. 2023 Dec 1;78(6):1922-1965.

doi: 10.1097/HEP.0000000000000466. Epub 2023 May 22.

AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma

Amit G Singal¹, Josep M Llovet^{2

3

4}, Mark Yarchoan⁵, Neil Mehta⁶, Julie K Heimbach⁷, Laura A Dawson⁸, Janice H Jou⁹, Laura M Kulik¹⁰, Vatche G Agopian¹¹, Jorge A Marrero¹², Mishal Mendiratta-Lala¹³, Daniel B Brown¹⁴, William S Rilling¹⁵, Lipika Goyal¹⁶, Alice C Wei¹⁷, Tamar H Taddei^{18

19}

Affiliations

¹ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
² Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA.
³ Translational Research in Hepatic Oncology, Liver Unit, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic, University of Barcelona, Catalonia, Spain.
⁴ Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
⁵ Department of Medical Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
⁶ University of California, San Francisco, San Francisco, California, USA.
⁷ Transplant Center, Mayo Clinic Rochester, Rochester, Minnesota, USA.
⁸ Radiation Medicine Program/University Health Network, Department of Radiation Oncology, University of Toronto, Toronto, Canada.
⁹ Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, Oregon, USA.
¹⁰ Northwestern Medical Faculty Foundation, Chicago, Illinois, USA.
¹¹ The Dumont-University of California, Los Angeles, Transplant Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
¹² Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
¹⁴ Department of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁵ Division of Interventional Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁶ Department of Medicine, Stanford School of Medicine, Palo Alto, California, USA.
¹⁷ Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
¹⁸ Department of Medicine (Digestive Diseases), Yale School of Medicine, New Haven, CT, USA.
¹⁹ Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.

PMID: 37199193
PMCID: PMC10663390
DOI: 10.1097/HEP.0000000000000466

AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma

Amit G Singal et al. Hepatology. 2023.

. 2023 Dec 1;78(6):1922-1965.

doi: 10.1097/HEP.0000000000000466. Epub 2023 May 22.

Authors

Affiliations

¹ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
² Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA.
³ Translational Research in Hepatic Oncology, Liver Unit, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic, University of Barcelona, Catalonia, Spain.
⁴ Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
⁵ Department of Medical Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
⁶ University of California, San Francisco, San Francisco, California, USA.
⁷ Transplant Center, Mayo Clinic Rochester, Rochester, Minnesota, USA.
⁸ Radiation Medicine Program/University Health Network, Department of Radiation Oncology, University of Toronto, Toronto, Canada.
⁹ Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, Oregon, USA.
¹⁰ Northwestern Medical Faculty Foundation, Chicago, Illinois, USA.
¹¹ The Dumont-University of California, Los Angeles, Transplant Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
¹² Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
¹⁴ Department of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁵ Division of Interventional Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁶ Department of Medicine, Stanford School of Medicine, Palo Alto, California, USA.
¹⁷ Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
¹⁸ Department of Medicine (Digestive Diseases), Yale School of Medicine, New Haven, CT, USA.
¹⁹ Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.

PMID: 37199193
PMCID: PMC10663390
DOI: 10.1097/HEP.0000000000000466

Erratum in

Erratum: AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma.
[No authors listed] [No authors listed] Hepatology. 2023 Dec 1;78(6):E105. doi: 10.1097/HEP.0000000000000621. Epub 2023 Oct 16. Hepatology. 2023. PMID: 37843497 No abstract available.

No abstract available

PubMed Disclaimer

Conflict of interest statement

Amit G. Singal consults for Genentech, AstraZeneca, Eisai, Bayer, Boston Scientific, Exelixis, FujiFilm Medical Sciences, Exact Sciences, Glycotest, and Universal Diagnostics. Joseph M. Llovet consults for and received grants from Eisai, Bayer, and Ipsen. He consults for Merck, Bristol-Myers Squibb, Eli Lilly, Roche, Genentech, Glycotest, Boston Scientific, Exelixis, Bluejay, AstraZeneca, Omega Therapeutics, Mina Alpha, and Captor. Mark Yarchoan consults for and received institutional grants from Genentech. He own stock in and has other interests in Adventris Pharmaceuticals. He consults for Exelixis, Eisai, AstraZeneca, Geneos, Replimune, and Hepion. He received institutional grants from Incyte and Bristol-Myers Squibb. Laura A. Dawson received institutional grants from Merck. Janice H. Jou received grants from Gilead. Laura M. Kulik consults for, advises and is on the speakers’ bureau for Eisai. She consults for and advises Eisai, Exelixis, Genetec, and AstraZeneca. She advises and is on the speakers’ bureau for Gilead. She consults for Merck and Bayer. She advises Hepion and Fujifilm. She received grants from HCC Target and Glycotest. Vatche G. Agopian received grants from Early Diagnostics. Jorge A. Marrero consults for Glycotest and AstraZeneca. Daniel B. Brown received institutional grants from Sirtex Medical and Guerbet. William S. Rilling consults for and advises Boston Scientific. He consults for Varian, Terumo, BD Bard, and AstraZeneca. Lipika Goyal advises and or consults for Alentis Therapeutics, Black Diamond, Exelixis, Genentech, H3Biomedicine, Kinnate, Incyte Corporation, QED Therapeutics, Merck, Servier, Sirtex Medical, Surface Oncology, Taiho Oncology, TranstheraBio, and Tyra Biosciences. She is on the DSMC for AstraZeneca. Alice C. Wei is on the speakers’ bureau for AstraZeneca. She consults for Histosonics and Biosapien. The remaining authors have no conflicts to report.

Figures

**FIGURE 1**
Worldwide incidence of HCC and most common risk factors. ASR, age standardized incidence rate; HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; Reprinted with permission from Llovet et al. ^[9] and the International Agency for Research on Cancer/World Health Organization.

**FIGURE 2**
Proven and emerging primary prevention strategies for hepatocellular carcinoma. Abbreviations: AFP, alpha fetoprotein; GALAD, Gender, Age, AFP-L3%, AFP, and DCP model; HBV, hepatitis B virus; HCV, hepatitis C virus. ¹Included in guidance statements given more favorable risk-benefit ratio compared with other potential strategies.

**FIGURE 3**
Data supporting benefits of hepatocellular carcinoma (HCC) surveillance. HCC surveillance has been shown to significantly reduce HCC-related mortality in a randomized controlled trial among patients with chronic HBV infection (left panel) and in several cohort studies among patients with cirrhosis from any etiology (right panel). Reprinted with permission from Zhang et al.^[55] and Singal et al.^[56]

**FIGURE 4**
Overall value of hepatocellular carcinoma (HCC) surveillance is determined by balance of benefits and harms.

**FIGURE 5**
Recall algorithm for hepatocellular carcinoma (HCC) surveillance. Abbreviations: AFP, alpha fetoprotein; CT, computed tomography; LI-RADS, Liver Imaging Reporting and Data System; MRI, magnetic resonance imaging; PET, positron emission tomography; US, ultrasound; Vis, visualization. ¹Increasing AFP represents doubling of AFP, increase on two consecutive tests, or ≥ 20 ng/ml. ²Can return to US q6 months if lesion stable on two exams. ³CT/MRI may be preferred particularly in patients with obesity, alcohol or NASH-related cirrhosis, or Child Pugh class B or C cirrhosis. ⁴Significantly elevated AFP: although no clear threshold has been established, AFP ≥ 200 ng/ml or ≥ 400 ng/ml may be considered significant elevations depending on clinical context. ⁵Can perform chest and pelvic imaging in addition to alternative modality. If these are negative, other workup, including PET, can be considered.

**FIGURE 6**
Liver Reporting and Data System (LI-RADS) classification of computed tomography (CT) or magnetic resonance imaging (MRI) liver observations in patients who are at risk. LR, LI-RADS. Reprinted with permission from the American College of Radiology Committee on LI-RADS.^[103]

**FIGURE 7**
Applicability of Liver Reporting and Data System (LI-RADS) in surveillance populations. Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PAGE-B score, platelet, age, and gender-hepatitis B score.

**FIGURE 8**
Risk of hepatocellular carcinoma (HCC) and recommended management strategy. Abbreviations: CT, computed tomography; LR, LI-RADS; MRI, magnetic resonance imaging.

**FIGURE 9**
Updated Barcelona Clinic Liver Cancer Staging System 2022. Abbreviations: AFP, alpha fetoprotein; ALBI, albumin-bilirubin; BSC, best supportive care; ECOG-PS, Eastern Cooperative Oncology Group-performance status; HCC, hepatocellular carcinoma; LT, liver transplant; MELD, Model for End-Stage Liver Disease; TACE, transarterial chemoembolization. Reprinted with permission from Reig et al.^[147]

**FIGURE 10**
Algorithm for surgical treatment of early-stage hepatocellular carcinoma (HCC). Abbreviations: CTP, Child-Turcotte-Pugh; UNOS-DS, United Network for Organ Sharing Down-Staging. ¹In non-liver transplant (LT) candidate, can consider surgical resection if >1 lesion in the same lobe. ²In non-LT candidate, can consider minor surgical resection if CTP score B7 and/or mild portal hyper-tension. ³E.g., varices, splenomegaly, platelets < 100 × 10⁹/L, hepatic venous pressure gradient >10 mmHg. ⁴Living donor liver transplant can be considered on a case-by-case basis for patients beyond UNOS-DS criteria. ⁵Eligible for Model for End-Stage Liver Disease exception without 6-month wait period.

**FIGURE 11**
Management of patients with recurrence during or after adjuvant therapy. ¹High-risk features include tumor size > 5 cm, more than 3 tumors, microvascular or macrovascular invasion, and poor tumor differentiation.

**FIGURE 12**
United Network for Organ Sharing (UNOS) hepatocellular carcinoma (HCC) policy timeline. Abbreviations: AFP, alpha feto-protein; MMaT-3, Median MELD at Transplant-3; MELD, Model for End-Stage Liver Disease. *Before completing local-regional therapy, tumor burden meets one of the following criteria: One lesion > 5 cm and ≤ 8 cm; two or three lesions that meet all of the following: at least one lesion > 3 cm, each lesion ≤ 5 cm, and a total diameter of all lesions ≤ 8 cm; or four or five lesions each < 3 cm, and a total diameter of all lesions ≤ 8 cm; AFP levels ≥ 1000 ng/mL are required to show a reduction in AFP level to < 500 ng/mL before liver transplantation. (Boxes shaded in gray denote historical policies; boxes in white reflect current policy.).

**FIGURE 13**
Management algorithm for unresectable T1 lesion/BCLC 0 in patient with cirrhosis. Abbreviations: AFP, alpha fetoprotein; CT, computed tomography; HPS, hepatopulmonary syndrome; LRT, locoregional therapy; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; PPHTN, portopulmonary hypertension. ¹If lesion not amenable to ablation, alternate options include transarterial chemoembolization (TACE), radiation segmentectomy, or stereotactic body radiation therapy (SBRT). ²Patient has higher risk of rapid tumor progression, defined as > 0.3 cm per month increase in tumor diameter.

**FIGURE 14**
Radiologic assessment of treatment response and recall strategy. Abbreviations: AE, adverse event; BCLC, Barcelona Clinic Liver Cancer; CTP, Child-Turcotte-Pugh; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PS, performance status; TACE, transarterial chemoembolization.

**FIGURE 15**
Timeline of systemic therapies for hepatocellular carcinoma (HCC) and resultant survival. (First line therapies are above the timeline; second line therapies are below the timeline.) ¹KEYNOTE 224 was a non-randomized phase 2 trial. Phase 3 studies of pembrolizumab versus sorafenib have had conflicting results, with improved median OS noted in an Asian population.

**FIGURE 16**
Treatment strategy for HCC with systemic therapies. Abbreviations: BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma. Solid arrows indicate treatments for which there is clear evidence; gray dotted arrows indicate treatments in the second/third line for which further studies are required. ¹Treatments that got FDA accelerated approval based on phase II studies. Reprinted with permission from Llovet et al.^[331]

See this image and copyright information in PMC

References

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1. Rich NE, Carr C, Yopp AC, Marrero JA, Singal AG. Racial and Ethnic Disparities in Survival Among Patients With Hepatocellular Carcinoma in the United States: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2022;20:e267–88. - PMC - PubMed

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AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma

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AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma

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