Hepatocellular carcinoma

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Last updated on 2024-12-02:44 regimens on this page
52 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==AASLD==
*2018: Marrero et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases EuroPMC
==ASCO==
*2024: Gordan et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update EuroPMC
**2020: Gordan et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline EuroPMC
==ESMO==
*2018: Vogel et al. Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2012: Verslype et al. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. EuroPMC
**2010: Jelic & Sotiropoulos. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Jelic. Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Parikh et al. Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
==French Intergroup==
*2021: Blanc et al. Hepatocellular carcinoma: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, AFEF, SIAD, SFR/FRI) EuroPMC
==ISRS==
*2023: Bae et al. Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Meta-Analysis and International Stereotactic Radiosurgery Society Practice Guidelines EuroPMC
==NCCN==
*NCCN Guidelines - Hepatocellular Carcinoma
**2021: Benson et al. Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. EuroPMC
**2006: Benson et al. Hepatobiliary cancers. Clinical practice guidelines in oncology. EuroPMC
**2003: Benson et al. Hepatobiliary cancer. Clinical practice guidelines in oncology. EuroPMC
==SITC==
*2021: Greten et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma link to PMC article EuroPMC
==TOS/ESMO==
*2020: Chen et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS–ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO EuroPMC
=Adjuvant therapy=
==Atezolizumab & Bevacizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Qin et al. 2023 (IMbrave050)	2019-12-31 to 2021-11-25	Phase 3 (E-esc)	Observation	Seems to have longer RFS (primary endpoint)Median RFS: NYR vs NYR(aHR 0.72, 95% CI 0.53-0.98)
====Preceding treatment====
*Curative surgical resection or ablation
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for 17 cycles (1 year)
===References===
#IMbrave050: Qin S, Chen M, Cheng AL, Kaseb AO, Kudo M, Lee HC, Yopp AC, Zhou J, Wang L, Wen X, Heo J, Tak WY, Nakamura S, Numata K, Uguen T, Hsiehchen D, Cha E, Hack SP, Lian Q, Ma N, Spahn JH, Wang Y, Wu C, Chow PKH; IMbrave050 investigators. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Nov 18;402(10415):1835-1847. Epub 2023 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04102098
==TACE monotherapy==
TACE: Trans-Arterial Chemo-Embolization
===Regimen variant #1, doxorubicin-based===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wang et al. 2018 (LCI-125-009)	2011-2014 	Phase 3 (E-esc)	Observation	Seems to have longer OS (secondary endpoint)OS36: 85.2% vs 77.4%(HR 0.59, 95% CI 0.36-0.97)
====Preceding treatment====
*Curative surgical resection
====Local therapy====
*TACE consisting of:
**Doxorubicin (Adriamycin) 20 to 30 mg/m2
**Lipiodol 3 to 5 mL
One or more treatments
===Regimen variant #2, carboplatin, epirubicin, mitomycin-based===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wei et al. 2018 (SYSUCC-HCC-ADTACE)	2009-2012 	Phase 3 (E-esc)	Observation	Longer DFS (primary endpoint)Median DFS: 17.45 vs 9.27 mo(HR 0.70, 95% CI 0.52-0.95)
====Preceding treatment====
*Curative surgical resection
====Local therapy====
*TACE consisting of:
**Carboplatin (Paraplatin) 200 mg/m2
**Mitomycin (Mutamycin) 6 mg/m2
**Epirubicin (Ellence) 40 mg/m2
**Lipiodol 4 to 5 mL
One or two treatments
===References===
#LCI-125-009: Wang Z, Ren Z, Chen Y, Hu J, Yang G, Yu L, Yang X, Huang A, Zhang X, Zhou S, Sun H, Wang Y, Ge N, Xu X, Tang Z, Lau W, Fan J, Wang J, Zhou J. Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study. Clin Cancer Res. 2018 May 1;24(9):2074-2081. Epub 2018 Feb 2. link to original article EuroPMC NCT01966133
#SYSUCC-HCC-ADTACE: Wei W, Jian PE, Li SH, Guo ZX, Zhang YF, Ling YH, Lin XJ, Xu L, Shi M, Zheng L, Chen MS, Guo RP. Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety. Cancer Commun (Lond). 2018 Oct 10;38(1):61. link to original article link to PMC article EuroPMC NCT02788526
=Local therapy for advanced disease=
==Axitinib & TACE==
===Regimen===
Study 	Dates of enrollment	Evidence
Chan et al. 2017 (HCC028)	2011-2014 	Phase 2
====Targeted therapy====
*Axitinib (Inlyta) 5 mg PO twice per day on days 1 to 56, held for 24 hours before and after TACE
====Local therapy====
*TACE IA once on day 36 +/- 4 days
8-week cycles
===References===
#HCC028: Chan SL, Yeo W, Mo F, Chan AWH, Koh J, Li L, Hui EP, Chong CCN, Lai PBS, Mok TSK, Yu SCH. A phase 2 study of the efficacy and biomarker on the combination of transarterial chemoembolization and axitinib in the treatment of inoperable hepatocellular carcinoma. Cancer. 2017 Oct 15;123(20):3977-3985. Epub 2017 Jun 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01352728
==Bevacizumab, Durvalumab, TACE==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sangro et al. 2025 (EMERALD-1)	2018-11-30 to 2021-07-19	Phase 3 (E-esc)	1. TACE 	Seems to have longer PFS (primary endpoint)Median PFS: 15 vs 8.2 mo(HR 0.77, 95% CI 0.61-0.98)
Sangro et al. 2025 (EMERALD-1)	2018-11-30 to 2021-07-19	Phase 3 (E-esc)	2. Durvalumab & TACE	Not reported
Note: bevacizumab starts once the TACE phase of treatment has ended; the instructions below assume that 4 courses of TACE are given.
====Targeted therapy====
*Bevacizumab (Avastin) as follows:
**Cycle 5 onwards: 15 mg/kg IV once on day 1
====Immunotherapy====
*Durvalumab (Imfinzi) as follows:
**Cycles 1 to 4: 1500 mg IV once on day 1
**Cycle 5 onwards: 1120 mg IV once on day 1
28-day cycle for 4 cycles, then 21-day cycles
====Local therapy====
*TACE
1 to 4 treatments (see note)
===References===
#EMERALD-1: Sangro B, Kudo M, Erinjeri JP, Qin S, Ren Z, Chan SL, Arai Y, Heo J, Mai A, Escobar J, Lopez Chuken YA, Yoon JH, Tak WY, Breder VV, Suttichaimongkol T, Bouattour M, Lin SM, Peron JM, Nguyen QT, Yan L, Chiu CF, Santos FA, Veluvolu A, Thungappa SC, Matos M, Żotkiewicz M, Udoye SI, Kurland JF, Cohen GJ, Lencioni R; EMERALD-1 Investigators. Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): a multiregional, randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2025 Jan 18;405(10474):216-232. Epub 2025 Jan 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03778957
==Lenvatinib & TACE==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Peng et al. 2022 (LAUNCH)	2019-2021 	Phase 3 (E-esc)	Lenvatinib	Longer OS (primary endpoint)Median OS: 17.8 vs 11.5 mo(HR 0.45, 95% CI 0.33-0.61)
====Targeted therapy====
*Lenvatinib (Lenvima) by the following weight-based criteria:
**Less than 60 kg: 8 mg PO once per day
**60 kg or more: 12 mg PO once per day
Continued indefinitely
====Local therapy====
*TACE
1 or more treatments
===References===
#LAUNCH: Peng Z, Fan W, Zhu B, Wang G, Sun J, Xiao C, Huang F, Tang R, Cheng Y, Huang Z, Liang Y, Fan H, Qiao L, Li F, Zhuang W, Peng B, Wang J, Li J, Kuang M. Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH). J Clin Oncol. 2023 Jan 1;41(1):117-127. Epub 2022 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03905967
==Lenvatinib, Pembrolizumab, TACE==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Kudo et al. 2025 (LEAP-012)	2020-05-22 to 2023-01-11	Phase 3 (E-esc)	TACE 	Longer PFS (co-primary endpoint)Median PFS: 14.6 vs 10 mo(HR 0.66, 95% CI 0.51-0.84)Did not meet co-primary endpoint of OSOS24: 75% vs 69%(HR 0.80, 95% CI 0.57-1.11)
====Targeted therapy====
*Lenvatinib (Lenvima) by the following weight-based criteria:
**Less than 60 kg: 8 mg PO once per day
**60 kg or more: 12 mg PO once per day
====Immunotherapy====
*Pembrolizumab (Keytruda) as follows:
**Cycles 1 to 18: 400 mg IV once on day 1
6-week cycles
====Local therapy====
*TACE
1 or more treatments
===References===
#LEAP-012: Kudo M, Ren Z, Guo Y, Han G, Lin H, Zheng J, Ogasawara S, Kim JH, Zhao H, Li C, Madoff DC, Ghobrial RM, Kawaoka T, Gerolami R, Ikeda M, Kumada H, El-Khoueiry AB, Vogel A, Peng X, Mody K, Dutcus C, Dubrovsky L, Siegel AB, Finn RS, Llovet JM; LEAP-012 investigators. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. Lancet. 2025 Jan 18;405(10474):203-215. Epub 2025 Jan 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03905967
==DEB-TACE==
DEB-TACE: Drug-Eluting Bead Trans-Arterial Chemo-Embolization
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Brown et al. 2016 (MSK 07-099)	2007-2012 	Randomized Phase 2 (E-esc)	Bland embolization 	Did not meet primary endpoint of ORR
Meyer et al. 2017 (TACE2) 	2010-2015 	Phase 3 (C) 	DEB-TACE & Sorafenib	Did not meet primary endpoint of PFS
Duan et al. 2024 	2021-01-01 to 2022-06-30	Phase 3 (C) 	DEB-TACE & Apatinib 	Shorter PFS (primary endpoint)Median PFS: 5.2 vs 7.1 mo(HR 1.79, 95% CI 1.37-2.27)Shorter OS (secondary endpoint)Median OS: 18.9 vs 23.3 mo(HR 1.89, 95% CI 1.35-2.70)
Note: TACE2 assessed the addition of concurrent sorafenib to DEB-TACE.
====Eligibility criteria====
*TACE2: Child-Pugh A liver disease, and ECOG PS 0 or 1
====Local therapy====
*TACE with drug-eluting beads
One or more courses
===References===
#MSK 07-099: Brown KT, Do RK, Gonen M, Covey AM, Getrajdman GI, Sofocleous CT, Jarnagin WR, D'Angelica MI, Allen PJ, Erinjeri JP, Brody LA, O'Neill GP, Johnson KN, Garcia AR, Beattie C, Zhao B, Solomon SB, Schwartz LH, DeMatteo R, Abou-Alfa GK. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016 Jun 10;34(17):2046-53. Epub 2016 Feb 1. link to original article link to PMC article EuroPMC NCT00539643
#TACE2: Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, Stubbs C, Stocken DD, Wall L, Watkinson A, Hacking N, Evans TRJ, Collins P, Hubner RA, Cunningham D, Primrose JN, Johnson PJ, Palmer DH. Sorafenib in combination with transarterial chemoembolization in patients with unresectable hepatocellular carcimoma (TACE2): a randomized placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Aug;2(8):565-575. Epub 2017 Jun 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01324076
#Duan X, Li H, Kuang D, Chen P, Zhang M, Li T, Jiao D, Li Y, He X, Xing C, Wang H, Liu Y, Xie L, Zhang S, Zhang Q, Zhu P, Chang Y, Xie J, Ren J, Han X. Comparison of drug-eluting bead transarterial chemoembolization combined with apatinib versus drug-eluting bead transarterial chemoembolization for the treatment of unresectable hepatocellular carcinoma: a randomized, prospective, multicenter phase III trial. Signal Transduct Target Ther. 2024 Nov 13;9(1):304. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR2000041170
==DEB-TACE & Apatinib==
DEB-TACE & Apatinib: Drug-Eluting Bead Trans-Arterial Chemo-Embolization & Apatinib
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Duan et al. 2024	2021-01-01 to 2022-06-30	Phase 3 (E-esc)	DEB-TACE 	Longer OS (secondary endpoint)Median OS: 23.3 vs 18.9 mo(HR 0.53, 95% CI 0.37-0.74)Longer PFS (primary endpoint)Median PFS: 7.1 vs 5.2 mo(HR 0.56, 95% CI 0.44-0.73)
====Local therapy====
*TACE with drug-eluting beads
====Targeted therapy====
*Apatinib (Aitan) 500 mg PO once per day, held for 3 days prior to each DEB-TACE administration
One or more courses
===References===
#Duan X, Li H, Kuang D, Chen P, Zhang M, Li T, Jiao D, Li Y, He X, Xing C, Wang H, Liu Y, Xie L, Zhang S, Zhang Q, Zhu P, Chang Y, Xie J, Ren J, Han X. Comparison of drug-eluting bead transarterial chemoembolization combined with apatinib versus drug-eluting bead transarterial chemoembolization for the treatment of unresectable hepatocellular carcinoma: a randomized, prospective, multicenter phase III trial. Signal Transduct Target Ther. 2024 Nov 13;9(1):304. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR2000041170
==FOLFOX-HAIC==
FOLFOX-HAIC: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin Hepatic Arterial Infusion Chemotherapy
===Regimen variant #1, longer duration===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Li et al. 2021 (HCC-S023)	2016-2018 	Phase 3 (E-switch-ooc)	TACE 	Longer OS (primary endpoint)Median OS: 23.1 vs 16.1 mo(HR 0.58, 95% CI 0.45-0.75)
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IA over 60 minutes once on day 1, given second
*Fluorouracil 400 mg/m2 IA bolus once on day 1, given third, then 2400 mg/m2 IA continuous infusion over 24 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin 130 mg/m2 IA over 2 hours once on day 1, given first
21-day cycle for up to 6 cycles
===Regimen variant #2, shorter duration===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Li et al. 2023 (B2017-006-01)	2016-06 to 2021-08 	Phase 3 (E-esc)	Observation	Longer DFS (primary endpoint)Median DFS: 20.3 vs 10 mo(HR 0.59, 95% CI 0.43-0.81)
====Preceding treatment====
*Curative surgical resection
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IA over 90 minutes once on day 1, given second
*Fluorouracil 400 mg/m2 IA over 2 hours once on day 1, given third, then 2400 mg/m2 IA continuous infusion over 24 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin 85 mg/m2 IA over 3 hours once on day 1, given first
28- to 35-day cycle for 1 to 2 cycles
===References===
#HCC-S023: Li QJ, He MK, Chen HW, Fang WQ, Zhou YM, Xu L, Wei W, Zhang YJ, Guo Y, Guo RP, Chen MS, Shi M. Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin Versus Transarterial Chemoembolization for Large Hepatocellular Carcinoma: A Randomized Phase III Trial. J Clin Oncol. 2022 Jan 10;40(2):150-160. Epub 2021 Oct 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02973685
#B2017-006-01: Li SH, Mei J, Cheng Y, Li Q, Wang QX, Fang CK, Lei QC, Huang HK, Cao MR, Luo R, Deng JD, Jiang YC, Zhao RC, Lu LH, Zou JW, Deng M, Lin WP, Guan RG, Wen YH, Li JB, Zheng L, Guo ZX, Ling YH, Chen HW, Zhong C, Wei W, Guo RP. Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study. J Clin Oncol. 2023 Apr 1;41(10):1898-1908. Epub 2022 Dec 16. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03192618
==FOFLFOX-HAIC & Sorafenib==
FOLFOX-HAIC & Sorafenib: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin Hepatic Arterial Infusion Chemotherapy & Sorafenib
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
He et al. 2019 (HCC-S021)	2016-04-01 to 2017-10-10	Phase 3 (E-esc)	Sorafenib 	Longer OS (primary endpoint)Median OS: 13.4 vs 7.1 mo(HR 0.35, 95% CI 0.26-0.48)
Note: All patient who were hepatitis B received preemptive antiviral therapy.
====Eligibility criteria====
*HCC with portal vein invasion confirmed by 2 imaging techniques, Child-Pugh A class liver function, and an ECOG PS of 0 to 2
*Excluded: Patients with esophageal or gastric variceal bleeding and hepatic encephalopathy
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IA over 60 minutes once on day 1, given second, from hours 2 to 3
*Fluorouracil 400 mg/m2 IA bolus once on day 1, then 2400 mg/m2 IA continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin 85 mg/m2 IA over 120 minutes once on day 1, given first, from hours 0 to 2
====Targeted therapy====
*Sorafenib 400 mg PO twice per day
21-day cycles
===References===
#HCC-S021: He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, Le Y, Zhou Z, Zhao M, Guo Y, Guo R, Chen M, Shi M. Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial. JAMA Oncol. 2019 Jul 1;5(7):953-960. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02774187
==Radioembolization==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Chow et al. 2018 (SIRveNIB) 	2010-2016 	Phase 3 (E-switch-ooc)	Sorafenib 	Did not meet primary endpoint of OS
Vilgrain et al. 2017 (SARAH)	2011-2015 	Phase 3 (E-switch-ooc)	Sorafenib 	Did not meet primary endpoint of OS
====Synopsis====
*SARAH was a multicenter European study that also included patients without two unsuccessful rounds of TACE. Primary endpoint of improved OS was not met; Y90 was associated with higher ORR, lower DCR, fewer AE, and similar survival. Additional post-hoc analysis showed patients who received Y90 at > or equal to 10000 cGy may derive a meaningful response as compared to sorafenib.
*SIRveNIB was a multicenter Asian study randomized newly diagnosed patients with locally advanced inoperable HCC to a single injection of Y90 or sorafenib until progressive disease or unacceptable toxicity. Primary endpoint of improved OS was not met; Y90 was associated with higher ORR, few SAE, and similar OS, similar OS and DCR.
====Radiotherapy====
*Selective internal radiotherapy (SIRT) with yttrium-90 resin microspheres
===References===
#SARAH: Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, Sibert A, Bouattour M, Lebtahi R, Allaham W, Barraud H, Laurent V, Mathias E, Bronowicki JP, Tasu JP, Perdrisot R, Silvain C, Gerolami R, Mundler O, Seitz JF, Vidal V, Aubé C, Oberti F, Couturier O, Brenot-Rossi I, Raoul JL, Sarran A, Costentin C, Itti E, Luciani A, Adam R, Lewin M, Samuel D, Ronot M, Dinut A, Castera L, Chatellier G; SARAH Trial Group. 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. 2017 Dec;18(12):1624-1636. Epub 2017 Oct 26. link to original article EuroPMC NCT01482442
##Update: Abstract: Hawkins NS, Ross PJ, Palmer DH, Chatellier G, Pereira H, Vilgrain V. Overall survival of patients with hepatocellular carcinoma receiving sorafenib versus selective internal radiation therapy with predicted osimetry in the SARAH trial. Annals of Oncology. 2019 Sept; 30 (suppl_5): v253-v324. Epub 2019 Sept 29.
#SIRveNIB: 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 AS, Goh ASW, Tay KH, Lo RHG, Goh BKP, Ng DCE, Lekurwale G, Liew WM, Gebski V, Mak KSW, Soo KC; Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018 Jul 1;36(19):1913-1921. Epub 2018 Mar 2. link to original article EuroPMC NCT01135056
==TACE monotherapy==
TACE: Trans-Arterial Chemo-Embolization
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Trinchet et al. 1995 	1990-1992 	Phase 3 (E-esc) 	Best supportive care 	Did not meet primary endpoint of OS
Llovet et al. 2002 	1996-2000 	Phase 3 (E-esc) 	Best supportive care 	Longer OS (primary endpoint)(HR 0.47, 95% CI 0.25-0.91)
Okusaka et al. 2009 	1999-2003 	Phase 3 (E-esc) 	TAI 	Did not meet primary endpoint of OS
Kudo et al. 2011 (Bayer 11721)	2006-2009 	Non-randomized part of phase 3 RCT	 	
Ikeda et al. 2017 	2008-2010 	Phase 3 (C) 	TACE with Miriplatin 	Did not meet primary endpoint of OS
Kudo et al. 2014 (BRISK TA) 	2009-2012 	Phase 3 (C) 	TACE & Brivanib 	Did not meet primary endpoint of OSMedian OS: 26.1 vs 26.4 mo(HR 1.11, 95% CI 0.81-1.52)
Kudo et al. 2017 (ORIENTAL) 	2010-2013 	Phase 3 (C) 	TACE & Orantinib 	Did not meet primary endpoint of OSMedian OS: 32.3 vs 31.1 mo(HR 0.92, 95% CI 0.74-1.14)
Sangro et al. 2025 (EMERALD-1)	2018-11-30 to 2021-07-19	Phase 3 (C) 	1. Bevacizumab, Durvalumab, TACE	Seems to have shorter PFS (primary endpoint)Median PFS: 8.2 vs 15 mo(HR 1.30, 95% CI 1.02-1.64)
Sangro et al. 2025 (EMERALD-1)	2018-11-30 to 2021-07-19	Phase 3 (C) 	2. Durvalumab & TACE 	Did not meet primary endpoint of PFSMedian PFS: 8.2 vs 10 mo(HR 1.06, 95% CI 0.84-1.33)
Fan et al. 2024 (TREATHCC) 	2019-10 to 2021-12 	Phase 3 (C) 	Sorafenib & TACE 	Shorter OS (primary endpoint)Median OS: 15.1 vs 22.2 mo(HR 1.82, 95% CI 1.28-2.56)
Note: TREAT has been renamed TREATHCC to avoid confusion with the trial by the same name in NSCLC.
====Synopsis====
*Bayer 11721 was a Japanese and Korean study including patients with Child-Pugh A cirrhosis with a primary endpoint of TTP, and secondary endpoint of OS. More than 50% of patients started sorafenib after 9 weeks post TACE. 73% of patients had dose reductions, and 91% of patients had dose interruptions. 
====Local therapy====
*TACE
1 or more treatments
====Subsequent treatment====
*Bayer 11721: Placebo versus adjuvant sorafenib
===References===
#Trinchet JC, Abou Rached A, Beaugrand M, Mathieu D, Chevret S, Chastang C; Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med. 1995 May 11;332(19):1256-61. link to original article EuroPMC
#Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Solà R, Rodés J, Bruix J; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1734-9. link to original article EuroPMC
#Okusaka T, Kasugai H, Shioyama Y, Tanaka K, Kudo M, Saisho H, Osaki Y, Sata M, Fujiyama S, Kumada T, Sato K, Yamamoto S, Hinotsu S, Sato T. Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial. J Hepatol. 2009 Dec;51(6):1030-6. Epub 2009 Oct 1. link to original article EuroPMC
#Bayer 11721: Kudo M, Imanaka K, Chida N, Nakachi K, Tak WY, Takayama T, Yoon JH, Hori T, Kumada H, Hayashi N, Kaneko S, Tsubouchi H, Suh DJ, Furuse J, Okusaka T, Tanaka K, Matsui O, Wada M, Yamaguchi I, Ohya T, Meinhardt G, Okita K. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2011 Sep;47(14):2117-27. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00494299
#BRISK TA: Kudo M, Han G, Finn RS, Poon RT, Blanc JF, Yan L, Yang J, Lu L, Tak WY, Yu X, Lee JH, Lin SM, Wu C, Tanwandee T, Shao G, Walters IB, Dela Cruz C, Poulart V, Wang JH. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial. Hepatology. 2014 Nov;60(5):1697-707. Epub 2014 Sep 29. link to original article EuroPMC NCT00908752
#Ikeda M, Kudo M, Aikata H, Nagamatsu H, Ishii H, Yokosuka O, Torimura T, Morimoto M, Ikeda K, Kumada H, Sato T, Kawai I, Yamashita T, Horio H, Okusaka T; Miriplatin TACE Study Group. Transarterial chemoembolization with miriplatin vs epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial. J Gastroenterol. 2018 Feb;53(2):281-290. Epub 2017 Aug 1. link to original article link to PMC article EuroPMC JapicCTI-080632
#ORIENTAL: Kudo M, Cheng AL, Park JW, Park JH, Liang PC, Hidaka H, Izumi N, Heo J, Lee YJ, Sheen IS, Chiu CF, Arioka H, Morita S, Arai Y. 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. 2018 Jan;3(1):37-46. Epub 2017 Oct 4. link to original article EuroPMC NCT01465464
#PRODIGE 16: Turpin A, de Baere T, Heurgué A, Le Malicot K, Ollivier-Hourmand I, Lecomte T, Perrier H, Vergniol J, Sefrioui D, Rinaldi Y, Edeline J, Jouve JL, Silvain C, Becouarn Y, Dauvois B, Baconnier M, Debette-Gratien M, Deplanque G, Dharancy S, Lepage C, Hebbar M; PRODIGE 16 investigators Collaborators. Liver transarterial chemoembolization and sunitinib for unresectable hepatocellular carcinoma: Results of the PRODIGE 16 study. Clin Res Hepatol Gastroenterol. 2021 Mar;45(2):101464. Epub 2020 Jun 21. link to original article EuroPMC NCT01164202
#TREATHCC: Fan W, Zhu B, Chen S, Wu Y, Zhao X, Qiao L, Huang Z, Tang R, Chen J, Lau WY, Chen M, Li J, Kuang M, Peng Z. Survival in Patients With Recurrent Intermediate-Stage Hepatocellular Carcinoma: Sorafenib Plus TACE vs TACE Alone Randomized Clinical Trial. JAMA Oncol. 2024 Aug 1;10(8):1047-1054. link to original article link to PMC article EuroPMC NCT04103398
#LEAP-012: Kudo M, Ren Z, Guo Y, Han G, Lin H, Zheng J, Ogasawara S, Kim JH, Zhao H, Li C, Madoff DC, Ghobrial RM, Kawaoka T, Gerolami R, Ikeda M, Kumada H, El-Khoueiry AB, Vogel A, Peng X, Mody K, Dutcus C, Dubrovsky L, Siegel AB, Finn RS, Llovet JM; LEAP-012 investigators. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. Lancet. 2025 Jan 18;405(10474):203-215. Epub 2025 Jan 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03905967
#EMERALD-1: Sangro B, Kudo M, Erinjeri JP, Qin S, Ren Z, Chan SL, Arai Y, Heo J, Mai A, Escobar J, Lopez Chuken YA, Yoon JH, Tak WY, Breder VV, Suttichaimongkol T, Bouattour M, Lin SM, Peron JM, Nguyen QT, Yan L, Chiu CF, Santos FA, Veluvolu A, Thungappa SC, Matos M, Żotkiewicz M, Udoye SI, Kurland JF, Cohen GJ, Lencioni R; EMERALD-1 Investigators. Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): a multiregional, randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2025 Jan 18;405(10474):216-232. Epub 2025 Jan 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03778957
==TACE, then 5-FU==
TACE, then 5-FU: Trans-Arterial ChemoEmbolization followed by 5-FluoroUracil
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kawata et al. 2001	1990-1993 	Phase 3 (C)	TACE, then 5-FU & Pravastatin	Shorter OS
===Induction===
====Local therapy====
*Doxorubicin (Adriamycin) 30 mg IA once on day 1, given first
*Gelatin-sponge particles and ethyl ester of poppyseed oil fatty acids containing 38% iodine by weight (Lipiodol; AndreGelbe Laboratories, Paris, France)
One treatment, followed in 2 weeks by:
===Consolidation===
====Chemotherapy====
*Fluorouracil (5-FU) 200 mg PO once per day
2-month course
===References===
#Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada M, Tamura S, Noda S, Imai Y, Matsuzawa Y. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma: a randomized controlled trial. Br J Cancer. 2001 Apr 6;84(7):886-91. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
=First-line therapy for advanced or metastatic disease=
Note: in this setting, first-line refers to first-line systemic therapy; many patients had resection, ablation, and/or TACE prior to systemic therapy. See individual trials for details.
==Apatinib & Camrelizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Qin et al. 2023 (CARES-310)	2019-06-28 to 2021-3-24	Phase 3 (E-esc)	Sorafenib 	Longer PFS (primary endpoint)Median PFS: 5.6 vs 3.7 mo(HR 0.52, 95% CI 0.41-0.65)Longer OS (secondary endpoint)Median OS: 22.1 vs 15.2 mo(HR 0.62, 95% CI 0.49-0.80)
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
====Targeted therapy====
*Apatinib (Aitan) 250 mg PO once per day on days 1 to 14
14-day cycles
===References===
#CARES-310: Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, Chen Z, Jia W, Jin Y, Guo Y, Hu X, Meng Z, Liang J, Cheng Y, Xiong J, Ren H, Yang F, Li W, Chen Y, Zeng Y, Sultanbaev A, Pazgan-Simon M, Pisetska M, Melisi D, Ponomarenko D, Osypchuk Y, Sinielnikov I, Yang TS, Liang X, Chen C, Wang L, Cheng AL, Kaseb A, Vogel A; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023 Sep 30;402(10408):1133-1146. Epub 2023 Jul 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03764293
==Atezolizumab & Bevacizumab==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Lee et al. 2020 (GO30140) 	2016-07-20 to 2018-07-31	Phase 1b 	 	
Finn et al. 2020 (IMbrave150)	2018-03-15 to 2019-01-30	Phase 3 (E-RT-esc)	Sorafenib 	Longer OS1 (co-primary endpoint)Median OS: 19.2 vs 13.4 mo(HR 0.66, 95% CI 0.52-0.85)
1Reported efficacy is based on the 2021 update.
====Eligibility criteria====
*Excluded: Child-Pugh class B and C, coinfection with hepatitis B or C virus, and untreated or incompletely treated esophageal or gastric varices
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1, given first
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1, given second
21-day cycles
===References===
#GO30140: Lee MS, Ryoo BY, Hsu CH, Numata K, Stein S, Verret W, Hack SP, Spahn J, Liu B, Abdullah H, Wang Y, He AR, Lee KH; GO30140 investigators. Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lancet Oncol. 2020 Jun;21(6):808-820. Erratum in: Lancet Oncol. 2020 Jul;21(7):e341. link to original article EuroPMC NCT02715531
#IMbrave150: Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03434379
##PRO analysis: Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, Kudo M, Breder V, Merle P, Kaseb A, Li D, Mulla S, Verret W, Xu DZ, Hernandez S, Ding B, Liu J, Huang C, Lim HY, Cheng AL, Ducreux M. Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):991-1001. Epub 2021 May 27. link to original article EuroPMC
##Update: Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022 Apr;76(4):862-873. Epub 2021 Dec 11. link to original article EuroPMC
==Bevacizumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Siegel et al. 2008	2003-2006 	Phase 2 	ORR: 13% (95% CI, 3-23)
Note: The dose here was a pre-planned escalation dose with initial dose of 5mg/kg. The study met and exceeded primary endpoint of determining whether bevacizumab improved 6 month PFS from 40-60% (observed 6 months PFS was 65%).
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once on day 1
14-day cycles
===References===
#Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, Chen H, Clark-Garvey S, Weinberg A, Mandeli J, Christos P, Mazumdar M, Popa E, Brown RS Jr, Rafii S, Schwartz JD. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008 Jun 20;26(18):2992-8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Capecitabine & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Hsu et al. 2010	2005-2006 	Phase 2 	ORR: 9%
====Chemotherapy====
*Capecitabine (Xeloda) 800 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycle for 6 or more cycles depending on response
===References===
#Hsu CH, Yang TS, Hsu C, Toh HC, Epstein RJ, Hsiao LT, Chen PJ, Lin ZZ, Chao TY, Cheng AL. Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. Br J Cancer. 2010 Mar 16;102(6):981-6. Epub 2010 Feb 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==CapeOx==
CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda (Capecitabine), OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Boige et al. 2007 (FFCD 03-03)	2003-2004 	Phase 2 	DCR: 72% (95% CI, 57-83)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycles
===References===
#FFCD 03-03: Boige V, Raoul JL, Pignon JP, Bouché O, Blanc JF, Dahan L, Jouve JL, Dupouy N, Ducreux M; Fédération Francophone de Cancérologie Digestive. Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial. Br J Cancer. 2007 Oct 8;97(7):862-7. Epub 2007 Sep 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==CapeOx & Bevacizumab==
CapeOX & Bevacizumab: Capecitabine, OXaliplatin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Sun et al. 2011	2004-2007 	Phase 2 	DCR: 77.5%
====Chemotherapy====
*Capecitabine (Xeloda) 825 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
**Infusion times are 75 to 105 minutes for the first dose, which if tolerated could be decreased to 50 to 70 minutes for the second dose, then 20 to 40 minutes for dose 3 and later
21-day cycles
===References===
#Sun W, Sohal D, Haller DG, Mykulowycz K, Rosen M, Soulen MC, Caparro M, Teitelbaum UR, Giantonio B, O'Dwyer PJ, Shaked A, Reddy R, Olthoff K. Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer. 2011 Jul 15;117(14):3187-92. Epub 2011 Jan 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Donafenib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Qin et al. 2021	2016-2018 	Phase 3 (E-switch-ic)	Sorafenib 	Seems to have longer OS (primary endpoint)Median OS: 12.1 vs 10.3 mo(HR 0.83, 95% CI 0.70-0.99)
====Targeted therapy====
*Donafenib (Zepsun) 200 mg PO twice per day on days 1 to 28
28-day cycles
===References===
#Qin S, Bi F, Gu S, Bai Y, Chen Z, Wang Z, Ying J, Lu Y, Meng Z, Pan H, Yang P, Zhang H, Chen X, Xu A, Cui C, Zhu B, Wu J, Xin X, Wang J, Shan J, Chen J, Zheng Z, Xu L, Wen X, You Z, Ren Z, Liu X, Qiu M, Wu L, Chen F. Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial. J Clin Oncol. 2021 Sep 20;39(27):3002-3011. Epub 2021 Jun 29. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Doxorubicin monotherapy==
===Regimen variant #1, 50 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Qin et al. 2013 (EACH)	2007-2009 	Phase 3 (C)	FOLFOX4 	Might have shorter OS (primary endpoint)Median OS: 5.0 vs 6.4 mo(HR 1.25, 95% CI 0.98-1.59)
Note: EACH included patients with both Child-Pugh stage A and B disease (AST or ALT less than 2.5x ULN, T bil less than 1.5x ULN, INR less than 1.5).
====Chemotherapy====
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 60 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnson et al. 1978 	1976-1977 	Non-randomized 	 	
Yeo et al. 2005 	1999-2003 	Phase 3 (C) 	PIAF 	Did not meet primary endpoint of OSMedian OS: 6.83 vs 8.67 mo(HR 1.03, 95% CI 0.76-1.41)
Gish et al. 2007 (ZARIX-ZX101-301) 	2000-2005 	Phase 3 (C) 	Nolatrexed 	Longer OS (primary endpoint)Median OS: 32.3 vs 22.3 wk(HR 0.75)
Abou-Alfa et al. 2010 (Study 11546)	2005-04 to 2006-10 	Randomized Phase 2 (C)	Doxorubicin & Sorafenib	Shorter OS (secondary endpoint)Median OS: 6.5 vs 13.7 mo(HR 2.04, 95% CI 1.25-3.33)Shorter TTP (primary endpoint)Median TTP: 2.8 vs 6.4 mo(HR 2.00, 95% CI 1.11-3.33)
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
21-day cycle for varying durations: 6 cycles (Yeo et al. 2005); 9 cycles (Johnson et al. 1978, Study 11546); indefinitely (Lai et al. 1988, ZARIX-ZX101-301)
====Dose and schedule modifications====
*ZARIX-ZX101-301: Initial dose reduction to 30 mg/m2 IV for patients with T bili greater than 1.2 mg/dL
===Regimen variant #3, 60 --> 75 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lai et al. 1988	Not reported 	Randomized (E-esc)	Best supportive care	Seems to have longer OSMedian OS: 10.6 vs 7.5 wk
Note: Dose is escalated only if starting dose is "well tolerated".
====Chemotherapy====
*Doxorubicin (Adriamycin) as follows:
**Cycle 1: 60 mg/m2 IV once on day 1
**Cycle 2 onwards: 75 mg/m2 IV once on day 1
21-day cycles
===References===
#Johnson PJ, Williams R, Thomas H, Sherlock S, Murray-Lyon IM. Induction of remission in hepatocellular carcinoma with doxorubicin. Lancet. 1978 May 13;1(8072):1006-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma: a prospective randomized trial. Cancer. 1988 Aug 1;62(3):479-83. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, Koh J, Mo FK, Yu SC, Chan AT, Hui P, Ma B, Lam KC, Ho WM, Wong HT, Tang A, Johnson PJ. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005 Oct 19;97(20):1532-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#ZARIX-ZX101-301: Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, Feun L, Jeziorski K, Leighton J, Gallo J, Kennealey GT. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007 Jul 20;25(21):3069-75. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00012324
#Study 11546: Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010 Nov 17;304(19):2154-60. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00108953
#EACH: Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. Epub 2013 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00471965
==Doxorubicin & Sorafenib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Abou-Alfa et al. 2010 (Study 11546)	2005-04 to 2006-10 	Randomized Phase 2 (E-esc)	Doxorubicin	Longer OS (secondary endpoint)Median OS: 13.7 vs 6.5 mo(HR 0.49, 95% CI 0.30-0.80)Longer TTP (primary endpoint)Median TTP: 6.4 vs 2.8 mo(HR 0.50, 95% CI 0.30-0.90)
====Targeted therapy====
*Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 21
====Chemotherapy====
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 up to 9: 60 mg/m2 IV once on day 1
21-day cycles
===References===
#Study 11546: Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010 Nov 17;304(19):2154-60. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00108953
==Durvalumab & Tremelimumab==
STRIDE: Single Tremelimumab Regular Interval Durvalumab
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Abou-Alfa et al. 2022 (HIMALAYA)	2017-2019 	Phase 3 (E-RT-switch-ooc)	1. Sorafenib 	Longer OS1 (primary endpoint)Median OS: 16.4 vs 13.8 mo(HR 0.78, 95% CI 0.78-0.92)
Abou-Alfa et al. 2022 (HIMALAYA)	2017-2019 	Phase 3 (E-RT-switch-ooc)	2. Durvalumab	Not reported
1Reported efficacy is based on the 2024 update.
====Immunotherapy====
*Durvalumab (Imfinzi) 1500 mg IV once on day 1
*Tremelimumab (Imjudo) as follows:
**Cycle 1: 300 mg IV once on day 1
28-day cycles
===References===
#HIMALAYA: Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, Rimassa L, Breder V, Vasilyev A, Heurgué A, Tam VC, Mody K, Thungappa SC, Ostapenko Y, Yau T, Azevedo S, Varela M, Cheng AL, Qin S, Galle PR, Ali S, Marcovitz M, Makowsky M, He P, Kurland JF, Negro A, Sangro B. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03298451
##Update: Sangro B, Chan SL, Kelley RK, Lau G, Kudo M, Sukeepaisarnjaroen W, Yarchoan M, De Toni EN, Furuse J, Kang YK, Galle PR, Rimassa L, Heurgué A, Tam VC, Van Dao T, Thungappa SC, Breder V, Ostapenko Y, Reig M, Makowsky M, Paskow MJ, Gupta C, Kurland JF, Negro A, Abou-Alfa GK; HIMALAYA investigators. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024 May;35(5):448-457. Epub 2024 Feb 19. link to original article EuroPMC
##PRO analysis: Sangro B, Galle PR, Kelley RK, Charoentum C, De Toni EN, Ostapenko Y, Heo J, Cheng AL, Wilson Woods A, Gupta C, Abraham J, McCoy CL, Patel N, Negro A, Vogel A, Abou-Alfa GK. Patient-Reported Outcomes From the Phase III HIMALAYA Study of Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2024 Aug 10;42(23):2790-2799. Epub 2024 May 28. link to original article EuroPMC
==Durvalumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Abou-Alfa et al. 2022 (HIMALAYA)	2017-2019 	Phase 3 (E-switch-ooc)	1. Sorafenib 	Non-inferior OS1 (secondary endpoint)Median OS: 16.6 vs 13.8 mo(HR 0.86, 95% CI 0.74-1.01)
Abou-Alfa et al. 2022 (HIMALAYA)	2017-2019 	Phase 3 (E-switch-ooc)	2. Durvalumab & Tremelimumab	Not reported
1Reported efficacy is based on the 2024 update.
====Immunotherapy====
*Durvalumab (Imfinzi) 1500 mg IV once on day 1
28-day cycles
===References===
#HIMALAYA: Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, Rimassa L, Breder V, Vasilyev A, Heurgué A, Tam VC, Mody K, Thungappa SC, Ostapenko Y, Yau T, Azevedo S, Varela M, Cheng AL, Qin S, Galle PR, Ali S, Marcovitz M, Makowsky M, He P, Kurland JF, Negro A, Sangro B. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03298451
##Update: Sangro B, Chan SL, Kelley RK, Lau G, Kudo M, Sukeepaisarnjaroen W, Yarchoan M, De Toni EN, Furuse J, Kang YK, Galle PR, Rimassa L, Heurgué A, Tam VC, Van Dao T, Thungappa SC, Breder V, Ostapenko Y, Reig M, Makowsky M, Paskow MJ, Gupta C, Kurland JF, Negro A, Abou-Alfa GK; HIMALAYA investigators. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024 May;35(5):448-457. Epub 2024 Feb 19. link to original article EuroPMC
##PRO analysis: Sangro B, Galle PR, Kelley RK, Charoentum C, De Toni EN, Ostapenko Y, Heo J, Cheng AL, Wilson Woods A, Gupta C, Abraham J, McCoy CL, Patel N, Negro A, Vogel A, Abou-Alfa GK. Patient-Reported Outcomes From the Phase III HIMALAYA Study of Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2024 Aug 10;42(23):2790-2799. Epub 2024 May 28. link to original article EuroPMC
==Erlotinib & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Thomas et al. 2009	Not reported 	Phase 2 	PFS16: 62.5%
Philip et al. 2011	2006-2008 	Phase 2 	ORR: 5% (95% CI, 0-23)
Note: Patients in Thomas et al. 2009 could have up to one prior systemic treatment.
====Targeted therapy====
*Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 28
*Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
===References===
#Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E, Kaseb A, Glover K, Davila M, Abbruzzese J. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009 Feb 20;27(6):843-50. Epub 2009 Jan 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Philip PA, Mahoney MR, Holen KD, Northfelt DW, Pitot HC, Picus J, Flynn PJ, Erlichman C. Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer. Cancer. 2012 May 1;118(9):2424-30. Epub 2011 Sep 27. link to original article link to PMC article EuroPMC
==FULV==
FULV: 5-FU & LeucoVorin
===Regimen===
Study 	Dates of enrollment 	Evidence	Efficacy
Porta et al. 1995	Not reported in abstract	Phase 2 	ORR: 28% (95% CI, 10-46)
Note: The full manuscript was not available for review.
====Chemotherapy====
*Fluorouracil (5-FU) 370 mg/m2 IV once per day on days 1 to 5
*Leucovorin (Folinic acid) 200 mg/m2 IV once per day on days 1 to 5
28-day cycles
===References===
#Porta C, Moroni M, Nastasi G, Arcangeli G. 5-Fluorouracil and d,l-leucovorin calcium are active to treat unresectable hepatocellular carcinoma patients: preliminary results of a phase II study. Oncology. 1995 Nov-Dec;52(6):487-91. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==FOLFOX4==
FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin 
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Qin et al. 2013 (EACH)	2007-2009 	Phase 3 (E-switch-ic)	Doxorubicin	Might have longer OS (primary endpoint)Median OS: 6.4 vs 5.0 mo(HR 0.80, 95% CI 0.63-1.02)
Note: This study included patients with both Child-Pugh stage A and B disease (AST or ALT less than 2.5x ULN, T bil less than 1.5x ULN, INR less than 1.5).
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, given second, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m2)
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
14-day cycles
===References===
#EACH: Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. Epub 2013 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00471965
#SHR-1210-III-305-HCC: NCT03605706
==mFOLFOX & Sorafenib==
mFOLFOX & Sorafenib: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Sorafenib
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Goyal et al. 2019 (MGH 12-218)	2013-2017 	Phase 2 	mTTP: 7.7 mo (95% CI, 4.4-8.9)
Note: Patients had improved mTTP, but increased incidence of hepatotoxicity. Note that the regimen specifies that 5-FU be given at 1200 mg/m2/day over 46 hours; the total dose is therefore unclear.
====Eligibility criteria====
*Child Pugh A with advanced HCC with no prior systemic therapy
====Chemotherapy====
*Fluorouracil 1200 mg/m2/day IV continuous infusion over 46 hours, started on day 1
*Leucovorin 200 mg/m2 IV once on day 1
*Oxaliplatin 85 mg/m2 IV once on day 1
====Targeted therapy====
*Sorafenib 400 mg PO twice per day
14-day cycles
===References===
#MGH 12-218: Goyal L, Zheng H, Abrams TA, Miksad R, Bullock AJ, Allen JN, Yurgelun MB, Clark JW, Kambadakone A, Muzikansky A, Knowles M, Galway A, Afflitto AJ, Dinicola CF, Regan E, Hato T, Mamessier E, Shigeta K, Jain RK, Duda DG, Zhu AX. A Phase II and Biomarker Study of Sorafenib Combined with Modified FOLFOX in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res. 2019 Jan 1;25(1):80-89. Epub 2018 Sep 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01775501
==GemOx==
GemOx: Gemcitabine, Oxaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Louafi et al. 2007	2002-2004 	Phase 2 	ORR: 18% (95% CI, 8–34)
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 2
14-day cycles
===References===
#Louafi S, Boige V, Ducreux M, Bonyhay L, Mansourbakht T, de Baere T, Asnacios A, Hannoun L, Poynard T, Taïeb J. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer. 2007 Apr 1;109(7):1384-90. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Retrospective: Zaanan A, Williet N, Hebbar M, Dabakuyo TS, Fartoux L, Mansourbakht T, Dubreuil O, Rosmorduc O, Cattan S, Bonnetain F, Boige V, Taïeb J. Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: A large multicenter AGEO study. J Hepatol. 2013 Jan;58(1):81-8. Epub 2012 Sep 16. link to original article EuroPMC
==GemOx & Sorafenib==
GemOx & Sorafenib: Gemcitabine, Oxaliplatin , Sorafenib
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Assenat et al. 2019 (PRODIGE 10)	2008-2011 	Randomized Phase 2 (E-esc)	Sorafenib 	Did not meet primary endpoint of PFS4
====Chemotherapy====
*Gemcitabine 1000 mg/m2 IV once on day 1
*Oxaliplatin 100 mg/m2 IV once on day 1
====Targeted therapy====
*Sorafenib 400 mg PO twice per day
14-day cycles
===References===
#PRODIGE 10: Assenat E, Pageaux GP, Thézenas S, Peron JM, Bécouarn Y, Seitz JF, Merle P, Blanc JF, Bouché O, Ramdani M, Poujol S, de Forges H, Ychou M, Boige V. Sorafenib alone vs sorafenib plus GEMOX as 1st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer. 2019 Apr;120(9):896-902. Epub 2019 Apr 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00941967
==Lenvatinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kudo et al. 2018 (REFLECT) 	2013-2015 	Phase 3 (E-RT-switch-ic)	Sorafenib 	Non-inferior OS (primary endpoint)Median OS: 13 vs 12.3 mo(HR 0.92, 95% CI 0.79-1.06)
Llovet et al. 2023 (LEAP-002) 	2019-01-17 to 2020-04-28	Phase 3 (C) 	Lenvatinib & Pembrolizumab	Might have shorter co-primary endpoint of OSMedian OS: 19 vs 21.2 mo(HR 1.19, 95% CI 1.00-1.41)Might have shorter co-primary endpoint of PFSMedian PFS: 8 vs 8.2 mo(HR 1.15, 95% CI 0.98-1.37)
Peng et al. 2022 (LAUNCH) 	2019-2021 	Phase 3 (C) 	Lenvatinib & TACE 	Shorter OSMedian OS: 11.5 vs 17.8 mo(HR 2.22, 95% CI 1.64-3.03)
Awaiting publication (CheckMate 9DW)	2019-ongoing 	Phase 3 (C) 	Ipilimumab & Nivolumab 	TBD if different primary endpoint of OS
Awaiting publication (CS1003-305) 	2019-ongoing 	Phase 3 (C) 	Lenvatinib & Nofazinlimab 	TBD if different primary endpoint of OS
====Targeted therapy====
*Lenvatinib (Lenvima) by the following weight-based criteria:
**Less than 60 kg: 8 mg PO once per day on days 1 to 28
**60 kg or more: 12 mg PO once per day on days 1 to 28
28-day cycles
===References===
#REFLECT: Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. Epub 2018 Feb 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01761266
##PRO analysis: Vogel A, Qin S, Kudo M, Su Y, Hudgens S, Yamashita T, Yoon JH, Fartoux L, Simon K, López C, Sung M, Mody K, Ohtsuka T, Tamai T, Bennett L, Meier G, Breder V. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Aug;6(8):649-658. Epub 2021 Jun 2. link to original article EuroPMC
#LAUNCH: Peng Z, Fan W, Zhu B, Wang G, Sun J, Xiao C, Huang F, Tang R, Cheng Y, Huang Z, Liang Y, Fan H, Qiao L, Li F, Zhuang W, Peng B, Wang J, Li J, Kuang M. Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH). J Clin Oncol. 2023 Jan 1;41(1):117-127. Epub 2022 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03905967
#LEAP-002: Llovet JM, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, Xu R, Edeline J, Ryoo BY, Ren Z, Masi G, Kwiatkowski M, Lim HY, Kim JH, Breder V, Kumada H, Cheng AL, Galle PR, Kaneko S, Wang A, Mody K, Dutcus C, Dubrovsky L, Siegel AB, Finn RS; LEAP-002 Investigators. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1399-1410. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03713593
#CheckMate 9DW: NCT04039607
#CS1003-305: NCT04194775
==Sorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Abou-Alfa et al. 2006b 	2002-2003 	Phase 2 	 	
Llovet et al. 2008 (SHARP) 	2005-03-10 to 2006-04-11	Phase 3 (E-RT-esc) 	Placebo 	Longer OS (co-primary endpoint)Median OS: 10.7 vs 7.9 mo(HR 0.69, 95% CI 0.55-0.87)
Cheng et al. 2008 (Sorafenib AP) 	2005-2007 	Phase 3 (E-esc) 	Placebo 	Seems to have longer OS (secondary endpoint)Median OS: 6.5 vs 4.2 mo(HR 0.68, 95% CI 0.50-0.93)
Pinter et al. 2009 	2006-2007 	Retrospective 	 	
Cheng et al. 2013 (SUN 1170) 	2008-2010 	Phase 3 (C) 	Sunitinib 	Longer OSMedian OS: 10.2 vs 7.9 mo(HR 0.77, 95% CI 0.67-0.88)
Johnson et al. 2013 (BRISK-FL) 	2009-2011 	Phase 3 (C) 	Brivanib 	Inconclusive whether non-inferior OS (primary endpoint)
Cainap et al. 2014 (LIGHT) 	Not reported 	Phase 3 (C) 	Linifanib 	Did not meet primary endpoint of OSMedian OS: 9.8 vs 9.1 mo(HR 0.96, 95% CI 0.82-1.12)
Zhu et al. 2014 (SEARCH) 	2009-2011 	Phase 3 (C) 	Erlotinib & Sorafenib 	Did not meet primary endpoint of OSMedian OS: 8.5 vs 9.5 mo(HR 1.08, 95% CI 0.90-1.28)
Koeberle et al. 2016 (SAKK 77/08; SASL 29)	2009-2013 	Randomized Phase 2 (C)	Everolimus & Sorafenib 	Did not meet primary endpoint of PFS3PFS3: 70% vs 68%
Abdel-Rahman et al. 2013 	2010-2011 	Randomized Phase 2 (C)	Capecitabine 	Longer OS (secondary endpoint)Median OS: 7.1 vs 5.1 mo(HR 0.42, 95% CI 0.21-0.85)
Kudo et al. 2018 (SILIUS) 	2010-2014 	Phase 3 (C) 	HAI CF & Sorafenib 	Did not meet primary endpoint of OSMedian OS: 11.5 vs 11.8 mo(HR 0.99, 95% CI 0.73-1.35)
Abou-Alfa et al. 2019 (CALGB 80802) 	2010-2015 	Phase 3 (C) 	Doxorubicin & Sorafenib 	Did not meet primary endpoint of OSMedian OS: 9.4 vs 9.3 mo(HR 0.95, 95% CI 0.76-1.20)
Jouve et al. 2019 (PRODIGE-11) 	2010-03 to 2013-11 	Phase 3 (C) 	Pravastatin & Sorafenib 	Did not meet primary endpoint of OSMedian OS: 10.5 vs 10.7 mo(HR 1.00)
Chow et al. 2018 (SIRveNIB) 	2010-2016 	Phase 3 (C) 	SIRT 	Did not meet primary endpoint of OSMedian OS: 10 vs 8.8 mo(HR 0.91, 95% CI 0.71-1.11)
Vilgrain et al. 2017 (SARAH) 	2011-2015 	Phase 3 (C) 	SIRT 	Did not meet primary endpoint of OSMedian OS: 9.9 vs 8 mo(HR 0.87, 95% CI 0.71-1.06)
Park et al. 2018 (STAH) 	2013-2015 	Phase 3 (C) 	Sorafenib & TACE 	Did not meet primary endpoint of OSMedian OS: 10.8 vs 12.8 mo(HR 1.10, 90% CI 0.83-1.45)
Kudo et al. 2018 (REFLECT) 	2013-2015 	Phase 3 (C) 	Lenvatinib 	Non-inferior OSMedian OS: 12.3 vs 13 mo(HR 1.09, 95% CI 0.94-1.27)
Yau et al. 2021 (CheckMate 459) 	2016-01-11 to 2017-05-24	Phase 3 (C) 	Nivolumab 	Might have shorter OSMedian OS: 14.7 vs 16.4 mo(HR 1.18, 95% CI 0.98-1.39)
He et al. 2019 (HCC-S021) 	2016-04-01 to 2017-10-10	Phase 3 (C) 	SoraHAIC 	Shorter OS (primary endpoint)Median OS: 7.1 vs 13.4 mo(HR 2.86, 95% CI 2.08-3.85)
Qin et al. 2021 	2016-2018 	Phase 3 (C) 	Donafenib 	Seems to have shorter OS (primary endpoint)Median OS: 10.3 vs 12.1 mo(HR 1.20, 95% CI 1.01-1.43)
Lyu et al. 2021 (FOHAIC-1) 	2017-2020 	Phase 3 (C) 	HAI FOLFOX 	Shorter OS
Abou-Alfa et al. 2022 (HIMALAYA) 	2017-2019 	Phase 3 (C) 	1. Durvalumab & Tremelimumab 	Shorter OS
Abou-Alfa et al. 2022 (HIMALAYA) 	2017-2019 	Phase 3 (C) 	2. Durvalumab 	Non-inferior OS (secondary endpoint)
Qin et al. (RATIONALE-301) 	2017-12-27 to 2019-10-02	Phase 3 (C) 	Tislelizumab 	Non-inferior OS (primary endpoint)Median OS: 14.1 vs 15.95 mo(HR 1.18, 95.003% CI 0.98-1.41)
Finn et al. 2020 (IMbrave150) 	2018-03-15 to 2019-01-30	Phase 3 (C) 	Atezolizumab & Bevacizumab 	Shorter OS1Median OS: 13.4 vs 19.2 mo(HR 1.52, 95% CI 1.18-1.92)
Kelley et al. 2022 (COSMIC-312) 	2018-2020 	Phase 3 (C) 	1. Cabozantinib & Atezolizumab	Seems to have shorter PFS2Did not meet co-primary endpoint of OS1
Kelley et al. 2022 (COSMIC-312) 	2018-2020 	Phase 3 (C) 	2. Cabozantinib 	Not reported
Ren et al. 2021 (ORIENT-32) 	2019-02-11 to 2020-01-15	Phase 3 (C) 	Bevacizumab-byva & Sintilimab 	Shorter OS (co-primary endpoint)Median OS: 10.4 vs NYR mo(HR 1.75, 95% CI 1.33-2.33)
Qin et al. 2023 (CARES-310) 	2019-06-28 to 2021-3-24 	Phase 3 (C) 	Apatinib & Camrelizumab 	Shorter PFS (primary endpoint)Median PFS: 3.7 vs 5.6 mo(HR 1.92, 95% CI 1.54-2.44)Shorter OS (secondary endpoint)Median OS: 15.2 vs 22.1 mo(HR 1.61, 95% CI 1.25-2.04)
1Reported efficacy for IMbrave150 is based on the 2021 update.
2Reported efficacy for COSMIC-312 is based on the 2024 update.
====Targeted therapy====
*Sorafenib (Nexavar) 400 mg PO twice per day
28-day cycles
====Dose and schedule modifications====
*Dose/schedule changes due to toxicity include 400 mg PO once per day, 400 mg PO every other day, 200 mg PO twice per day, 200 mg PO once per day
===References===
#Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006 Sep 10;24(26):4293-300. Epub 2006 Aug 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#SHARP: Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, Cosme de Oliveira A, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00105443
##Subgroup analysis: Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, Galle PR, Santoro A, Beaugrand M, Sangiovanni A, Porta C, Gerken G, Marrero JA, Nadel A, Shan M, Moscovici M, Voliotis D, Llovet JM. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012 Oct;57(4):821-9. Epub 2012 Jun 19. link to original article EuroPMC
#Sorafenib AP: Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. 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. 2009 Jan;10(1):25-34. Epub 2008 Dec 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00492752
##Subgroup analysis: Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Yang TS, Tak WY, Pan H, Yu S, Xu J, Fang F, Zou J, Lentini G, Voliotis D, Kang YK. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer. 2012 Jul;48(10):1452-65. Epub 2012 Jan 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Retrospective: Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Königsberg R, Weissmann A, Kornek G, Plank C, Peck-Radosavljevic M. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist. 2009 Jan;14(1):70-6. Epub 2009 Jan 14. link to original article EuroPMC
#Abdel-Rahman O, Abdel-Wahab M, Shaker M, Abdel-Wahab S, Elbassiony M, Ellithy M. Sorafenib versus capecitabine in the management of advanced hepatocellular carcinoma. Med Oncol. 2013 Sep;30(3):655. Epub 2013 Jul 4. link to original article EuroPMC
#BRISK-FL: Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013 Oct 1;31(28):3517-24. Epub 2013 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00858871
#SUN 1170: Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G, Omata M, Pitman Lowenthal S, Lanzalone S, Yang L, Lechuga MJ, Raymond E. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013 Nov 10;31(32):4067-75. Epub 2013 Sep 30. link to original article EuroPMC NCT00699374
#LIGHT: Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, Kudo M, Kang YK, Chen PJ, Toh HC, Gorbunova V, Eskens FA, Qian J, McKee MD, Ricker JL, Carlson DM, El-Nowiem S. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015 Jan 10;33(2):172-9. Epub 2014 Dec 8. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01009593
#SEARCH: Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, Bruix J, Qin S, Thuluvath PJ, Llovet JM, Leberre MA, Jensen M, Meinhardt G, Kang YK. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015 Feb 20;33(6):559-66. Epub 2014 Dec 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00901901
#SAKK 77/08; SASL 29: Koeberle D, Dufour JF, Demeter G, Li Q, Ribi K, Samaras P, Saletti P, Roth AD, Horber D, Buehlmann M, Wagner AD, Montemurro M, Lakatos G, Feilchenfeldt J, Peck-Radosavljevic M, Rauch D, Tschanz B, Bodoky G; Swiss Group for Clinical Cancer Research; SASL. Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann Oncol. 2016 May;27(5):856-61. Epub 2016 Feb 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01005199
#SARAH: Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, Sibert A, Bouattour M, Lebtahi R, Allaham W, Barraud H, Laurent V, Mathias E, Bronowicki JP, Tasu JP, Perdrisot R, Silvain C, Gerolami R, Mundler O, Seitz JF, Vidal V, Aubé C, Oberti F, Couturier O, Brenot-Rossi I, Raoul JL, Sarran A, Costentin C, Itti E, Luciani A, Adam R, Lewin M, Samuel D, Ronot M, Dinut A, Castera L, Chatellier G; SARAH Trial Group. 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. 2017 Dec;18(12):1624-1636. Epub 2017 Oct 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01482442
#REFLECT: Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. Epub 2018 Feb 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01761266
##PRO analysis: Vogel A, Qin S, Kudo M, Su Y, Hudgens S, Yamashita T, Yoon JH, Fartoux L, Simon K, López C, Sung M, Mody K, Ohtsuka T, Tamai T, Bennett L, Meier G, Breder V. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Aug;6(8):649-658. Epub 2021 Jun 2. link to original article EuroPMC
#SIRveNIB: 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 AS, Goh ASW, Tay KH, Lo RHG, Goh BKP, Ng DCE, Lekurwale G, Liew WM, Gebski V, Mak KSW, Soo KC; Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018 Jul 1;36(19):1913-1921. Epub 2018 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01135056
#SILIUS: Kudo M, Ueshima K, Yokosuka O, Ogasawara S, Obi S, Izumi N, Aikata H, Nagano H, Hatano E, Sasaki Y, Hino K, Kumada T, Yamamoto K, Imai Y, Iwadou S, Ogawa C, Okusaka T, Kanai F, Akazawa K, Yoshimura KI, Johnson P, Arai Y; SILIUS study group. 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. 2018 Jun;3(6):424-432. Epub 2018 Apr 7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01214343
#STAH: Park JW, Kim YJ, Kim DY, Bae SH, Paik SW, Lee YJ, Kim HY, Lee HC, Han SY, Cheong JY, Kwon OS, Yeon JE, Kim BH, Hwang J. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial. J Hepatol. 2019 Apr;70(4):684-691. Epub 2018 Dec 6. link to original article EuroPMC NCT01829035
#PRODIGE-11: Jouve JL, Lecomte T, Bouché O, Barbier E, Khemissa Akouz F, Riachi G, Nguyen Khac E, Ollivier-Hourmand I, Debette-Gratien M, Faroux R, Villing AL, Vergniol J, Ramee JF, Bronowicki JP, Seitz JF, Legoux JL, Denis J, Manfredi S, Phelip JM; FFCD. Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. J Hepatol. 2019 Sep;71(3):516-522. Epub 2019 May 22. link to original article EuroPMC NCT01075555
#HCC-S021: He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, Le Y, Zhou Z, Zhao M, Guo Y, Guo R, Chen M, Shi M. Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial. JAMA Oncol. 2019 Jul 1;5(7):953-960. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02774187
#CALGB 80802: Abou-Alfa GK, Shi Q, Knox JJ, Kaubisch A, Niedzwiecki D, Posey J, Tan BR Jr, Kavan P, Goel R, Lammers PE, Bekaii-Saab TS, Tam VC, Rajdev L, Kelley RK, El Dika I, Zemla T, Potaracke RI, Balletti J, El-Khoueiry AB, Harding JH, Suga JM, Schwartz LH, Goldberg RM, Bertagnolli MM, Meyerhardt J, O'Reilly EM, Venook AP. Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1582-1588. Epub 2019 Sep 5. link to original article link to PMC article EuroPMC NCT01015833
#IMbrave150: Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03434379
##PRO analysis: Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, Kudo M, Breder V, Merle P, Kaseb A, Li D, Mulla S, Verret W, Xu DZ, Hernandez S, Ding B, Liu J, Huang C, Lim HY, Cheng AL, Ducreux M. Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):991-1001. Epub 2021 May 27. link to original article EuroPMC
##Update: Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022 Apr;76(4):862-873. Epub 2021 Dec 11. link to original article EuroPMC
#ORIENT-32: Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, Li Q, Lu Y, Chen Y, Guo Y, Chen Z, Liu B, Jia W, Wu J, Wang J, Shao G, Zhang B, Shan Y, Meng Z, Wu J, Gu S, Yang W, Liu C, Shi X, Gao Z, Yin T, Cui J, Huang M, Xing B, Mao Y, Teng G, Qin Y, Wang J, Xia F, Yin G, Yang Y, Chen M, Wang Y, Zhou H, Fan J; ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021 Jul;22(7):977-990. Epub 2021 Jun 15. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03794440
#Qin S, Bi F, Gu S, Bai Y, Chen Z, Wang Z, Ying J, Lu Y, Meng Z, Pan H, Yang P, Zhang H, Chen X, Xu A, Cui C, Zhu B, Wu J, Xin X, Wang J, Shan J, Chen J, Zheng Z, Xu L, Wen X, You Z, Ren Z, Liu X, Qiu M, Wu L, Chen F. Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial. J Clin Oncol. 2021 Sep 20;39(27):3002-3011. Epub 2021 Jun 29. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#CheckMate 459: Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Harding JJ, Merle P, Rosmorduc O, Wyrwicz L, Schott E, Choo SP, Kelley RK, Sieghart W, Assenat E, Zaucha R, Furuse J, Abou-Alfa GK, El-Khoueiry AB, Melero I, Begic D, Chen G, Neely J, Wisniewski T, Tschaika M, Sangro B. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022 Jan;23(1):77-90. Epub 2021 Dec 13. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02576509
#FOHAIC-1: Lyu N, Wang X, Li JB, Lai JF, Chen QF, Li SL, Deng HJ, He M, Mu LW, Zhao M. Arterial Chemotherapy of Oxaliplatin Plus Fluorouracil Versus Sorafenib in Advanced Hepatocellular Carcinoma: A Biomolecular Exploratory, Randomized, Phase III Trial (FOHAIC-1). J Clin Oncol. 2022 Feb 10;40(5):468-480. Epub 2021 Dec 14. link to original article EuroPMC NCT03164382
#COSMIC-312: Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Banerjee K, Hazra S, Fawcett J, Yau T. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):995-1008. Epub 2022 Jul 4. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03755791
##Update: Yau T, Kaseb A, Cheng AL, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Milwee S, Wang Z, Curran D, Kelley RK, Rimassa L. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study. Lancet Gastroenterol Hepatol. 2024 Apr;9(4):310-322. Epub 2024 Feb 13. link to original article EuroPMC
#CARES-310: Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, Chen Z, Jia W, Jin Y, Guo Y, Hu X, Meng Z, Liang J, Cheng Y, Xiong J, Ren H, Yang F, Li W, Chen Y, Zeng Y, Sultanbaev A, Pazgan-Simon M, Pisetska M, Melisi D, Ponomarenko D, Osypchuk Y, Sinielnikov I, Yang TS, Liang X, Chen C, Wang L, Cheng AL, Kaseb A, Vogel A; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023 Sep 30;402(10408):1133-1146. Epub 2023 Jul 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03764293
#HIMALAYA: Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, Rimassa L, Breder V, Vasilyev A, Heurgué A, Tam VC, Mody K, Thungappa SC, Ostapenko Y, Yau T, Azevedo S, Varela M, Cheng AL, Qin S, Galle PR, Ali S, Marcovitz M, Makowsky M, He P, Kurland JF, Negro A, Sangro B. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03298451
##Update: Sangro B, Chan SL, Kelley RK, Lau G, Kudo M, Sukeepaisarnjaroen W, Yarchoan M, De Toni EN, Furuse J, Kang YK, Galle PR, Rimassa L, Heurgué A, Tam VC, Van Dao T, Thungappa SC, Breder V, Ostapenko Y, Reig M, Makowsky M, Paskow MJ, Gupta C, Kurland JF, Negro A, Abou-Alfa GK; HIMALAYA investigators. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024 May;35(5):448-457. Epub 2024 Feb 19. link to original article EuroPMC
##PRO analysis: Sangro B, Galle PR, Kelley RK, Charoentum C, De Toni EN, Ostapenko Y, Heo J, Cheng AL, Wilson Woods A, Gupta C, Abraham J, McCoy CL, Patel N, Negro A, Vogel A, Abou-Alfa GK. Patient-Reported Outcomes From the Phase III HIMALAYA Study of Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2024 Aug 10;42(23):2790-2799. Epub 2024 May 28. link to original article EuroPMC
#RATIONALE-301: Qin S, Kudo M, Meyer T, Bai Y, Guo Y, Meng Z, Satoh T, Marino D, Assenat E, Li S, Chen Y, Boisserie F, Abdrashitov R, Finn RS, Vogel A, Zhu AX. Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2023 Dec 1;9(12):1651-1659. Epub 2023 Oct 5. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03412773
##HRQoL analysis: Finn RS, Kudo M, Barnes G, Meyer T, Boisserie F, Abdrashitov R, Chen Y, Li S, Zhu AX, Qin S, Vogel A. Tislelizumab versus Sorafenib in First-Line Treatment of Unresectable Hepatocellular Carcinoma: Impact on Health-Related Quality of Life in RATIONALE-301 Study. Liver Cancer. 2024 Feb 21;13(5):548-560. link to original article link to PMC article EuroPMC
#CheckMate 9DW: NCT04039607
#RTOG 1112: NCT01730937
==Tislelizumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Qin et al. (RATIONALE-301)	2017-12-27 to 2019-10-02	Phase 3 (E-switch-ooc)	Sorafenib 	Non-inferior OS (primary endpoint)Median OS: 15.95 vs 14.1 mo(HR 0.85, 95.003% CI 0.71-1.02)
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-301: Qin S, Kudo M, Meyer T, Bai Y, Guo Y, Meng Z, Satoh T, Marino D, Assenat E, Li S, Chen Y, Boisserie F, Abdrashitov R, Finn RS, Vogel A, Zhu AX. Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2023 Dec 1;9(12):1651-1659. Epub 2023 Oct 5. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03412773
##HRQoL analysis: Finn RS, Kudo M, Barnes G, Meyer T, Boisserie F, Abdrashitov R, Chen Y, Li S, Zhu AX, Qin S, Vogel A. Tislelizumab versus Sorafenib in First-Line Treatment of Unresectable Hepatocellular Carcinoma: Impact on Health-Related Quality of Life in RATIONALE-301 Study. Liver Cancer. 2024 Feb 21;13(5):548-560. link to original article link to PMC article EuroPMC
=Advanced or metastatic disease, second-line=
==Pembrolizumab monotherapy==
===Regimen variant #1, q3wk===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Zhu et al. 2018 (KEYNOTE-224) 	2016-06-07 to 2017-02-09	Phase 2 (RT) 	 	ORR: 17% (95% CI, 11–26)
Finn et al. 2020 (KEYNOTE-240)	2016-05-31 to 2017-11-23	Phase 3 (E-esc) 	Placebo 	Seems to have longer OS (co-primary endpoint)Median OS: 13.9 vs 10.6 mo(HR 0.78, 95% CI 0.61-0.998)
Qin et al. 2023 (KEYNOTE-394) 	2017-05-31 to 2019-12-11	Phase 3 (E-RT-esc)	Placebo 	Seems to have longer OS (primary endpoint)Median OS: 14.6 vs 13 mo(HR 0.79, 95% CI 0.63-0.99)
Note: All patients in KEYNOTE-240 were Child-Pugh class A. 21.5-25.9% had hepatitis B infection and 15.5-15.6% of patients had hepatitic C infection.
====Prior treatment criteria====
*Sorafenib
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===Regimen variant #2, q6wk===
FDA-recommended dose
====Immunotherapy====
*Pembrolizumab (Keytruda) 400 mg IV once on day 1
6-week cycles
===References===
#Abstract: Lala  M﻿, Li  M﻿, Sinha  V﻿, de Alwis  D﻿, Chartash  E﻿, Jain  L.﻿﻿  A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation. ﻿J Clin Oncol. 2018;36(15, supp):3062. link to original article FDA approval
#KEYNOTE-224: Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul;19(7):940-952. Epub 2018 Jun 3. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02702414
##Update: Kudo M, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer DH, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Yau T, Gurary EB, Siegel AB, Wang A, Cheng AL, Zhu AX; KEYNOTE-224 Investigators. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Eur J Cancer. 2022 May;167:1-12. Epub 2022 Mar 29. link to original article EuroPMC
#KEYNOTE-240: Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox J, Daniele B, Ebbinghaus SW, Chen E, Siegel AB, Zhu AX, Cheng AL; KEYNOTE-240 investigators. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020 Jan 20;38(3):193-202. Epub 2019 Dec 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02702401
##Update: Merle P, Kudo M, Edeline J, Bouattour M, Cheng AL, Chan SL, Yau T, Garrido M, Knox J, Daniele B, Breder V, Lim HY, Ogasawara S, Cattan S, Chao Y, Siegel AB, Martinez-Forero I, Wei Z, Liu CC, Finn RS. Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial. Liver Cancer. 2023 Feb 14;12(4):309-320. link to original article link to PMC article EuroPMC
#KEYNOTE-394: Qin S, Chen Z, Fang W, Ren Z, Xu R, Ryoo BY, Meng Z, Bai Y, Chen X, Liu X, Xiao J, Ho GF, Mao Y, Wang X, Ying J, Li J, Zhong W, Zhou Y, Siegel AB, Hao C. Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2023 Mar 1;41(7):1434-1443. Epub 2022 Dec 1. link to original article link to PMC article dosing details in abstract have been reviewed by our editors EuroPMC NCT03062358
##HRQoL analysis: Qin S, Fang W, Ren Z, Ou S, Lim HY, Zhang F, Lee KC, Choi HJ, Tong J, Tao M, Xu A, Cheng A, Lu CH, Chiu CF, Abdul Wahid MI, Kamble S, Norquist JM, Zhong W, Li C, Chen Z. A Phase 3 Study of Pembrolizumab versus Placebo for Previously Treated Patients from Asia with Hepatocellular Carcinoma: Health-Related Quality of Life Analysis from KEYNOTE-394. Liver Cancer. 2024 Jan 10;13(4):389-400. link to original article link to PMC article EuroPMC
==Ramucirumab monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zhu et al. 2015 (REACH-HCC)	2010-2013 	Phase 3 (E-esc) 	Placebo 	Did not meet primary endpoint of OS
Zhu et al. 2019 (REACH-2) 	2015-2017 	Phase 3 (E-RT-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 8.5 vs 7.3 mo(HR 0.71, 95% CI 0.53-0.95)
Note: REACH should not be confused for the trial of the same name in CLL.
====Targeted therapy====
*Ramucirumab (Cyramza) 8 mg/kg IV once on day 1
14-day cycles
===References===
#REACH-HCC: Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015 Jul;16(7):859-70. Epub 2015 Jun 18. link to original article EuroPMC NCT01140347
##Pooled PRO analysis: Zhu AX, Nipp RD, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Girvan A, Gable J, Bowman L, Wang C, Hsu Y, Abada PB, Kudo M. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open. 2020 Aug;5(4):e000797. link to original article link to PMC article EuroPMC
#REACH-2: Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; REACH-2 study investigators. 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. 2019 Feb;20(2):282-296. Epub 2019 Jan 18. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02435433
##Pooled PRO analysis: Zhu AX, Nipp RD, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Girvan A, Gable J, Bowman L, Wang C, Hsu Y, Abada PB, Kudo M. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open. 2020 Aug;5(4):e000797. link to original article link to PMC article EuroPMC
==Regorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Bruix et al. 2016 (RESORCE)	2013-05-14 to 2015-12-31	Phase 3 (E-RT-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 10.6 vs 7.8 mo(HR 0.63, 95% CI 0.50-0.79)
Note: The RESORCE study required patients with sorafenib tolerance of at least 400 mg/day for at least 20 days of the last 28 days of treatment, and who were ECOS PG 0-1, and with Child-Pugh A status.
====Prior treatment criteria====
*Sorafenib
====Targeted therapy====
*Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21
28-day cycles
===References===
#RESORCE: Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66. Epub 2016 Dec 6. Erratum in: Lancet. 2017 Jan 7;389(10064):36. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01774344
=Subsequent lines of therapy=
==Apatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Qin et al. 2021 (AHELP)	2014-2017 	Phase 3 (E-esc)	Placebo 	Seems to have longer OS (primary endpoint)Median OS: 8.7 vs 6.8 mo(HR 0.79, 95% CI 0.62-0.998)
====Targeted therapy====
*Apatinib (Aitan) 750 mg PO once per day on days 1 to 28
28-day cycles
===References===
#AHELP: 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 Jul;6(7):559-568. Epub 2021 May 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02329860
==Cabozantinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Abou-Alfa et al. 2018 (CELESTIAL)	2013-2017 	Phase 3 (E-RT-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 10.2 vs 8 mo(HR 0.76, 95% CI 0.63-0.92)
Note: Retrospective analysis demonstrated cabozantinib was safe and effective in patients with patients with Child Pugh class A and patients who progressed to Child Pugh class B.
====Targeted therapy====
*Cabozantinib (Cometriq) 60 mg PO once per day on days 1 to 28
28-day cycles
===References===
#CELESTIAL: Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018 Jul 5;379(1):54-63. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01908426
##Subgroup analysis: Abstract: El-Khoueiry A, Meyer T, Cheng A, Rimassa L, Sen S, Milwee S , Kelley R, Abou-Alfa G. Outcomes for patients with advanced hepatocellular carcinoma and Child-Pugh B liver function in the phase 3 CELESTIAL study of cabozantinib vs placebo. Annals of Oncology. 2020 Jul 1-4;31(3):S220. link to abstract
==Camrelizumab monotherapy==
===Regimen variant #1, q2wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Qin et al. 2020 (SHR-1210-II/III-HCC)	2016-2017 	Randomized Phase 2 (E-esc)	Camrelizumab; q3wk	Not reported
====Immunotherapy====
*Camrelizumab (AiRuiKa) 3 mg/kg IV once on day 1
14-day cycles
===Regimen variant #2, q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Qin et al. 2020 (SHR-1210-II/III-HCC)	2016-2017 	Randomized Phase 2 (E-de-esc)	Camrelizumab; q2wk	Not reported
====Immunotherapy====
*Camrelizumab (AiRuiKa) 3 mg/kg IV once on day 1
21-day cycles
===References===
#SHR-1210-II/III-HCC: Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J, Bai Y, Yang L, Zhu H, Fang W, Lin X, Chen X, Li E, Wang L, Chen C, Zou J. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet. 2020 Apr;21(4):571-580. Epub 2020 Feb 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02989922
==Doxorubicin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Qin et al. 2013 (EACH) 	2007-2009 	Phase 3 (C)	FOLFOX4 	Might have shorter OS (primary endpoint)Median OS: 5.0 vs 6.4 mo(HR 1.25, 95% CI 0.98-1.59)
Merle et al. 2019 (RELIVE)	2012-2017 	Phase 3 (C)	Doxorubicin-loaded nanoparticles	Did not meet primary endpoint of OS
Note: The EACH study required evidence of HBV or HCV with cirrhosis, and included patients with both Child-Pugh stage A and B disease (AST or ALT less than 2.5x ULN, T bili less than 1.5x ULN, INR less than 1.5x ULN; patients with AST and ALT less than 5x ULN were included if T bili was within normal limits). RELIVE did not specify control regimens in the abstract but stated "any systemic anticancer therapy (except sorafenib) as per investigator decision."
====Chemotherapy====
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
21-day cycles
===References===
#EACH: Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. Epub 2013 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00471965
#RELIVE: Merle P, Blanc JF, Phelip JM, Pelletier G, Bronowicki JP, Touchefeu Y, Pageaux G, Gerolami R, Habersetzer F, Nguyen-Khac E, Casadei-Gardini A, Borbath I, Tran A, Wege H, Saad AS, Colombo M, Abergel A, Richou C, Waked I, Yee NS, Molé A, Attali P, Le Boulicaut J, Vasseur B; RELIVE Investigators. Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 Jun;4(6):454-465. Epub 2019 Apr 4. link to original article EuroPMC NCT01655693
==FOLFOX4==
FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin 
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Qin et al. 2013 (EACH)	2007-2009 	Phase 3 (E-switch-ic)	Doxorubicin	Might have longer OS (primary endpoint)Median OS: 6.4 vs 5.0 mo(HR 0.80, 95% CI 0.63-1.02)
Note: The EACH study required evidence of HBV or HCV with cirrhosis, and included patients with both Child-Pugh stage A and B disease (AST or ALT less than 2.5x ULN, T bili less than 1.5x ULN, INR less than 1.5 ULN; patients with AST and ALT less than 5x ULN were included if T bili was within normal limits).
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, given second, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m2)
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
14-day cycles
===References===
#EACH: Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. Epub 2013 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00471965
==Ipilimumab & Nivolumab==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence
Yau et al. 2020 (CheckMate 040combo)	2016-01-04 to 2016-09-26	Phase 1/2 (RT)
Note: this was Arm A of this extension of the CheckMate 040 trial, which compared three variants of ipi/nivo dosing.
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Cycles 1 to 4: 3 mg/kg IV once on day 1
*Nivolumab (Opdivo) as follows:
**Cycles 1 to 4: 1 mg/kg IV once on day 1
**Cycle 5 onwards: 240 mg IV once on day 1
21-day cycle for 4 cycles, then 14-day cycles
===References===
#CheckMate 040combo: Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, Ruth He A, El-Rayes BF, Acosta-Rivera M, Lim HY, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. 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. 2020 Nov 1;6(11):e204564. Epub 2020 Oct 1. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01658878
==Lenvatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (IMbrave251)	2021-ongoing 	Phase 3 (C)	1a. Lenvatinib & Atezolizumab1b. Sorafenib & Atezolizumab	TBD if different primary endpoint of OS
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Prior treatment criteria====
*Exposure to Atezolizumab & Bevacizumab, with progression
====Targeted therapy====
*Lenvatinib (Lenvima) by the following weight-based criteria:
**Less than 60 kg: 8 mg PO once per day on days 1 to 21
**60 kg or more: 12 mg PO once per day on days 1 to 21
21-day cycles
===References===
#IMbrave251: dosing details on CT.gov have been reviewed by our editors NCT04770896
==Nivolumab monotherapy==
===Regimen variant #1, 3 mg/kg===
Study 	Dates of enrollment	Evidence 	Efficacy
El-Khoueiry et al. 2017 (CheckMate 040)	2012-2016 	Phase 1/2 (RT)	ORR (dose-expansion phase): 20% (95% CI, 15–26)
Note: This is the dose used in the expansion cohort of this study; patients were required to have ECOG PS 1 or less, and Child-Pugh scores of 6 or less (Child-Pugh A) for the dose expansion; Child-Pugh B7 patients were eligible for the dose-escalation phase. Patients with HBV infection were required to be receiving effective antiviral therapy (viral load less than 100 IU/mL). 68% of patients in the dose expansion phase received prior sorafenib therapy.
====Immunotherapy====
*Nivolumab (Opdivo) 3 mg/kg IV once on day 1
14-day cycles
===Regimen variant #2, 240 mg===
FDA-recommended dose
Note: This is the FDA-recommended dose; we are not aware of a published trial using this dose in this context.
====Immunotherapy====
*Nivolumab (Opdivo) 240 mg IV once on day 1
14-day cycles
===Regimen variant #3, 480 mg===
FDA-recommended dose
Note: This is the FDA-recommended dose; we are not aware of a published trial using this dose in this context.
====Immunotherapy====
*Nivolumab (Opdivo) 480 mg IV once on day 1
28-day cycles
===References===
#CheckMate 040: El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH 3rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. Epub 2017 Apr 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01658878
##Update: El-Khoueiry AB, Trojan J, Meyer T, Yau T, Melero I, Kudo M, Hsu C, Kim TY, Choo SP, Kang YK, Yeo W, Chopra A, Soleymani S, Yao J, Neely J, Tschaika M, Welling TH, Sangro B. Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040. Ann Oncol. 2024 Apr;35(4):381-391. Epub 2023 Dec 25. link to original article EuroPMC
==Sorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (IMbrave251)	2021-ongoing 	Phase 3 (C)	1a. Lenvatinib & Atezolizumab1b. Sorafenib & Atezolizumab	TBD if different primary endpoint of OS
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Prior treatment criteria====
*Exposure to Atezolizumab & Bevacizumab, with progression
====Targeted therapy====
*Sorafenib (Nexavar) 400 mg PO twice per day
21-day cycles
===References===
#IMbrave251: dosing details on CT.gov have been reviewed by our editors NCT04770896
==Tislelizumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Awaiting publication (RATIONALE-208)	2018 to not reported	Phase 2
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
# RATIONALE-208: dosing details on CT.gov have been reviewed by our editors NCT03419897
Category:Hepatocellular carcinoma regimens
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Category:Hepatobiliary cancers