Staging for Hepatocellular Carcinoma: Complex and Confusing

Abstract

See “Development of Hong Kong Liver Cancer Staging System with treatment stratification for patients with hepatocellular carcinoma,” by Yau T, Tang VYF, Yao T–J, et al, on page 1691. See “Development of Hong Kong Liver Cancer Staging System with treatment stratification for patients with hepatocellular carcinoma,” by Yau T, Tang VYF, Yao T–J, et al, on page 1691. In this issue, a group of investigators from Hong Kong present a new, Hong Kong Liver Cancer (HKLC) staging system for hepatocellular carcinoma (HCC).1Yau T. Tang V.Y.F. Yao T.J. et al.Development of Hong Kong Liver Cancer Staging System with treatment stratification for patients with hepatocellular carcinoma.Gastroenterology. 2014; 146: 1691-1700Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar They compare their staging system with the widely used Barcelona Clinic Liver Cancer (BCLC) system and conclude that the Hong Kong system provides better prognostic differentiation. Furthermore, they claim to show that within their system aggressive treatment (ie, resection) provides better survival than the treatments recommended by the BCLC system for patients with similar stage of disease. Establishing a cancer staging system requires a large set of patients at various stages of disease on presentation, who ideally remain untreated until death. This allows different categories of prognosis to be defined. Various factors at presentation predictive of death are identified and their contribution to prognosis determined by multivariable regression. These factors have traditionally included tumor size, number, vascular invasion, and the presence of local nodal or distant metastases. Patient's performance score is also an important predictor. In patients with cirrhosis an additional factor is liver function, because this is probably the major determinant of outcome. Although it is desirable to evaluate histology or markers of tumor behavior as predictors, these are not included in any HCC staging system so far. In this study,1Yau T. Tang V.Y.F. Yao T.J. et al.Development of Hong Kong Liver Cancer Staging System with treatment stratification for patients with hepatocellular carcinoma.Gastroenterology. 2014; 146: 1691-1700Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar the authors have assembled a large cohort of patients primarily with hepatitis B virus infection, but the majority of patients had some form of treatment. Because treatment may alter prognosis, survival in each stage is influenced by treatment. The magnitude of this effect is hard to measure. However, it is inconceivable that any new staging system today can be developed using an untreated cohort. There are now ≥7 different HCC staging systems.2Llovet J.M. Brú C. Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification.Semin Liver Dis. 1999; 19: 329-338Crossref PubMed Scopus (2941) Google Scholar, 3Kudo M. Chung H. Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score).J Gastroenterol. 2003; 38: 207-215Crossref PubMed Scopus (558) Google Scholar, 4Chevret S. Trinchet J.C. Mathieu D. et al.A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire.J Hepatol. 1999; 31: 133-141Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar, 5Daniele B. Annunziata M. Barletta E. et al.Cancer of the Liver Italian Program (CLIP) score for staging hepatocellular carcinoma.Hepatol Res. 2007; 37: S206-S209Crossref PubMed Google Scholar, 6Vauthey J.N. Klimstra D. Blumgart L.H. A simplified staging system for hepatocellular carcinomas.Gastroenterology. 1995; 108: 617-618Abstract Full Text PDF PubMed Scopus (24) Google Scholar, 7Ikai I. Takayasu K. Omata M. et al.Liver Cancer Study Group of Japan. A modified Japan Integrated Stage score for prognostic assessment in patients with hepatocellular carcinoma.J Gastroenterol. 2006; 41: 8843892Crossref Scopus (67) Google Scholar, 8Leung T.W. Tang A.M. Zee B. et al.Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients.Cancer. 2002; 94: 1760-1769Crossref PubMed Scopus (497) Google Scholar Of these, the BCLC is widely used in Europe and North America, but is not in Asia. In part, this is because in Asia resection of tumors that present in advanced stages and in patients with less than perfect liver function has been part of the armamentarium of HCC treatment.9Torzilli G. Donadon M. Marconi M. et al.Hepatectomy for stage B and stage C hepatocellular carcinoma in the Barcelona Clinic Liver Cancer classification: results of a prospective analysis.Arch Surg. 2008; 143: 1082-1090Crossref PubMed Scopus (127) Google Scholar, 10Yang T. Lin C. Zhai J. et al.Surgical resection for advanced hepatocellular carcinoma according to Barcelona Clinic Liver Cancer (BCLC) staging.J Cancer Res Clin Oncol. 2012; 138: 1121-1129Crossref PubMed Scopus (65) Google Scholar, 11Andreou A. Vauthey J.N. Cherqui D. et al.International Cooperative Study Group on Hepatocellular Carcinoma. Improved long-term survival after major resection for hepatocellular carcinoma: a multicenter analysis based on a new definition of major hepatectomy.J Gastrointest Surg. 2013; 17: 66-77Crossref PubMed Scopus (92) Google Scholar, 12Pawlik T.M. Poon R.T. Abdalla E.K. et al.Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results of a multicenter study.Surgery. 2005; 137: 403-410Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 13Ng K.K. Vauthey J.N. Pawlik T.M. et al.International Cooperative Study Group on Hepatocellular Carcinoma. Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multi-institutional database.Ann Surg Oncol. 2005; 12: 364-373Crossref PubMed Scopus (214) Google Scholar Results of resection of such HCCs have been reported in uncontrolled cohort studies indicating that survival apparently exceeded that expected from the treatment prescribed by the BCLC.9Torzilli G. Donadon M. Marconi M. et al.Hepatectomy for stage B and stage C hepatocellular carcinoma in the Barcelona Clinic Liver Cancer classification: results of a prospective analysis.Arch Surg. 2008; 143: 1082-1090Crossref PubMed Scopus (127) Google Scholar, 10Yang T. Lin C. Zhai J. et al.Surgical resection for advanced hepatocellular carcinoma according to Barcelona Clinic Liver Cancer (BCLC) staging.J Cancer Res Clin Oncol. 2012; 138: 1121-1129Crossref PubMed Scopus (65) Google Scholar, 11Andreou A. Vauthey J.N. Cherqui D. et al.International Cooperative Study Group on Hepatocellular Carcinoma. Improved long-term survival after major resection for hepatocellular carcinoma: a multicenter analysis based on a new definition of major hepatectomy.J Gastrointest Surg. 2013; 17: 66-77Crossref PubMed Scopus (92) Google Scholar, 12Pawlik T.M. Poon R.T. Abdalla E.K. et al.Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results of a multicenter study.Surgery. 2005; 137: 403-410Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 13Ng K.K. Vauthey J.N. Pawlik T.M. et al.International Cooperative Study Group on Hepatocellular Carcinoma. Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multi-institutional database.Ann Surg Oncol. 2005; 12: 364-373Crossref PubMed Scopus (214) Google Scholar Furthermore, the multiplicity of staging systems suggests than none are completely satisfactory (although regional preferences may also be playing a role in that the BCLC is used in Europe, the Japanese Integrated System in Japan, etc). The BCLC staging,2Llovet J.M. Brú C. Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification.Semin Liver Dis. 1999; 19: 329-338Crossref PubMed Scopus (2941) Google Scholar which identifies clinical stages based on clinical practice, allows an appropriate treatment strategy to be applied to each BCLC stage. Although the criteria for the treatment associated with each stage were determined before the development of the staging system, these were refined by the studies that led to development of the staging system. Prognosis of untreated patients was derived from the survival of untreated controls in randomized studies. An alternative and more conventional method is to identify factors that affect prognosis by multivariate regression analysis, combine the different factors in different ways that seemed clinically appropriate, and use Kaplan–Meier statistics to determine whether the groupings provides adequate separation. The disadvantage of this method is that it does not provide any information about appropriate treatment. Nonetheless, this method does provide different groupings in which new treatments can be tested. The current Hong Kong staging system has 9 stages and substages (Table 1), identified by criteria associated with prognosis. These include Eastern Cooperative Group performance status, Child–Pugh score, tumor extent, and extrahepatic disease. Although the authors claim that their staging system provides good separation of prognosis, the Kaplan–Meier survival curves of the different stages do not demonstrate the kind of separation one would like to see (see Figure 1 in the article1Yau T. Tang V.Y.F. Yao T.J. et al.Development of Hong Kong Liver Cancer Staging System with treatment stratification for patients with hepatocellular carcinoma.Gastroenterology. 2014; 146: 1691-1700Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar). Some of the groups with similar survival could be condensed without loss of information. For example, stages IIIb, IVa, IVb, and Vb all have similar survival curves. Stages IIa and IIb are also similar. There is an anomaly in the survival in that stage Va, essentially late stage disease, is better than stages IVa and IVb. The authors do not provide P values for the log-rank test, so we cannot tell whether the curves are truly different.Table 1Comparison Between the Barcelona Clinic Liver Cancer Staging System and the Hong Kong Liver Cancer Staging System: Clinical FeaturesHong Kong StageMaximum Tumor Size (cm)Maximum No. of TumorsIntra-hepatic Vascular InvasionExtrahepatic DiseaseChild ClassEastern Cooperative Group StatusBarcelona Clinic Liver Cancer StageI53NoNoA00 or AIIa53NoNoB1BIIb53YesNoA0–1C5>3No>5<4NoIIIa53YesNoB0–1D5>3No>5<4NoIIIb5>3YesNoA/B0–1C or D>53Yes>5>3YesDiffuseAnyYesIVaAnyAnyAnyYesA0–1C or DIVbAnyAnyAnyYesB0–1DVa53NoNoC2–4DVb5>3YesYesC2–4D>53Yes>5>3YesDiffuseAnyYes Open table in a new tab The HKLC staging system was developed using a training and a test set. The authors then compare the HKLC staging system with the BCLC, using receiver operating characteristic curves. This analysis suggested that the HKLC system was better able to predict survival than the BCLC. For this analysis, they used the 5 main groupings of the HKLC system (I-V), but they used a variant of the BCLC that is difficult to understand. They classify BCLC stage A into A1-A4, something that the originators of the BCLC did not do. Nor is this BCLC variant referenced, so is it is difficult to know whether they are comparing apples with apples. Because the indications for resection in Hong Kong are broader than specified by the BCLC, the authors were able to compare outcomes in patients within BCLC B and C who were within HKLC-II and -III who were treated with transarterial chemoembolization (TACE) or resection. For patients beyond BCLC A who were classified as HKLC II, resection provided much better outcomes than TACE. In the HKLC classification, HKLC-II includes early HCC (within Milan criteria) and Child B liver function, intermediate-stage tumors with Child A liver function, and locally advanced tumors with Child A or B liver function. Intermediate-stage tumors include those within Milan criteria but with intrahepatic vascular invasion, or HCC consisting of >3 lesions, none >5 cm with no vascular invasion, or ≤3 lesions >5 cm with no vascular invasion. Locally advanced HCC was defined as >3 lesions <5 cm with intrahepatic vascular invasion, or <4 lesions that may be >5 cm, and with vascular invasion, or diffuse disease with any number of nodules with or without intrahepatic vascular invasion (Table 1). Although survival in HKLC-III was better with resection, the 5-year survival rate was dismal for both groups (9% and 1%). This study highlights one of the ongoing controversies that surround the BCLC system. Surgeons as a group have resisted strict application of the BCLC system.9Torzilli G. Donadon M. Marconi M. et al.Hepatectomy for stage B and stage C hepatocellular carcinoma in the Barcelona Clinic Liver Cancer classification: results of a prospective analysis.Arch Surg. 2008; 143: 1082-1090Crossref PubMed Scopus (127) Google Scholar, 10Yang T. Lin C. Zhai J. et al.Surgical resection for advanced hepatocellular carcinoma according to Barcelona Clinic Liver Cancer (BCLC) staging.J Cancer Res Clin Oncol. 2012; 138: 1121-1129Crossref PubMed Scopus (65) Google Scholar, 11Andreou A. Vauthey J.N. Cherqui D. et al.International Cooperative Study Group on Hepatocellular Carcinoma. Improved long-term survival after major resection for hepatocellular carcinoma: a multicenter analysis based on a new definition of major hepatectomy.J Gastrointest Surg. 2013; 17: 66-77Crossref PubMed Scopus (92) Google Scholar, 12Pawlik T.M. Poon R.T. Abdalla E.K. et al.Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results of a multicenter study.Surgery. 2005; 137: 403-410Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 13Ng K.K. Vauthey J.N. Pawlik T.M. et al.International Cooperative Study Group on Hepatocellular Carcinoma. Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multi-institutional database.Ann Surg Oncol. 2005; 12: 364-373Crossref PubMed Scopus (214) Google Scholar They claim that surgery can be beneficial for groups of patients for whom BCLC recommends only chemoembolization or systemic therapy. However, the vast majority of these studies are retrospective analyses of patients who have had surgery with no comparison group treated with other methods. One well-quoted article that is used to support this contention looked at patients undergoing resection who were stratified by the presence or absence of portal hypertension and/or macrovascular invasion.14Ishizawa T. Hasegawa K. Aoki T. et al.Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma.Gastroenterology. 2008; 134: 1908-1916Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar Survival was reduced among those who had one of these adverse features, and was even worse when both were present. We have always known that there are some patients in whom resection is beneficial despite the presence of predictors of a bad outcome. The question, however, was whether surgery was the best option with BCLC B or C disease, or whether some other treatment such as TACE might provide a better outcome. There has to date only been a single comparative study, again retrospective. This study suggested that the outcomes were better with resection than with TACE.15Lin C.T. Hsu K.F. Chen T.W. et al.Comparing hepatic resection and transarterial chemoembolization for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma: change for treatment of choice?.World J Surg. 2010; 34: 2155-2161Crossref PubMed Scopus (81) Google Scholar Because both the earlier study15Lin C.T. Hsu K.F. Chen T.W. et al.Comparing hepatic resection and transarterial chemoembolization for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma: change for treatment of choice?.World J Surg. 2010; 34: 2155-2161Crossref PubMed Scopus (81) Google Scholar and the current study were retrospective, there was likely an unintentional selection bias. Patients who were selected for resection over TACE must have had features that gave the surgeon confidence of a good outcome, whereas those selected for TACE likely lacked such features. This immediately introduces a bias against TACE. The net result is that these results are interesting, but cannot be used to support a generalized approach of more aggressive resection for HCC. That is not to say that no such resection should be done. Clearly, there are patients with advanced disease (BCLC B mainly) who will benefit from resection more than from TACE. The problem is how to identify those individuals. Unfortunately, neither this current study nor the earlier one provides answers to that question. Furthermore, although many of the retrospective analyses of survival after aggressive resection do evaluate predictors of a good survival, these may well be predictors of a good survival after other treatment. Identification of patients beyond BCLC A who might benefit from resection remains an art rather than a science. It is worth exploring why the BCLC and HKLC system have different results. The authors postulate that the difference might stem from the underlying liver disease. In Spain, where the BCLC was born, hepatitis C is the dominant liver disease causing HCC. In Hong Kong, the dominant liver disease is hepatitis B. Patients with hepatitis B who develop HCC generally have better liver function than those with hepatitis C, because hepatitis B disease frequently inactivates before the development of HCC, allowing some recovery to occur, whereas hepatitis C remains active throughout the disease course. However, inclusion of the Child score into the staging algorithms should have equalized the differences between the 2 populations. Could it be that patients with advanced liver disease and HCC owing to hepatitis B had more liver reserve than those with hepatitis C, despite having the same Child score? Certainly the Child score is a blunt instrument to measure liver function. Could the ongoing hepatitis C inflammation contribute to post resection liver failure, whereas in hepatitis B this is not a factor? These questions remain unanswered. The HKLC staging system requires external validation both in Asia and elsewhere before being introduced more widely. It should also be tested in patients with liver disease other than hepatitis B. The other message from this work is that more aggressive surgery may be warranted in patients with some degree of portal hypertension, vascular invasion, or Child B liver disease, such as those with a platelet count limit somewhat lower than the generally accepted cut-off of 100,000/mL or a Child-Pugh score of 7, but more study is necessary before aggressive surgery can be widely recommended. Table 2 illustrates some of the differences in the development and application of the BCLC and HKLC staging systems.Table 2Comparison Between the Barcelona Clinic Liver Cancer Staging System and the Hong Kong Liver Cancer Staging System: Methods and ValidationFactorBarcelona Clinic Liver CancerHong Kong Liver CancerDevelopmentClinical studies, including some untreated controls with advanced diseaseMultiple logistic regression; no untreated cohortsPopulationMainly hepatitis CMainly hepatitis BAssociated indicated treatmentYesPartiallyExternally validatedYesNot yetAdoptionWidely used in Europe; used in randomized, controlled trials of new drugs for hepatocellular carcinomaNot yetDifferent stages clearly separatedYesNo Open table in a new tab Development of Hong Kong Liver Cancer Staging System With Treatment Stratification for Patients With Hepatocellular CarcinomaGastroenterologyVol. 146Issue 7PreviewWe aimed to develop a prognostic classification scheme with treatment guidance for Asian patients with hepatocellular carcinoma (HCC). 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