Correction to: Hepatocellular carcinoma (Nature Reviews Disease Primers, (2021), 7, 1, (6), 10.1038/s41572-020-00240-3);Hepatocellular carcinoma

Nature Reviews Disease Primers

Volumn 7, Issue 1, 2021, Pages

  Llovet, Josep M ^a,b,c   Kelley, Robin Kate ^d   Villanueva, Augusto ^a   Singal, Amit G ^e   Pikarsky, Eli ^f   Roayaie, Sasan ^g   Lencioni, Riccardo ^h,i   Koike, Kazuhiko ^j   Zucman Rossi, Jessica ^k,l   Finn, Richard S ^m  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF BARCELONA   (Spain)

^c INSTITUCIÓ CATALANA DE RECERCA I ESTUDIS AVANÇATS ICREA   (Spain)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^f HEBREW UNIVERSITY OF JERUSALEM   (Israel)

^g White Plains Hospital Center   (United States)

^h UNIVERSITY OF PISA   (Italy)

ⁱ MIAMI CANCER INSTITUTE   (United States)

^j UNIVERSITY OF TOKYO   (Japan)

^k SORBONNE UNIVERSITÉ   (France)

^l ASSISTANCE PUBLIQUE HÔPITAUX DE PARIS   (France)

^m UNIVERSITY OF CALIFORNIA   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ATEZOLIZUMAB; BEVACIZUMAB; CABOZANTINIB; DURVALUMAB; IPILIMUMAB; LENVATINIB; NIVOLUMAB; PEMBROLIZUMAB; RAMUCIRUMAB; REGORAFENIB; SORAFENIB; TICILIMUMAB; TUMOR MARKER;

ABLATION THERAPY; ADAPTIVE IMMUNITY; ADVERSE EVENT; ALCOHOL CONSUMPTION; ALCOHOL LIVER DISEASE; CANCER CLASSIFICATION; CANCER COMBINATION CHEMOTHERAPY; CANCER DIAGNOSIS; CANCER EPIDEMIOLOGY; CANCER GENETICS; CANCER PREVENTION; CANCER RADIOTHERAPY; CANCER RISK; CANCER SCREENING; CANCER SURGERY; CANCER THERAPY; CELL INFILTRATION; CHEMOEMBOLIZATION; CHRONIC INFLAMMATION; CORONAVIRUS DISEASE 2019; DELTA AGENT HEPATITIS; DIAGNOSTIC IMAGING; DISEASE ASSOCIATION; FATTY LIVER; GENE MUTATION; HEPATITIS B; HEPATITIS C; HISTOPATHOLOGY; HUMAN; IMAGE GUIDED ABLATION; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER RESECTION; LIVER TRANSPLANTATION; META ANALYSIS (TOPIC); MICROWAVE THERMOTHERAPY; MOLECULAR PATHOLOGY; MULTICENTER STUDY (TOPIC); NONALCOHOLIC FATTY LIVER; NONALCOHOLIC STEATOHEPATITIS; NONHUMAN; OXIDATIVE STRESS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; QUALITY OF LIFE; RADIOFREQUENCY ABLATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK FACTOR; SYSTEMIC THERAPY; TREATMENT RESPONSE; TUMOR ABLATION; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; IMMUNOTHERAPY; LIVER TUMOR; MULTIMODALITY CANCER THERAPY;

CARCINOMA, HEPATOCELLULAR; COMBINED MODALITY THERAPY; HUMANS; IMMUNOTHERAPY; LIVER NEOPLASMS; SORAFENIB;

EID: 85099739895     PISSN: None     EISSN: 2056676X     Source Type: Journal    
DOI: 10.1038/s41572-024-00500-6     Document Type: Erratum

References (302)

1. Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 2, 16018 (2016).
2. Villanueva, A. Hepatocellular carcinoma. N. Engl. J. Med. 380, 1450–1462 (2019).
3. International Agency for Research on Cancer. GLOBOCAN 2018. IARC https://gco.iarc.fr/today/online-analysis-map?v=2020&mode=population&mode_population=continents&population=900&populations=900&key=asr&sex=0&cancer=11&type=0&statistic=5&prevalence=0&population_groupearth&color_palette=default&map_scale=quantile&map_nb_colors=5&continent=0&rotate=%255B10%252C0%255D (2020).
4. Akinyemiju, T. et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level. JAMA Oncol. 3, 1683 (2017).
5. Kanwal, F. et al. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 153, 996–1005.e1 (2017).
6. Estes, C., Razavi, H., Loomba, R., Younossi, Z. & Sanyal, A. J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123–133 (2018).
7. Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47, 505–511 (2015). A comprehensive genomic study conducted in HCC describing the landscape of mutations and mutational signatures.
8. Llovet, J. M., Montal, R., Sia, D. & Finn, R. S. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 15, 599–616 (2018).
9. Zucman-Rossi, J., Villanueva, A., Nault, J.-C. & Llovet, J. M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149, 1226–1239.e4 (2015).
10. Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019).
11. Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).
12. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).
13. Marrero, J. A. et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 68, 723–750 (2018).
14. Simon, T. G. et al. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N. Engl. J. Med. 382, 1018–1028 (2020).
15. Llovet, J. M. et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 10.1038/s41575-020-00395-0 (2020).
16. Tabrizian, P. et al. A US multicenter analysis of 2529 HCC patients undergoing liver transplantation: 10-year outcome assessing the role of down-staging to within Milan criteria [abstract 15]. Hepatology 70, 10–11 (2019).
17. Llovet, J. & Bruix, J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37, 429–442 (2003). This paper is a meta-analysis of randomized studies providing the rationale to use transarterial chemoembolization in intermediate HCC as standard of care.
18. Salem, R. et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 151, 1155–1163.e2 (2016).
19. Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020). This paper is the first study demonstrating survival benefit for any systemic therapies compared with the standard of care sorafenib in advanced HCC.
20. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008). The first study demonstrating survival benefit for systemic therapies (sorafenib) in advanced HCC compared with placebo.
21. Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163–1173 (2018). This is the first study demonstrating a survival benefit similar to the standard of care sorafenib in advanced HCC compared with placebo.
22. Bruix, J. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56–66 (2017). The first study demonstrating survival benefit in second-line treatment for patients with advanced HCC progressing to sorafenib therapy.
23. Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).
24. Zhu, A. X. et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 282–296 (2019).
25. El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389, 2492–2502 (2017).
26. Finn, R. S. et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J. Clin. Oncol. 38, 193–202 (2020).
27. McGlynn, K. A., Petrick, J. L. & London, W. T. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin. Liver Dis. 19, 223–238 (2015).
28. Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).
29. Trinchet, J.-C. et al. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort). Hepatology 62, 737–750 (2015).
30. Fracanzani, A. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non–iron-related chronic liver disease. Hepatology 33, 647–651 (2001).
31. Wang, J., Chenivesse, X., Henglein, B. & Bréchot, C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343, 555–557 (1990).
32. Kew, M. C. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int. 23, 405–409 (2003).
33. Chang, M. H. et al. Long-term effects of hepatitis B immunization of infants in preventing liver cancer. Gastroenterology 151, 472–480.e1 (2016).
34. Jain, M. K. et al. Evaluation of a multifaceted intervention to reduce health disparities in hepatitis C screening: a pre-post analysis. Hepatology 70, 40–50 (2019).
35. Ioannou, G. N. et al. Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology 157, 1264–1278.e4 (2019).
36. Llovet, J. M. & Villanueva, A. Effect of HCV clearance with direct-acting antiviral agents on HCC. Nat. Rev. Gastroenterol. Hepatol. 13, 561–562 (2016).
37. Puigvehí, M., Moctezuma-Velázquez, C., Villanueva, A. & Llovet, J. M. The oncogenic role of hepatitis delta virus in hepatocellular carcinoma. JHEP Rep. 1, 120–130 (2019).
38. Jepsen, P., Ott, P., Andersen, P. K., Sørensen, H. T. & Vilstrup, H. Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis. Ann. Intern. Med. 156, 841 (2012).
39. Lin, C. W. et al. Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis. J. Hepatol. 58, 730–735 (2013).
40. Welzel, T. M. et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am. J. Gastroenterol. 108, 1314–1321 (2013).
41. Kanwal, F. et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 155, 1828–1837.e2 (2018).
42. Mittal, S. et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 14, 124–131.e1 (2016).
43. Rich, N. E., Yopp, A. C., Singal, A. G. & Murphy, C. C. Hepatocellular carcinoma incidence is decreasing among younger adults in the United States. Clin. Gastroenterol. Hepatol. 18, 242–248.e5 (2020).
44. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J. Clin. 68, 394–424 (2018).
45. Rich, N. E. et al. Racial and ethnic differences in presentation and outcomes of hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 17, 551–559.e1 (2019).
46. Lee, Y.-C. A. et al. Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer. Int. J. Epidemiol. 38, 1497–1511 (2009).
47. Bravi, F., Bosetti, C., Tavani, A., Gallus, S. & La Vecchia, C. Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. Clin. Gastroenterol. Hepatol. 11, 1413–1421.e1 (2013).
48. Sia, D., Villanueva, A., Friedman, S. L. & Llovet, J. M. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152, 745–761 (2017).
49. Pikarsky, E. Neighbourhood deaths cause a switch in cancer subtype. Nature 562, 45–46 (2018).
50. Seehawer, M. et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562, 69–75 (2018).
51. Guichard, C. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44, 694–698 (2012).
52. Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 68, 6779–6788 (2008).
53. Calderaro, J., Ziol, M., Paradis, V. & Zucman-Rossi, J. Molecular and histological correlations in liver cancer. J. Hepatol. 71, 616–630 (2019).
54. Hyman, D. M., Taylor, B. S. & Baselga, J. Implementing genome-driven oncology. Cell 168, 584–599 (2017).
55. Bressac, B., Kew, M., Wands, J. & Ozturk, M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429–431 (1991).
56. Wang, B. et al. Null genotypes of GSTM1 and GSTT1 contribute to hepatocellular carcinoma risk: Evidence from an updated meta-analysis. J. Hepatol. 53, 508–518 (2010).
57. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
58. Buch, S. et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat. Genet. 47, 1443–1448 (2015).
59. Paterlini-Bréchot, P. et al. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 22, 3911–3916 (2003).
60. Nault, J.-C., Ningarhari, M., Rebouissou, S. & Zucman-Rossi, J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 16, 544–558 (2019).
61. Bayard, Q. et al. Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Nat. Commun. 9, 5235 (2018).
62. Nault, J.-C. et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 47, 1187–1193 (2015).
63. Letouzé, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat. Commun. 8, 1315 (2017).
64. Ng, A. W. T. et al. Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia. Sci. Transl. Med. 9, eaan6446 (2017).
65. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
66. Rebouissou, S. & Nault, J.-C. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J. Hepatol. 72, 215–229 (2020).
67. Hoshida, Y. et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 69, 7385–7392 (2009).
68. Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169, 1327–1341.e23 (2017).
69. Lee, J.-S. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat. Med. 12, 410–416 (2006).
70. Boyault, S. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45, 42–52 (2007).
71. Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017).
72. Lachenmayer, A. et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin. Cancer Res. 18, 4997–5007 (2012).
73. Ruiz de Galarreta, M. et al. β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124–1141 (2019).
74. Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).
75. Sutti, S. & Albano, E. Adaptive immunity: an emerging player in the progression of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 17, 81–92 (2020).
76. Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).
77. Nishida, N. et al. Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 31, 1646–1653 (2016).
78. + synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell 26, 826–839 (2014).
79. Gomes, A. L. et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 30, 161–175 (2016).
80. Guri, Y. et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell 32, 807–823.e12 (2017).
81. Liu, D. et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci. Transl. Med. 10, eaap9840 (2018).
82. Umemura, A. et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29, 935–948 (2016).
83. Grohmann, M. et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 175, 1289–1306.e20 (2018).
84. Henderson, J. M., Zhang, H. E., Polak, N. & Gorrell, M. D. Hepatocellular carcinoma: mouse models and the potential roles of proteases. Cancer Lett. 387, 106–113 (2017).
85. Negro, F. Natural history of NASH and HCC. Liver Int. 40, 72–76 (2020).
86. Rudalska, R. et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med. 20, 1138–1146 (2014).
87. Martinez-Quetglas, I. et al. IGF2 is up-regulated by epigenetic mechanisms in hepatocellular carcinomas and is an actionable oncogene product in experimental models. Gastroenterology 151, 1192–1205 (2016).
88. Doudna, J. A. & Charpentier, E. The new frontier of genome engineering with CRISPR-Cas9. Science 346, 1258096 (2014).
89. Cook, N., Jodrell, D. I. & Tuveson, D. A. Predictive in vivo animal models and translation to clinical trials. Drug Discov. Today 17, 253–260 (2012).
90. Singh, M. & Ferrara, N. Modeling and predicting clinical efficacy for drugs targeting the tumor milieu. Nat. Biotechnol. 30, 648–657 (2012).
91. Newell, P., Villanueva, A., Friedman, S. L., Koike, K. & Llovet, J. M. Experimental models of hepatocellular carcinoma. J. Hepatol. 48, 858–879 (2008).
92. Bresnahan, E., Ramadori, P., Heikenwalder, M., Zender, L. & Lujambio, A. Novel patient-derived preclinical models of liver cancer. J. Hepatol. 72, 239–249 (2020).
93. Moriya, K. et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat. Med. 4, 1065–1067 (1998).
94. Hagel, M. et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 5, 424–437 (2015).
95. Day, C.-P., Merlino, G. & Van Dyke, T. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163, 39–53 (2015).
96. Jayson, G. & Harris, J. How participants in cancer trials are chosen: ethics and conflicting interests. Nat. Rev. Cancer 6, 330–336 (2006).
97. Febbraio, M. A. et al. Preclinical models for studying NASH-driven HCC: how useful are they? Cell Metab. 29, 18–26 (2019).
98. Sharpless, N. E. & DePinho, R. A. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov. 5, 741–754 (2006).
99. + T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014).
100. + T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).
101. Malehmir, M. et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat. Med. 25, 641–655 (2019).
102. Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).
103. Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).
104. Wada, Y., Nakashima, O., Kutami, R., Yamamoto, O. & Kojiro, M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 27, 407–414 (1998).
105. Yuan, D. et al. Kupffer cell-derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell 31, 771–789.e6 (2017).
106. Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).
107. Horwitz, E. et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to Sorafenib treatment. Cancer Discov. 4, 730–743 (2014).
108. Finn, R. S. et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J. Clin. Oncol. 38, 2960–2970 (2020).
109. Hou, J., Zhang, H., Sun, B. & Karin, M. The immunobiology of hepatocellular carcinoma in humans and mice: basic concepts and therapeutic implications. J. Hepatol. 72, 167–182 (2020).
110. Hoshida, Y. et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359, 1995–2004 (2008). This study is the first molecular indication of the importance of the cancer field effect in the outcome of patients with HCC.
111. + cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).
112. Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
113. + T-cell responses in hepatocellular carcinoma. Hepatology 59, 1415–1426 (2014).
114. Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e16 (2017).
115. Langhans, B. et al. Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma. Cancer Immunol. Immunother. 68, 2055–2066 (2019).
116. Garnelo, M. et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 66, 342–351 (2017).
117. Bruno, T. C. New predictors for immunotherapy responses sharpen our view of the tumour microenvironment. Nature 577, 474–476 (2020).
118. Schneider, C. et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61, 1733–1743 (2012).
119. Sautès-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).
120. Calderaro, J. et al. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J. Hepatol. 70, 58–65 (2019).
121. Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).
122. Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397–411 (2017).
123. Higashi, T., Friedman, S. L. & Hoshida, Y. Hepatic stellate cells as key target in liver fibrosis. Adv. Drug Deliv. Rev. 121, 27–42 (2017).
124. Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012).
125. Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360, eaan5931 (2018).
126. Hoshida, Y. et al. Prognostic gene expression signature for patients with hepatitis C–related early-stage cirrhosis. Gastroenterology 144, 1024–1030 (2013).
127. Budhu, A. et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10, 99–111 (2006).
128. Moeini, A. et al. An immune gene expression signature associated with development of human hepatocellular carcinoma identifies mice that respond to chemopreventive agents. Gastroenterology 157, 1383–1397.e11 (2019).
129. Singal, A. G., Lampertico, P. & Nahon, P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J. Hepatol. 72, 250–261 (2020).
130. Papatheodoridis, G. et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J. Hepatol. 64, 800–806 (2016).
131. Shinmura, R. et al. Cirrhotic nodules: association between MR imaging signal intensity and intranodular blood supply. Radiology 237, 512–519 (2005).
132. van der Pol, C. B. et al. Accuracy of the liver imaging reporting and data system in computed tomography and magnetic resonance image analysis of hepatocellular carcinoma or overall malignancy — a systematic review. Gastroenterology 156, 976–986 (2019).
133. Paisant, A. et al. Comparison of extracellular and hepatobiliary MR contrast agents for the diagnosis of small HCCs. J. Hepatol. 72, 937–945 (2020).
134. Kojiro, M. et al. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49, 658–664 (2009).
135. Forner, A. et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 47, 97–104 (2007).
136. Zhang, B.-H., Yang, B.-H. & Tang, Z.-Y. Randomized controlled trial of screening for hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 130, 417–422 (2004).
137. Lederle, F. A. Screening for liver cancer: the rush to judgment. Ann. Intern. Med. 156, 387 (2012).
138. Poustchi, H. et al. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology 54, 1998–2004 (2011).
139. Singal, A. G., Pillai, A. & Tiro, J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med. 11, e1001624 (2014). This paper is a meta-analysis defining the accuracy of distinct surveillance strategies for the early detection of HCC.
140. Andersson, K. L., Salomon, J. A., Goldie, S. J. & Chung, R. T. Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 6, 1418–1424 (2008).
141. Trinchet, J.-C. et al. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology 54, 1987–1997 (2011).
142. Atiq, O. et al. An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis. Hepatology 65, 1196–1205 (2017).
143. Marrero, J. A. et al. α-Fetoprotein, DES-γ carboxyprothrombin, and lectin-bound α-fetoprotein in early hepatocellular carcinoma. Gastroenterology 137, 110–118 (2009).
144. Pepe, M. S. et al. Phases of biomarker development for early detection of cancer. J. Natl. Cancer Inst. 93, 1054–1061 (2001).
145. Tzartzeva, K. et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology 154, 1706–1718.e1 (2018).
146. Labgaa, I. et al. A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma. Oncogene 37, 3740–3752 (2018).
147. Kisiel, J. B. et al. Hepatocellular carcinoma detection by plasma methylated DNA: discovery, phase I pilot, and phase II clinical validation. Hepatology 69, 1180–1192 (2019).
148. Xu, R. et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat. Mater. 16, 1155–1161 (2017).
149. Qu, C. et al. Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy. Proc. Natl Acad. Sci. USA 116, 6308–6312 (2019).
150. Oh, C. R. et al. Genome-wide copy number alteration and VEGFA amplification of circulating cell-free DNA as a biomarker in advanced hepatocellular carcinoma patients treated with Sorafenib. BMC Cancer 19, 292 (2019).
151. Torga, G. & Pienta, K. J. Patient-paired sample congruence between 2 commercial liquid biopsy tests. JAMA Oncol. 4, 868 (2018).
152. Papatheodoridis, G. V., Chan, H. L.-Y., Hansen, B. E., Janssen, H. L. A. & Lampertico, P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J. Hepatol. 62, 956–967 (2015).
153. Chang, M.-H. et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N. Engl. J. Med. 336, 1855–1859 (1997).
154. Singh, S., Singh, P. P., Singh, A. G., Murad, M. H. & Sanchez, W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144, 323–332 (2013).
155. Kennedy, O. J. et al. Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose–response meta-analysis. BMJ Open 7, e013739 (2017).
156. Llovet, J. M. et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology 10.1002/hep.31327 (2020). DOI: 10.1002/hep.31327
157. Llovet, J., Brú, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19, 329–338 (1999). The first description of the BCLC classification widely used in guidelines of management of HCC.
158. D’Amico, G. et al. Clinical states of cirrhosis and competing risks. J. Hepatol. 68, 563–576 (2018).
159. Llovet, J. M. et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 29, 62–67 (1999).
160. Shrager, B., Jibara, G., Schwartz, M. & Roayaie, S. Resection of hepatocellular carcinoma without cirrhosis. Ann. Surg. 255, 1135–1143 (2012).
161. Viganò, L. et al. Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: a multicenter matched analysis with HCV-related HCC. J. Hepatol. 63, 93–101 (2015).
162. Piscaglia, F. et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology 63, 827–838 (2016).
163. Zhou, X.-D. et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer 91, 1479–1486 (2001).
164. Johnson, P. J. et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach — the ALBI grade. J. Clin. Oncol. 33, 550–558 (2015).
165. Pinato, D. J. et al. The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma. J. Hepatol. 66, 338–346 (2017).
166. Roayaie, S. et al. The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology 62, 440–451 (2015).
167. Berardi, G. et al. Development of a nomogram to predict outcome after liver resection for hepatocellular carcinoma in Child-Pugh B cirrhosis. J. Hepatol. 72, 75–84 (2020).
168. Ishizawa, T. et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 134, 1908–1916 (2008).
169. Citterio, D. et al. Hierarchic interaction of factors associated with liver decompensation after resection for hepatocellular carcinoma. JAMA Surg. 151, 846–853 (2016).
170. Vitale, A. et al. Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona clinic liver cancer stages: a multicentre study. J. Hepatol. 62, 617–624 (2015).
171. Yin, L. et al. Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan criteria: a RCT. J. Hepatol. 61, 82–88 (2014).
172. Kokudo, T. et al. Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J. Hepatol. 65, 938–943 (2016).
173. Roayaie, S., Jibara, G., Taouli, B. & Schwartz, M. Resection of hepatocellular carcinoma with macroscopic vascular invasion. Ann. Surg. Oncol. 20, 3754–3760 (2013).
174. Roayaie, S. et al. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology 57, 1426–1435 (2013).
175. Imamura, H. et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J. Hepatol. 38, 200–207 (2003).
176. Shi, M. et al. Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: a prospective randomized trial. Ann. Surg. 245, 36–43 (2007).
177. Hidaka, M. et al. Impact of anatomical resection for hepatocellular carcinoma with microportal invasion (vp1): a multi-institutional study by the Kyushu study group of liver surgery. Ann. Surg. 271, 339–346 (2020).
178. Samuel, M., Chow, P. K. H., Shih-Yen, E. C., Machin, D. & Soo, K. C. Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma. Cochrane Database Syst. Rev. 2009, CD001199 (2009).
179. Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e6 (2015).
180. Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).
181. Yin, J. et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J. Clin. Oncol. 31, 3647–3655 (2013).
182. Singal, A. G. et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 157, 1253–1263.e2 (2019).
183. Waziry, R. et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J. Hepatol. 67, 1204–1212 (2017).
184. Reig, M. et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J. Hepatol. 65, 719–726 (2016).
185. Tabrizian, P., Jibara, G., Shrager, B., Schwartz, M. & Roayaie, S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann. Surg. 261, 947–955 (2015).
186. Ferrer-Fàbrega, J. et al. Prospective validation of ab initio liver transplantation in hepatocellular carcinoma upon detection of risk factors for recurrence after resection. Hepatology 63, 839–849 (2016).
187. Mazzaferro, V. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 334, 693–700 (1996). This is a landmark study establishing the criteria for liver transplantation in HCC.
188. Franssen, B., Jibara, G., Tabrizian, P., Schwartz, M. E. & Roayaie, S. Actual 10-year survival following hepatectomy for hepatocellular carcinoma. HPB 16, 830–835 (2014).
189. Cucchetti, A. et al. The chances of hepatic resection curing hepatocellular carcinoma. J. Hepatol. 72, 711–717 (2020).
190. Llovet, J. M., Fuster, J. & Bruix, J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30, 1434–1440 (1999).
191. Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 33, 1394–1403 (2001).
192. Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am. J. Transplant. 7, 2587–2596 (2007).
193. Mazzaferro, V. et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 10, 35–43 (2009).
194. Commander, S. J. et al. A long-term experience with expansion of Milan criteria for liver transplant recipients. Clin. Transplant. 32, e13254 (2018).
195. Ravaioli, M. et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am. J. Transpl. 8, 2547–2557 (2008).
196. Mazzaferro, V. et al. Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma. Gastroenterology 154, 128–139 (2018).
197. Hong, G. et al. Alpha-fetoprotein and 18F-FDG positron emission tomography predict tumor recurrence better than Milan criteria in living donor liver transplantation. J. Hepatol. 64, 852–859 (2016).
198. Kulik, L. et al. Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: a systematic review and meta-analysis. Hepatology 67, 381–400 (2018).
199. Yao, F. Y. et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology 61, 1968–1977 (2015).
200. Cucchetti, A. et al. Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant. J. Hepatol. 73, 342–348 (2020).
201. Halazun, K. J. et al. Is it time to abandon the Milan criteria? Results of a bicoastal US collaboration to redefine hepatocellular carcinoma liver transplantation selection policies. Ann. Surg. 268, 690–699 (2018).
202. Kulik, L. M. et al. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am. J. Transpl. 12, 2997–3007 (2012).
203. Miltiadous, O. et al. Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. J. Hepatol. 63, 1368–1377 (2015).
204. Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma. Transplantation 100, 116–125 (2016).
205. Heimbach, J. K. et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67, 358–380 (2018).
206. Lencioni, R. & Llovet, J. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).
207. Lencioni, R. New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma. Clin. Cancer Res. 19, 1312–1314 (2013).
208. Llovet, J. M. & Lencioni, R. mRECIST for HCC: performance and novel refinements. J. Hepatol. 72, 288–306 (2020).
209. Meyer, T. et al. mRECIST to predict survival in advanced hepatocellular carcinoma: analysis of two randomised phase II trials comparing nintedanib vs sorafenib. Liver Int. 37, 1047–1055 (2017).
210. Lencioni, R. et al. Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC. J. Hepatol. 66, 1166–1172 (2017).
211. Kudo, M. et al. Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT). J. Clin. Oncol. 37, 186–186 (2019).
212. Lencioni, R. A. et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228, 235–240 (2003).
213. Lin, S.-M., Lin, C.-J., Lin, C.-C., Hsu, C.-W. & Chen, Y.-C. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma ≤4 cm. Gastroenterology 127, 1714–1723 (2004).
214. Shiina, S. et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129, 122–130 (2005).
215. Ng, K. K. C. et al. Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma. Br. J. Surg. 104, 1775–1784 (2017).
216. Xu, X.-L., Liu, X.-D., Liang, M. & Luo, B.-M. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: systematic review of randomized controlled trials with meta-analysis and trial sequential analysis. Radiology 287, 461–472 (2018).
217. Izumi, N. et al. A multicenter randomized controlled trial to evaluate the efficacy of surgery vs. radiofrequency ablation for small hepatocellular carcinoma (SURF trial). J. Clin. Oncol. 37, 4002–4002 (2019).
218. Xia, Y. et al. Long-term effects of repeat hepatectomy vs percutaneous radiofrequency ablation among patients with recurrent hepatocellular carcinoma. JAMA Oncol. 6, 255–263 (2020).
219. Lencioni, R. et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 234, 961–967 (2005).
220. Sala, M. et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 40, 1352–1360 (2004).
221. Breen, D. J. & Lencioni, R. Image-guided ablation of primary liver and renal tumours. Nat. Rev. Clin. Oncol. 12, 175–186 (2015).
222. Yu, J. et al. Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial. Gut 66, 1172–1173 (2017).
223. Hu, J. et al. Image-guided percutaneous microwave ablation versus cryoablation for hepatocellular carcinoma in high-risk locations: intermediate-term results. Cancer Manag. Res. 11, 9801–9811 (2019).
224. Cheng, R. G., Bhattacharya, R., Yeh, M. M. & Padia, S. A. Irreversible electroporation can effectively ablate hepatocellular carcinoma to complete pathologic necrosis. J. Vasc. Interv. Radiol. 26, 1184–1188 (2015).
225. Sutter, O. et al. Safety and efficacy of irreversible electroporation for the treatment of hepatocellular carcinoma not amenable to thermal ablation techniques: a retrospective single-center case series. Radiology 284, 877–886 (2017).
226. Peng, Z.-W. et al. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J. Clin. Oncol. 31, 426–432 (2013).
227. Tak, W. Y. et al. Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions. Clin. Cancer Res. 24, 73–83 (2018).
228. Wang, C. et al. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. Hepatology 61, 1579–1590 (2015).
229. Xu, J. et al. Radiofrequency ablation vs. cryoablation for localized hepatocellular carcinoma: a propensity-matched population study. Anticancer. Res. 38, 6381–6386 (2018).
230. Di Costanzo, G. G. et al. Radiofrequency ablation versus laser ablation for the treatment of small hepatocellular carcinoma in cirrhosis: a randomized trial. J. Gastroenterol. Hepatol. 30, 559–565 (2015).
231. Bujold, A. et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J. Clin. Oncol. 31, 1631–1639 (2013).
232. Hong, T. S. et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Clin. Oncol. 34, 460–468 (2016).
233. Tse, R. V. et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Clin. Oncol. 26, 657–664 (2008).
234. Yang, J.-F. et al. Stereotactic ablative radiotherapy versus conventionally fractionated radiotherapy in the treatment of hepatocellular carcinoma with portal vein invasion: a retrospective analysis. Radiat. Oncol. 14, 180 (2019).
235. Wahl, D. R. et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J. Clin. Oncol. 34, 452–459 (2016).
236. Shen, P. C. et al. Comparison of stereotactic body radiation therapy and transarterial chemoembolization for unresectable medium-sized hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 105, 307–318 (2019).
237. Kim, T. H. et al. Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial. J. Hepatol. 10.1016/j.jhep.2020.09.026 (2020)
238. Llovet, J. M. et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359, 1734–1739 (2002).
239. Lo, C. et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35, 1164–1171 (2002).
240. Vogel, A. et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29 (Suppl. 4), iv238–iv255 (2018).
241. Lencioni, R., de Baere, T., Soulen, M. C., Rilling, W. S. & Geschwind, J.-F. H. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology 64, 106–116 (2016).
242. Meyer, T. et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol. Hepatol. 2, 565–575 (2017).
243. Kudo, M. et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology 60, 1697–1707 (2014).
244. Okusaka, T. et al. Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial. J. Hepatol. 51, 1030–1036 (2009).
245. Chau, I. et al. Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study. Br. J. Cancer 119, 19–26 (2018).
246. Lammer, J. et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc. Intervent. Radiol. 33, 41–52 (2010).
247. Varela, M. et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J. Hepatol. 46, 474–481 (2007).
248. Burrel, M. et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using drug eluting beads. Implications for clinical practice and trial design. J. Hepatol. 56, 1330–1335 (2012).
249. Vincenzi, B. et al. Prognostic relevance of objective response according to EASL criteria and mRECIST criteria in hepatocellular carcinoma patients treated with loco-regional therapies: a literature-based meta-analysis. PLoS ONE 10, e0133488 (2015).
250. Lencioni, R. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J. Hepatol. 64, 1090–1098 (2016).
251. Kudo, M. et al. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol. Hepatol. 3, 37–46 (2018).
252. Kudo, M. et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. Lancet Gastroenterol. Hepatol. 3, 424–432 (2018).
253. Park, J. W. et al. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial. J. Hepatol. 70, 684–691 (2019).
254. Kudo, M. et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur. J. Cancer 47, 2117–2127 (2011).
255. Hilgard, P. et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 52, 1741–1749 (2010).
256. Salem, R. et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 138, 52–64 (2010).
257. Mazzaferro, V. et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 57, 1826–1837 (2013).
258. Vilgrain, V. et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 18, 1624–1636 (2017).
259. Chow, P. K. H. et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J. Clin. Oncol. 36, 1913–1921 (2018).
260. Ricke, J. et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J. Hepatol. 71, 1164–1174 (2019).
261. Bruix, J. et al. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J. Hepatol. 67, 999–1008 (2017).
262. Finn R. S. et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib(sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J. Clin. Oncol. 39, (suppl 3; abstr 267) (2021).
263. Yau, T. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 6, e204564 (2020).
264. Zhu, A. X. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 19, 940–952 (2018).
265. Llovet, J. M., Montal, R. & Villanueva, A. Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J. Hepatol. 70, 1262–1277 (2019).
266. Office of the Commissioner. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma (2020).
267. Yau, T. et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann. Oncol. 30, v874–v875 (2019).
268. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04039607 (2019).
269. Zappasodi, R., Merghoub, T. & Wolchok, J. D. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 33, 581–598 (2018).
270. Rahma, O. E. & Hodi, F. S. The intersection between tumor angiogenesis and immune suppression. Clin. Cancer Res. 25, 5449–5457 (2019).
271. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03713593 (2018).
272. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03755791 (2018).
273. Bergerot, P., Lamb, P., Wang, E. & Pal, S. K. Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence. Mol. Cancer Ther. 18, 2185–2193 (2019).
274. Ott, P. A., Hodi, F. S., Kaufman, H. L., Wigginton, J. M. & Wolchok, J. D. Combination immunotherapy: a road map. J. Immunother. Cancer 5, 16 (2017).
275. Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
276. Kelley, R. K. et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J. Clin. Oncol. 38, 4508–4508 (2020).
277. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03298451 (2017).
278. Schmidt, E. V. et al. Assessment of clinical activity of PD-1 checkpoint inhibitor combination therapies reported in clinical trials. JAMA Netw. Open 3, e1920833 (2020).
279. Montal, R. et al. Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials. Br. J. Cancer 121, 340–343 (2019).
280. Galle, P. R. et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int. 39, 2214–2229 (2019).
281. Teufel, M. et al. Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma. Gastroenterology 156, 1731–1741 (2019).
282. Pinyol, R. et al. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial. Gut 68, 1065–1075 (2019).
283. Li, X.-S., Li, J.-W., Li, H. & Jiang, T. Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis. Biosci. Rep. 40, BSR20200459 (2020).
284. Kim, R. D. et al. First-in-human phase I study of Fisogatinib (BLU-554) validates aberrant fibroblast growth factor 19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 9, 1696–1707 (2019).
285. Lim, H. Y. et al. Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular carcinoma. Clin. Cancer Res. 24, 4650–4661 (2018).
286. Rimassa, L. et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 19, 682–693 (2018).
287. Tapper, E. B. & Asrani, S. K. The COVID-19 pandemic will have a long-lasting impact on the quality of cirrhosis care. J. Hepatol. 10.1016/j.jhep.2020.04.005 (2020). DOI: 10.1016/j.jhep.2020.04.005
288. US Census Bureau. Coronavirus (COVID-19) pandemic. US Census Bureau https://www.census.gov/coronavirus (2020).
289. Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).
290. International Liver Cancer Association. Management of HCC during COVID-19: ILCA guidance. ILCA https://ilca-online.org/news/management-of-hcc-during-covid-19-ilca-guidance/ (2020).
291. Cheng, A. L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25–34 (2009).
292. Sangro, B. et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J. Hepatol. 72, 320–341 (2020).
293. Zhu, A. X. et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 312, 57–67 (2014).
294. Blazeby, J. M. et al. Development of a questionnaire module to supplement the EORTC QLQ-C30 to assess quality of life in patients with hepatocellular carcinoma, the EORTC QLQ-HCC18. Eur. J. Cancer 40, 2439–2444 (2004).
295. Heffernan, N. et al. Measuring health-related quality of life in patients with hepatobiliary cancers: the functional assessment of Cancer Therapy-Hepatobiliary Questionnaire. J. Clin. Oncol. 20, 2229–2239 (2002).
296. Fan, S. Y., Eiser, C. & Ho, M. C. Health-related quality of life in patients with hepatocellular carcinoma: a systematic review. Clin. Gastroenterol. Hepatol. 8, 559–564 (2010).
297. Diouf, M. et al. The added value of quality of life (QoL) for prognosis of overall survival in patients with palliative hepatocellular carcinoma. J. Hepatol. 58, 509–521 (2013).
298. Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).
299. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).
300. Kalbasi, A. & Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20, 25–39 (2020).
301. Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J. Exp. Clin. Cancer Res. 38, 255 (2019).
302. Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147–167 (2020).