An evaluation of hepatocellular carcinoma practice guidelines from a radiation oncology perspective


      • This is the first study evaluating HCC guidelines using AGREE II method, from the radiation oncologists’ perspective.
      • In our evaluation, four guidelines from the NCCN, EASL, AASLD, and KLCSG were deemed applicable without modification.
      • All domains except “Scope and Purpose” (63.9%) and “Clarity of Presentation” (65.7%) had median scores <50%, and “Applicability” (36.1%) domain had the lowest score.
      • Future guidelines should emphasize more of “Applicability,” as modern HCC treatment requires multidisciplinary approaches involving up-to-date techniques and systemic agents.



      External beam radiotherapy (EBRT) is actively used for hepatocellular carcinoma (HCC) treatment in clinical practice but has not got attention in several guidelines owing to the lack of high-level evidences. We evaluated HCC treatment guidelines from the radiation oncology perspective using the Appraisal of Guidelines for Research and Evaluation (AGREE II) model, to provide information to choose suitable guidelines and for future guidelines developments.


      Guidelines and consensuses for HCC management involving EBRT that have been published until May 2019 were included. Seven appraisers from 6 countries participated; all were radiation oncologists specialized in HCC. Guidelines were assessed using the AGREE II (December 2017 update), and we added an additional domain, “Radiotherapy Content,” to evaluate the fidelity of evidence and participation of relevant specialists. Inconsistency among appraisers was evaluated, and standard deviations (SD) among the average scores of each domain were calculated.


      Eighteen guidelines or consensuses were included; 4 of them (NCCN, EASL, AASLD, and KLCSG)* were considered applicable without modification. Overall scores were evenly and significantly affected by all domain scores, with “Rigour of Development” showing the most significant correlation. The median scores were the highest for “Scope and Purpose” (63.9%) and “Clarity of Presentation” (65.7%) and the lowest for “Applicability” (36.1%). Inconsistency among appraisers was higher in “Editorial Independence” (median SD: 1.96) than in other domains.


      Although the median overall score was moderate (64.3%), further efforts are necessary as all domains had scores <50% except “Scope and Purpose” and “Clarity of Presentation”. Future guidelines need to consider more on “Applicability” because modern HCC treatment requires multidisciplinary approaches involving up-to-date techniques and systemic agents. The independency of development and role of funders should be comprehensively described in future guidelines.
      *National Cancer Comprehensive Network, European Association for the Study of the Liver, American Association for the Study of the Liver Disease, Korean Liver Cancer Study Group.


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        • Torre L.A.
        • Bray F.
        • Siegel R.L.
        • Ferlay J.
        • Lortet‐Tieulent J.
        • Jemal A.
        Global cancer statistics, 2012.
        CA: Cancer J Clin. 2015; 65: 87-108
      1. Kudo M, Kang Y-K, Park J-W, Qin S, Inaba Y, Assenat E, et al. Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced Hepatocellular Carcinoma: From a Randomized Phase II Study. 2018;7(2):148-64

        • Sinn D.H.
        • Gwak G.-Y.
        • Cho J.
        • Paik S.W.
        • Yoo B.C.
        Comparison of clinical manifestations and outcomes between hepatitis B virus-and hepatitis C virus-related hepatocellular carcinoma: analysis of a nationwide cohort.
        PLoS One. 2014; 9e112184
        • Choo S.P.
        • Tan W.L.
        • Goh B.K.
        • Tai W.M.
        • Zhu A.X.
        Comparison of hepatocellular carcinoma in E astern versus W estern populations.
        Cancer. 2016; 122: 3430-3446
        • Bertot L.C.
        • Adams L.A.
        Trends in hepatocellular carcinoma due to non-alcoholic fatty liver disease.
        Expert Rev Gastroenterol Hepatol. 2019; 13: 179-187
        • Kudo M.
        Surveillance, diagnosis, treatment, and outcome of liver cancer in Japan.
        Liver Cancer. 2015; 4: 39-50
        • Park J.W.
        • Chen M.
        • Colombo M.
        • Roberts L.R.
        • Schwartz M.
        • Chen P.J.
        • et al.
        Global patterns of hepatocellular carcinoma management from diagnosis to death.
        BRIDGE Study. 2015; 35: 2155-2166
        • Park S.
        • Yoon W.S.
        • Rim C.H.
        Indications of external radiotherapy for hepatocellular carcinoma from updated clinical guidelines: Diverse global viewpoints.
        World J Gastroenterol. 2020; 26: 393
        • Chen S.
        • Peng Z.
        • Wei M.
        • Liu W.
        • Dai Z.
        • Wang H.
        • et al.
        Sorafenib versus Transarterial chemoembolization for advanced-stage hepatocellular carcinoma: a cost-effectiveness analysis.
        BMC Cancer. 2018; 18: 392
        • Graham G.
        • Mancher M.
        • Miller Wolman D.
        • Greenfield S.
        • Steinberg E.
        Clinical practice guidelines we can trust. Institute of Medicine, Shaping the Future for Health.
        The National Academies Press, Washington, DC2011
        • Rim C.H.
        • Yim H.J.
        • Park S.
        • Seong J.
        Recent clinical applications of external beam radiotherapy for hepatocellular carcinoma according to guidelines, major trials and meta-analyses.
        J Med Imaging Radiat Oncol. 2019;
        • Association K.L.C.
        2018 Korean liver cancer association-national cancer center Korea practice guidelines for the management of hepatocellular carcinoma.
        Gut and Liver. 2019; 13: 227-299
        • Bossé D.
        • Ng T.
        • Ahmad C.
        • Alfakeeh A.
        • Alruzug I.
        • Biagi J.
        • et al.
        Eastern Canadian gastrointestinal cancer consensus conference 2016.
        Current Oncol. 2016; 23e605
        • Burak K.W.
        • Sherman M.
        Hepatocellular carcinoma: consensus, controversies and future directions: a report from the Canadian Association for the Study of the Liver Hepatocellular Carcinoma Meeting.
        Can J Gastroenterol Hepatol. 2015; 29: 178-184
        • Cheung T.T.-T.
        • Kwok P.C.-H.
        • Chan S.
        • Cheung C.-C.
        • Lee A.-S.
        • Lee V.
        • et al.
        Kong consensus statements for the management of unresectable hepatocellular carcinoma.
        Liver Cancer. 2018; 7: 40-54
        • Chow P.K.
        • Choo S.P.
        • Ng D.C.
        • Lo R.H.
        • Wang M.L.
        • Toh H.C.
        • et al.
        National cancer centre Singapore consensus guidelines for hepatocellular carcinoma.
        Liver Cancer. 2016; 5: 97-106
        • Feliu J.
        • Sastre J.
        • Maurel J.
        • Isla D.
        Hepatocellular and biliary tract carcinomas: SEOM clinical guidelines.
        Clin Transl Oncol. 2011; 13: 536-544
        • Forner A.
        • Reig M.
        • Varela M.
        • Burrel M.
        • Feliu J.
        • Briceño J.
        • et al.
        Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH.
        Medicina Clínica (English Edition). 2016; 146 (511. e1-. e22)
        • Galle P.R.
        • Forner A.
        • Llovet J.M.
        • Mazzaferro V.
        • Piscaglia F.
        • Raoul J.-L.
        • et al.
        EASL clinical practice guidelines: management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Heimbach J.K.
        • Kulik L.M.
        • Finn R.S.
        • Sirlin C.B.
        • Abecassis M.M.
        • Roberts L.R.
        • et al.
        AASLD guidelines for the treatment of hepatocellular carcinoma.
        Hepatology. 2018; 67: 358-380
        • Hsu C.
        • Chen B.-B.
        • Chen C.-H.
        • Ho M.-C.
        • Cheng J.C.-H.
        • Kokudo N.
        • et al.
        Consensus development from the 5th Asia-Pacific primary liver cancer expert meeting (APPLE 2014).
        Liver Cancer. 2015; 4: 96-105
        • Kumar A.
        • Acharya S.K.
        • Singh S.P.
        • Saraswat V.A.
        • Arora A.
        • Duseja A.
        • et al.
        The Indian National Association for Study of the Liver (INASL) consensus on prevention, diagnosis and management of hepatocellular carcinoma in India: the Puri recommendations.
        J Clin Experiment Hepatol. 2014; 4: S3-S26
        • Lu S.-N.
        • Wang J.-H.
        • Su C.-W.
        • Wang T.-E.
        • Dai C.-Y.
        • Chen C.-H.
        • et al.
        Management consensus guideline for hepatocellular carcinoma: 2016 updated by the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan.
        J Formos Med Assoc. 2018; 117: 381-403
        • Méndez-Sánchez N.
        • Ridruejo E.
        • de Mattos A.A.
        • Chávez-Tapia N.C.
        • Zapata R.
        • Paraná R.
        • et al.
        Latin American Association for the Study of the Liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma.
        Ann Hepatol. 2014; 13: S4-S40
        • Omata M.
        • Cheng A.-L.
        • Kokudo N.
        • Kudo M.
        • Lee J.M.
        • Jia J.
        • et al.
        Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
        Hep Intl. 2017; 11: 317-370
        • Vogel A.
        • Cervantes A.
        • Chau I.
        • Daniele B.
        • Llovet J.
        • Meyer T.
        • et al.
        Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2018; 29: iv238-iv55
        • Zhou J.
        • Sun H.-C.
        • Wang Z.
        • Cong W.-M.
        • Wang J.-H.
        • Zeng M.-S.
        • et al.
        Guidelines for diagnosis and treatment of primary liver cancer in China (2017 edition).
        Liver Cancer. 2018; 7: 235-260
        • Pan C.C.
        • Kavanagh B.D.
        • Dawson L.A.
        • Li X.A.
        • Das S.K.
        • Miften M.
        • et al.
        Radiation-associated liver injury.
        Int J Radiat Oncol Biol Phys. 2010; 76: S94-S100
        • Rim C.H.
        • Seong J.
        Application of radiotherapy for hepatocellular carcinoma in current clinical practice guidelines.
        Radiat Oncol J. 2016; 34: 160-167
        • Rim C.H.
        • Kim C.Y.
        • Yang D.S.
        • Yoon W.S.
        Comparison of radiation therapy modalities for hepatocellular carcinoma with portal vein thrombosis: A meta-analysis and systematic review.
        Radiother Oncol. 2018; 129: 112-122
        • Rim C.H.
        • Kim H.J.
        • Seong J.
        Clinical feasibility and efficacy of stereotactic body radiotherapy for hepatocellular carcinoma: A systematic review and meta-analysis of observational studies.
        Radiother Oncol. 2019; 131: 135-144
      2. National Comprehensive Cancer Network (NCCN)®. NCCN Guidelines version 1. 2018, hepatobiliary cancers. Available from: Accessed April 2, 2018.

        • Brouwers M.C.
        • Kho M.E.
        • Browman G.P.
        • Burgers J.S.
        • Cluzeau F.
        • Feder G.
        • et al.
        AGREE II: advancing guideline development, reporting and evaluation in health care.
        CMAJ. 2010; 182: E839-E842
        • Foerster F.
        • Galle P.R.
        Hepatocellular carcinoma: one world, one cancer—different guidelines?.
        Hepatobil Surg Nutr. 2018; 7: 41-43
        • Gavriilidis P.
        • Roberts K.J.
        • Askari A.
        • Sutcliffe R.P.
        • Liu P.-H.
        • Hidalgo E.
        • et al.
        Evaluation of the current guidelines for resection of hepatocellular carcinoma using the Appraisal of Guidelines for Research and Evaluation II instrument.
        J Hepatol. 2017; 67: 991-998
        • Yu S.J.
        A concise review of updated guidelines regarding the management of hepatocellular carcinoma around the world: 2010–2016.
        Clin Mol Hepatol. 2016; 22: 7-17
      3. National Cancer Comprehensive Network. NCCN guidelines version 2.2019, Hepatobiliary cancers. Assessed April 1st, 2019. available at:

      4. Egyptian Society of Liver Cancer. Egyptian Guidelines for Management of Hepatocellular Carcinoma. 2011. assesed April 2nd, 2019. Available at:

      5. Yu Y. Feng M. Radiotherapy for hepatocellular carcinoma. Seminars in radiation oncology. Elsevier, 2018
        • Holvoet T.
        • Raevens S.
        • Vandewynckel Y.-P.
        • Van Biesen W.
        • Geboes K.
        • Van Vlierberghe H.
        Systematic review of guidelines for management of intermediate hepatocellular carcinoma using the Appraisal of Guidelines Research and Evaluation II instrument.
        Digestive Liver Disease. 2015; 47: 877-883
        • Alonso-Coello P.
        • Irfan A.
        • Solà I.
        • Gich I.
        • Delgado-Noguera M.
        • Rigau D.
        • et al.
        The quality of clinical practice guidelines over the last two decades: a systematic review of guideline appraisal studies.
        Qual Saf Health Care. 2010; 19e58
        • Llovet J.M.
        • Brú C.
        • Bruix J.
        Prognosis of hepatocellular carcinoma: the BCLC staging classification.
        Semin Liver Dis. 1999; 19: 329-338
      6. National Cancer Comprehensive Network. NCCN Categories of Evidence and Consensus. Available at: Assessed Oct 2nd, 2019.

        • Foerster F.
        • Galle P.R.
        Comparison of the current international guidelines on the management of HCC.
        Jhep Rep. 2019; 1: 114-119
        • Wang Y.
        • Luo Q.
        • Li Y.
        • Wang H.
        • Deng S.
        • Wei S.
        • et al.
        Quality assessment of clinical practice guidelines on the treatment of hepatocellular carcinoma or metastatic liver cancer.
        PLoS One. 2014; 9e103939
      7. Pocock SJ, Stone GWJNEJoM. The primary outcome is positive—is that good enough? 2016;375(10):971-9.

      8. Agarwal PD, Phillips P, Hillman L, Lucey MR, Lee F, Mezrich JD, et al. Multidisciplinary management of hepatocellular carcinoma improves access to therapy and patient survival. 2017;51(9):845-9.