Reference Citation Analysis: Find an Article, Find a Category, Find a Journal, Find a Scholar

For: Chow PKH, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, Soo KC. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. Hepatology 2002;36:1221-6. [PMID: 12395333 DOI: 10.1053/jhep.2002.36824] [Citation(s) in RCA: 150] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]

For:	Chow PKH, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, Soo KC. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. Hepatology 2002;36:1221-6. [PMID: 12395333 DOI: 10.1053/jhep.2002.36824] [Citation(s) in RCA: 150] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]

Number

Cited by Other Article(s)

Zhang JW, Zhang N, Lyu Y, Zhang XF. Influence of Sex in the Development of Liver Diseases. Semin Liver Dis 2025;45:15-32. [PMID: 39809453 DOI: 10.1055/a-2516-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]

Affiliation(s)

Jie-Wen Zhang Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
Nan Zhang Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
Yi Lyu Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
Xu-Feng Zhang Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China

Collapse

Boye A, Osei SA, Brah AS. Therapeutic prospects of sex hormone receptor signaling in hormone-responsive cancers. Biomed Pharmacother 2024;180:117473. [PMID: 39326105 DOI: 10.1016/j.biopha.2024.117473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/11/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open

Naing C, Ni H, Aung HH. Tamoxifen for adults with hepatocellular carcinoma. Cochrane Database Syst Rev 2024;8:CD014869. [PMID: 39132750 PMCID: PMC11318082 DOI: 10.1002/14651858.cd014869.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]

Abstract

RATIONALE

Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Tamoxifen has been evaluated in randomised clinical trials in people with hepatocellular cancer. The reported results have been inconsistent.

OBJECTIVES

To evaluate the benefits and harms of tamoxifen or tamoxifen plus any other anticancer drugs compared with no intervention, placebo, any type of standard care, or alternative treatment in adults with hepatocellular carcinoma, irrespective of sex, administered dose, type of formulation, and duration of treatment.

SEARCH METHODS

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and major trials registries, and handsearched reference lists up to 26 March 2024.

ELIGIBILITY CRITERIA

Parallel-group randomised clinical trials including adults (aged 18 years and above) diagnosed with advanced or unresectable hepatocellular carcinoma. Had we found cross-over trials, we would have included only the first trial phase. We did not consider data from quasi-randomised trials for analysis.

OUTCOMES

Our critical outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our important outcomes were disease progression, and adverse events considered non-serious.

RISK OF BIAS

We assessed risk of bias using the RoB 2 tool.

SYNTHESIS METHODS

We used standard Cochrane methods and Review Manager. We meta-analysed the outcome data at the longest follow-up. We presented the results of dichotomous outcomes as risk ratios (RR) and continuous data as mean difference (MD), with 95% confidence intervals (CI) using the random-effects model. We summarised the certainty of evidence using GRADE.

INCLUDED STUDIES

We included 10 trials that randomised 1715 participants with advanced, unresectable, or terminal stage hepatocellular carcinoma. Six were single-centre trials conducted in Hong Kong, Italy, and Spain, while three were conducted as multicentre trials in single countries (France, Italy, and Spain), and one trial was conducted in nine countries in the Asia-Pacific region (Australia, Hong Kong, Indonesia, Malaysia, Myanmar, New Zealand, Singapore, South Korea, and Thailand). The experimental intervention was tamoxifen in all trials. The control interventions were no intervention (three trials), placebo (six trials), and symptomatic treatment (one trial). Co-interventions were best supportive care (three trials) and standard care (one trial). The remaining six trials did not provide this information. The number of participants in the trials ranged from 22 to 496 (median 99), mean age was 63.7 (standard deviation 4.18) years, and mean proportion of men was 74.7% (standard deviation 42%). Follow-up was three months to five years.

SYNTHESIS OF RESULTS

Ten trials evaluated oral tamoxifen at five different dosages (ranging from 20 mg per day to 120 mg per day). All trials investigated one or more of our outcomes. We performed meta-analyses when at least two trials assessed similar types of tamoxifen versus similar control interventions. Eight trials evaluated all-cause mortality at varied follow-up points. Tamoxifen versus the control interventions (i.e. no treatment, placebo, and symptomatic treatment) results in little to no difference in mortality between one and five years (RR 0.99, 95% CI 0.92 to 1.06; 8 trials, 1364 participants; low-certainty evidence). In total, 488/682 (71.5%) participants died in the tamoxifen groups versus 487/682 (71.4%) in the control groups. The separate analysis results for one, between two and three, and five years were comparable to the analysis result for all follow-up periods taken together. The evidence is very uncertain about the effect of tamoxifen versus no treatment on serious adverse events at one-year follow-up (RR 0.44, 95% CI 0.19 to 1.06; 1 trial, 36 participants; very low-certainty evidence). A total of 5/20 (25.0%) participants in the tamoxifen group versus 9/16 (56.3%) participants in the control group experienced serious adverse events. One trial measured health-related quality of life at baseline and at nine months' follow-up, using the Spitzer Quality of Life Index. The evidence is very uncertain about the effect of tamoxifen versus no treatment on health-related quality of life (MD 0.03, 95% CI -0.45 to 0.51; 1 trial, 420 participants; very low-certainty evidence). A second trial found no appreciable difference in global health-related quality of life scores. No further data were provided. Tamoxifen versus control interventions (i.e. no treatment, placebo, or symptomatic treatment) results in little to no difference in disease progression between one and five years' follow-up (RR 1.02, 95% CI 0.91 to 1.14; 4 trials, 720 participants; low-certainty evidence). A total of 191/358 (53.3%) participants in the tamoxifen group versus 198/362 (54.7%) participants in the control group had progression of hepatocellular carcinoma. Tamoxifen versus control interventions (i.e. no treatment or placebo) may have little to no effect on adverse events considered non-serious during treatment, but the evidence is very uncertain (RR 1.17, 95% CI 0.45 to 3.06; 4 trials, 462 participants; very low-certainty evidence). A total of 10/265 (3.8%) participants in the tamoxifen group versus 6/197 (3.0%) participants in the control group had adverse events considered non-serious. We identified no trials with participants diagnosed with early stages of hepatocellular carcinoma. We identified no ongoing trials.

AUTHORS' CONCLUSIONS

Based on the low- and very low-certainty evidence, the effects of tamoxifen on all-cause mortality, disease progression, serious adverse events, health-related quality of life, and adverse events considered non-serious in adults with advanced, unresectable, or terminal stage hepatocellular carcinoma when compared with no intervention, placebo, or symptomatic treatment could not be established. Our findings are mostly based on trials at high risk of bias with insufficient power (fewer than 100 participants), and a lack of trial data on clinically important outcomes. Therefore, firm conclusions cannot be drawn. Trials comparing tamoxifen administered with any other anticancer drug versus standard care, usual care, or alternative treatment as control interventions were lacking. Evidence on the benefits and harms of tamoxifen in participants at the early stages of hepatocellular carcinoma was also lacking.

FUNDING

This Cochrane review had no dedicated funding.

REGISTRATION

Protocol available via DOI: 10.1002/14651858.CD014869.

Collapse

Nie Y, Yan J, Huang X, Jiang T, Zhang S, Zhang G. Dihydrotanshinone I targets ESR1 to induce DNA double-strand breaks and proliferation inhibition in hepatocellular carcinoma. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024;130:155767. [PMID: 38833789 DOI: 10.1016/j.phymed.2024.155767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 02/28/2024] [Accepted: 03/28/2024] [Indexed: 06/06/2024]

Abstract

BACKGROUND

Due to its high incidence and elevated mortality, hepatocellular carcinoma (HCC) has emerged as a formidable global healthcare challenge. The intricate interplay between gender-specific disparities in both incidence and clinical outcomes has prompted a progressive recognition of the substantial influence exerted by estrogen and its corresponding receptors (ERs) upon HCC pathogenesis. Estrogen replacement therapy (ERT) emerged for the treatment of HCC by administering exogenous estrogen. However, the powerful side effects of estrogen, including the promotion of breast cancer and infertility, hinder the further application of ERT. Identifying effective therapeutic targets for estrogen and screening bioactive ingredients without E2-like side effects is of great significance for optimizing HCC ERT.

METHODS

In this study, we employed an integrative approach, harnessing data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, clinical paraffin sections, adenoviral constructs as well as in vivo studies, to unveil the association between estrogen, estrogen receptor α (ESR1) and HCC. Leveraging methodologies encompassing molecular dynamics simulation and cellular thermal shift assay (CETSA) were used to confirm whether ESR1 is a molecular target of DHT. Multiple in vitro and in vivo experiments were used to identify whether i) ESR1 is a crucial gene that promotes DNA double-strand breaks (DSBs) and proliferation inhibition in HCC, ii) Dihydrotanshinone I (DHT), a quinonoid monomeric constituent derived from Salvia miltiorrhiza (Dan shen) exerts anti-HCC effects by regulating ESR1 and subsequent DSBs, iii) DHT has the potential to replace E2.

RESULTS

DHT could target ESR1 and upregulate its expression in a concentration-dependent manner. This, in turn, leads to the downregulation of breast cancer type 1 susceptibility protein (BRCA1), a pivotal protein involved in the homologous recombination repair (HRR) process. The consequence of this downregulation is manifested through the induction of DSBs in HCC, subsequently precipitating a cascade of downstream events, including apoptosis and cell cycle arrest. Of particular significance is the comparative assessment of DHT and isodose estradiol treatments, which underscores DHT's excellent HCC-suppressive efficacy without concomitant perturbation of endogenous sex hormone homeostasis.

CONCLUSION

Our findings not only confirm ESR1 as a therapeutic target in HCC management but also underscores DHT's role in upregulating ESR1 expression, thereby impeding the proliferation and invasive tendencies of HCC. In addition, we preliminarily identified DHT has the potential to emerge as an agent in optimizing HCC ERT through the substitution of E2.

Collapse

Nuermaimaiti A, Chang L, Yan Y, Sun H, Xiao Y, Song S, Feng K, Lu Z, Ji H, Wang L. The role of sex hormones and receptors in HBV infection and development of HBV-related HCC. J Med Virol 2023;95:e29298. [PMID: 38087447 DOI: 10.1002/jmv.29298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/02/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023]

Affiliation(s)

Abudulimutailipu Nuermaimaiti National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Le Chang National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
Ying Yan National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
Huizhen Sun National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Yingzi Xiao National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Shi Song National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Kaihao Feng National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Zhuoqun Lu National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
Huimin Ji National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
Lunan Wang National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

Collapse

Chu YD, Chen CW, Lai MW, Lim SN, Lin WR. Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly. World J Gastroenterol 2023;29:4499-4527. [PMID: 37621758 PMCID: PMC10445009 DOI: 10.3748/wjg.v29.i29.4499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/02/2023] Open

Abstract

Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.

Collapse

Nevola R, Tortorella G, Rosato V, Rinaldi L, Imbriani S, Perillo P, Mastrocinque D, La Montagna M, Russo A, Di Lorenzo G, Alfano M, Rocco M, Ricozzi C, Gjeloshi K, Sasso FC, Marfella R, Marrone A, Kondili LA, Esposito N, Claar E, Cozzolino D. Gender Differences in the Pathogenesis and Risk Factors of Hepatocellular Carcinoma. BIOLOGY 2023;12:984. [PMID: 37508414 PMCID: PMC10376683 DOI: 10.3390/biology12070984] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/30/2023]

Affiliation(s)

Riccardo Nevola Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.) Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (D.M.); (N.E.); (E.C.)
Giovanni Tortorella Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Valerio Rosato Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (D.M.); (N.E.); (E.C.)
Luca Rinaldi Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Simona Imbriani Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Pasquale Perillo Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (D.M.); (N.E.); (E.C.)
Davide Mastrocinque Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (D.M.); (N.E.); (E.C.)
Marco La Montagna Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Antonio Russo Department of Mental Health and Public Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
Giovanni Di Lorenzo Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Maria Alfano Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Maria Rocco Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Carmen Ricozzi Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Klodian Gjeloshi Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Ferdinando Carlo Sasso Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Raffaele Marfella Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Aldo Marrone Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)
Loreta Anesti Kondili Center for Global Health, Istituto Superiore di Sanità, 00161 Rome, Italy;
Nicolino Esposito Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (D.M.); (N.E.); (E.C.)
Ernesto Claar Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (D.M.); (N.E.); (E.C.)
Domenico Cozzolino Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.T.); (L.R.); (S.I.); (M.L.M.); (G.D.L.); (M.A.); (M.R.); (C.R.); (K.G.); (F.C.S.); (R.M.); (A.M.); (D.C.)

Collapse

Merle P, Blanc JF, Edeline J, Le Malicot K, Allaire M, Assenat E, Guarssifi M, Bouattour M, Péron JM, Laurent-Puig P, Levrero M, Costentin C, Guiu B, Sokol H, Tougeron D, Aparicio T, Nault JC, Phelip JM. Ipilimumab with atezolizumab-bevacizumab in patients with advanced hepatocellular carcinoma: The PRODIGE 81-FFCD 2101-TRIPLET-HCC trial. Dig Liver Dis 2023;55:464-470. [PMID: 36804053 DOI: 10.1016/j.dld.2023.01.161] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 01/27/2023] [Indexed: 02/23/2023]

Affiliation(s)

Philippe Merle Hepatology Unit, University Hospital La Croix-Rousse, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Jean-Frédéric Blanc University Hospital of Bordeaux, Digestive Oncology Unit, Bordeaux, France
Julien Edeline INSERM, Univ Rennes, Department of Medical Oncology, CLCC Eugène Marquis, COSS [(Chemistry Oncogenesis Stress Signaling)] - UMR_S 1242, Rennes, France
Karine Le Malicot Fédération Francophone de Cancérologie Digestive, EPICAD INSERM LNC-UMR 1231, Bourgogne Franche-Comté University, Dijon, France
Manon Allaire AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France
Eric Assenat Medical Oncology, St-Eloi University Hospital, Montpellier, France
Meriem Guarssifi Fédération Francophone de Cancérologie Digestive, EPICAD INSERM LNC-UMR 1231, Bourgogne Franche-Comté University, Dijon, France
Mohamed Bouattour AP-HP, Hôpital Universitaire Beaujon, Unité Fonctionnelle Oncologie Hépatique et Innovation Thérapeutique, Clichy France
Jean-Marie Péron Service d'Hépato-Gastroentérologie, Hôpital Purpan, Toulouse, France
Pierre Laurent-Puig INSERM U 775 - Faculté des Sciences Fondamentales et Biomédicales, Center Universitaire des Saints-Pères, Université des Saints Pères, Paris Descartes, Paris, France
Massimo Levrero Hepatology Unit, University Hospital La Croix-Rousse, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France
Charlotte Costentin Grenoble Alpes University, Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, Gastroenterology, hepatology and GI oncology department, Digidune, Grenoble Alpes University Hospital, La Tronche, France
Boris Guiu Department of Radiology, St-Eloi University Hospital, Montpellier, France
Harry Sokol Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint-Antoine Hospital, Gastroenterology Department, Paris, France; Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France; Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris, France
David Tougeron Department of Hepato-Gastroenterology, University Hospital of Poitiers, Poitiers, France
Thomas Aparicio Service de Gastroentérologie, Hôpital Saint Louis, APHP, Université de Paris, Paris, France
Jean-Charles Nault AP-HP Paris Nord, Hôpital Universitaire Avicenne, Service d'hépatologie, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, team « Functional Genomics of Solid Tumors », Paris, France; Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, France
Jean-Marc Phelip Service d'Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Nord de Saint -Etienne, Saint Priest en Jarez, France

Collapse

The neuroprotective effects of estrogen and estrogenic compounds in spinal cord injury. Neurosci Biobehav Rev 2023;146:105074. [PMID: 36736846 DOI: 10.1016/j.neubiorev.2023.105074] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 01/29/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]

Xu C, Cheng S, Chen K, Song Q, Liu C, Fan C, Zhang R, Zhu Q, Wu Z, Wang Y, Fan J, Zheng H, Lu L, Chen T, Zhao H, Jiao Y, Qu C. Sex Differences in Genomic Features of Hepatitis B-Associated Hepatocellular Carcinoma With Distinct Antitumor Immunity. Cell Mol Gastroenterol Hepatol 2022;15:327-354. [PMID: 36272708 PMCID: PMC9772570 DOI: 10.1016/j.jcmgh.2022.10.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 10/13/2022] [Accepted: 10/13/2022] [Indexed: 01/28/2023]

Abstract

BACKGROUND & AIMS

Aflatoxin exposure increases the risk for hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-infected individuals, particularly males. We investigated sex-based differences in the HCC genome and antitumor immunity.

METHODS

Whole-genome, whole-exome, and RNA sequencing were performed on 101 HCC patient samples (47 males, 54 females) that resulted from HBV infection and aflatoxin exposure from Qidong. Androgen on the expression of aflatoxin metabolism-related genes and nonhomologous DNA end joining (NHEJ) factors were examined in HBV-positive HCC cell lines, and further tested in tumor-bearing syngeneic mice.

RESULTS

Qidong HCC differed between males and females in genomic landscape and transcriptional dysfunction pathways. Compared with females, males expressed higher levels of aflatoxin metabolism-related genes, such as AHR and CYP1A1, and lower levels of NHEJ factors, such as XRCC4, LIG4, and MRE11, showed a signature of up-regulated type I interferon signaling/response and repressed antitumor immunity. Treatment with AFB1 in HBV-positive cells, the addition of 2 nmol/L testosterone to cultures significantly increased the expression of aflatoxin metabolism-related genes, but reduced NHEJ factors, resulting in more nuclear DNA leakage into cytosol to activate cGAS-STING. In syngeneic tumor-bearing mice that were administrated tamoxifen daily via oral gavage, favorable androgen signaling repressed NHEJ factor expression and activated cGAS-STING in tumors, increasing T-cell infiltration and improving anti-programmed cell death protein 1 treatment effect.

CONCLUSIONS

Androgen signaling in the context of genotoxic stress repressed DNA damage repair. The alteration caused more nuclear DNA leakage into cytosol to activate the cGAS-STING pathway, which increased T-cell infiltration into tumor mass and improved anti-programmed cell death protein 1 immunotherapy in HCCs.

Collapse

Affiliation(s)

Chungui Xu State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Shaoyan Cheng State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Kun Chen State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Qianqian Song State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Chang Liu State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Chunsun Fan Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
Ruochan Zhang State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Qing Zhu State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Zhiyuan Wu State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Yuting Wang State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Jian Fan Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
Hongwei Zheng Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
Lingling Lu Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
Taoyang Chen Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
Hong Zhao State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Yuchen Jiao State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Chunfeng Qu State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.

Collapse

Kim DH. Combination of interventional oncology local therapies and immunotherapy for the treatment of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2022;22:93-102. [PMID: 37383404 PMCID: PMC10035730 DOI: 10.17998/jlc.2022.03.28] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/18/2022] [Accepted: 03/28/2022] [Indexed: 06/30/2023]

Wang R, Chen J, Yu H, Wei Z, Ma M, Ye X, Wu W, Chen H, Fu Z. Downregulation of estrogen receptor-α36 expression attenuates metastasis of hepatocellular carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2022;37:1113-1123. [PMID: 35044086 DOI: 10.1002/tox.23469] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 06/14/2023]

Meng X, Liu X. Therapeutic Value of Estrogen Receptor α in Hepatocellular Carcinoma Based on Molecular Mechanisms. J Clin Transl Hepatol 2022;10:140-146. [PMID: 35233383 PMCID: PMC8845150 DOI: 10.14218/jcth.2021.00224] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 12/04/2022] Open

Hendi M, Mou Y, Lv J, Zhang B, Cai X. Hepatic Arterial Infusion Chemotherapy Is a Feasible Treatment Option for Hepatocellular Carcinoma: A New Update. Gastrointest Tumors 2021;8:145-152. [PMID: 34722467 DOI: 10.1159/000516405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/28/2021] [Indexed: 12/24/2022] Open

Finney CA, Shvetcov A, Westbrook RF, Morris MJ, Jones NM. Tamoxifen offers long-term neuroprotection after hippocampal silent infarct in male rats. Horm Behav 2021;136:105085. [PMID: 34749277 DOI: 10.1016/j.yhbeh.2021.105085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 11/19/2022]

Haber PK, Puigvehí M, Castet F, Lourdusamy V, Montal R, Tabrizian P, Buckstein M, Kim E, Villanueva A, Schwartz M, Llovet JM. Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002-2020). Gastroenterology 2021;161:879-898. [PMID: 34126063 DOI: 10.1053/j.gastro.2021.06.008] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 12/20/2022]

Affiliation(s)

Philipp K Haber Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Marc Puigvehí Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hepatology Section, Gastroenterology Department, Parc de Salut Mar, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
Florian Castet Translational Research in Hepatic Oncology, Liver Unit, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Hospital Clinic, University of Barcelona, Catalonia, Spain
Vennis Lourdusamy Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Robert Montal Cancer Biomarkers Research Group, Department of Medical Oncology, Hospital Universitari Arnau de Vilanova-IRBLleida, Lleida, Catalonia, Spain
Parissa Tabrizian Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Michael Buckstein Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Edward Kim Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Augusto Villanueva Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Myron Schwartz Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Josep M Llovet Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Translational Research in Hepatic Oncology, Liver Unit, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Hospital Clinic, University of Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.

Collapse

El-Kaream SAA, Ebied SAEM, Sadek NA, Saad DM, Nadwan EA. Serum estrogen and its soluble receptor levels in Egyptian patients with acute leukemia: case-control study. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-021-00186-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open

Finney CA, Shvetcov A, Westbrook RF, Morris MJ, Jones NM. The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury 24 h after hippocampal silent infarct in male Sprague-Dawley rats. Horm Behav 2021;134:105016. [PMID: 34242875 DOI: 10.1016/j.yhbeh.2021.105016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 06/03/2021] [Accepted: 06/05/2021] [Indexed: 02/07/2023]

Wohlleber K, Heger P, Probst P, Engel C, Diener MK, Mihaljevic AL. Health-related quality of life in primary hepatic cancer: a systematic review assessing the methodological properties of instruments and a meta-analysis comparing treatment strategies. Qual Life Res 2021;30:2429-2466. [PMID: 34283381 PMCID: PMC8405513 DOI: 10.1007/s11136-021-02810-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 11/25/2022]

Abstract

PURPOSE

Patient-reported outcomes including health-related quality of life (HRQoL) are important oncological outcome measures. The validation of HRQoL instruments for patients with hepatocellular and cholangiocellular carcinoma is lacking. Furthermore, studies comparing different treatment options in respect to HRQoL are sparse. The objective of the systematic review and meta-analysis was, therefore, to identify all available HRQoL tools regarding primary liver cancer, to assess the methodological quality of these HRQoL instruments and to compare surgical, interventional and medical treatments with regard to HRQoL.

METHODS

A systematic literature search was conducted in MEDLINE, the Cochrane library, PsycINFO, CINAHL and EMBASE. The methodological quality of all identified HRQoL instruments was performed according to the COnsensus-based Standards for the selection of health status Measurements INstruments (COSMIN) standard. Consequently, the quality of reporting of HRQoL data was assessed. Finally, wherever possible HRQoL data were extracted and quantitative analyses were performed.

RESULTS

A total of 124 studies using 29 different HRQoL instruments were identified. After the methodological assessment, only 10 instruments fulfilled the psychometric criteria and could be included in subsequent analyses. However, quality of reporting of HRQoL data was insufficient, precluding meta-analyses for 9 instruments.

CONCLUSION

Using a standardized methodological assessment, specific HRQoL instruments are recommended for use in patients with hepatocellular and cholangiocellular carcinoma. HRQoL data of patients undergoing treatment of primary liver cancers are sparse and reporting falls short of published standards. Meaningful comparison of established treatment options with regard to HRQoL was impossible indicating the need for future research.

Collapse

Qin S, Li Q, Gu S, Chen X, Lin L, Wang Z, Xu A, Chen X, Zhou C, Ren Z, Yang L, Xu L, Bai Y, Chen L, Li J, Pan H, Cao B, Fang W, Wu W, Wang G, Cheng Y, Yu Z, Zhu X, Jiang D, Lu Y, Wang H, Xu J, Bai L, Liu Y, Lin H, Wu C, Zhang Y, Yan P, Jin C, Zou J. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2021;6:559-568. [PMID: 33971141 DOI: 10.1016/s2468-1253(21)00109-6] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023]

Abstract

BACKGROUND

Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumour activity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitors have been done in populations with a high prevalence of hepatitis B virus infection. The aim of this study was to evaluate the efficacy and safety of apatinib in patients with pretreated advanced hepatocellular carcinoma.

METHODS

AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31 hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinoma who had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receive apatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocation was done with a central randomisation system, with a block size of six, and was stratified by Eastern Cooperative Oncology Group performance status, previous sorafenib treatment, and presence of vascular invasion or extrahepatic metastasis. The primary endpoint was overall survival, which was defined as time from randomisation to death from any cause, and was analysed in patients who were randomly assigned and received at least one dose of the study drug. Safety analyses were done in patients who received at least one dose of the study treatment and had post-dose safety assessments. This trial is registered with ClinicalTrials.gov, NCT02329860.

FINDINGS

Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinib group and one in the placebo group) did not receive study treatment and were excluded from efficacy analyses. Overall survival was significantly improved in the apatinib group compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients (257 in the apatinib group and 130 in the placebo group) had a safety assessment after study treatment and were included in safety analyses. The most common treatment-related adverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinib group vs three [2%] in the placebo group), hand-foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo group died due to adverse events, but none of these deaths were deemed to be related to treatment by investigators.

INTERPRETATION

Apatinib significantly improved overall survival in patients with pretreated advanced hepatocellular carcinoma compared with placebo, with a manageable safety profile.

FUNDING

Jiangsu Hengrui Medicine.

Collapse

Affiliation(s)

Shukui Qin Department of Medical Oncology, Cancer Center of Bayi Hospital, Nanjing Chinese Medicine University, Nanjing, China.
Qiu Li Cancer Center, West China Hospital, Sichuan University, Chengdu, China
Shanzhi Gu Department of Intervention, Hunan Cancer Hospital, Changsha, China
Xiaoming Chen Department of Invasive Technology, Guangdong Provincial People's Hospital, Guangzhou, China
Lizhu Lin Cancer Center, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
Zishu Wang Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
Aibing Xu Department of Interventional Therapy, Nantong Tumor Hospital, Nantong, China
Xi Chen Department of Oncology, The 900th Hospital of Joint Logistics Support Force, Fuzhou, China
Cuncai Zhou Department of Hepatobiliary Interventional, Jiangxi Cancer Hospital, Nanchang, China
Zhenggang Ren Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
Lin Yang Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Li Xu Department of Hepatobiliary and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
Yuxian Bai Department of Gastroenterology, Harbin Medical University Cancer Hospital, Harbin, China
Lei Chen Department of Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China
Jun Li Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Hongming Pan Department of Oncology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine, Hangzhou, China
Bangwei Cao Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Weijia Fang Department of Oncology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
Wei Wu Department of Hepatopathy, The Sixth People's Hospital of Shenyang, Shenyang, China
Ge Wang Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
Ying Cheng Department of Internal Medicine-Oncology, Jilin Cancer Hospital, Changchun, China
Zhuang Yu Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
Xu Zhu Department of Interventional Therapy Unit, Beijing Cancer Hospital, Beijing, China
Da Jiang Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
Yinying Lu Comprehensive Liver Cancer Centre, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, China
Huaming Wang Department of Interventional Therapy, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, China
Jianming Xu Department of Digestive Oncology, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, China
Li Bai Department of Oncology, Chinese PLA General Hospital, Beijing, China
Yunpeng Liu Department of Oncology, The First Hospital of China Medical University, Shenyang, China
Hailan Lin Department of Intervention, Fujian Cancer Hospital, Fuzhou, China
Changping Wu Department of Medical Oncology, The First People's Hospital of Changzhou, Changzhou, China
Yang Zhang Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
Ping Yan Clinical Research and Development, Jiangsu Hengrui Medicine, Shanghai, China
Chunlei Jin Clinical Research and Development, Jiangsu Hengrui Medicine, Shanghai, China
Jianjun Zou Clinical Research and Development, Jiangsu Hengrui Medicine, Shanghai, China

Collapse

Merle P. The New Immuno-Oncology-Based Therapies and Their Perspectives in Hepatocellular Carcinoma. Cancers (Basel) 2021;13:cancers13020238. [PMID: 33440630 PMCID: PMC7826922 DOI: 10.3390/cancers13020238] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/03/2021] [Accepted: 01/07/2021] [Indexed: 12/13/2022] Open

Abstract

Simple Summary

Hepatocellular carcinoma is a frequent and poor prognosis tumor, with most patients facing up, soon or later, to systemic therapies. So far, systemic therapies based on tyrosine kinase inhibitor monotherapies have been of modest benefit. The aim of this review article was to characterize the profile of efficacy and safety of immuno-oncology-based monotherapies that failed to demonstrate significant benefit, for comparison with the immuno-oncology-based combinational strategies. One of them has proven its drastic benefit in phase-3, whereas others have only shown promising data in phase-1/2, although the corresponding phase-3 results are pending. We showed that objective response rates and duration of response are important parameters for increased median overall survival and long survivals. We also pointed out that, being aware that there is an urgent unmet need for biomarkers, the pattern of safety and quality of life will guide the physician for the choice on the possible future combinations.

Abstract

Hepatocellular carcinoma is a poor prognosis tumor. Systemic therapies are frequently used due to frequent recurrences after surgical or radiologic treatments. Anti-angiogenic tyrosine kinase inhibitors have shown efficacy in monotherapy, but with very low rates of long survival and exceptional recovery. Immuno-oncology based on immune checkpoint inhibitors has revolutionized the systemic therapies since showing long survival rates without any tumor progression or recurrence for some patients in partial or complete response, and possibly for some patients in stable disease. However, the rate of responders under immuno-oncology monotherapy is too low to increase significantly the median overall survival of the treated patients. The immuno-oncology-based combinations with different types of immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 inhibitors such as nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, tremelimumab), or the association of immune checkpoint inhibitors plus anti-angiogenic agents (bevacizumab, lenvatinib, cabozantinib), have led to a breakthrough in the treatment of hepatocellular carcinoma. Indeed, the first phase-3 trial, combining atezolizumab with bevacizumab, has dramatically changed the outcome of patients. Data from several other types of combinations assessed in phase-3 trials are pending, and if positive, will drastically arm the physicians to efficiently treat the patients, and disrupt the current algorithm of hepatocellular carcinoma treatment.

Collapse

Chan KS, Ho BCS, Shelat VG. A pilot study of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC). Transl Gastroenterol Hepatol 2021;6:9. [PMID: 33409403 PMCID: PMC7724184 DOI: 10.21037/tgh.2020.02.16] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/10/2020] [Indexed: 02/05/2023] Open

Guo Y, Wu G, Yi J, Yang Q, Jiang W, Lin S, Yang X, Cai X, Mao L. Anti-Hepatocellular Carcinoma Effect and Molecular Mechanism of the Estrogen Signaling Pathway. Front Oncol 2021;11:763539. [PMID: 35096574 PMCID: PMC8789654 DOI: 10.3389/fonc.2021.763539] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/14/2021] [Indexed: 12/18/2022] Open

Llovet JM, Villanueva A, Marrero JA, Schwartz M, Meyer T, Galle PR, Lencioni R, Greten TF, Kudo M, Mandrekar SJ, Zhu AX, Finn RS, Roberts LR. Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference. Hepatology 2021;73 Suppl 1:158-191. [PMID: 32430997 DOI: 10.1002/hep.31327] [Citation(s) in RCA: 260] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 12/13/2022]

Targeting the estrogen receptor alpha (ERα)-mediated circ-SMG1.72/miR-141-3p/Gelsolin signaling to better suppress the HCC cell invasion. Oncogene 2020;39:2493-2508. [PMID: 31996784 DOI: 10.1038/s41388-019-1150-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 12/03/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023]

Shwartz A, Goessling W, Yin C. Macrophages in Zebrafish Models of Liver Diseases. Front Immunol 2019;10:2840. [PMID: 31867007 PMCID: PMC6904306 DOI: 10.3389/fimmu.2019.02840] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 11/19/2019] [Indexed: 12/16/2022] Open

Li H, Lu JW, Huo X, Li Y, Li Z, Gong Z. Effects of sex hormones on liver tumor progression and regression in Myc/xmrk double oncogene transgenic zebrafish. Gen Comp Endocrinol 2019;277:112-121. [PMID: 30926469 DOI: 10.1016/j.ygcen.2019.03.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 03/21/2019] [Accepted: 03/24/2019] [Indexed: 02/07/2023]

Llovet JM, Montal R, Villanueva A. Randomized trials and endpoints in advanced HCC: Role of PFS as a surrogate of survival. J Hepatol 2019;70:1262-1277. [PMID: 30943423 DOI: 10.1016/j.jhep.2019.01.028] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 12/21/2018] [Accepted: 01/29/2019] [Indexed: 02/08/2023]

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Around half of patients with HCC will receive systemic therapies during their life span. The pivotal positive sorafenib trial and regulatory approval in 2007 was followed by a decade of negative studies with drugs leading to marginal antitumoral efficacy, toxicity, or trials with a lack of enrichment strategies. This trend has changed over the last 2 years with several compounds, such as lenvatinib (in first-line) and regorafenib, cabozantinib, ramucirumab and nivolumab (in second-line), showing clinical benefit. These successes came at a cost of increasing the complexity of decision-making, and ultimately, impacting the design of future clinical trials. Nowadays, life expectancy with single active agents has surpassed the threshold of 1 year and sequential strategies have provided encouraging outcomes. Overall survival (OS) remains the main endpoint in phase III investigations, but as in other solid tumours, there is a clear need to define surrogate endpoints that both reliably recapitulate survival benefits and can be assessed before additional efficacious drugs are administered. A thorough analysis of 21 phase III trials published in advanced HCC demonstrated a moderate correlation between progression-free survival (PFS) or time to progression (TTP) and OS (R = 0.84 and R = 0.83, respectively). Nonetheless, the significant differences in PFS identified in 7 phase III studies only correlated with differences in OS in 3 cases. In these cases, the hazard ratio (HR) for PFS was ≤0.6. Thus, this threshold is herein proposed as a potential surrogate endpoint of OS in advanced HCC. Conversely, PFS with an HR between 0.6-0.7, despite significance, was not associated with better survival, and thus these magnitudes are considered uncertain surrogates. In the current review, we discuss the reasons for positive or negative phase III trials in advanced HCC, and the strengths and limitations of surrogate endpoints (PFS, TTP and objective response rate [ORR]) to predict survival.

Collapse

Chaturantabut S, Shwartz A, Evason KJ, Cox AG, Labella K, Schepers AG, Yang S, Aravena M, Houvras Y, Mancio-Silva L, Romano S, Gorelick DA, Cohen DE, Zon LI, Bhatia SN, North TE, Goessling W. Estrogen Activation of G-Protein-Coupled Estrogen Receptor 1 Regulates Phosphoinositide 3-Kinase and mTOR Signaling to Promote Liver Growth in Zebrafish and Proliferation of Human Hepatocytes. Gastroenterology 2019;156:1788-1804.e13. [PMID: 30641053 PMCID: PMC6532055 DOI: 10.1053/j.gastro.2019.01.010] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/04/2019] [Accepted: 01/07/2019] [Indexed: 02/07/2023]

Abstract

BACKGROUND & AIMS

Patients with cirrhosis are at high risk for hepatocellular carcinoma (HCC) and often have increased serum levels of estrogen. It is not clear how estrogen promotes hepatic growth. We investigated the effects of estrogen on hepatocyte proliferation during zebrafish development, liver regeneration, and carcinogenesis. We also studied human hepatocytes and liver tissues.

METHODS

Zebrafish were exposed to selective modifiers of estrogen signaling at larval and adult stages. Liver growth was assessed by gene expression, fluorescent imaging, and histologic analyses. We monitored liver regeneration after hepatocyte ablation and HCC development after administration of chemical carcinogens (dimethylbenzanthrazene). Proliferation of human hepatocytes was measured in a coculture system. We measured levels of G-protein-coupled estrogen receptor (GPER1) in HCC and nontumor liver tissues from 68 patients by immunohistochemistry.

RESULTS

Exposure to 17β-estradiol (E2) increased proliferation of hepatocytes and liver volume and mass in larval and adult zebrafish. Chemical genetic and epistasis experiments showed that GPER1 mediates the effects of E2 via the phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin pathway: gper1-knockout and mtor-knockout zebrafish did not increase liver growth in response to E2. HCC samples from patients had increased levels of GPER1 compared with nontumor tissue samples; estrogen promoted proliferation of human primary hepatocytes. Estrogen accelerated hepatocarcinogenesis specifically in male zebrafish. Chemical inhibition or genetic loss of GPER1 significantly reduced tumor development in the zebrafish.

CONCLUSIONS

In an analysis of zebrafish and human liver cells and tissues, we found GPER1 to be a hepatic estrogen sensor that regulates liver growth during development, regeneration, and tumorigenesis. Inhibitors of GPER1 might be developed for liver cancer prevention or treatment.

TRANSCRIPT PROFILING

The accession number in the Gene Expression Omnibus is GSE92544.

Collapse

Affiliation(s)

Saireudee Chaturantabut Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Arkadi Shwartz Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Kimberley J. Evason Department of Pathology, University of Utah, Salt Lake City, Utah
Andrew G. Cox Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts;,3Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Kyle Labella Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Arnout G. Schepers Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
Song Yang Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts
Marianna Aravena Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York
Yariv Houvras Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York
Liliana Mancio-Silva Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
Shannon Romano Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama
Daniel A. Gorelick Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama
David E. Cohen Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York
Leonard I. Zon Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts;,9Howard Hughes Medical Institute, Chevy Chase, Maryland;,10Harvard Stem Cell Institute, Cambridge, Massachusetts;,11Dana-Farber Cancer Institute, Boston, Massachusetts
Sangeeta N. Bhatia Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts;,12Harvard–MIT Division of Health Sciences and Technology, Cambridge, Massachusetts;,13Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Trista E. North Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts;,10Harvard Stem Cell Institute, Cambridge, Massachusetts
Wolfram Goessling Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts; Dana-Farber Cancer Institute, Boston, Massachusetts; Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Divison of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts.

Collapse

Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies. Dig Dis Sci 2019;64:1016-1029. [PMID: 30887150 DOI: 10.1007/s10620-019-05582-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]

Zou J, Zhu W, Meng H, Luo P, Zhang J. Efficacy and safety of selective internal radiotherapy versus sorafenib for intermediate-locally advanced hepatocellular carcinoma: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2019;13:271-279. [PMID: 30791765 DOI: 10.1080/17474124.2019.1570135] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 2018;15:599-616. [PMID: 30061739 DOI: 10.1038/s41571-018-0073-4] [Citation(s) in RCA: 1347] [Impact Index Per Article: 192.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]

Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, Schirmacher P, Vilgrain V. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018;69:182-236. [PMID: 29628281 DOI: 10.1016/j.jhep.2018.03.019] [Citation(s) in RCA: 5888] [Impact Index Per Article: 841.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 02/06/2023]

Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, Choo SP, Cheow PC, Chotipanich C, Lim K, Lesmana LA, Manuaba TW, Yoong BK, Raj A, Law CS, Cua IHY, Lobo RR, Teh CSC, Kim YH, Jong YW, Han HS, Bae SH, Yoon HK, Lee RC, Hung CF, Peng CY, Liang PC, Bartlett A, Kok KYY, Thng CH, Low ASC, Goh ASW, Tay KH, Lo RHG, Goh BKP, Ng DCE, Lekurwale G, Liew WM, Gebski V, Mak KSW, Soo KC. SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma. J Clin Oncol 2018;36:1913-1921. [PMID: 29498924 DOI: 10.1200/jco.2017.76.0892] [Citation(s) in RCA: 462] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open

Abstract

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

Collapse

Affiliation(s)

Pierce K H Chow Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Mihir Gandhi Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Say-Beng Tan Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Maung Win Khin Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Ariunaa Khasbazar Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Janus Ong Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Su Pin Choo Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Peng Chung Cheow Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Chanisa Chotipanich Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Kieron Lim Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Laurentius A Lesmana Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Tjakra W Manuaba Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Boon Koon Yoong Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Aloysius Raj Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Chiong Soon Law Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Ian H Y Cua Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Rolley R Lobo Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Catherine S C Teh Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Yun Hwan Kim Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Yun Won Jong Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Ho-Seong Han Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Si-Hyun Bae Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Hyun-Ki Yoon Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Rheun-Chuan Lee Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Chien-Fu Hung Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Cheng-Yuan Peng Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Po-Chin Liang Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Adam Bartlett Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Kenneth Y Y Kok Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Choon-Hua Thng Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Albert Su-Chong Low Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Anthony S W Goh Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Kiang Hiong Tay Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Richard H G Lo Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Brian K P Goh Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
David C E Ng Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Ganesh Lekurwale Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Wei Ming Liew Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Val Gebski Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Kenneth S W Mak Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia
Khee Chee Soo Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia

Collapse

Ray EM, Sanoff HK. Optimal therapy for patients with hepatocellular carcinoma and resistance or intolerance to sorafenib: challenges and solutions. J Hepatocell Carcinoma 2017;4:131-138. [PMID: 29184856 PMCID: PMC5687453 DOI: 10.2147/jhc.s124366] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open

Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish. Sci Rep 2017;7:10315. [PMID: 28871112 PMCID: PMC5583234 DOI: 10.1038/s41598-017-10529-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/09/2017] [Indexed: 02/07/2023] Open

Sim HW, Knox J, Dawson LA. An Update on Randomized Clinical Trials in Hepatocellular Carcinoma. Surg Oncol Clin N Am 2017;26:647-666. [PMID: 28923223 DOI: 10.1016/j.soc.2017.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

Li L, Yeo W. Value of quality of life analysis in liver cancer: A clinician's perspective. World J Hepatol 2017;9:867-883. [PMID: 28804570 PMCID: PMC5534362 DOI: 10.4254/wjh.v9.i20.867] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 05/15/2017] [Accepted: 05/22/2017] [Indexed: 02/06/2023] Open

Subramanian S, Pandey U, Chaudhari P, Tyagi M, Gupta S, Singh G, Dash A, Samuel G, Venkatesh M. Preliminary evaluation of indigenous ⁹⁰ Y-labelled microspheres for therapy of hepatocellular carcinoma. Indian J Med Res 2017;143:S74-S81. [PMID: 27748281 PMCID: PMC5080932 DOI: 10.4103/0971-5916.191786] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open

Zhao Y, Li H, Bai W, Liu J, Lv W, Sahu S, Guan S, Qin X, Wang W, Ren W, Mu W, Guo W, Gu S, Ma Y, Yin Z, Guo W, Wang W, Wang Y, Duran R, Fan D, Zhang Z, Han G. Early sorafenib-related adverse events predict therapy response of TACE plus sorafenib: A multicenter clinical study of 606 HCC patients. Int J Cancer 2017;139:928-37. [PMID: 27038145 DOI: 10.1002/ijc.30124] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 02/04/2016] [Accepted: 03/22/2016] [Indexed: 12/18/2022]

Affiliation(s)

Yan Zhao Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China
Hailiang Li Department of Interventional Radiology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Wei Bai Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China
Jueshi Liu Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People's Hospital, Changsha, China
Weifu Lv Department of Radiology, Anhui Provincial Hospital, Hefei, China
Sonia Sahu Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston
Sheng Guan Second Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Xiao Qin Department of Hepatobiliary Surgery & Vascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
Wenhui Wang Department of Interventional Medicine, The First Affiliated Hospital of Lanzhou University, Lanzhou, China
Weixin Ren Department of Interventional Radiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
Wei Mu Department of Radiology, The Southwest Hospital, Third Military Medical University, Chongqing, China
Weidong Guo Cancer Treatment Center, Baogang Hospital of Inner Mongolia, Baotou, China
Shanzhi Gu Department of Interventional Radiology, Hunan Cancer Hospital of Central South University, Changsha, China
Yilong Ma Department of Interventional Therapy, Tumor Hospital of Guangxi Medical University, Nanning, China
Zhanxin Yin Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China
Wengang Guo Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China
Wenjun Wang Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China
Yongji Wang Department of Medical Statistics, Fourth Military Medical University, Xi'an, China
Rafael Duran Department of Radiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
Daiming Fan Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China.,State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
Zhuoli Zhang Department of Radiology, Northwestern University, Chicago
Guohong Han Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China

Collapse

Kim DW, Talati C, Kim R. Hepatocellular carcinoma (HCC): beyond sorafenib-chemotherapy. J Gastrointest Oncol 2017;8:256-265. [PMID: 28480065 DOI: 10.21037/jgo.2016.09.07] [Citation(s) in RCA: 238] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open

Roccarina D, Majumdar A, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS. Management of people with intermediate-stage hepatocellular carcinoma: an attempted network meta-analysis. Cochrane Database Syst Rev 2017;3:CD011649. [PMID: 28281295 PMCID: PMC6464331 DOI: 10.1002/14651858.cd011649.pub2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]

Abstract

BACKGROUND

There is significant uncertainty in the treatment of intermediate-stage hepatocellular carcinoma which is defined by the Barcelona Clinic Liver Cancer (BCLC) as hepatocellular carcinoma stage B with large, multi-nodular, Child-Pugh status A to B, performance status 0 to 2, and without vascular occlusion or extrahepatic disease.

OBJECTIVES

To assess the comparative benefits and harms of different interventions used in the treatment of intermediate-stage hepatocellular carcinoma (BCLC stage B) through a network meta-analysis and to generate rankings of the available interventions according to their safety and efficacy. However, we found only one comparison. Therefore, we did not perform the network meta-analysis, and we assessed the comparative benefits and harms of different interventions versus each other, or versus placebo, sham, or no intervention (supportive treatment only) using standard Cochrane methodology.

SEARCH METHODS

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised clinical trials registers to September 2016 to identify randomised clinical trials on hepatocellular carcinoma.

SELECTION CRITERIA

We included only randomised clinical trials, irrespective of language, blinding, or publication status, in participants with intermediate-stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, size, or number of the tumours (provided they met the criteria of intermediate-stage hepatocellular carcinoma), of presence or absence of portal hypertension, of aetiology of hepatocellular carcinoma, and of the future remnant liver volume. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various interventions compared with each other or with no active intervention (supportive treatment only). We excluded trials which compared variations of the same intervention: for example, different methods of performing transarterial chemoembolisation.

DATA COLLECTION AND ANALYSIS

We used standard methodological procedures expected by Cochrane. We calculated the hazard ratio (HR) with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and assessed the quality of the evidence using GRADE.

MAIN RESULTS

Three randomised clinical trials, including 430 participants, met the inclusion criteria for this review; however, data from two trials with 412 participants could be included in only one primary outcome (i.e. mortality). All three trials were at high risk of bias. All three trials included supportive care as cointervention. The comparisons included in the two trials reporting on mortality were: systemic chemotherapy with sorafenib versus no active intervention; and transarterial chemoembolisation plus systemic chemotherapy with sorafenib versus transarterial chemoembolisation alone. The trials did not report the duration of follow-up; however, it appeared that the participants were followed up for a period of about 18 to 30 months. The majority of the participants in the trials had cirrhotic livers. The trials included participants with intermediate-stage hepatocellular carcinoma arising from viral and non-viral aetiologies. The trials did not report the portal hypertension status of the participants. The mortality was 50% to 70% over a median follow-up period of 18 to 30 months. There was no evidence of difference in mortality at maximal follow-up between systemic chemotherapy versus no chemotherapy (hazard ratio 0.85, 95% CI 0.60 to 1.18; participants = 412; studies = 2; I2 = 0%; very low quality evidence). A subgroup analysis performed by stratifying the analysis by the presence or absence of transarterial chemoembolisation as cointervention did not alter the results. None of the trials reported on serious adverse events other than mortality, health-related quality of life, recurrence of hepatocellular carcinoma, or length of hospital stay. One of the trials providing data was funded by the pharmaceutical industry, the other did not report the source of funding, and the trial with no data for the review was also funded by the pharmaceutical industry. We found two ongoing trials.

AUTHORS' CONCLUSIONS

Currently, there is no evidence from randomised clinical trials that people with intermediate-stage hepatocellular carcinoma would benefit from systemic chemotherapy with sorafenib either alone or when transarterial chemoembolisation was used as a cointervention (very low quality evidence). We need high-quality randomised clinical trials designed to measure differences in clinically important outcomes (e.g. all-cause mortality or health-related quality of life).

Collapse

Yan C, Yang Q, Gong Z. Tumor-Associated Neutrophils and Macrophages Promote Gender Disparity in Hepatocellular Carcinoma in Zebrafish. Cancer Res 2017;77:1395-1407. [PMID: 28202512 DOI: 10.1158/0008-5472.can-16-2200] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 12/12/2016] [Accepted: 12/26/2016] [Indexed: 11/16/2022]

Alternative splicing of estrogen receptor alpha in hepatocellular carcinoma. BMC Cancer 2016;16:926. [PMID: 27899088 PMCID: PMC5129602 DOI: 10.1186/s12885-016-2928-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 11/06/2016] [Indexed: 12/29/2022] Open

Gandhi M, Choo SP, Thng CH, Tan SB, Low ASC, Cheow PC, Goh ASW, Tay KH, Lo RHG, Goh BKP, Wong JS, Ng DCE, Soo KC, Liew WM, Chow PKH. Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial. BMC Cancer 2016;16:856. [PMID: 27821083 PMCID: PMC5100089 DOI: 10.1186/s12885-016-2868-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 10/13/2016] [Indexed: 02/08/2023] Open

Abstract

Background

Approximately 20 % of hepatocellular carcinoma (HCC) patients diagnosed in the early stages may benefit from potentially curative ablative therapies such as surgical resection, transplantation or radiofrequency ablation. For patients not eligible for such options, prognosis is poor. Sorafenib and Selective Internal Radiation Therapy (SIRT) are clinically proven treatment options in patients with unresectable HCC, and this study aims to assess overall survival following either SIRT or Sorafenib therapy for locally advanced HCC patients.

Methods

This investigator-initiated, multi-centre, open-label, randomized, controlled trial will enrol 360 patients with locally advanced HCC, as defined by Barcelona Clinic Liver Cancer stage B or stage C, without distant metastases, and which is not amenable to immediate curative treatment. Exclusion criteria include previous systemic therapy, metastatic disease, complete occlusion of the main portal vein, or a Child-Pugh score of >7. Eligible patients will be randomised 1:1 and stratified by centre and presence or absence of portal vein thrombosis to receive either a single administration of SIRT using yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia) targeted at HCC in the liver by the trans-arterial route or continuous oral Sorafenib (Nexavar®, Bayer Pharma AG, Berlin, Germany) at a dose of 400 mg twice daily until disease progression, no further response, complete regression or unacceptable toxicity. Patients for both the Sorafenib and SIRT arms will be followed-up every 4 weeks for the first 3 months and 12 weekly thereafter. Overall survival is the primary endpoint, assessed for the intention-to-treat population. Secondary endpoints are tumour response rate, time-to-tumour progression, progression free survival, quality of life and down-staging to receive potentially curative therapy.

Discussion

Definitive data comparing these two therapies will help to determine clinical practice in the large group of patients with locally advanced HCC and improve outcomes for such patients.

Trial registration

ClinicalTrials.gov identifier, NCT01135056, first received 24, May 2010.

Collapse

Affiliation(s)

Mihir Gandhi Biostatistics, Singapore Clinical Research Institute, #02-01, Nanos, 31 Biopolis Way, Singapore, Singapore.,Centre for Quantitative Medicine, Duke-NUS Medical School, 8 College Road, Singapore, Singapore.,Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tempere, Finland
Su Pin Choo Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, Singapore
Choon Hua Thng Division of Oncologic Imaging, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, Singapore
Say Beng Tan Office of Research, Singapore Health Services, 31 Third Hospital Avenue, #03-03 Bowyer Block C, Singapore, Singapore.,Clinical Sciences, Duke-NUS Medical School, 8 College Road, Singapore, Singapore
Albert Su Chong Low Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore, Singapore
Peng Chung Cheow Department of Hepato-pancreato-biliary and Transplant Surgery, Singapore General Hospital, Outram Road, Singapore, Singapore
Anthony Soon Whatt Goh Department of Nuclear Medicine and PET, Singapore General Hospital, Outram Road, Singapore, Singapore
Kiang Hiong Tay Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore, Singapore
Richard Hoau Gong Lo Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore, Singapore
Brian Kim Poh Goh Department of Hepato-pancreato-biliary and Transplant Surgery, Singapore General Hospital, Outram Road, Singapore, Singapore
Jen San Wong Department of Hepato-pancreato-biliary and Transplant Surgery, Singapore General Hospital, Outram Road, Singapore, Singapore
David Chee Eng Ng Department of Nuclear Medicine and PET, Singapore General Hospital, Outram Road, Singapore, Singapore
Khee Chee Soo Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, Singapore
Wei Ming Liew Project Management, Singapore Clinical Research Institute, #02-01, Nanos, 31 Biopolis Way, Singapore, Singapore
Pierce K H Chow Department of Hepato-pancreato-biliary and Transplant Surgery, Singapore General Hospital, Outram Road, Singapore, Singapore. .,Office of Clinical, Academic and Faculty Affairs, Duke-NUS Medical School, 8 College Road, Singapore, Singapore. .,Program in Translational and Clinical Liver Research, National Cancer Centre Singapore, Singapore, Singapore.

Collapse

FEATURES. ACTA ACUST UNITED AC 2016. [DOI: 10.1142/s0219030316000252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]

Ikeda M, Mitsunaga S, Ohno I, Hashimoto Y, Takahashi H, Watanabe K, Umemoto K, Okusaka T. Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and Future. Diseases 2015;3:360-381. [PMID: 28943630 PMCID: PMC5548259 DOI: 10.3390/diseases3040360] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Revised: 11/19/2015] [Accepted: 11/19/2015] [Indexed: 12/18/2022] Open

Abstract

Systemic chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). Before the introduction of sorafenib, cytotoxic agents, hormonal therapies, or many combinations of these were the mainly used modalities for systemic chemotherapy of advanced HCC. However, such regimens were of only limited value in clinical practice, because some randomized controlled studies comparing promising regimens with no treatment or doxorubicin alone failed to show any overall survival advantage. In two pivotal phase III placebo-controlled studies, the SHARP trial and the Asia-Pacific trial, sorafenib was demonstrated to significantly delay the time to progression and the overall survival time in patients with advanced HCC. Therefore, sorafenib therapy has come to be acknowledged as a standard therapy for advanced HCC worldwide. After the introduction of sorafenib, a number of phase III trials of various molecular-targeted agents vs. sorafenib as first-line chemotherapy and of various molecular-targeted agents vs. placebo as second-line chemotherapy have been conducted to determine if any of these agents could offer a survival benefit, however, none of the agents examined so far has been demonstrated to provide any survival benefit over sorafenib or placebo. Recently, favorable treatment efficacies have been reported in some clinical trials of molecular-targeted agents in the biomarker-enriched population. Development of individualized cancer treatments using molecular-targeted agents based on the results of genome-sequencing is aggressively ongoing. Furthermore, immune-oncologic agents, such as anti-CTLA-4 antibody and anti-PD-1/PD-L1 antibody, have been reported to provide promising outcomes. Thus, various novel systemic chemotherapeutic agents are currently under development, and further improvements in the treatment outcomes are expected.

Collapse

Fitzmorris P, Shoreibah M, Anand BS, Singal AK. Management of hepatocellular carcinoma. J Cancer Res Clin Oncol 2015;141:861-876. [PMID: 25158999 DOI: 10.1007/s00432-014-1806-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 08/08/2014] [Indexed: 02/07/2023]

Vilarinho S, Taddei T. Therapeutic strategies for hepatocellular carcinoma: new advances and challenges. ACTA ACUST UNITED AC 2015;13:219-34. [PMID: 25791207 DOI: 10.1007/s11938-015-0049-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]

Abstract

OPINION STATEMENT

Hepatocellular carcinoma (HCC) is the fastest growing malignancy in the USA, and its prognosis remains poor with a 5-year survival around 12 %. Clinical data demonstrate that 85 % of cases occur in individuals with underlying cirrhosis and only 15 % develop in non-cirrhotic livers. Therefore, American and European guidelines recommend routine HCC screening for high-risk individuals (patients with cirrhosis) with abdominal ultrasound every 6 months. Once a lesion is identified or suspected on ultrasound, dynamic imaging is then indicated. The diagnosis of HCC is established in a patient with cirrhosis when a lesion measures at least 1 cm in diameter and demonstrates arterial enhancement and portal venous washout on contrast-enhanced computerized tomography or magnetic resonance imaging. Indeterminate lesions should be followed with surveillance imaging or further investigated with biopsy according to the level of suspicion for malignancy. Given the clinical, pathological, and molecular heterogeneity of HCC, there are multiple therapeutic modalities available. These may be curative, such as surgical resection, liver transplantation, and local ablation, or palliative, such as catheter-directed therapies (transarterial chemo, radio, or bland embolization), and systemic therapy (sorafenib). Patients with a single lesion, good performance status, and preserved liver synthetic function should be offered curative surgical resection or ablation therapy. Patients with HCC and decompensated liver disease should be evaluated and listed for liver transplantation. For unresectable disease or tumor burden precluding transplantation or curative ablation, palliative therapeutic modalities should be offered. Sorafenib is indicated for patients with vascular invasion and/or extra-hepatic metastasis if the estimated life expectancy is more than 3 months. Systemic internal radiation therapy using yttrium-90 microspheres in cases of multifocal bi-lobar disease and/or portal vein occlusion is an emerging therapy. Best supportive care is recommended for patients who lack the hepatic reserve to tolerate therapy.

Collapse

Gomaa AI, Waked I. Recent advances in multidisciplinary management of hepatocellular carcinoma. World J Hepatol 2015;7:673-87. [PMID: 25866604 PMCID: PMC4388995 DOI: 10.4254/wjh.v7.i4.673] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/17/2014] [Accepted: 01/15/2015] [Indexed: 02/06/2023] Open