Latest revision as of 17:51, 23 June 2024

Back to Top

Section editor
	Eric I. Marks, MD Boston University Boston, MA, USA

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.

38 regimens on this page 48 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 PubMed

ASCO

2024: Gordan et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update PubMed
- 2020: Gordan et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline PubMed

ESMO

2018: Vogel et al. Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2012: Verslype et al. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
- 2010: Jelic & Sotiropoulos. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Jelic. Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Parikh et al. Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed

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) PubMed

ISRS

2023: Bae et al. Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Meta-Analysis and International Stereotactic Radiosurgery Society Practice Guidelines PubMed

NCCN

NCCN Guidelines - Hepatocellular Carcinoma
- 2021: Benson et al. Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. PubMed
- 2006: Benson et al. Hepatobiliary cancers. Clinical practice guidelines in oncology. PubMed
- 2003: Benson et al. Hepatobiliary cancer. Clinical practice guidelines in oncology. PubMed

SITC

2021: Greten et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma PubMed

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 PubMed

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 superior 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 contains dosing details in abstract PubMed 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 superior 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	Superior 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 PubMed 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 PubMed 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, held before and after TACE

Local therapy

TACE

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 PubMed NCT01352728

Lenvatinib & TACE

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Peng et al. 2022 (LAUNCH)	2019-2021	Phase 3 (E-esc)	Lenvatinib	Superior 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 contains dosing details in abstract PubMed 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

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 loaded with Doxorubicin (Adriamycin) 150 mg

One treatment

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 PubMed 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 contains dosing details in manuscript PubMed NCT01324076

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	Superior 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	Superior 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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript PubMed 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	Superior 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 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 contains dosing details in manuscript link to PMC article PubMed 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 PubMed NCT01482442
1. 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. link to original article
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 PubMed 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	Superior 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 OS
Kudo et al. 2017 (ORIENTAL)	2010-2013	Phase 3 (C)	TACE & Orantinib	Did not meet primary endpoint of OS

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 PubMed
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 PubMed
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 PubMed
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 contains dosing details in abstract PubMed 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 PubMed 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 PubMed 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 PubMed 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 PubMed NCT01164202

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	Inferior 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 contains dosing details in manuscript link to PMC article PubMed

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	Superior PFS (primary endpoint) Median PFS: 5.6 vs 3.7 mo (HR 0.52, 95% CI 0.41-0.65) Superior 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 contains dosing details in manuscript PubMed 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	Superior 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 PubMed 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 contains dosing details in manuscript PubMed NCT03434379
1. 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 PubMed

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 contains dosing details in manuscript link to PMC article PubMed

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 contains dosing details in manuscript link to PMC article PubMed

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 contains dosing details in manuscript link to PMC article PubMed

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 contains dosing details in manuscript PubMed

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 superior OS (primary endpoint) Median OS: 12.1 vs 10.3 mo (HR 0.83, 95% 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 contains dosing details in manuscript link to PMC article PubMed

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 inferior OS

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 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yeo et al. 2005	1999-2003	Phase 3 (C)	PIAF	Did not meet primary endpoint of OS

Chemotherapy

Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen variant #3, 60 mg/m² x 9

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 1978	1976-1977	Non-randomized
Abou-Alfa et al. 2010 (Study 11546)	2005-04 to 2006-10	Randomized Phase 2 (C)	Doxorubicin & Sorafenib	Inferior OS

Chemotherapy

Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycle for up to 9 cycles

Regimen variant #4, 60 mg/m², indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lai et al. 1988	NR	Randomized (E-esc)	Best supportive care	Seems to have superior OS
Gish et al. 2007 (ZARIX-ZX101-301)	2000-2005	Phase 3 (C)	Nolatrexed	Superior OS

Note: this was the lower bound of the dosing range provided by Lai et al. 1988.

Chemotherapy

Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycles

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 #5, 60 --> 75 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yeo et al. 2005	1999-2003	Phase 3 (C)	PIAF	Did not meet primary endpoint of OS

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 contains dosing details in abstract PubMed
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 contains dosing details in abstract PubMed
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 contains dosing details in manuscript PubMed
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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript PubMed 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	Superior OS (secondary endpoint) Median OS: 13.7 vs 6.5 mo (HR 0.49, 95% CI 0.30-0.80) Superior 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 contains dosing details in manuscript PubMed 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	Superior 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 Evidence. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. link to original article contains dosing details in manuscript PubMed NCT03298451
1. 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 PubMed

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 Evidence. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. link to original article contains dosing details in manuscript PubMed NCT03298451
1. 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 PubMed

Erlotinib & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Thomas et al. 2009	NR	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 contains dosing details in manuscript PubMed
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 PubMed

FULV

FULV: 5-FU & LeucoVorin

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Porta et al. 1995	NR in abstract	Phase 2	ORR: 28% (95% CI, 10-46)

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 contains dosing details in abstract PubMed

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 superior 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 contains dosing details in manuscript PubMed 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 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 contains dosing details in manuscript link to PMC article PubMed 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 contains dosing details in manuscript PubMed
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 PubMed

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 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 contains dosing details in manuscript link to PMC article PubMed 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 inferior co-primary endpoints of PFS/OS
Peng et al. 2022 (LAUNCH)	2019-2021	Phase 3 (C)	Lenvatinib & TACE	Inferior OS
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 contains dosing details in abstract PubMed NCT01761266
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 contains dosing details in abstract PubMed 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 contains dosing details in abstract PubMed 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	Superior 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 superior 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	Superior OS Median 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)	NR	Phase 3 (C)	Linifanib	Did not meet primary endpoint of OS
Zhu et al. 2014 (SEARCH)	2009-2011	Phase 3 (C)	Erlotinib & Sorafenib	Did not meet primary endpoint of OS
Koeberle et al. 2016 (SAKK 77/08; SASL 29)	2009-2013	Randomized Phase 2 (C)	Everolimus & Sorafenib	Did not meet primary endpoint of PFS3
Abdel-Rahman et al. 2013	2010-2011	Randomized Phase 2 (C)	Capecitabine	Superior 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 OS
Abou-Alfa et al. 2019 (CALGB 80802)	2010-2015	Phase 3 (C)	Doxorubicin & Sorafenib	Did not meet primary endpoint of OS
Chow et al. 2018 (SIRveNIB)	2010-2016	Phase 3 (C)	SIRT	Did not meet primary endpoint of OS
Jouve et al. 2019 (PRODIGE-11)	2010-NR in abstract	Phase 3 (C)	Pravastatin & Sorafenib	Did not meet primary endpoint of OS
Vilgrain et al. 2017 (SARAH)	2011-2015	Phase 3 (C)	SIRT	Did not meet primary endpoint of OS
Park et al. 2018 (STAH)	2013-2015	Phase 3 (C)	Sorafenib & TACE	Did not meet primary endpoint of OS
Kudo et al. 2018 (REFLECT)	2013-2015	Phase 3 (C)	Lenvatinib	Non-inferior OS
Yau et al. 2021 (CheckMate 459)	2016-01-11 to 2017-05-24	Phase 3 (C)	Nivolumab	Might have inferior OS
He et al. 2019 (HCC-S021)	2016-04-01 to 2017-10-10	Phase 3 (C)	SoraHAIC	Inferior OS
Qin et al. 2021	2016-2018	Phase 3 (C)	Donafenib	Seems to have inferior OS
Lyu et al. 2021 (FOHAIC-1)	2017-2020	Phase 3 (C)	HAI FOLFOX	Inferior OS
Abou-Alfa et al. 2022 (HIMALAYA)	2017-2019	Phase 3 (C)	1. Durvalumab & Tremelimumab	Inferior 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)
Finn et al. 2020 (IMbrave150)	2018-03-15 to 2019-01-30	Phase 3 (C)	Atezolizumab & Bevacizumab	Inferior OS
Kelley et al. 2022 (COSMIC-312)	2018-2020	Phase 3 (C)	1. Cabozantinib & Atezolizumab	Seems to have inferior PFS¹ Did 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)	IBI-305 & Sintilimab	Inferior OS
Qin et al. 2023 (CARES-310)	2019-06-28 to 2021-3-24	Phase 3 (C)	Apatinib & Camrelizumab	Inferior PFS/OS

¹Reported efficacy for COSMIC-312 is based on the 2024 update.

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

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 contains dosing details in manuscript PubMed
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 contains dosing details in manuscript PubMed NCT00105443
1. 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 PubMed
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 contains dosing details in manuscript PubMed NCT00492752
1. 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 contains dosing details in manuscript PubMed
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 PubMed
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 PubMed
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 contains dosing details in manuscript PubMed 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 PubMed 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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript PubMed 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 contains dosing details in abstract PubMed 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 contains dosing details in abstract PubMed NCT01761266
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 PubMed 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 contains dosing details in abstract PubMed 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 PubMed 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 PubMed 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 contains dosing details in manuscript PubMed 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 PubMed 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 contains dosing details in manuscript PubMed NCT03434379
1. 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 PubMed
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 contains dosing details in abstract PubMed 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 contains dosing details in manuscript link to PMC article PubMed
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 contains dosing details in abstract PubMed 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 PubMed 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 contains dosing details in abstract PubMed NCT03755791
1. 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 PubMed
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 PubMed 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 Evidence. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. link to original article contains dosing details in manuscript PubMed NCT03298451
1. 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 PubMed
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 PubMed NCT03412773
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 contains dosing details in manuscript PubMed NCT03412773

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 superior 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-esc)	Placebo	Seems to have superior 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 contains dosing details in abstract PubMed NCT02702414
1. 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 PubMed
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 contains dosing details in manuscript PubMed NCT02702401
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 contais dosing details in abstract PubMed NCT03062358

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	Superior 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 PubMed NCT01140347
1. 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 PubMed
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 contains dosing details in abstract PubMed NCT02435433
1. 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 PubMed

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	Superior 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 contains dosing details in abstract PubMed 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 superior 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 contains dosing details in abstract PubMed 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	Superior 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 contains dosing details in abstract link to PMC article PubMed NCT01908426
Retrospective: 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 original article

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 contains dosing details in manuscript PubMed 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 inferior OS
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 contains dosing details in manuscript PubMed 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 PubMed 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 superior 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 contains dosing details in manuscript PubMed NCT00471965

Ipilimumab & Nivolumab

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Yau et al. 2020 (CheckMate 040_combo)	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 040_combo: 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 contains dosing details in abstract PubMed NCT01658878

Lenvatinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (IMbrave251)	2021-ongoing	Phase 3 (C)	1a. Lenvatinib & Atezolizumab 1b. 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: contains dosing details on CT.gov 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 contains dosing details in abstract link to PMC article PubMed NCT01658878
1. 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 PubMed

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (IMbrave251)	2021-ongoing	Phase 3 (C)	1a. Lenvatinib & Atezolizumab 1b. 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: contains dosing details on CT.gov NCT04770896

Tislelizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Awaiting publication (RATIONALE-208)	2018-NR	Phase 2

Immunotherapy

Tislelizumab (Baizean) 200 mg IV once on day 1

21-day cycles

References

RATIONALE-208: contains dosing details on CT.gov NCT03419897

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:100%;"
+<span id="BackToTop"></span>
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''
+[[#top|Back to Top]]
-|-
+</div>
-| style="background-color:#F0F0F0; width:15%" |[[File:C Schwartz.jpg|frameless|upright=0.3|center]]
+{{#lst:Editorial board transclusions|giei}}
-| style="width:35%" |<big>[[User:Candiceschwartz|Candice Schwartz, MD]]<br>University of Illinois at Chicago<br>Chicago, IL</big>
+''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Hepatocellular_carcinoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Hepatocellular carcinoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.
-| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]
-| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big>
-|-
-|}
-''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Hepatocellular_carcinoma_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''.
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 17: / Line 12: @@
 {{TOC limit|limit=3}}
 =Guidelines=
-==[http://www.esmo.org/ ESMO]==
+'''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. [https://doi.org/10.1002/hep.29913 Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases] [https://www.ncbi.nlm.nih.gov/pubmed/29624699 PubMed]
-*'''2018:''' Vogel et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Hepatocellular-Carcinoma Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+==[http://www.asco.org/ ASCO]==
+*'''2024:''' Gordan et al. [https://doi.org/10.1200/jco.23.02745 Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/38502889/ PubMed]
+**'''2020:''' Gordan et al. [https://doi.org/10.1200/jco.20.02672 Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/33197225 PubMed]
-===Older===
+==[https://www.esmo.org/ ESMO]==
+*'''2018:''' Vogel et al. [https://doi.org/10.1093/annonc/mdy308 Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/30285213/ PubMed]
+**'''2012:''' Verslype et al. [https://doi.org/10.1093/annonc/mds225 Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/22997453/ PubMed]
+**'''2010:''' Jelic & Sotiropoulos. [https://doi.org/10.1093/annonc/mdq166 Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555104/ PubMed]
+**'''2009:''' Jelic. [https://doi.org/10.1093/annonc/mdp124 Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454459/ PubMed]
+**'''2008:''' Parikh et al. [https://doi.org/10.1093/annonc/mdn114 Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456757/ PubMed]
+==French Intergroup==
+*'''2021:''' Blanc et al. [https://doi.org/10.1016/j.clinre.2020.101590 Hepatocellular carcinoma: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, AFEF, SIAD, SFR/FRI)] [https://pubmed.ncbi.nlm.nih.gov/33780876/ PubMed]
-*'''2012:''' Verslype et al. [http://annonc.oxfordjournals.org/content/23/suppl_7/vii41.full.pdf+html Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/22997453 PubMed]
+==ISRS==
+*'''2023:''' Bae et al. [https://doi.org/10.1016/j.ijrobp.2023.08.015 Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Meta-Analysis and International Stereotactic Radiosurgery Society Practice Guidelines] [https://pubmed.ncbi.nlm.nih.gov/37597757/ PubMed]
+==NCCN==
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1514 NCCN Guidelines - Hepatocellular Carcinoma]
+**'''2021:''' Benson et al. [https://doi.org/10.6004/Jnccn.2021.0022 Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/34030131/ PubMed]
+**'''2006:''' Benson et al. [https://doi.org/10.6004/Jnccn.2006.0064 Hepatobiliary cancers. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/16948952/ PubMed]
+**'''2003:''' Benson et al. [https://doi.org/10.6004/Jnccn.2003.0010 Hepatobiliary cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19764153/ PubMed]
-==[https://www.nccn.org/ NCCN]==
+==SITC==
+*'''2021:''' Greten et al. [http://dx.doi.org/10.1136/jitc-2021-002794 Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma] [https://www.ncbi.nlm.nih.gov/pubmed/34518290 PubMed]
-*[https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf NCCN Guidelines - Hepatobiliary Cancers]
+==TOS/ESMO==
+*'''2020:''' Chen et al. [https://doi.org/10.1016/j.annonc.2019.12.001 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] [https://www.ncbi.nlm.nih.gov/pubmed/32067677 PubMed]
-=Local therapy=
+=Adjuvant therapy=
-==Axitinib & TACE {{#subobject:ffb7ae|Regimen=1}}==
+==Atezolizumab & Bevacizumab {{#subobject:7gj5tc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:cjngab|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s0140-6736(23)01796-8 Qin et al. 2023 (IMbrave050)]
+|2019-12-31 to 2021-11-25
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Observation|Observation]]
+| style="background-color:#91cf60" |Seems to have superior RFS (primary endpoint)<br>Median RFS: NYR vs NYR<br>(aHR 0.72, 95% CI 0.53-0.98)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Curative [[Surgery#Hepatobiliary_cancer_surgery|surgical resection]] or [[Surgery#Ablation|ablation]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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)'''
+</div></div>
+===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. [https://doi.org/10.1016/s0140-6736(23)01796-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37871608/ PubMed] [https://clinicaltrials.gov/study/NCT04102098 NCT04102098]
+==TACE monotherapy {{#subobject:50f9da|Regimen=1}}==
+TACE: '''<u>T</u>'''rans-'''<u>A</u>'''rterial '''<u>C</u>'''hemo-'''<u>E</u>'''mbolization
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, doxorubicin-based {{#subobject:f55d49|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[http://clincancerres.aacrjournals.org/content/24/9/2074 Wang et al. 2018 (LCI-125-009)]
+|2011-2014
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Observation|Observation]]
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>OS36: 85.2% vs 77.4%<br>(HR 0.59, 95% CI 0.36-0.97)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Curative [[Surgery#Hepatobiliary_cancer_surgery|surgical resection]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Local therapy====
+*[[TACE]] consisting of:
+**[[Doxorubicin (Adriamycin)]] 20 to 30 mg/m<sup>2</sup>
+**Lipiodol 3 to 5 mL
+'''One or more treatments'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, carboplatin, epirubicin, mitomycin-based {{#subobject:f66e49|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235393/ Wei et al. 2018 (SYSUCC-HCC-ADTACE)]
+|2009-2012
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Observation|Observation]]
+| style="background-color:#1a9850" |Superior DFS (primary endpoint)<br>Median DFS: 17.45 vs 9.27 mo<br>(HR 0.70, 95% CI 0.52-0.95)
 |-
-|[[#top|back to top]]
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Curative [[Surgery#Hepatobiliary_cancer_surgery|surgical resection]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Local therapy====
+*[[TACE]] consisting of:
+**[[Carboplatin (Paraplatin)]] 200 mg/m<sup>2</sup>
+**[[Mitomycin (Mutamycin)]] 6 mg/m<sup>2</sup>
+**[[Epirubicin (Ellence)]] 40 mg/m<sup>2</sup>
+**Lipiodol 4 to 5 mL
+'''One or two treatments'''
+</div></div>
+===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. [http://clincancerres.aacrjournals.org/content/24/9/2074 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29420221/ PubMed] [https://clinicaltrials.gov/study/NCT01966133 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. [https://cancercommun.biomedcentral.com/articles/10.1186/s40880-018-0331-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235393/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30305149/ PubMed] [https://clinicaltrials.gov/study/NCT02788526 NCT02788526]
+=Local therapy for advanced disease=
+==Axitinib & TACE {{#subobject:ffb7ae|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:48d017|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 33%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.30825 Chan et al. 2017]
+|[https://doi.org/10.1002/cncr.30825 Chan et al. 2017 (HCC028)]
-| style="background-color:#91cf61" |Phase II
+|2011-2014
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Axitinib (Inlyta)]] 5 mg PO twice per day, held before and after TACE
+====Local therapy====
 *[[TACE]]
+</div></div>
+===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. [https://doi.org/10.1002/cncr.30825 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28640364/ PubMed] [https://clinicaltrials.gov/study/NCT01352728 NCT01352728]
+==Lenvatinib & TACE {{#subobject:c1gjc9|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:318cb5|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.22.00392 Peng et al. 2022 (LAUNCH)]
+|2019-2021
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Lenvatinib_monotherapy|Lenvatinib]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 17.8 vs 11.5 mo<br>(HR 0.45, 95% CI 0.33-0.61)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div></div>
 ===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. [https://doi.org/10.1200/jco.22.00392 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35921605/ PubMed] [https://clinicaltrials.gov/study/NCT03905967 NCT03905967]
-#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. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.30825 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28640364 PubMed]
 ==DEB-TACE {{#subobject:7acb7b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 DEB-TACE: '''<u>D</u>'''rug-'''<u>E</u>'''luting '''<u>B</u>'''ead '''<u>T</u>'''rans-'''<u>A</u>'''rterial '''<u>C</u>'''hemo-'''<u>E</u>'''mbolization
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:35a248|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966514/ Brown et al. 2016 (MSK 07-099)]
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
+|2007-2012
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 |Bland embolization
 | style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30156-5/fulltext Meyer et al. 2017 (TACE2)]
+|[https://doi.org/10.1016/S2468-1253(17)30156-5 Meyer et al. 2017 (TACE2)]
-| style="background-color:#1a9851" |Phase III (C)
+|2010-2015
+| style="background-color:#1a9851" |Phase 3 (C)
 |DEB-TACE & Sorafenib
-| style="background-color:#ffffbf" |Did not meet primary outcome of PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
-''TACE2 assessed the addition of concurrent sorafenib to DEB-TACE; patients had Child-Pugh A liver disease, and ECOG PS 0 or 1.''
+''Note: TACE2 assessed the addition of concurrent sorafenib to DEB-TACE.''
+<div class="toccolours" style="background-color:#fdcdac">
-====Chemotherapy====
+====Eligibility criteria====
+*TACE2: Child-Pugh A liver disease, and ECOG PS 0 or 1
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Local therapy====
 *[[TACE]] with drug-eluting beads loaded with [[Doxorubicin (Adriamycin)]] 150 mg
 '''One treatment'''
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2015.64.0821 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966514/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26834067/ PubMed] [https://clinicaltrials.gov/study/NCT00539643 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. [https://doi.org/10.1016/S2468-1253(17)30156-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28648803/ PubMed] [https://clinicaltrials.gov/study/NCT01324076 NCT01324076]
+==FOLFOX-HAIC {{#subobject:jiuga2|Variant=1}}==
+FOLFOX-HAIC: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin '''<u>H</u>'''epatic '''<u>A</u>'''rterial '''<u>I</u>'''nfusion '''<u>C</u>'''hemotherapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, longer duration {{#subobject:1v568 |Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.21.00608 Li et al. 2021 (HCC-S023)]
+|2016-2018
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|[[#TACE_monotherapy|TACE]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 23.1 vs 16.1 mo<br>(HR 0.58, 95% CI 0.45-0.75)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IA over 60 minutes once on day 1, '''given second'''
+*[[Fluorouracil (5-FU)|Fluorouracil]] 400 mg/m<sup>2</sup> IA bolus once on day 1, '''given third''', then 2400 mg/m<sup>2</sup> IA continuous infusion over 24 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)|Oxaliplatin]] 130 mg/m<sup>2</sup> IA over 2 hours once on day 1, '''given first'''
+'''21-day cycle for up to 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, shorter duration {{#subobject:1v568c |Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082249/ Li et al. 2023 (B2017-006-01)]
+|2016-06 to 2021-08
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Observation|Observation]]
+| style="background-color:#1a9850" |Superior DFS (primary endpoint)<br>Median DFS: 20.3 vs 10 mo<br>(HR 0.59, 95% CI 0.43-0.81)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Curative [[Surgery#Hepatobiliary_cancer_surgery|surgical resection]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IA over 90 minutes once on day 1, '''given second'''
+*[[Fluorouracil (5-FU)|Fluorouracil]] 400 mg/m<sup>2</sup> IA over 2 hours once on day 1, '''given third''', then 2400 mg/m<sup>2</sup> IA continuous infusion over 24 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)|Oxaliplatin]] 85 mg/m<sup>2</sup> IA over 3 hours once on day 1, '''given first'''
+'''28- to 35-day cycle for 1 to 2 cycles'''
+</div></div>
+===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. [https://doi.org/10.1200/jco.21.00608 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34648352/ PubMed] [https://clinicaltrials.gov/study/NCT02973685 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. [https://doi.org/10.1200/JCO.22.01142 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082249/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36525610/ PubMed] [https://clinicaltrials.gov/study/NCT03192618 NCT03192618]
+==FOFLFOX-HAIC & Sorafenib {{#subobject:jix4b2|Variant=1}}==
+FOLFOX-HAIC & Sorafenib: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin '''<u>H</u>'''epatic '''<u>A</u>'''rterial '''<u>I</u>'''nfusion '''<u>C</u>'''hemotherapy & Sorafenib
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:0eb568 |Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512278/ He et al. 2019 (HCC-S021)]
+|2016-04-01 to 2017-10-10
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Sorafenib_monotherapy|Sorafenib]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 13.4 vs 7.1 mo<br>(HR 0.35, 95% CI 0.26-0.48)
+|-
+|}
+''Note: All patient who were hepatitis B received preemptive antiviral therapy.''
+<div class="toccolours" style="background-color:#fdcdac">
+====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
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IA over 60 minutes once on day 1, '''given second, from hours 2 to 3'''
+*[[Fluorouracil (5-FU)|Fluorouracil]] 400 mg/m<sup>2</sup> IA bolus once on day 1, then 2400 mg/m<sup>2</sup> IA continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)|Oxaliplatin]] 85 mg/m<sup>2</sup> IA over 120 minutes once on day 1, '''given first, from hours 0 to 2'''
+====Targeted therapy====
+*[[Sorafenib (Nexavar)|Sorafenib]] 400 mg twice per day
+'''21-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1001/jamaoncol.2019.0250 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512278/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31070690/ PubMed] [https://clinicaltrials.gov/study/NCT02774187 NCT02774187]
-#'''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. [https://doi.org/10.1200/JCO.2015.64.0821 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966514/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26834067 PubMed]
-#'''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. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30156-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28648803 PubMed]
 ==Radioembolization {{#subobject:4f040c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:ea43b3|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30683-6/fulltext Vilgrain et al. 2017 (SARAH)]
+|[https://doi.org/10.1200/JCO.2017.76.0892 Chow et al. 2018 (SIRveNIB)]
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
+|2010-2016
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 |[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#ffffbf" |Did not meet primary outcome of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://doi.org/10.1200/JCO.2017.76.0892 Chow et al. 2018 (SIRveNIB)]
+|[https://doi.org/10.1016/S1470-2045(17)30683-6 Vilgrain et al. 2017 (SARAH)]
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
+|2011-2015
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 |[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#ffffbf" |Did not meet primary outcome of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |}
-''SARAH: This multicenter European study 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 100 Gy may derive a meaningful response as compared to sorafenib.''
+====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: This 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.''
+*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.
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Radiotherapy====
 *[[Brachytherapy|Selective internal radiotherapy (SIRT) with yttrium-90 resin microspheres]]
+</div></div>
 ===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. [https://doi.org/10.1016/S1470-2045(17)30683-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29107679/ PubMed] [https://clinicaltrials.gov/study/NCT01482442 NCT01482442]
-#'''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 randomized controlled phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1624-1636. Epub 2017 Oct 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30683-6/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29107679 PubMed]
 ##'''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. [https://academic.oup.com/annonc/article/30/Supplement_5/mdz247.063/5576666 link to original article]
-<!-- # '''Abstract:''' Chow PHW, Gandhi M. Phase III multi-centre open-label randomized controlled trial of selective internal radiation therapy (SIRT) versus sorafenib in locally advanced hepatocellular carcinoma: The SIRveNIB study (abstract). J Clin Oncol 35, 2017 suppl; abstr 4002). [http://abstracts.asco.org/199/AbstView_199_187604.html link to abstract] -->
+#'''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. [https://doi.org/10.1200/JCO.2017.76.0892 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29498924/ PubMed] [https://clinicaltrials.gov/study/NCT01135056 NCT01135056]
-#'''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. [https://doi.org/10.1200/JCO.2017.76.0892 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29498924 PubMed]
 ==TACE monotherapy {{#subobject:f96a1b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 TACE: '''<u>T</u>'''rans-'''<u>A</u>'''rterial '''<u>C</u>'''hemo-'''<u>E</u>'''mbolization
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:93050b|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199505113321903 Trinchet et al. 1995]
+|[https://doi.org/10.1056/NEJM199505113321903 Trinchet et al. 1995]
 |1990-1992
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[Hepatocellular_carcinoma_-_null_regimens#Best_supportive_care|Best supportive care]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08649-X/fulltext Llovet et al. 2002]
+|[https://doi.org/10.1016/S0140-6736(02)08649-X Llovet et al. 2002]
 |1996-2000
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[Hepatocellular_carcinoma_-_null_regimens#Best_supportive_care|Best supportive care]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>(HR 0.47, 95% CI 0.25-0.91)
 |-
-|[https://www.journal-of-hepatology.eu/article/S0168-8278(09)00588-1/fulltext Okusaka et al. 2009]
+|[https://doi.org/10.1016/j.jhep.2009.09.004 Okusaka et al. 2009]
-|{{#subobject:xx|ToDo=1}}
+|1999-2003
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |TAI
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.ejcancer.com/article/S0959-8049(11)00324-8/fulltext Kudo et al. 2011 (Bayer 11721)]
+|[https://doi.org/10.1016/j.ejca.2011.05.007 Kudo et al. 2011 (Bayer 11721)]
-|{{#subobject:xx|ToDo=1}}
+|2006-2009
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.27290 Kudo et al. 2014 (BRISK TA)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846877/ Ikeda et al. 2017]
-|{{#subobject:xx|ToDo=1}}
+|2008-2010
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|TACE & Brivanib
+|TACE with Miriplatin
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846877/ Ikeda et al. 2017]
+|[https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.27290 Kudo et al. 2014 (BRISK TA)]
-|{{#subobject:xx|ToDo=1}}
+|2009-2012
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|TACE with Miriplatin
+|[[#TACE_.26_Brivanib_999|TACE & Brivanib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30290-X/fulltext Kudo et al. 2017 (ORIENTAL)]
+|[https://doi.org/10.1016/S2468-1253(17)30290-X Kudo et al. 2017 (ORIENTAL)]
-|{{#subobject:xx|ToDo=1}}
+|2010-2013
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|TACE & Orantinib
+|[[#TACE_.26_Orantinib_999|TACE & Orantinib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''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.''
+====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.
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Local therapy====
 *[[TACE]]
 '''1 or more treatments'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*Bayer 11721: [[Hepatocellular_carcinoma_-_null_regimens#Placebo|Placebo]] versus adjuvant [[#Sorafenib_monotherapy_999|sorafenib]]
-*Bayer 11721: [[Hepatocellular_carcinoma_-_null_regimens#Placebo|Placebo]] versus sorafenib
+</div></div>
 ===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. [https://doi.org/10.1056/NEJM199505113321903 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7708069/ PubMed]
+#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. [https://doi.org/10.1016/S0140-6736(02)08649-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/12049862/ PubMed]
+#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. [https://doi.org/10.1016/j.jhep.2009.09.004 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19864035/ PubMed]
+#'''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. [https://doi.org/10.1016/j.ejca.2011.05.007 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21664811/ PubMed] [https://clinicaltrials.gov/study/NCT00494299 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. [https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.27290 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24996197/ PubMed] [https://clinicaltrials.gov/study/NCT00908752 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. [https://doi.org/10.1007/s00535-017-1374-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28766016/ PubMed] 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. [https://doi.org/10.1016/S2468-1253(17)30290-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/28988687/ PubMed] [https://clinicaltrials.gov/study/NCT01465464 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. [https://doi.org/10.1016/j.clinre.2020.05.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32576496/ PubMed] [https://clinicaltrials.gov/study/NCT01164202 NCT01164202]
-#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. [https://www.nejm.org/doi/full/10.1056/NEJM199505113321903 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7708069 PubMed]
+==TACE, then 5-FU {{#subobject:572d2d|Regimen=1}}==
-#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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08649-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12049862 PubMed]
+TACE, then 5-FU: '''<u>T</u>'''rans-'''<u>A</u>'''rterial '''<u>C</u>'''hemo'''<u>E</u>'''mbolization followed by '''<u>5</u>'''-'''<u>F</u>'''luoro'''<u>U</u>'''racil
-#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. [https://www.journal-of-hepatology.eu/article/S0168-8278(09)00588-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/19864035 PubMed]
+<div class="toccolours" style="background-color:#c8a2c8">
-#'''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. [https://www.ejcancer.com/article/S0959-8049(11)00324-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21664811 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#'''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. [https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.27290 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24996197 PubMed]
-#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. [https://link.springer.com/article/10.1007%2Fs00535-017-1374-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28766016 PubMed]
-#'''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. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30290-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28988687 PubMed]
-=Adjuvant therapy=
-==TACE monotherapy {{#subobject:50f9da|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-TACE: '''<u>T</u>'''rans-'''<u>A</u>'''rterial '''<u>C</u>'''hemo-'''<u>E</u>'''mbolization
-===Regimen variant #1, doxorubicin-based {{#subobject:f55d49|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://clincancerres.aacrjournals.org/content/24/9/2074 Wang et al. 2018 (LCI-125-009)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363838/ Kawata et al. 2001]
-|2011-2014
+|1990-1993
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Hepatocellular_carcinoma_-_null_regimens#Observation|Observation]]
+|[[#TACE.2C_then_5-FU_.26_Pravastatin_888|TACE, then 5-FU & Pravastatin]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-====Preceding treatment====
+<div class="toccolours" style="background-color:#eeeeee">
+===Induction {{#subobject:b440c9|Variant=1}}===
-*Curative [[Surgery#Hepatobiliary_cancer_surgery|surgical resection]]
+<div class="toccolours" style="background-color:#b3e2cd">
+====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:'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Consolidation===
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 200 mg PO once per day
+'''2-month course'''
+</div></div></div>
+===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. [https://doi.org/10.1054/bjoc.2000.1716 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363838/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/11286466/ PubMed]
-*[[TACE]] consisting of:
+=First-line therapy for advanced or metastatic disease=
-**[[Doxorubicin (Adriamycin)]] 20 to 30 mg/m<sup>2</sup>
+''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.''
-**Lipiodol 3 to 5 mL
+==Apatinib & Camrelizumab {{#subobject:7dogcc|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-'''One or more treatments'''
+===Regimen {{#subobject:59bu4c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===Regimen variant #2, carboplatin, epirubicin, mitomycin-based {{#subobject:f66e49|Variant=1}}===
+! style="width: 20%" |Study
-{| class="wikitable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Study
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235393/ Wei et al. 2018 (SYSUCC-HCC-ADTACE)]
+|[https://doi.org/10.1016/s0140-6736(23)00961-3 Qin et al. 2023 (CARES-310)]
-| style="background-color:#1a9851" |Phase III (E-esc)
+|2019-06-28 to 2021-3-24
-|[[Hepatocellular_carcinoma_-_null_regimens#Observation|Observation]]
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-| style="background-color:#91cf60" |Seems to have superior DFS
+|[[#Sorafenib_monotherapy|Sorafenib]]
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 5.6 vs 3.7 mo<br>(HR 0.52, 95% CI 0.41-0.65)<br><br>Superior OS (secondary endpoint)<br>Median OS: 22.1 vs 15.2 mo<br>(HR 0.62, 95% CI 0.49-0.80)
 |-
 |}
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
-*Curative [[Surgery#Hepatobiliary_cancer_surgery|surgical resection]]
+*[[Camrelizumab (AiRuiKa)]] 200 mg IV once on day 1
+====Targeted therapy====
-====Chemotherapy====
+*[[Apatinib (Aitan)]] 250 mg PO once per day on days 1 to 14
+'''14-day cycles'''
-*[[TACE]] consisting of:
+</div></div>
-**[[Carboplatin (Paraplatin)]] 200 mg/m<sup>2</sup>
-**[[Mitomycin (Mutamycin)]] 6 mg/m<sup>2</sup>
-**[[Epirubicin (Ellence)]] 40 mg/m<sup>2</sup>
-**Lipiodol 4 to 5 mL
-'''One or two treatments'''
 ===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. [https://doi.org/10.1016/s0140-6736(23)00961-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37499670/ PubMed] [https://clinicaltrials.gov/study/NCT03764293 NCT03764293]
-#'''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. [http://clincancerres.aacrjournals.org/content/24/9/2074 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29420221 PubMed] 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. [https://cancercommun.biomedcentral.com/articles/10.1186/s40880-018-0331-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235393/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30305149 PubMed]
-=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.''
 ==Atezolizumab & Bevacizumab {{#subobject:7d73tc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:59biab|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 283: / Line 499: @@
 |-
 |}
-''Excluded Child-Pugh class B and C, coinfection with hepatitis B or C virus, and untreated or incompletely treated esophageal or gastric varices.''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s1470-2045(20)30156-x Lee et al. 2020 (GO30140)]
+|2016-07-20 to 2018-07-31
+| style="background-color:#91cf61" |Phase 1b
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
 |[https://doi.org/10.1056/nejmoa1915745 Finn et al. 2020 (IMbrave150)]
-|2018-2019
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-215-1 <span style="color:white;">ESMO-MCBS (5)</span>]'''
+|-
+|} -->
+|2018-03-15 to 2019-01-30
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 19.2 vs 13.4 mo<br>(HR 0.66, 95% CI 0.52-0.85)
 |-
 |}
-====Chemotherapy====
+''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br>
+<div class="toccolours" style="background-color:#fdcdac">
+====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
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div></div>
 ===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. [https://doi.org/10.1016/s1470-2045(20)30156-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/32502443/ PubMed] [https://clinicaltrials.gov/study/NCT02715531 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. [https://doi.org/10.1056/nejmoa1915745 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32402160 PubMed]
+#'''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. [https://doi.org/10.1056/nejmoa1915745 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32402160/ PubMed] [https://clinicaltrials.gov/study/NCT03434379 NCT03434379]
+##'''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. [https://doi.org/10.1016/j.jhep.2021.11.030 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34902530/ PubMed]
 ==Bevacizumab monotherapy {{#subobject:7dbb4c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:51c13b|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635806/ Siegel et al. 2008]
-| style="background-color:#91cf61" |Phase II
+|2003-2006
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#88419d; color:white " |ORR: 13% (95% CI, 3-23)
 |-
 |}
-''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%).''
+''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%).''
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 '''14-day cycles'''
+</div></div>
-===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. [http://jco.ascopubs.org/content/26/18/2992.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635806/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18565886 PubMed]
-==Capecitabine monotherapy {{#subobject:729cf1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:34d254|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://link.springer.com/article/10.1007%2Fs12032-013-0655-z Abdel-Rahman et al. 2013]
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ooc)
-|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|}
-''Neither the primary outcome (progression-free survival) or secondary outcome (overall survival) were met.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-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. [https://doi.org/10.1200/jco.2007.15.9947 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635806/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18565886/ PubMed]
-#'''Retrospective:''' Patt YZ, Hassan MM, Aguayo A, Nooka AK, Lozano RD, Curley SA, Vauthey JN, Ellis LM, Schnirer II, Wolff RA, Charnsangavej C, Brown TD. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004 Aug 1;101(3):578-86. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.20368/full link to original article] [https://pubmed.ncbi.nlm.nih.gov/15274071 PubMed]
-#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. [http://link.springer.com/article/10.1007%2Fs12032-013-0655-z link to original article] [https://pubmed.ncbi.nlm.nih.gov/23824645 PubMed]
 ==Capecitabine & Bevacizumab {{#subobject:b24110|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:f3fd07|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844032/ Hsu et al. 2010]
-| style="background-color:#91cf61" |Phase II
+|2005-2006
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#6e016b; color:white " |ORR: 9%
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> 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'''
+</div></div>
 ===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. [https://doi.org/10.1038/sj.bjc.6605580 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844032/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20160718/ PubMed]
-#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. [https://www.nature.com/bjc/journal/v102/n6/full/6605580a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844032/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20160718 PubMed]
 ==CapeOx {{#subobject:a86027|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin
 <br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:912834|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360397/ Boige et al. 2007 (FFCD 03-03)]
-| style="background-color:#91cf61" |Phase II
+|2003-2004
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#bfd3e6" |DCR: 72% (95% CI, 57-83)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 *[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
 '''21-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1038/sj.bjc.6603956 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360397/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17876335/ PubMed]
-#'''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. [https://www.nature.com/bjc/journal/v97/n7/full/6603956a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360397/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17876335 PubMed]
 ==CapeOx & Bevacizumab {{#subobject:32787f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 CapeOX & Bevacizumab: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Bevacizumab
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:231bcb|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.25889/abstract Sun et al. 2011]
+|[https://doi.org/10.1002/cncr.25889 Sun et al. 2011]
-| style="background-color:#91cf61" |Phase II
+|2004-2007
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#e0ecf4" |DCR: 77.5%
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 *[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> 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'''
+</div></div>
+===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. [https://doi.org/10.1002/cncr.25889 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21264839/ PubMed]
+==Donafenib monotherapy {{#subobject:2e9dor|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:50eyyr|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445562/ Qin et al. 2021]
+|2016-2018
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Sorafenib_monotherapy|Sorafenib]]
+| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 12.1 vs 10.3 mo<br>(HR 0.83, 95% 0.70-0.99)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Donafenib (Zepsun)]] 200 mg PO twice per day on days 1 to 28
+'''28-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1200/jco.21.00163 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445562/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34185551/ PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25889/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21264839 PubMed]
 ==Doxorubicin monotherapy {{#subobject:2e9077|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen variant #1, 50 mg/m<sup>2</sup> {{#subobject:50ecb0|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://doi.org/10.1200/JCO.2012.44.5643 Qin et al. 2013 (EACH)]
-| style="background-color:#1a9851" |Phase III (C)
+|2007-2009
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#FOLFOX4|FOLFOX4]]
-| style="background-color:#fee08b" |Trend towards inferior OS
+| style="background-color:#fee08b" |Might have inferior OS
 |-
 |}
-''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).''
+''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).''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 60 mg/m<sup>2</sup> x 6 {{#subobject:16d763|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://academic.oup.com/jnci/article/97/20/1532/2521445 Yeo et al. 2005]
-| style="background-color:#1a9851" |Phase III (C)
+|1999-2003
-|PIAF
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#PIAF_999|PIAF]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycle for up to 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #3, 60 mg/m<sup>2</sup> x 9 {{#subobject:16h213|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673678907353/fulltext Johnson et al. 1978]
+|[https://doi.org/10.1016/s0140-6736(78)90735-3 Johnson et al. 1978]
-| style="background-color:#91cf61" |Phase II
+|1976-1977
+| style="background-color:#91cf61" |Non-randomized
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
 |[https://jamanetwork.com/journals/jama/fullarticle/186918 Abou-Alfa et al. 2010 (Study 11546)]
-| style="background-color:#1a9851" |Phase III (C)
+|2005-04 to 2006-10
-|Doxorubicin & Sorafenib
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#Doxorubicin_.26_Sorafenib|Doxorubicin & Sorafenib]]
 | style="background-color:#d73027" |Inferior OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycle for up to 9 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #4, 60 mg/m<sup>2</sup>, indefinite {{#subobject:1a8b63|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19880801)62:3%3C479::AID-CNCR2820620306%3E3.0.CO;2-L Lai et al. 1988]
+|[https://doi.org/10.1002/1097-0142(19880801)62:3%3C479::AID-CNCR2820620306%3E3.0.CO;2-L Lai et al. 1988]
-| style="background-color:#1a9851" |Phase III (E-esc)
+|NR
-|Best supportive care
+| style="background-color:#1a9851" |Randomized (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Best_supportive_care|Best supportive care]]
 | style="background-color:#91cf60" |Seems to have superior OS
 |-
-|[http://jco.ascopubs.org/content/25/21/3069.long Gish et al. 2007]
+|[https://doi.org/10.1200/jco.2006.08.4046 Gish et al. 2007 (ZARIX-ZX101-301)]
-| style="background-color:#1a9851" |Phase III (C)
+|2000-2005
-|Nolatrexed
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Nolatrexed_monotherapy_999|Nolatrexed]]
 | style="background-color:#1a9850" |Superior OS
 |-
 |}
 ''Note: this was the lower bound of the dosing range provided by Lai et al. 1988.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
-**Gish et al. 2007: Initial dose reduction to 30 mg/m<sup>2</sup> IV for patients with T bili <u>greater than</u> 1.2 mg/dL
 '''21-day cycles'''
+</div>
-===Regimen variant #5, 75 mg/m<sup>2</sup> {{#subobject:1a9963|Variant=1}}===
+<div class="toccolours" style="background-color:#fff2ae">
-{| class="wikitable" style="width: 100%; text-align:center;"
+====Dose and schedule modifications====
-! style="width: 25%" |Study
+*ZARIX-ZX101-301: Initial dose reduction to 30 mg/m<sup>2</sup> IV for patients with T bili <u>greater than</u> 1.2 mg/dL
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+</div></div><br>
-! style="width: 25%" |Comparator
+<div class="toccolours" style="background-color:#eeeeee">
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+===Regimen variant #5, 60 --> 75 mg/m<sup>2</sup> {{#subobject:1a9963|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://academic.oup.com/jnci/article/97/20/1532/2521445 Yeo et al. 2005]
-| style="background-color:#1a9851" |Phase III (C)
+|1999-2003
-|PIAF
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#PIAF_999|PIAF]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+''Note: Dose is escalated only if starting dose is "well tolerated".''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Doxorubicin (Adriamycin)]] as follows:
 **Cycle 1: 60 mg/m<sup>2</sup> IV once on day 1
-**Cycle 2 onwards, if "well tolerated": 75 mg/m<sup>2</sup> IV once on day 1
+**Cycle 2 onwards: 75 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycles'''
+</div></div>
+===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. [https://doi.org/10.1016/s0140-6736(78)90735-3 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/76932/ PubMed]
+#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. [https://doi.org/10.1002/1097-0142(19880801)62:3%3C479::AID-CNCR2820620306%3E3.0.CO;2-L link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2839280/ PubMed]
+#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. [https://academic.oup.com/jnci/article/97/20/1532/2521445 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16234567/ PubMed]
+#'''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. [https://doi.org/10.1200/jco.2006.08.4046 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17634485/ PubMed] [https://clinicaltrials.gov/study/NCT00012324 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. [https://jamanetwork.com/journals/jama/fullarticle/186918 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21081728/ PubMed] [https://clinicaltrials.gov/study/NCT00108953 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. [https://doi.org/10.1200/JCO.2012.44.5643 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23980077/ PubMed] [https://clinicaltrials.gov/study/NCT00471965 NCT00471965]
+==Doxorubicin & Sorafenib {{#subobject:2sof77|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:16usb3|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://jamanetwork.com/journals/jama/fullarticle/186918 Abou-Alfa et al. 2010 (Study 11546)]
+|2005-04 to 2006-10
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|[[#Doxorubicin_monotherapy|Doxorubicin]]
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 13.7 vs 6.5 mo<br>(HR 0.49, 95% CI 0.30-0.80)<br><br>Superior TTP (primary endpoint)<br>Median TTP: 6.4 vs 2.8 mo<br>(HR 0.50, 95% CI 0.30-0.90)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====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/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
+</div></div>
 ===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. [https://jamanetwork.com/journals/jama/fullarticle/186918 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21081728/ PubMed] [https://clinicaltrials.gov/study/NCT00108953 NCT00108953]
+==Durvalumab & Tremelimumab {{#subobject:87gaf8|Regimen=1}}==
+STRIDE: '''<u>S</u>'''ingle '''<u>T</u>'''remelimumab '''<u>R</u>'''egular '''<u>I</u>'''nterval '''<u>D</u>'''urvalumab
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:112b09|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1056/EVIDoa2100070 Abou-Alfa et al. 2022 (HIMALAYA)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-358-1 <span style="color:white;">ESMO-MCBS (5)</span>]'''
+|-
+|} -->
+| rowspan="2" |2017-2019
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|1. [[#Sorafenib_monotherapy|Sorafenib]]
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 16.4 vs 13.8 mo<br>(HR 0.78, 95% CI 0.78-0.92)
+|-
+|2. [[#Durvalumab_monotherapy|Durvalumab]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+|}
+''<sup>1</sup>Reported efficacy is based on the 2024 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div></div>
-#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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673678907353/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/76932 PubMed]
+===References===
-#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. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19880801)62:3%3C479::AID-CNCR2820620306%3E3.0.CO;2-L link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/2839280 PubMed]
+#'''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 Evidence. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. [https://doi.org/10.1056/EVIDoa2100070 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38319892/ PubMed] [https://clinicaltrials.gov/study/NCT03298451 NCT03298451]
-#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. [https://academic.oup.com/jnci/article/97/20/1532/2521445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16234567 PubMed]
+##'''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. [https://doi.org/10.1016/j.annonc.2024.02.005 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38382875/ PubMed]
-#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. [http://jco.ascopubs.org/content/25/21/3069.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17634485 PubMed]
-#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. [https://jamanetwork.com/journals/jama/fullarticle/186918 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21081728 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2012.44.5643 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23980077 PubMed]
-==Erlotinib & Bevacizumab {{#subobject:9afef8|Regimen=1}}==
+==Durvalumab monotherapy {{#subobject:87gig9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:aibb09|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1056/EVIDoa2100070 Abou-Alfa et al. 2022 (HIMALAYA)]
+| rowspan="2" |2017-2019
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|1. [[#Sorafenib_monotherapy|Sorafenib]]
+| style="background-color:#eeee01" |Non-inferior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 16.6 vs 13.8 mo<br>(HR 0.86, 95% CI 0.74-1.01)
+|-
+|2. [[#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
+| style="background-color:#d3d3d3" |Not reported
 |-
-|[[#top|back to top]]
 |}
+''<sup>1</sup>Reported efficacy is based on the 2024 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Durvalumab (Imfinzi)]] 1500 mg IV once on day 1
+'''28-day cycles'''
+</div></div>
+===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 Evidence. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. [https://doi.org/10.1056/EVIDoa2100070 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38319892/ PubMed] [https://clinicaltrials.gov/study/NCT03298451 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. [https://doi.org/10.1016/j.annonc.2024.02.005 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38382875/ PubMed]
+==Erlotinib & Bevacizumab {{#subobject:9afef8|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:112b09|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/27/6/843.long Thomas et al. 2009]
+|[https://doi.org/10.1200/jco.2008.18.3301 Thomas et al. 2009]
-| style="background-color:#91cf61" |Phase II
+|NR
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#9ebcda" |PFS<sub>16</sub>: 62.5%
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896238/ Philip et al. 2011]
-| style="background-color:#91cf61" |Phase II
+|2006-2008
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#6e016b; color:white " |ORR: 5% (95% CI, 0-23)
 |-
 |}
-''Patients in Thomas et al. 2009 could have up to one prior systemic treatment.''
+''Note: Patients in Thomas et al. 2009 could have up to one prior systemic treatment.''
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day
+*[[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'''
+</div></div>
 ===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. [https://doi.org/10.1200/jco.2008.18.3301 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19139433/ PubMed]
-#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. [http://jco.ascopubs.org/content/27/6/843.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19139433 PubMed]
+#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. [https://doi.org/10.1002/cncr.26556 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896238/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21953248/ PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.26556/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896238/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21953248 PubMed]
 ==FULV {{#subobject:7bb459|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin
-|-
+<div class="toccolours" style="background-color:#eeeeee">
-|[[#top|back to top]]
-|}
-FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
 ===Regimen {{#subobject:d1e198|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://www.karger.com/Article/Abstract/227516 Porta et al. 1995]
+|[https://doi.org/10.1159/000227516 Porta et al. 1995]
-| style="background-color:#91cf61" |Phase II
+|NR in abstract
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#8c6bb1" |ORR: 28% (95% CI, 10-46)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
 '''28-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1159/000227516 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7478436/ PubMed]
-#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. [http://www.karger.com/Article/Abstract/227516 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7478436 PubMed]
 ==FOLFOX4 {{#subobject:deff6c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+FOLFOX4: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-|-
+<div class="toccolours" style="background-color:#eeeeee">
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 ===Regimen {{#subobject:3cca17|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://doi.org/10.1200/JCO.2012.44.5643 Qin et al. 2013 (EACH)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|2007-2009
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 |[[#Doxorubicin_monotherapy|Doxorubicin]]
-| style="background-color:#d9ef8b" |Might have superior OS
+| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 6.4 vs 5.0 mo<br>(HR 0.80, 95% CI 0.63-1.02)
+|-
 |}
-''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).''
+''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).''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given second''', then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
 '''14-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1200/JCO.2012.44.5643 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23980077/ PubMed] [https://clinicaltrials.gov/study/NCT00471965 NCT00471965]
-#'''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. [https://doi.org/10.1200/JCO.2012.44.5643 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23980077 PubMed]
+#'''SHR-1210-III-305-HCC:''' [https://clinicaltrials.gov/study/NCT03605706 NCT03605706]
 ==mFOLFOX & Sorafenib {{#subobject:7dbb4c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+mFOLFOX & Sorafenib: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Sorafenib
-|-
+<div class="toccolours" style="background-color:#eeeeee">
-|[[#top|back to top]]
-|}
-mFOLFOX & Sorafenib: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Sorafenib
 ===Regimen {{#subobject:51c13b|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320284/ Goyal et al. 2019 (MGH 12-218)]
-| style="background-color:#91cf61" |Phase II
+|2013-2017
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#88419d; color:white " |mTTP: 7.7 mo (95% CI, 4.4-8.9)
 |-
 |}
-''Inclusion criteria: Child Pugh A with advanced HCC with no prior systemic therapy''. ''Patients had improved mTTP, but increased incidence of hepatotoxicity.''
+''Note: Patients had improved mTTP, but increased incidence of hepatotoxicity. Note that the regimen specifies that 5-FU be given at 1200 mg/m<sup>2</sup>/day over 46 hours; the total dose is therefore unclear.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*Child Pugh A with advanced HCC with no prior systemic therapy
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)|Fluorouracil]] 1200 mg/m<sup>2</sup>/day IV continuous infusion over 46 hours, started on day 1
-*[[Fluorouracil (5-FU)|Fluorouracil]] 1200 mg/m<sup>2</sup> IV over 46 hours, starting on day 1
+*[[Leucovorin (Folinic acid)|Leucovorin]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Folinic acid (Leucovorin)|Leucovorin]] 200 mg/m<sup>2</sup> IV once on day 1
 *[[Oxaliplatin (Eloxatin)|Oxaliplatin]] 85 mg/m<sup>2</sup> IV once on day 1
+====Targeted therapy====
 *[[Sorafenib (Nexavar)|Sorafenib]] 400 mg twice per day
 '''14-day cycles'''
+</div></div>
 ===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. [https://clincancerres.aacrjournals.org/content/25/1/80 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320284/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30190369/ PubMed] [https://clinicaltrials.gov/study/NCT01775501 NCT01775501]
-#'''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. [https://clincancerres.aacrjournals.org/content/25/1/80 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320284/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30190369 PubMed]
 ==GemOx {{#subobject:b3749a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:a6a6da|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.22532/full Louafi et al. 2007]
+|[https://doi.org/10.1002/cncr.22532 Louafi et al. 2007]
-| style="background-color:#91cf61" |Phase II
+|2002-2004
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#88419d; color:white " |ORR: 18% (95% CI, 8–34)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once on day 1
 *[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2
 '''14-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1002/cncr.22532 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17330837/ PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.22532/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17330837 PubMed]
+#'''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. [http://www.journal-of-hepatology.eu/article/S0168-8278(12)00695-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22989572/ PubMed]
-#'''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. [http://www.journal-of-hepatology.eu/article/S0168-8278(12)00695-2/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22989572 PubMed]
 ==GemOx & Sorafenib {{#subobject:32787f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 GemOx & Sorafenib: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin , '''<u>Sorafenib</u>'''
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:231bcb|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 744: / Line 1,055: @@
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734663/ Assenat et al. 2019 (PRODIGE 10)]
 |2008-2011
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 |[[#Sorafenib_monotherapy|Sorafenib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS4
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Gemcitabine (Gemzar)|Gemcitabine]] 1000 mg/m<sup>2</sup> IV once on day 1
 *[[Oxaliplatin (Eloxatin)|Oxaliplatin]] 100 mg/m<sup>2</sup> IV once on day 1
+====Targeted therapy====
 *[[Sorafenib (Nexavar)|Sorafenib]] 400 mg twice per day
+'''14-day cycles'''
-'''14 day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1038/s41416-019-0443-4 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734663/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30944458/ PubMed] [https://clinicaltrials.gov/study/NCT00941967 NCT00941967]
-#'''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. [https://pubmed.ncbi.nlm.nih.gov/30944458 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734663/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30944458 PubMed]
-==HAIC & Sorafenib {{#subobject:jix4b2|Variant=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:0eb568 |Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512278/ He et al. 2019 (HCC-S021)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Sorafenib (Nexavar)|Sorafenib]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-''Patients had HCC with portal vein invasion confirmed by 2 imaging techniques, Child-Pugh A class liver function, and an Eastern Cooperative Oncology Group performance status of 0 to 2. All patient who were hepatitis B received preemptive antiviral therapy. Patients with esophageal or gastric variceal bleeding and hepatic encephalopathy were excluded.''
-====Chemotherapy====
-*HAIC as follows:
-**[[Oxaliplatin (Eloxatin)|Oxaliplatin]] 85 mg/m<sup>2</sup> IA once on day 1
-**[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IA once on day 1
-**[[Fluorouracil (5-FU)|Fluorouracil]] 400 mg/m<sup>2</sup> IA bolus once on day 1, then 2400 mg/m<sup>2</sup> IA over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Sorafenib (Nexavar)|Sorafenib]] 400 mg 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. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2733130 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512278/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31070690 PubMed]
 ==Lenvatinib monotherapy {{#subobject:c13df9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen {{#subobject:3a12b5|Variant=1}}===
-|[[#top|back to top]]
-|}
-===Regimen variant #1, 8 mg/day {{#subobject:3a12b5|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
 |<small>'''FDA-recommended dose'''</small>
 |-
 |}
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30207-1/fulltext Kudo et al. 2018 (REFLECT)]
+|[https://doi.org/10.1016/S0140-6736(18)30207-1 Kudo et al. 2018 (REFLECT)]
 |2013-2015
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 |[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#eeee01" |Non-inferior OS
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)<br>Median OS: 13 vs 12.3 mo<br>(HR 0.92, 95% CI 0.79-1.06)
+|-
+|[https://doi.org/10.1016/s1470-2045(23)00469-2 Llovet et al. 2023 (LEAP-002)]
+|2019-01-17 to 2020-04-28
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Lenvatinib_.26_Pembrolizumab_333|Lenvatinib & Pembrolizumab]]
+| style="background-color:#fee08b" |Might have inferior co-primary endpoints of PFS/OS
 |-
-|}
+|[https://doi.org/10.1200/jco.22.00392 Peng et al. 2022 (LAUNCH)]
-''This dosing is intended for patients weighing less than 60 kg.''
+|2019-2021
-====Chemotherapy====
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Lenvatinib_.26_TACE|Lenvatinib & TACE]]
-*[[Lenvatinib (Lenvima)]] 8 mg PO once per day
+| style="background-color:#d73027" |Inferior OS
-'''28-day cycles'''
-===Regimen variant #2, 12 mg/day {{#subobject:f801bc|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
 |-
-|}
+|[https://clinicaltrials.gov/study/NCT04039607 Awaiting publication (CheckMate 9DW)]
-{| class="wikitable" style="width: 100%; text-align:center;"
+|2019-ongoing
-! style="width: 20%" |Study
+| style="background-color:#1a9851" |Phase 3 (C)
-! style="width: 20%" |Years of enrollment
+|[[#Ipilimumab_.26_Nivolumab_666|Ipilimumab & Nivolumab]]
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of OS
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30207-1/fulltext Kudo et al. 2018 (REFLECT)]
+|[https://clinicaltrials.gov/study/NCT04194775 Awaiting publication (CS1003-305)]
-|2013-2015
+|2019-ongoing
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Sorafenib_monotherapy|Sorafenib]]
+|[[#Lenvatinib_.26_Nofazinlimab_777|Lenvatinib & Nofazinlimab]]
-| style="background-color:#eeee01" |Non-inferior OS
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of OS
 |-
 |}
-''This dosing is intended for patients weighing at least 60 kg.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Targeted therapy====
+*[[Lenvatinib (Lenvima)]] by the following weight-based criteria:
-*[[Lenvatinib (Lenvima)]] 12 mg PO once per day
+**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'''
+</div></div>
 ===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. [https://doi.org/10.1016/S0140-6736(18)30207-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29433850/ PubMed] [https://clinicaltrials.gov/study/NCT01761266 NCT01761266]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30207-1/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29433850 PubMed]
+#'''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. [https://doi.org/10.1200/jco.22.00392 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35921605/ PubMed] [https://clinicaltrials.gov/study/NCT03905967 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. [https://doi.org/10.1016/s1470-2045(23)00469-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/38039993/ PubMed] [https://clinicaltrials.gov/study/NCT03713593 NCT03713593]
-==Nivolumab monotherapy {{#subobject:10ee99|Regimen=1}}==
+#'''CheckMate 9DW:''' [https://clinicaltrials.gov/study/NCT04039607 NCT04039607]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+#'''CS1003-305:''' [https://clinicaltrials.gov/study/NCT04194775 NCT04194775]
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, weight-based {{#subobject:98564a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |Years of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31046-2/abstract El-Khoueiry et al. 2017 (CheckMate 040)]
-|2012-2016
-| style="background-color:#91cf61" |Phase I/II (RT)
-| style="background-color:#88419d; color:white " |ORR: 20% (95% CI, 15–26)
-|-
-|}
-''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. 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, flat dosing {{#subobject:98582a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/30/Supplement_5/mdz394.029/5577900 Yau et al. 2019 (CheckMate 459)]
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#d9ef8b" |Might have superior OS
-|}
-''Note: Overall survival for patients receiving nivolumab was increased (16.4 months) compared to sorafenib (14.7 months), however, it did not meet the predefined threshold for statistically significance. Nivolumab was approved based on clinical significance.''
-''Study included patients with Child-Pugh class B (5-9), hepatitis B and C infections.''
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
-'''14-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.[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31046-2/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28434648 PubMed]
-#'''Abstract:''' Yau T, Park JW, Finn RS, Cheng A, Mathurin P, Edeline J, Kudo M, Han K, Harding JJ, Merle P, Rosmorduc O, Wyrwicz L, Schott E, Choo SP, Kelley RK, Begic D, Chen G, Neely J, Anderson J, Sangro B. CheckMate 459: A randomized, multi-center phase 3 study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Annals of Oncology. 2019 Sept; 30 (suppl_5): v851-v934. Epub 2019 Sept 27. [https://academic.oup.com/annonc/article/30/Supplement_5/mdz394.029/5577900 link to astract]
 ==Sorafenib monotherapy {{#subobject:b38f69|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:f3a095|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/24/26/4293.long Abou-Alfa et al. 2006b]
+|[https://doi.org/10.1200/jco.2005.01.3441 Abou-Alfa et al. 2006b]
-|{{#subobject:xx|ToDo=1}}
+|2002-2003
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa0708857 Llovet et al. 2008 (SHARP)]
+|[https://doi.org/10.1056/NEJMoa0708857 Llovet et al. 2008 (SHARP)]
-|2005-2006
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-328-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
+|2005-03-10 to 2006-04-11
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[Hepatocellular_carcinoma_-_null_regimens#Placebo_2|Placebo]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>Median OS: 10.7 vs 7.9 mo<br>(HR 0.69, 95% CI 0.55-0.87)
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2808%2970285-7/fulltext Cheng et al. 2008 (Sorafenib AP)]
+|[https://doi.org/10.1016/S1470-2045%2808%2970285-7 Cheng et al. 2008 (Sorafenib AP)]
 |2005-2007
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[Hepatocellular_carcinoma_-_null_regimens#Placebo_2|Placebo]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 6.5 vs 4.2 mo<br>(HR 0.68, 95% CI 0.50-0.93)
 |-
-|[http://theoncologist.alphamedpress.org/content/14/1/70.long Pinter et al. 2009]
+|[https://doi.org/10.1634/theoncologist.2008-0191 Pinter et al. 2009]
-|
+|2006-2007
 | style="background-color:#ffffbe" |Retrospective
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[http://link.springer.com/article/10.1007%2Fs12032-013-0655-z Abdel-Rahman et al. 2013]
+|[https://doi.org/10.1200/jco.2012.45.8372 Cheng et al. 2013 (SUN 1170)]
-|{{#subobject:xx|ToDo=1}}
+|2008-2010
-| style="background-color:#1a9851" |Randomized Phase II (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Capecitabine_monotherapy|Capecitabine]]
+|[[Hepatocellular_carcinoma_-_historical#Sunitinib_monotherapy|Sunitinib]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#1a9850" |Superior OS<br>Median OS: 10.2 vs 7.9 mo<br>(HR 0.77, 95% CI 0.67-0.88)
 |-
 |[https://doi.org/10.1200/JCO.2012.48.4410 Johnson et al. 2013 (BRISK-FL)]
 |2009-2011
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Brivanib
+|[[#Brivanib_monotherapy_999|Brivanib]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS (primary endpoint)
-|-
-|[https://doi.org/10.1200/jco.2012.45.8372 Cheng et al. 2013 (SUN 1170)]
-|{{#subobject:xx|ToDo=1}}
-| style="background-color:#1a9851" |Phase III (C)
-|[[Hepatocellular_carcinoma_-_historical#Sunitinib_monotherapy|Sunitinib]]
-| style="background-color:#1a9850" |Superior OS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279237/ Cainap et al. 2014 (LIGHT)]
 |NR
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Linifanib
+|[[#Linifanib_monotherapy_999|Linifanib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |[https://doi.org/10.1200/JCO.2013.53.7746 Zhu et al. 2014 (SEARCH)]
 |2009-2011
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Erlotinib & Sorafenib
+|[[#Erlotinib_.26_Sorafenib_999|Erlotinib & Sorafenib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |[https://doi.org/10.1093/annonc/mdw054 Koeberle et al. 2016 (SAKK 77/08; SASL 29)]
 |2009-2013
-| style="background-color:#1a9851" |Randomized Phase II (C)
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|Everolimus & Sorafenib
+|[[#Everolimus_.26_Sorafenib_999|Everolimus & Sorafenib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS3
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30683-6/fulltext Vilgrain et al. 2017 (SARAH)]
+|[https://link.springer.com/article/10.1007/s12032-013-0655-z Abdel-Rahman et al. 2013]
-|{{#subobject:xx|ToDo=1}}
+|2010-2011
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|[[#Radioembolization|SIRT]]
+|[[Hepatocellular_carcinoma_-_historical#Capecitabine_monotherapy|Capecitabine]]
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 7.1 vs 5.1 mo<br>(HR 0.42, 95% CI 0.21-0.85)
+|-
+|[https://doi.org/10.1016/s2468-1253(18)30078-5 Kudo et al. 2018 (SILIUS)]
+|2010-2014
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#HAI_Cisplatin_.26_Fluorouracil_.28CF.29_.26_Sorafenib_999|HAI CF & Sorafenib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735405/ Abou-Alfa et al. 2019 (CALGB 80802)]
+|2010-2015
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Doxorubicin_.26_Sorafenib_999|Doxorubicin & Sorafenib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |[https://doi.org/10.1200/JCO.2017.76.0892 Chow et al. 2018 (SIRveNIB)]
-|{{#subobject:xx|ToDo=1}}
+|2010-2016
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Radioembolization|SIRT]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://doi.org/10.1016/s2468-1253(18)30078-5 Kudo et al. 2018 (SILIUS)]
+|[https://doi.org/10.1016/j.jhep.2019.04.021 Jouve et al. 2019 (PRODIGE-11)]
-|2010-2014
+|2010-NR in abstract
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|HAI CF & Sorafenib
+|[[#Pravastatin_.26_Sorafenib_999|Pravastatin & Sorafenib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.journal-of-hepatology.eu/article/S0168-8278(18)32580-7/fulltext Park et al. 2018 (STAH)]
+|[https://doi.org/10.1016/S1470-2045(17)30683-6 Vilgrain et al. 2017 (SARAH)]
-|{{#subobject:xx|ToDo=1}}
+|2011-2015
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Sorafenib & TACE
+|[[#Radioembolization|SIRT]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735405/ Abou-Alfa et al. 2019 (CALGB 80802)]
+|[https://doi.org/10.1016/j.jhep.2018.11.029 Park et al. 2018 (STAH)]
-|2010-2015
+|2013-2015
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Doxorubicin & Sorafenib
+|[[#TACE_.26_Sorafenib_999|Sorafenib & TACE]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30207-1/fulltext Kudo et al. 2018 (REFLECT)]
+|[https://doi.org/10.1016/S0140-6736(18)30207-1 Kudo et al. 2018 (REFLECT)]
 |2013-2015
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Lenvatinib_monotherapy|Lenvatinib]]
 | style="background-color:#eeee01" |Non-inferior OS
+|-
+|[https://doi.org/10.1016/s1470-2045(21)00604-5 Yau et al. 2021 (CheckMate 459)]
+|2016-01-11 to 2017-05-24
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Hepatocellular_carcinoma_-_historical#Nivolumab_monotherapy|Nivolumab]]
+| style="background-color:#fee08b" |Might have inferior OS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512278/ He et al. 2019 (HCC-S021)]
+|2016-04-01 to 2017-10-10
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#HAIC_.26_Sorafenib|SoraHAIC]]
+| style="background-color:#d73027" |Inferior OS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445562/ Qin et al. 2021]
+|2016-2018
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Donafenib_monotherapy|Donafenib]]
+| style="background-color:#fc8d59" |Seems to have inferior OS
+|-
+|[https://doi.org/10.1200/jco.21.01963 Lyu et al. 2021 (FOHAIC-1)]
+|2017-2020
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#HAI_FOLFOX_888|HAI FOLFOX]]
+| style="background-color:#d73027" |Inferior OS
+|-
+| rowspan="2" |[https://doi.org/10.1056/EVIDoa2100070 Abou-Alfa et al. 2022 (HIMALAYA)]
+| rowspan="2" |2017-2019
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
+| style="background-color:#d73027" |Inferior OS
+|-
+|2. [[#Durvalumab_monotherapy|Durvalumab]]
+| style="background-color:#eeee01" |Non-inferior OS (secondary endpoint)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10557031/ Qin et al. (RATIONALE-301)]
+|2017-12-27 to 2019-10-02
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Tislelizumab_monotherapy|Tislelizumab]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
 |-
 |[https://doi.org/10.1056/nejmoa1915745 Finn et al. 2020 (IMbrave150)]
-|2018-2019
+|2018-03-15 to 2019-01-30
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Atezolizumab_.26_Bevacizumab|Atezolizumab & Bevacizumab]]
+|[[#Atezolizumab_.26_Bevacizumab_2|Atezolizumab & Bevacizumab]]
+| style="background-color:#d73027" |Inferior OS
+|-
+| rowspan="2" |[https://doi.org/10.1016/s1470-2045(22)00326-6 Kelley et al. 2022 (COSMIC-312)]
+| rowspan="2" |2018-2020
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Cabozantinib_.26_Atezolizumab_333|Cabozantinib & Atezolizumab]]
+| style="background-color:#fc8d59" |Seems to have inferior PFS<sup>1</sup><br><br>Did not meet co-primary endpoint of OS<sup>1</sup>
+|-
+|2. [[#Cabozantinib_monotherapy_666|Cabozantinib]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+|[https://doi.org/10.1016/s1470-2045(21)00252-7 Ren et al. 2021 (ORIENT-32)]
+|2019-02-11 to 2020-01-15
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#IBI-305_.26_Sintilimab_777|IBI-305 & Sintilimab]]
 | style="background-color:#d73027" |Inferior OS
+|-
+|[https://doi.org/10.1016/s0140-6736(23)00961-3 Qin et al. 2023 (CARES-310)]
+|2019-06-28 to 2021-3-24
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Apatinib_.26_Camrelizumab|Apatinib & Camrelizumab]]
+| style="background-color:#d73027" |Inferior PFS/OS
 |-
 |}
-====Chemotherapy====
+''<sup>1</sup>Reported efficacy for COSMIC-312 is based on the 2024 update.''<br>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Sorafenib (Nexavar)]] 400 mg PO twice per day
-**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
 '''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====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
+</div></div>
 ===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. [https://doi.org/10.1200/jco.2005.01.3441 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16908937/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa0708857 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18650514/ PubMed] [https://clinicaltrials.gov/study/NCT00105443 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. [https://doi.org/10.1016/j.jhep.2012.06.014 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22727733/ PubMed]
+#'''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. [https://doi.org/10.1016/S1470-2045%2808%2970285-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19095497/ PubMed] [https://clinicaltrials.gov/study/NCT00492752 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. [https://doi.org/10.1016/j.ejca.2011.12.006 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22240282/ PubMed]
+#'''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. [https://doi.org/10.1634/theoncologist.2008-0191 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19144684/ PubMed]
+#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. [https://link.springer.com/article/10.1007/s12032-013-0655-z link to original article] [https://pubmed.ncbi.nlm.nih.gov/23824645/ PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2012.48.4410 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23980084/ PubMed] [https://clinicaltrials.gov/study/NCT00858871 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. [https://doi.org/10.1200/jco.2012.45.8372 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24081937/ PubMed] [https://clinicaltrials.gov/study/NCT00699374 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. [https://doi.org/10.1200/JCO.2013.54.3298 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279237/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25488963/ PubMed] [https://clinicaltrials.gov/study/NCT01009593 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. [https://doi.org/10.1200/JCO.2013.53.7746 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25547503/ PubMed] [https://clinicaltrials.gov/study/NCT00901901 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. [https://doi.org/10.1093/annonc/mdw054 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26884590/ PubMed] [https://clinicaltrials.gov/study/NCT01005199 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. [https://doi.org/10.1016/S1470-2045(17)30683-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29107679/ PubMed] [https://clinicaltrials.gov/study/NCT01482442 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. [https://doi.org/10.1016/S0140-6736(18)30207-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29433850/ PubMed] [https://clinicaltrials.gov/study/NCT01761266 NCT01761266]
+#'''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. [https://doi.org/10.1200/JCO.2017.76.0892 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29498924/ PubMed] [https://clinicaltrials.gov/study/NCT01135056 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. [https://doi.org/10.1016/s2468-1253(18)30078-5 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29631810/ PubMed] [https://clinicaltrials.gov/study/NCT01214343 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. [https://doi.org/10.1016/j.jhep.2018.11.029 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30529387/ PubMed] [https://clinicaltrials.gov/study/NCT01829035 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. [https://doi.org/10.1016/j.jhep.2019.04.021 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31125576/ PubMed] [https://clinicaltrials.gov/study/NCT01075555 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. [https://doi.org/10.1001/jamaoncol.2019.0250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512278/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31070690/ PubMed] [https://clinicaltrials.gov/study/NCT02774187 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. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2749258 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735405/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31486832/ PubMed] [https://clinicaltrials.gov/study/NCT01015833 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. [https://doi.org/10.1056/nejmoa1915745 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32402160/ PubMed] [https://clinicaltrials.gov/study/NCT03434379 NCT03434379]
+##'''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. [https://doi.org/10.1016/j.jhep.2021.11.030 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34902530/ PubMed]
+#'''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. [https://doi.org/10.1016/s1470-2045(21)00252-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34143971/ PubMed] [https://clinicaltrials.gov/study/NCT03794440 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. [https://doi.org/10.1200/jco.21.00163 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445562/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34185551/ PubMed]
+#'''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. [https://doi.org/10.1016/s1470-2045(21)00604-5 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34914889/ PubMed] [https://clinicaltrials.gov/study/NCT02576509 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. [https://doi.org/10.1200/jco.21.01963 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34905388/ PubMed] [https://clinicaltrials.gov/study/NCT03164382 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. [https://doi.org/10.1016/s1470-2045(22)00326-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35798016/ PubMed] [https://clinicaltrials.gov/study/NCT03755791 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. [https://doi.org/10.1016/s2468-1253(23)00454-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38364832/ PubMed]
+#'''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. [https://doi.org/10.1016/s0140-6736(23)00961-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37499670/ PubMed] [https://clinicaltrials.gov/study/NCT03764293 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 Evidence. 2022 Aug;1(8):EVIDoa2100070. Epub 2022 Jun 6. [https://doi.org/10.1056/EVIDoa2100070 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38319892/ PubMed] [https://clinicaltrials.gov/study/NCT03298451 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. [https://doi.org/10.1016/j.annonc.2024.02.005 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38382875/ PubMed]
+#'''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. [https://doi.org/10.1001/jamaoncol.2023.4003 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10557031/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37796513/ PubMed] [https://clinicaltrials.gov/study/NCT03412773 NCT03412773]
+#'''CheckMate 9DW:''' [https://clinicaltrials.gov/study/NCT04039607 NCT04039607]
+#'''RTOG 1112:''' [https://clinicaltrials.gov/study/NCT01730937 NCT01730937]
-#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. [http://jco.ascopubs.org/content/24/26/4293.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16908937 PubMed]
+==Tislelizumab monotherapy {{#subobject:ti297d|Regimen=1}}==
-#'''SHARP:''' Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa0708857 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18650514 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-##'''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. [https://www.journal-of-hepatology.eu/article/S0168-8278(12)00440-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/22727733 PubMed]
+===Regimen {{#subobject:4rgbv5|Variant=1}}===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2808%2970285-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19095497 PubMed] NCT00492752
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-##'''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. [https://www.ejcancer.com/article/S0959-8049(11)01031-8/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22240282 PubMed]
+! style="width: 20%" |Study
-#'''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. [http://theoncologist.alphamedpress.org/content/14/1/70.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/19144684 PubMed]
+! style="width: 20%" |Dates of enrollment
-#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. [http://link.springer.com/article/10.1007%2Fs12032-013-0655-z link to original article] [https://pubmed.ncbi.nlm.nih.gov/23824645 PubMed]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-#'''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. [https://doi.org/10.1200/JCO.2012.48.4410 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23980084 PubMed]
+! style="width: 20%" |Comparator
-<!-- Presented at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011. -->
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-#'''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. [https://doi.org/10.1200/jco.2012.45.8372 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24081937 PubMed]
+|-
-#'''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. [https://doi.org/10.1200/JCO.2013.54.3298 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279237/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25488963 PubMed]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10557031/ Qin et al. (RATIONALE-301)]
-#'''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. [https://doi.org/10.1200/JCO.2013.53.7746 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25547503 PubMed]
+|2017-12-27 to 2019-10-02
-#'''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. [https://doi.org/10.1093/annonc/mdw054 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26884590 PubMed] NCT01005199
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30683-6/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29107679 PubMed]
+|[[#Sorafenib_monotherapy|Sorafenib]]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30207-1/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29433850 PubMed]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)<br>Median OS: 15.95 vs 14.1 mo<br>(HR 0.85, 95.003% CI 0.71-1.02)
-#'''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. [https://doi.org/10.1200/JCO.2017.76.0892 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29498924 PubMed]
+|-
-#'''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. [https://doi.org/10.1016/s2468-1253(18)30078-5 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29631810 PubMed]
+|}
-#'''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. [https://www.journal-of-hepatology.eu/article/S0168-8278(18)32580-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30529387 PubMed] NCT01829035
+<div class="toccolours" style="background-color:#b3e2cd">
-#'''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 Sep 5. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2749258 Link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735405/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31486832 PubMed]
+====Immunotherapy====
-#'''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. [https://doi.org/10.1056/nejmoa1915745 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32402160 PubMed]
+*[[Tislelizumab (Baizean)]] 200 mg IV once on day 1
+'''21-day cycles'''
+</div></div>
+===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. [https://doi.org/10.1001/jamaoncol.2023.4003 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10557031/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37796513/ PubMed] [https://clinicaltrials.gov/study/NCT03412773 NCT03412773]
-==TACE, then 5-FU {{#subobject:572d2d|Regimen=1}}==
+=Advanced or metastatic disease, second-line=
-{| class="wikitable" style="float:right; margin-left: 5px;"
+==Pembrolizumab monotherapy {{#subobject:a15f9f|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, q3wk {{#subobject:0adfd3|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s1470-2045(18)30351-6 Zhu et al. 2018 (KEYNOTE-224)]
+|2016-06-07 to 2017-02-09
+| style="background-color:#91cf61" |Phase 2 (RT)
+|
+|ORR: 17% (95% CI, 11–26)
+|-
+|[https://doi.org/10.1200/jco.19.01307 Finn et al. 2020 (KEYNOTE-240)]
+|2016-05-31 to 2017-11-23
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
+| style="background-color:#91cf60" |Seems to have superior OS (co-primary endpoint)<br>Median OS: 13.9 vs 10.6 mo<br>(HR 0.78, 95% CI 0.61-0.998)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995104/ Qin et al. 2023 (KEYNOTE-394)]
+|2017-05-31 to 2019-12-11
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
+| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 14.6 vs 13 mo<br>(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.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*Sorafenib
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+'''21-day cycle for up to 35 cycles (2 years)'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, q6wk {{#subobject:0adfd3|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 400 mg IV once on day 1
+'''6-week cycles'''
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2018.36.15_suppl.3062 link to original article] [https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-new-dosing-regimen-pembrolizumab 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. [https://doi.org/10.1016/s1470-2045(18)30351-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29875066/ PubMed] [https://clinicaltrials.gov/study/NCT02702414 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. [https://doi.org/10.1016/j.ejca.2022.02.009 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35364421/ PubMed]
+#'''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. [https://doi.org/10.1200/jco.19.01307 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31790344/ PubMed] [https://clinicaltrials.gov/study/NCT02702401 NCT02702401]
+#'''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. [https://doi.org/10.1200/JCO.22.00620 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995104/ link to PMC article] '''contais dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/36455168/ PubMed] [https://clinicaltrials.gov/study/NCT03062358 NCT03062358]
+==Ramucirumab monotherapy {{#subobject:bc251c|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:981bb2|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(15)00050-9 Zhu et al. 2015 (REACH-HCC)]
+|2010-2013
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://doi.org/10.1016/S1470-2045(18)30937-9 Zhu et al. 2019 (REACH-2)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-140-1 <span style="color:white;">ESMO-MCBS (1)</span>]'''
+|-
+|} -->
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 8.5 vs 7.3 mo<br>(HR 0.71, 95% CI 0.53-0.95)
 |-
-|[[#top|back to top]]
 |}
-TACE, then 5-FU: '''<u>T</u>'''rans-'''<u>A</u>'''rterial '''<u>C</u>'''hemo'''<u>E</u>'''mbolization followed by '''<u>5</u>'''-'''<u>F</u>'''luoro'''<u>U</u>'''racil
+''Note: REACH should not be confused for the trial of the same name in CLL.''
-===Protocol {{#subobject:b440c9|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="width: 100%; text-align:center;"
+====Targeted therapy====
-! style="width: 25%" |Study
+*[[Ramucirumab (Cyramza)]] 8 mg/kg IV once on day 1
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+'''14-day cycles'''
-! style="width: 25%" |Comparator
+</div></div>
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+===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. [https://doi.org/10.1016/S1470-2045(15)00050-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26095784/ PubMed] [https://clinicaltrials.gov/study/NCT01140347 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. [https://doi.org/10.1136/esmoopen-2020-000797 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7437873/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32817068/ PubMed]
+#'''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. [https://doi.org/10.1016/S1470-2045(18)30937-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30665869/ PubMed] [https://clinicaltrials.gov/study/NCT02435433 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. [https://doi.org/10.1136/esmoopen-2020-000797 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7437873/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32817068/ PubMed]
+==Regorafenib monotherapy {{#subobject:3c587e|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1c2329|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363838/ Kawata et al. 2001]
+|[https://doi.org/10.1016/S0140-6736(16)32453-9 Bruix et al. 2016 (RESORCE)]
-| style="background-color:#1a9851" |Phase III (C)
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|TACE, then 5-FU & Pravastatin
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-116-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-| style="background-color:#d73027" |Inferior OS
 |-
+|} -->
+|2013-05-14 to 2015-12-31
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 10.6 vs 7.8 mo<br>(HR 0.63, 95% CI 0.50-0.79)
 |}
-====Chemotherapy, TACE portion====
+''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.''
+<div class="toccolours" style="background-color:#fdcdac">
-*[[TACE]] as follows:
+====Prior treatment criteria====
-**[[Doxorubicin (Adriamycin)]] 30 mg IA once on day 1, '''given first'''
+*Sorafenib
-**Gelatin-sponge particles and ethyl ester of poppyseed oil fatty acids containing 38% iodine by weight (Lipiodol; AndreGelbe Laboratories, Paris, France)
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-'''One treatment, followed in 2 weeks by:'''
+====Targeted therapy====
+*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21
-====Chemotherapy====
+'''28-day cycles'''
+</div></div>
-*[[Fluorouracil (5-FU)]] 200 mg PO once per day
-'''2-month course'''
 ===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. [https://doi.org/10.1016/S0140-6736(16)32453-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27932229/ PubMed] [https://clinicaltrials.gov/study/NCT01774344 NCT01774344]
-#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. [https://www.nature.com/articles/6691716 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363838/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/11286466 PubMed]
 =Subsequent lines of therapy=
-==Cabozantinib monotherapy {{#subobject:a20f66 |Regimen=1}}==
+==Apatinib monotherapy {{#subobject:ao594c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:913ap2|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/s2468-1253(21)00109-6 Qin et al. 2021 (AHELP)]
+|2014-2017
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Hepatocellular_carcinoma_-_null_regimens#Placebo|Placebo]]
+| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 8.7 vs 6.8 mo<br>(HR 0.79, 95% CI 0.62-0.998)
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Apatinib (Aitan)]] 750 mg PO once per day on days 1 to 28
+'''28-day cycles'''
+</div></div>
+===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. [https://doi.org/10.1016/s2468-1253(21)00109-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33971141/ PubMed] [https://clinicaltrials.gov/study/NCT02329860 NCT02329860]
+==Cabozantinib monotherapy {{#subobject:a20f66 |Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:0eb568 |Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1717002 Abou-Alfa et al. 2018 (CELESTIAL)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7523244/ Abou-Alfa et al. 2018 (CELESTIAL)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-115-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
 |2013-2017
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
+|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_4|Placebo]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 10.2 vs 8 mo<br>(HR 0.76, 95% CI 0.63-0.92)
 |-
 |}
-====Chemotherapy====
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Cabozantinib (Cometriq)]] 60 mg PO once per day
+====Targeted therapy====
+*[[Cabozantinib (Cometriq)]] 60 mg PO once per day on days 1 to 28
-'''Continued indefinitely'''
+'''28-day cycles'''
+</div></div>
+===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. [https://doi.org/10.1056/NEJMoa1717002 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7523244/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29972759/ PubMed] [https://clinicaltrials.gov/study/NCT01908426 NCT01908426]
+#'''Retrospective:''' 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. [https://www.sciencedirect.com/science/article/pii/S0923753420393236 link to original article]
+==Camrelizumab monotherapy {{#subobject:c701c3|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, q2wk {{#subobject:d1dde0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(20)30011-5 Qin et al. 2020 (SHR-1210-II/III-HCC)]
+|2016-2017
+| style="background-color:#91cf61" |Randomized Phase 2 (E-esc)
+|[[#Camrelizumab_monotherapy|Camrelizumab]]; q3wk
+| style="background-color:#d3d3d3" |Not reported
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Camrelizumab (AiRuiKa)]] 3 mg/kg IV once on day 1
+'''14-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, q3wk {{#subobject:d1hg20|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(20)30011-5 Qin et al. 2020 (SHR-1210-II/III-HCC)]
+|2016-2017
+| style="background-color:#91cf61" |Randomized Phase 2 (E-de-esc)
+|[[#Camrelizumab_monotherapy|Camrelizumab]]; q2wk
+| style="background-color:#d3d3d3" |Not reported
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Camrelizumab (AiRuiKa)]] 3 mg/kg IV once on day 1
+'''21-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1016/S1470-2045(20)30011-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32112738/ PubMed] [https://clinicaltrials.gov/study/NCT02989922 NCT02989922]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1717002 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29972759 PubMed]
 ==Doxorubicin monotherapy {{#subobject:5e66ea|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:f77e8e|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://doi.org/10.1200/JCO.2012.44.5643 Qin et al. 2013 (EACH)]
-| style="background-color:#1a9851" |Phase III (C)
+|2007-2009
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#FOLFOX4_2|FOLFOX4]]
-| style="background-color:#fee08b" |Trend toward inferior OS
+| style="background-color:#fee08b" |Might have inferior OS
 |-
-|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30040-8/fulltext Merle et al. 2019 (RELIVE)]
+|[https://doi.org/10.1016/S2468-1253(19)30040-8 Merle et al. 2019 (RELIVE)]
-| style="background-color:#1a9851" |Phase III (C)
+|2012-2017
+| style="background-color:#1a9851" |Phase 3 (C)
 |Doxorubicin-loaded nanoparticles
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''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."''
+''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."''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1200/JCO.2012.44.5643 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23980077/ PubMed] [https://clinicaltrials.gov/study/NCT00471965 NCT00471965]
-#'''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. [https://doi.org/10.1200/JCO.2012.44.5643 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23980077 PubMed]
+#'''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. [https://doi.org/10.1016/S2468-1253(19)30040-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30954567/ PubMed] [https://clinicaltrials.gov/study/NCT01655693 NCT01655693]
-#'''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. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30040-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30954567 PubMed]
 ==FOLFOX4 {{#subobject:dd7aac|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+FOLFOX4: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-|-
+<div class="toccolours" style="background-color:#eeeeee">
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 ===Regimen {{#subobject:bf1b55|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://doi.org/10.1200/JCO.2012.44.5643 Qin et al. 2013 (EACH)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|2007-2009
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 |[[#Doxorubicin_monotherapy_2|Doxorubicin]]
-| style="background-color:#d9ef8b" |Trend towards superior OS
+| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 6.4 vs 5.0 mo<br>(HR 0.80, 95% CI 0.63-1.02)
 |}
-''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 < 2.5x ULN, T bil < than 1.5x ULN, INR < 1.5 ULN; patients with AST and ALT < 5x ULN were included if T bili was within normal limits).''
+''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).''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given second''', then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
 '''14-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1200/JCO.2012.44.5643 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23980077/ PubMed] [https://clinicaltrials.gov/study/NCT00471965 NCT00471965]
+==Ipilimumab & Nivolumab {{#subobject:7391fe|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1c2329|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7530824/ Yau et al. 2020 (CheckMate 040<sub>combo</sub>)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-251-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
+|2016-01-04 to 2016-09-26
+| style="background-color:#91cf61" |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.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div></div>
+===References===
+#'''CheckMate 040<sub>combo</sub>:''' 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. [https://doi.org/10.1001/jamaoncol.2020.4564 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7530824/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33001135/ PubMed] [https://clinicaltrials.gov/study/NCT01658878 NCT01658878]
-#'''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. [https://doi.org/10.1200/JCO.2012.44.5643 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23980077 PubMed]
+==Lenvatinib monotherapy {{#subobject:blen19|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Nivolumab monotherapy {{#subobject:7391fe|Regimen=1}}==
+===Regimen {{#subobject:a9obns|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.clinicaltrials.gov/study/NCT04770896 Awaiting publication (IMbrave251)]
+|2021-ongoing
+| style="background-color:#1a9851" |Phase 3 (C)
+|1a. [[#Lenvatinib_.26_Atezolizumab_666|Lenvatinib & Atezolizumab]]<br>1b. [[#Sorafenib_.26_Atezolizumab_666|Sorafenib & Atezolizumab]]
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of OS
 |-
-|[[#top|back to top]]
 |}
+''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.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*Exposure to [[#Atezolizumab_.26_Bevacizumab_2|Atezolizumab & Bevacizumab]], with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div></div>
+===References===
+#'''IMbrave251:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT04770896 NCT04770896]
+==Nivolumab monotherapy {{#subobject:7391fe|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, 3 mg/kg {{#subobject:1c2329|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 25%"|Study
-! style="width: 25%" |Years of enrollment
+!style="width: 25%"|Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]] '''(dose-expansion phase)'''
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31046-2/abstract El-Khoueiry et al. 2017 (CheckMate 040)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7539326/ El-Khoueiry et al. 2017 (CheckMate 040)]
 |2012-2016
-| style="background-color:#91cf61" |Phase I/II (RT)
+| style="background-color:#91cf61" |Phase 1/2 (RT)
-| style="background-color:#88419d; color:white " |ORR: 20% (95% CI, 15–26)
+| style="background-color:#88419d; color:white " |ORR (dose-expansion phase): 20% (95% CI, 15–26)
 |-
 |}
-''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 < 100 IU/mL). 68% of patients in the dose expansion phase received prior sorafenib therapy.''
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
 '''14-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 240 mg {{#subobject:cc97e9|Variant=1}}===
@@ Line 1,217: / Line 1,775: @@
 |-
 |}
-''This is the FDA-recommended dose. See [https://hemonc.org/wiki/Hepatocellular_carcinoma#Nivolumab_monotherapy first line therapy] above.''
+''Note: This is the FDA-recommended dose; we are not aware of a published trial using this dose in this context.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
 '''14-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #3, 480 mg {{#subobject:2e37a4|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 1,229: / Line 1,787: @@
 |-
 |}
-''This is the FDA-recommended dose; we are not aware of a published trial using this dose in this context.''
+''Note: This is the FDA-recommended dose; we are not aware of a published trial using this dose in this context.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
 '''28-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1016/S0140-6736(17)31046-2 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7539326/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28434648/ PubMed] [https://clinicaltrials.gov/study/NCT01658878 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. [https://doi.org/10.1016/j.annonc.2023.12.008 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38151184/ PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31046-2/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28434648 PubMed]
+==Sorafenib monotherapy {{#subobject:b3hy19|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Pembrolizumab monotherapy {{#subobject:a15f9f|Regimen=1}}==
+===Regimen {{#subobject:f3b9os|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen 1 {{#subobject:0adfd3|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-''All patients were Child-Pugh class A. 21.5-25.9% had hepatitis B infection and 15.5-15.6% of patients had hepatitic C infection.''
-{| class="wikitable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30351-6/fulltext Zhu et al. 2018 (KEYNOTE-224)]
+|[https://www.clinicaltrials.gov/study/NCT04770896 Awaiting publication (IMbrave251)]
-|2016-2017
+|2021-ongoing
-| style="background-color:#91cf61" |Phase II (RT)
+| style="background-color:#1a9851" |Phase 3 (C)
-|
+|1a. [[#Lenvatinib_.26_Atezolizumab_666|Lenvatinib & Atezolizumab]]<br>1b. [[#Sorafenib_.26_Atezolizumab_666|Sorafenib & Atezolizumab]]
-|ORR: 17% (95% CI, 11–26)
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of OS
-|-
-|[https://doi.org/10.1200/jco.19.01307 Finn et al. 2020 (KEYNOTE-240)]
-|2016-2017
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#d9ef8b" |Might have superior OS
 |-
 |}
-====Immunotherapy====
+''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.''
+<div class="toccolours" style="background-color:#fdcdac">
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+====Prior treatment criteria====
+*Exposure to [[#Atezolizumab_.26_Bevacizumab_2|Atezolizumab & Bevacizumab]], with progression
-'''21-day cycle for up to 35 cycles (2 years)'''
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
+'''21-day cycles'''
+</div></div>
 ===References===
+#'''IMbrave251:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT04770896 NCT04770896]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30351-6/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29875066 PubMed]
+==Tislelizumab monotherapy {{#subobject:13vc7d|Regimen=1}}==
-#'''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. [https://doi.org/10.1200/jco.19.01307 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31790344 PubMed] NCT02702401
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:6klcv5|Variant=1}}===
-===Regimen 2 {{#subobject:0adfd3|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-{| class="wikitable" style="color:white; background-color:#404040"
+!style="width: 33%"|Study
-|<small>'''FDA-recommended dose'''</small>
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://clinicaltrials.gov/study/NCT03419897 Awaiting publication (RATIONALE-208)]
+|2018-NR
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Tislelizumab (Baizean)]] 200 mg IV once on day 1
-*[[Pembrolizumab (Keytruda)]] 400 mg IV once on day 1
+'''21-day cycles'''
+</div></div>
-'''6 week cycle'''
 ===References===
+# '''RATIONALE-208:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03419897 NCT03419897]
-#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. [https://ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.3062 link to original article] [https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-new-dosing-regimen-pembrolizumab FDA approval]
-==Ramucirumab monotherapy {{#subobject:bc251c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:981bb2|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00050-9/fulltext Zhu et al. 2015 (REACH-HCC)]
-|2010-2013
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#ffffbf" |Did not meet primary outcome of OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30937-9/fulltext Zhu et al. 2019 (REACH-2)]
-|2015-2017
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note that REACH should not be confused for the trial of the same name in CLL.''
-====Chemotherapy====
-*[[Ramucirumab (Cyramza)]] 8 mg/kg IV once on day 1
-'''14-day cycles'''
-===References===
-#'''REACH:''' 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00050-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26095784 PubMed] NCT01140347
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30937-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30665869 PubMed]
-==Regorafenib monotherapy {{#subobject:3c587e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:1c2329|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32453-9/fulltext Bruix et al. 2016 (RESORCE)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[Hepatocellular_carcinoma_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |Superior OS
-|}
-''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.''
-====Chemotherapy====
-*[[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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32453-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/27932229 PubMed]
-<br />
-== Camrelizumab [edit | edit source] ==
-{| class="wikitable"
-|[[Hepatocellular carcinoma#top|back to top]]
-|}
-=== Regimen[edit | edit source] ===
-{| class="wikitable"
-!Study
-![[Levels of Evidence#Evidence|Evidence]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30011-5/fulltext Qin et al.]
-|Phase II
-|}
-==== Immunotherapy[edit | edit source] ====
-* Camrelizumab 3 mg/kg intravenously every 2 or 3 weeks
-Indefinitely until toxicity or progression
-=== References[edit | edit source] ===
-# 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 April; 21(4)571-580. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30011-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/32112738/ PubMed]
-=Investigational agents=
-*[[Refametinib (BAY 869766)]]
 [[Category:Hepatocellular carcinoma regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Hepatobiliary cancers]]

Difference between revisions of "Hepatocellular carcinoma"

Latest revision as of 17:51, 23 June 2024

Guidelines

AASLD

ASCO

ESMO

French Intergroup

ISRS

NCCN

SITC

TOS/ESMO

Adjuvant therapy

Atezolizumab & Bevacizumab

Regimen

Preceding treatment

Immunotherapy

Targeted therapy

References

TACE monotherapy

Regimen variant #1, doxorubicin-based

Preceding treatment

Local therapy

Regimen variant #2, carboplatin, epirubicin, mitomycin-based

Preceding treatment

Local therapy

References

Local therapy for advanced disease

Axitinib & TACE

Regimen

Targeted therapy

Local therapy

References

Lenvatinib & TACE

Regimen

Targeted therapy

Local therapy

References

DEB-TACE

Regimen

Eligibility criteria

Local therapy

References

FOLFOX-HAIC

Regimen variant #1, longer duration

Chemotherapy

Regimen variant #2, shorter duration

Preceding treatment

Chemotherapy

References

FOFLFOX-HAIC & Sorafenib

Regimen

Eligibility criteria

Chemotherapy

Targeted therapy

References

Radioembolization

Regimen

Synopsis

Radiotherapy

References

TACE monotherapy

Regimen

Synopsis

Local therapy

Subsequent treatment

References

TACE, then 5-FU

Induction

Local therapy

Consolidation

Chemotherapy

References

First-line therapy for advanced or metastatic disease

Apatinib & Camrelizumab

Regimen

Immunotherapy

Targeted therapy

References

Atezolizumab & Bevacizumab

Regimen

Regimen variant #1, 50 mg/m²

Regimen variant #2, 60 mg/m² x 6

Regimen variant #3, 60 mg/m² x 9

Regimen variant #4, 60 mg/m², indefinite

Regimen variant #5, 60 --> 75 mg/m²