Hepatocellular carcinoma

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Neeta K. Venepalli, MD, MBA
Chicago, IL

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22 regimens on this page
22 variants on this page

Contents


Guidelines

ESMO

NCCN

Local therapy

Concurrent TACE plus Sorafenib

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Regimen

Study Evidence Comparator Efficacy
Meyer et al. 2017 (TACE2) Phase III TACE plus placebo Did not meet primary outcome of improved PFS

This European study assessed the addition of concurrent sorafenib to DEB-TACE; patients had Child-Pugh A liver disease, and ECOG PS 0 or 1.

Chemotherapy

28-day cycles

References

  1. TACE2: Meyer T, Fox R, Ma YT, Ross P,J, 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 PubMed

TACE followed by Sorafenib

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Regimen

Study Evidence Comparator Efficacy
Kudo et al. 2011 Phase III TACE followed by placebo Did not meet primary outcome of improved TTP

This 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

28-day cycles

References

  1. 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 PubMed

Radioembolization

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Regimen

Study Evidence Comparator Efficacy
Vilgrain et al. 2017 (SARAH) Phase III Sorafenib Did not meet primary outcome of improved OS
Chow et al. 2018 (SIRveNIB) Phase III Sorafenib Did not meet primary outcome of improved 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.

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.

Chemotherapy

28-day cycles

References

  1. 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 Mar 2. [Epub ahead of print] link to original article PubMed
  2. 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. link to original article PubMed

Adjuvant therapy

Observation

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Regimen

Study Evidence Comparator Efficacy
Wang et al. 2018 (LCI-125-009) Phase III (C) TACE Seems to have inferior OS

No treatment after surgery.

Preceding treatment

  • Curative surgical resection

References

  1. 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 Feb 2. [Epub ahead of print] link to original article PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
Bruix et al. 2015 (STORM) Phase III (C) Sorafenib Seems not superior

No active antineoplastic treatment.

Preceding treatment

  • Resection or ablation

References

  1. STORM: Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, Cai J, Poon RT, Han KH, Tak WY, Lee HC, Song T, Roayaie S, Bolondi L, Lee KS, Makuuchi M, Souza F, Berre MA, Meinhardt G, Llovet JM; STORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015 Oct;16(13):1344-54. Epub 2015 Sep 8. link to original article PubMed

TACE

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TACE: Trans-Arterial Chemo-Embolization

Regimen

Study Evidence Comparator Efficacy
Wang et al. 2018 (LCI-125-009) Phase III (C) Observation Seems to have superior OS

Preceding treatment

  • Curative surgical resection

Chemotherapy

  • TACE (details to be completed)

References

  1. 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 Feb 2. [Epub ahead of print] link to original 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.

Bevacizumab monotherapy

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Regimen

Study Evidence Efficacy
Siegel et al. 2008 Phase II 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%).

Chemotherapy

14-day cycles

References

  1. 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 verified protocol link to PMC article PubMed

Capecitabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Abdel-Rahman et al. 2013 Randomized Phase II Sorafenib Inferior OS

Neither the primary outcome (progression-free survival) or secondary outcome (overall survival) were met.

Chemotherapy

21-day cycles

References

  1. 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. link to original article PubMed
  2. 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

Capecitabine & Bevacizumab

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Regimen

Study Evidence Efficacy
Hsu et al. 2010 Phase II ORR: 9%

Chemotherapy

21-day cycle for 6 or more cycles depending on response

References

  1. 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 verified protocol link to PMC article PubMed

CapeOx

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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda (Capecitabine), OXaliplatin

Regimen

Study Evidence Efficacy
Boige et al. 2007 (FFCD 03-03) Phase II DCR: 72% (95% CI, 57-83)

Chemotherapy

21-day cycles

References

  1. 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 verified protocol link to PMC article PubMed

CapeOx & Bevacizumab

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CapeOX & Bevacizumab: Capecitabine, OXaliplatin, Bevacizumab

Regimen

Study Evidence Efficacy
Sun et al. 2011 Phase II DCR: 77.5%

Chemotherapy

  • Capecitabine (Xeloda) 825 mg/m2 PO BID on days 1 to 14
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
  • 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

  1. 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 verified protocol PubMed

Doxorubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Gish et al. 2007 Phase III Nolatrexed Superior OS
Qin et al. 2013 (EACH) Phase III FOLFOX4 Trend towards 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).

Chemotherapy

21-day cycles

References

  1. 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 verified protocol PubMed
  2. 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 verified protocol PubMed

Erlotinib & Bevacizumab

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Regimen

Study Evidence Efficacy
Thomas et al. 2009 Phase II PFS16: 62.5%
Philip et al. 2011 Phase II ORR: 5% (95% CI, 0-23)

Patients in Thomas et al. 2009 could have up to one prior systemic treatment.

Chemotherapy

28-day cycles

References

  1. 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 verified protocol PubMed
  2. 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

Fluorouracil & Folinic acid

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Regimen

Study Evidence
Porta et al. 1995 Phase II ORR: 28% (95% CI, 10-46)

Chemotherapy

28-day cycles

References

  1. 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 PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Qin et al. 2013 (EACH) Phase III Doxorubicin Might have superior OS

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

14-day cycles

References

  1. 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 verified protocol PubMed

GemOx

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GemOx: Gemcitabine, Oxaliplatin

Regimen

Study Evidence Efficacy
Louafi et al. 2007 Phase II ORR: 18% (95% CI, 8–34)

Chemotherapy

14-day cycles, given until progression of disease, unacceptable toxicity, or patient choice

References

  1. 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 verified protocol PubMed
  2. 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

Lenvatinib monotherapy

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Regimen #1, 8 mg/d

Study Evidence Comparator Efficacy
Kudo et al. 2018 Phase III (E) Sorafenib Non-inferior OS

This dosing is intended for patients weighing less than 60 kg.

Chemotherapy

28-day cycles

Regimen #2, 12 mg/d

Study Evidence Comparator Efficacy
Kudo et al. 2018 Phase III (E) Sorafenib Non-inferior OS

This dosing is intended for patients weighing at least 60 kg.

Chemotherapy

28-day cycles

References

  1. 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 Feb 9. [Epub ahead of print] link to original article contains protocol PubMed

Nivolumab monotherapy

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Regimen

Study Evidence Efficacy
El-Khoueiry et al. 2017 (CheckMate 040) Phase I/II 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

14-day cycles

References

  1. CheckMate 040: El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, 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 protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
Llovet et al. 2008 (SHARP) Phase III (C) Sorafenib Inferior OS
Cheng et al. 2009 Phase III (C) Sorafenib No predetermined endpoint; seems to have inferior OS

No active antineoplastic treatment.

References

  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. link to original article contains verified protocol PubMed
  2. 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 verified protocol PubMed
    1. Subset 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 verified protocol PubMed

Sorafenib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Abou-Alfa et al. 2006 Phase II
Llovet et al. 2008 (SHARP) Phase III (E) Placebo Superior OS
Cheng et al. 2008 Phase III (E) Placebo Seems to have superior OS
Pinter et al. 2009 Retrospective
Abdel-Rahman et al. 2013 Randomized Phase II Capecitabine Superior OS
Johnson et al. 2013 (BRISK-FL) Phase III (C) Brivanib Inconclusive whether non-inferior
Cheng et al. 2013 (SUN 1170) Phase III (C) Sunitinib Superior OS
Cainap et al. 2014 (LIGHT) Phase III (C) Linifanib Seems not superior
Zhu et al. 2014 (SEARCH) Phase III (C) Erlotinib & Sorafenib Seems not superior
Vilgrain et al. 2017 (SARAH) Phase III SIRT Seems not superior
Kudo et al. 2018 Phase III (C) Lenvatinib Non-inferior OS

Chemotherapy

  • Sorafenib (Nexavar) 400 mg PO BID
    • Dose/schedule changes due to toxicity include 400 mg PO once per day, 400 mg PO every other day, 200 mg PO BID, 200 mg PO once per day

Given until progression of disease or unacceptable toxicity

References

  1. 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 verified protocol PubMed
  2. 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. link to original article contains verified protocol PubMed
  3. 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 verified protocol PubMed
    1. Subset 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 verified protocol PubMed
  4. 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
  5. 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
  6. 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 protocol PubMed
  7. 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
  8. 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 contains protocol link to PMC article PubMed
  9. 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 verified protocol PubMed
  10. 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 protocol PubMed
  11. 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 Feb 9. [Epub ahead of print] link to original article contains protocol PubMed

TACE, then 5-FU

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TACE, then 5-FU: Trans-Arterial ChemoEmbolization followed by 5-FluoroUracil

Regimen

Study Evidence Comparator Efficacy
Kawata et al. 2001 Phase III (C) TACE, then 5-FU & Pravastatin Inferior OS

Chemotherapy, TACE portion

  • Doxorubicin (Adriamycin) 30 mg IA once, given first
  • Gelatin-sponge particles and ethyl ester of poppyseed oil fatty acids containing 38% iodine by weight (Lipiodol; AndreGelbe Laboratories, Paris, France)

One course, followed in 2 weeks by:

Chemotherapy

2-month course

References

  1. 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 verified protocol link to PMC article PubMed

Subsequent lines of therapy

Doxorubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Qin et al. 2013 (EACH) Phase III FOLFOX4 Trend toward inferior 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 < 2.5x ULN, T bil < than 1.5x ULN, INR < 1.5 ULN; patients with AST and ALT < 5x ULN were included if T bil was within normal limits).

Chemotherapy

21-day cycles

References

  1. 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 verified protocol PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Qin et al. 2013 (EACH) Phase III Doxorubicin Trend towards superior 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 < 2.5x ULN, T bil < than 1.5x ULN, INR < 1.5 ULN; patients with AST and ALT < 5x ULN were included if T bil was within normal limits).

Chemotherapy

14-day cycles

References

  1. 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 verified protocol PubMed

Nivolumab monotherapy

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Regimen

Study Evidence Efficacy (dose expansion phase)
El-Khoueiry et al. 2017 (CheckMate 040) Phase I/II 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; 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.

Immunotherapy

14-day cycles

References

  1. CheckMate 040: El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, 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 protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
Zhu et al. 2015 (REACH) Phase III (C) Ramucirumab Did not meet primary outcome of improved overall survival
Bruix et al. 2016 (RESORCE) Phase III (C) Regorafenib Inferior OS
Zhu et al. 2014 (EVOLVE-1) Phase III (C) Everolimus Did not meet primary outcome of improved overall survival
Rimassa et al. 2018 (METIV-HCC) Phase III (C) Tivantinib Did not meet primary outcome of improved overall survival

No active antineoplastic treatment.

References

  1. 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. link to original article PubMed
  2. 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 protocol PubMed
  3. EVOLVE-1: Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, Poon RT, Blanc JF, Vogel A, Chen CL, Dorval E, Peck-Radosavljevic M, Santoro A, Daniele B, Furuse J, Jappe A, Perraud K, Anak O, Sellami DB, Chen LT. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014 Jul 2;312(1):57-67. link to original article PubMed
  4. METIV-HCC: Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, Rota Caremoli E, Porta C, Daniele B, Bolondi L, Mazzaferro V, Harris W, Damjanov N, Pastorelli D, Reig M, Knox J, Negri F, Trojan J, López López C, Personeni N, Decaens T, Dupuy M, Sieghart W, Abbadessa G, Schwartz B, Lamar M, Goldberg T, Shuster D, Santoro A, Bruix J. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018 Apr 3. [Epub ahead of print] link to original article PubMed

Regorafenib monotherapy

Regimen

Study Evidence Comparator Efficacy
Bruix et al. 2016 (RESORCE) Phase III Placebo Superior OS

The RESORCE study required patients with sorafenib tolerance > 400mg/day > 20 days of the last 28 days of treatment, and who were ECOS PG 0-1, and with Child-Pugh A status.

Chemotherapy

28 Day Cycles

References

  1. 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 protocol PubMed