis of the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI), which demonstrated that these endpoints did not correlate with a reduction in disease-specific mortality.12 There are several sources of bias to be considered in assessing reports of surveillance studies, such as lead- time bias and length bias. Only an RCT can eliminate these biases completely. Several studies have shown that surveillance does indeed detect earlier disease (stage migration).13-16 Uncontrolled studies, all subject to lead-time bias, have also suggested that survival is improved after surveillance.13,14 Surveillance for HCC is widely practiced and can generally be recommended for certain at-risk groups. HCC detected after the onset of symptoms has a dismal prognosis (0%-10% 5-year survival).17 In contrast, small HCC’s such as those that can be detected by surveillance can be cured with an appreciable frequency.17-21. Five-year disease- free survival exceeding 50% has been reported for both resection and liver transplantation.17,22-30 Patients surviving free of disease for this duration should be considered cured. For these patients it is highly likely that surveillance did indeed decrease mortality. In addition, since major advances in our ability to treat HCC are less likely to come from treating late stage disease, it is therefore important to find early stage disease. Definition of the At-Risk Population The decision to enter a patient into a surveillance program is determined by the level of risk for HCC. This, in turn, is related to the incidence of HCC, and it is incidence that most people use to assess risk. However, there are no experimental data to indicate what level of risk or what incidence of HCC should trigger surveillance. Instead, decision analysis has been used to provide some guidelines as to the incidence of HCC at which surveillance may become effective. An intervention is considered effective if it provides an increase in longevity of about 100 days, i.e., about 3 months.31 Although the levels were set years ago, and may not be appropriate today, interventions that can be achieved at a cost of less than about $50,000/year of life gained are considered cost-effective.32 There are now several published decision analysis/cost-effective- ness models for HCC surveillance. The models differ in the nature of the theoretical population being ana- lyzed, and in the intervention being applied. Nonethe- less, these models have several results in common. They all find that surveillance is cost-effective, although in some cases only marginally so, and most find that the efficacy of surveillance is highly depend- ent on the incidence of HCC. For example, Sarasin et al.33 studied a theoretical cohort of patients with Table 1. Levels of Evidence According to Study Design Grade Definition III Randomized controlled trials II-1 Controlled trials without randomization II-2 Cohort or case control analytic studies II-3 Multiple time series Dramatic uncontrolled experiments III Opinion of respected experts Descriptive epidemiology Table 2. Definitions l Screening—application of diagnostic tests in patients at risk for HCC, but in whom there is no a priori reason to suspect that HCC is present. l Surveillance—the repeated application of screening tests. l Enhanced follow-up—the series of investigations required to confirm of refute a diagnosis of HCC in patients in whom a surveillance test result is abnormal. In addition to the use of additional diagnostic tests the interval between assessments is shorter than for surveillance since there is a concern that a cancer already exists. l Lead-time bias—This is the apparent improved survival that comes from the diagnosis being made earlier in