Difference between revisions of "Hepatocellular carcinoma"
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# '''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. [http://ascopubs.org/doi/full/10.1200/JCO.2017.76.0892 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29498924 PubMed] | # '''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. [http://ascopubs.org/doi/full/10.1200/JCO.2017.76.0892 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29498924 PubMed] | ||
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## '''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/276 Project Data Sphere] | ## '''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/276 Project Data Sphere] | ||
− | ==TACE {{#subobject:50f9da|Regimen=1}}== | + | ==TACE monotherapy {{#subobject:50f9da|Regimen=1}}== |
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Revision as of 20:44, 7 February 2019
Section editor | |
---|---|
Neeta K. Venepalli, MD, MBA University of Illinois at Chicago Chicago, IL |
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. 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
ESMO
- 2018: Vogel et al. Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Older
- 2012: Verslype et al. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
NCCN
Local therapy
Axitinib & TACE
back to top |
Regimen
Study | Evidence |
---|---|
Chan et al. 2017 | Phase II |
Chemotherapy
- Axitinib (Inlyta) 5 mg PO twice per day, held before and after TACE
- TACE
References
- 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
DEB-TACE
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DEB-TACE: Drug-Eluting Bead Trans-Arterial Chemo-Embolization
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Brown et al. 2016 (MSK 07-099) | Randomized Phase II (E) | Bland embolization | Seems not superior |
Meyer et al. 2017 (TACE2) | Phase III (C) | DEB-TACE & Sorafenib | Did not meet primary outcome of improved PFS |
TACE2 assessed the addition of concurrent sorafenib to DEB-TACE; patients had Child-Pugh A liver disease, and ECOG PS 0 or 1.
Chemotherapy
- 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
- 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 verified protocol PubMed
Radioembolization
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Vilgrain et al. 2017 (SARAH) | Phase III (E) | Sorafenib | Did not meet primary outcome of improved OS |
Chow et al. 2018 (SIRveNIB) | Phase III (E) | 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.
Radiotherapy
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 randomized controlled phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1624-1636. Epub 2017 Oct 26. link to original article PubMed
- 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
TACE monotherapy
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TACE: Trans-Arterial Chemo-Embolization
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Trinchet et al. 1995 | Phase III (E) | Best supportive care | Seems not superior |
Llovet et al. 2002 | Phase III (E) | Best supportive care | Seems to have superior OS |
Kudo et al. 2011 | Non-randomized portion of RCT | ||
Kudo et al. 2014 | Phase III (C) | TACE & Brivanib | Seems not superior |
Kudo et al. 2017 (ORIENTAL) | Phase III (C) | TACE & Orantinib | Seems not superior |
Kudo et al. 2011 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
1 or more treatments
Subsequent treatment
- Kudo et al. 2011: 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
- 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 protocol PubMed
- 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
- 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
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
- 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
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kudo et al. 2011 | Phase III (C) | Sorafenib | Did not meet primary outcome of improved TTP |
Bruix et al. 2015 (STORM) | Phase III (C) | Sorafenib | Seems not superior |
No active antineoplastic treatment.
Preceding treatment
References
- 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 protocol PubMed
- 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
- Dataset: Project Data Sphere
TACE monotherapy
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TACE: Trans-Arterial Chemo-Embolization
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wang et al. 2018 (LCI-125-009) | Phase III (E) | Observation | Seems to have superior OS |
Preceding treatment
- Curative surgical resection
Chemotherapy
- TACE consisting of:
- Doxorubicin (Adriamycin) 20 to 30 mg/m2
- Lipiodol 3 to 5 mL
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
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.
Best supportive care
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Trinchet et al. 1995 | Phase III (C) | TACE | Seems not superior |
CLIP Group (CLIP-1) | Phase III (C) | Tamoxifen | Seems not superior |
Llovet et al. 2002 | Phase III (C) | TACE | Seems to have inferior OS |
No antineoplastic treatment.
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
- CLIP-1: Gallo C, Daniele B, Gaeta GB, Perrone F, Pignata S; CLIP Group (Cancer of the Liver Italian Programme). Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. Lancet. 1998 Jul 4;352(9121):17-20. 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
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
- 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 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 (E) | Sorafenib | Inferior OS |
Neither the primary outcome (progression-free survival) or secondary outcome (overall survival) were met.
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
References
- 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
- 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
- Capecitabine (Xeloda) 800 mg/m2 PO twice per day on days 1 to 14
- 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 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
- 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 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 twice per day 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
- 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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Variant #1, 50 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Qin et al. 2013 (EACH) | Phase III (C) | 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
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
21-day cycles
Variant #2, 60 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Johnson et al. 1978 | Phase II | ||
Lai et al. 1988 | Phase III (E) | Best supportive care | Seems to have superior OS |
Yeo et al. 2005 | Phase III (C) | PIAF | Seems not superior |
Gish et al. 2007 | Phase III (C) | Nolatrexed | Superior OS |
Abou-Alfa et al. 2010 (Study 11546) | Phase III (C) | Doxorubicin & Sorafenib | Inferior OS |
Note: this was the lower bound of the range specified by Lai et al. 1988.
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Gish et al. 2007: Initial dose reduction to 30 mg/m2 IV for patients with T bili greater than 1.2 mg/dL
21-day cycle for up to 6 cycles (Yeo et al. 2005), 9 cycles (Study 11546), or indefinitely (Gish et al. 2007)
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 protocol 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 protocol 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 verified protocol 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. link to original article contains verified protocol 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. link to original article contains verified protocol 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. 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
- Erlotinib (Tarceva) 150 mg PO once per day
- 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 verified protocol 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
Fluorouracil & Folinic acid
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Regimen
Study | Evidence | Efficacy |
---|---|---|
Porta et al. 1995 | Phase II | ORR: 28% (95% CI, 10-46) |
Chemotherapy
- Fluorouracil (5-FU) 370 mg/m2 IV once per day on days 1 to 5
- Folinic acid (Leucovorin) 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 PubMed
FOLFOX4
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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Qin et al. 2013 (EACH) | Phase III (E) | 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
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2 at hour 2, then 600 mg/m2/day IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m2)
- Folinic acid (Leucovorin) 200 mg/m2 IV hour 0 to hour 2 once per day on days 1 and 2
- 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 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
- 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 verified protocol 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
Lenvatinib monotherapy
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Regimen #1, 8 mg/day
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kudo et al. 2018 (REFLECT) | Phase III (E) | Sorafenib | Non-inferior OS |
This dosing is intended for patients weighing less than 60 kg.
Chemotherapy
- Lenvatinib (Lenvima) 8 mg PO once per day
28-day cycles
Regimen #2, 12 mg/day
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kudo et al. 2018 (REFLECT) | Phase III (E) | Sorafenib | Non-inferior OS |
This dosing is intended for patients weighing at least 60 kg.
Chemotherapy
- Lenvatinib (Lenvima) 12 mg PO once per day
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 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
- Nivolumab (Opdivo) 3 mg/kg 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.link to original article contains protocol PubMed
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Chow et al. 2002 | Phase III (C) | Tamoxifen | Seems to have superior OS |
Llovet et al. 2008 (SHARP) | Phase III (C) | Sorafenib | Inferior OS |
Cheng et al. 2008 (Sorafenib AP) | Phase III (C) | Sorafenib | No predetermined endpoint; seems to have inferior OS |
No active antineoplastic treatment.
References
- Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, Soo KC; Asian-Pacific Hepatocellular Carcinoma Trials Group. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology. 2002 Nov;36(5):1221-6. link to original article PubMed
- 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
- 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 verified protocol PubMed
- 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 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 (Sorafenib AP) | Phase III (E) | Placebo | Seems to have superior OS |
Pinter et al. 2009 | Retrospective | ||
Abdel-Rahman et al. 2013 | Randomized Phase II (C) | 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 (C) | SIRT | Seems not superior |
Kudo et al. 2018 (REFLECT) | Phase III (C) | Lenvatinib | Non-inferior OS |
Chow et al. 2018 (SIRveNIB) | Phase III (C) | SIRT | Seems not superior |
Kudo et al. 2018 (SILIUS) | Phase III (C) | HAI CF & Sorafenib | Seems not superior |
Chemotherapy
- 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
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 verified protocol PubMed
- 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
- 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 verified protocol PubMed
- 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 verified protocol 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 protocol PubMed
- 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
- 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
- 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
- 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
- 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 protocol PubMed
- 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
- 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 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
- TACE as follows:
- 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
- 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 verified protocol link to PMC article PubMed
Subsequent lines of therapy
Cabozantinib monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Abou-Alfa et al. 2018 (CELESTIAL) | Phase III (E) | Placebo | Superior OS |
Chemotherapy
- Cabozantinib (Cometriq) 60 mg PO once per day
Continued indefinitely
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 protocol PubMed
Doxorubicin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Qin et al. 2013 (EACH) | Phase III (C) | 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
- 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 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 (E) | 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 bili was within normal limits).
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2 at hour 2, then 600 mg/m2/day IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m2)
- Folinic acid (Leucovorin) 200 mg/m2 IV hour 0 to hour 2 once per day on days 1 and 2
- 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 verified protocol PubMed
Nivolumab monotherapy
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Variant #1, 3 mg/kg
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
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
14-day cycles
Variant #2, 240 mg
FDA-recommended dose |
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
Variant #3, 480 mg
FDA-recommended dose |
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 protocol PubMed
Pembrolizumab monotherapy
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Regimen
FDA-recommended dose |
Study | Evidence | Efficacy (dose expansion phase) |
---|---|---|
Zhu et al. 2018 (KEYNOTE-224) | Phase II | ORR: 17% (95% CI, 11–26) |
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for approximately 2 years
References
- 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 protocol PubMed
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Barbare et al. 2009 | Phase III (C) | Octreotide LAR | Did not meet primary outcome of improved overall survival |
Llovet et al. 2013 (BRISK-PS) | Phase III (C) | Brivanib | Did not meet primary outcome of improved overall survival |
Zhu et al. 2014 (EVOLVE-1) | Phase III (C) | Everolimus | Did not meet primary outcome of improved overall survival |
Zhu et al. 2015 (REACH-HCC) | Phase III (C) | Ramucirumab | Did not meet primary outcome of improved overall survival |
Bruix et al. 2016 (RESORCE) | Phase III (C) | Regorafenib | Inferior OS |
Kudo et al. 2017 (S-CUBE) | Phase III (C) | S-1 | 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 |
Abou-Alfa et al. 2018 (CELESTIAL) | Phase III (C) | Cabozantinib | Inferior OS |
No active antineoplastic treatment. Note that REACH should not be confused for the trial of the same name in CLL.
References
- Barbare JC, Bouché O, Bonnetain F, Dahan L, Lombard-Bohas C, Faroux R, Raoul JL, Cattan S, Lemoine A, Blanc JF, Bronowicki JP, Zarski JP, Cazorla S, Gargot D, Thevenot T, Diaz E, Bastie A, Aparicio T, Bedenne L. Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a phase III multicentre, randomised, double blind placebo-controlled study. Eur J Cancer. 2009 Jul;45(10):1788-97. Epub 2009 Mar 19. link to original article PubMed
- BRISK-PS: Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013 Oct 1;31(28):3509-16. Epub 2013 Aug 26. link to original article PubMed
- 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
- 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
- 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
- S-CUBE: Kudo M, Moriguchi M, Numata K, Hidaka H, Tanaka H, Ikeda M, Kawazoe S, Ohkawa S, Sato Y, Kaneko S, Furuse J, Takeuchi M, Fang X, Date Y, Takeuchi M, Okusaka T. S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Jun;2(6):407-417. Epub 2017 Apr 6. link to SD article PubMed
- 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 May;19(5):682-693. Epub 2018 Apr 3. link to original article PubMed
- 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 protocol PubMed
Regorafenib monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Bruix et al. 2016 (RESORCE) | Phase III (E) | Placebo | Superior OS |
The RESORCE study required patients with sorafenib tolerance of at least 400mg/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. link to original article contains protocol PubMed