Hepatocellular carcinoma - null regimens

The purpose of this page is to provide references to "null therapy" such as placebo and observation. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the main HCC page for current regimens.

Adjuvant therapy

Observation

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Takayama et al. 2000 (IIC-I01)	1992-1995	Phase 3 (C)	Adoptive immunotherapy	Inferior RFS
Chen et al. 2012 (T1297)	1997-2003	Phase 3 (C)	Interferon alfa-2b	Did not meet primary endpoint of RFS
Wang et al. 2018 (LCI-125-009)	2011-2014	Phase 3 (C)	TACE	Seems to have inferior OS

No treatment after surgery or ablation.

Preceding treatment

• Curative surgical resection or ablation

References

1. IIC-I01: Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000 Sep 2;356(9232):802-7. Erratum in: Lancet 2000 Nov 11;356(9242):1690. link to original article PubMed NCT00699816
2. T1297: Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL, Lee WC, Chau GY, Chen YS, Lui WY, Hsiao CF, Whang-Peng J, Chen PJ; Disease Committee of Adjuvant Therapy for Postoperative Hepatocellular Carcinoma, Taiwan Cooperative Oncology Group, National Health Research Institutes, Zhunan, Taiwan. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg. 2012 Jan;255(1):8-17. link to original article PubMed NCT00149565
3. 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

Placebo

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kudo et al. 2011 (Bayer 11721)	2006-2009	Phase 3 (C)	Sorafenib	Did not meet primary outcome of TTP
Bruix et al. 2015 (STORMHCC)	2008-2010	Phase 3 (C)	Sorafenib	Did not meet primary endpoint of RFS

No active antineoplastic treatment. Note that there is another STORM trial in multiple myeloma.

Preceding treatment

• Bayer 11721: TACE x 1-2
• STORM: Resection or ablation

References

1. 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 protocol PubMed NCT00494299
2. STORM_HCC: 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 NCT00692770
   1. Dataset: Project Data Sphere

First-line therapy for advanced or metastatic disease

Best supportive care

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Trinchet et al. 1995	1990-1992	Phase 3 (C)	TACE	Did not meet primary endpoint of OS
Gallo et al. 1998 (CLIP-1)	1995-1997	Phase 3 (C)	Tamoxifen	Did not meet primary endpoint of OS
Llovet et al. 2002	1996-2000	Phase 3 (C)	TACE	Seems to have inferior OS

No antineoplastic treatment.

References

1. 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
2. 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
3. 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

Placebo

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Chow et al. 2002 (NMRC-AHCC01)	1997-2000	Phase 3 (C)	Tamoxifen	Seems to have superior OS
Chow et al. 2011 (NMRC-AHCC02)	2002-2007	Phase 3 (C)	Megestrol	Did not meet primary endpoint of OS
Llovet et al. 2008 (SHARP)	2005-2006	Phase 3 (C)	Sorafenib	Inferior OS
Cheng et al. 2008 (Sorafenib AP)	2005-2007	Phase 3 (C)	Sorafenib	No predetermined endpoint; seems to have inferior OS

No active antineoplastic treatment.

References

1. NMRC-AHCC01: 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 NCT00003424
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 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
3. 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 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 verified protocol PubMed
4. NMRC-AHCC02: Chow PK, Machin D, Chen Y, Zhang X, Win KM, Hoang HH, Nguyen BD, Jin MY, Lobo R, Findlay M, Lim CH, Tan SB, Gandhi M, Soo KC; Asia-Pacific Hepatocellular Carcinoma Trials Group. Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. Br J Cancer. 2011 Sep 27;105(7):945-52. Epub 2011 Aug 23. link to original article link to PMC article PubMed NCT00041275

Subsequent lines of therapy

Placebo

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Barbare et al. 2009	2002-2003	Phase 3 (C)	Octreotide LAR	Did not meet primary endpoint of OS
Dollinger et al. 2010	2002-2005	Phase 3 (C)	Thymostimulin	Did not meet primary endpoint of OS12
Llovet et al. 2013 (BRISK-PS)	2009-2011	Phase 3 (C)	Brivanib	Did not meet primary endpoint of OS
Kudo et al. 2017 (S-CUBE)	2009-2012	Phase 3 (C)	S-1	Did not meet primary endpoint of OS
Zhu et al. 2014 (EVOLVE-1)	2010-2012	Phase 3 (C)	Everolimus	Did not meet primary endpoint of OS
Zhu et al. 2015 (REACH-HCC)	2010-2013	Phase 3 (C)	Ramucirumab	Did not meet primary endpoint of OS
Rimassa et al. 2018 (METIV-HCC)	2012-2015	Phase 3 (C)	Tivantinib	Did not meet primary endpoint of OS
Bruix et al. 2016 (RESORCE)	2013-2015	Phase 3 (C)	Regorafenib	Inferior OS
Abou-Alfa et al. 2018 (POLARIS 2009-001)	NR	Phase 3 (C)	ADI-PEG 20	Did not meet primary endpoint of OS
Abou-Alfa et al. 2018 (CELESTIAL)	2013-2017	Phase 3 (C)	Cabozantinib	Inferior OS
Kudo et al. 2020 (JET-HCC)	2014-2016	Phase 3 (C)	Tivantinib	Might have inferior PFS
Zhu et al. 2019 (REACH-2)	2015-2017	Phase 3 (C)	Ramucirumab	Seems to have inferior OS

No active antineoplastic treatment. Note that REACH should not be confused for the trial of the same name in CLL.

References

1. 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
2. Dollinger MM, Lautenschlaeger C, Lesske J, Tannapfel A, Wagner AD, Schoppmeyer K, Nehls O, Welker MW, Wiest R, Fleig WE; AIO Hepatobiliary Study Group. Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma: a phase III clinical trial. BMC Cancer. 2010 Aug 24;10:457. link to original article link to PMC article PubMed ISRCTN64487365
3. 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 NCT00825955
4. 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 NCT01035229
5. 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 NCT01140347
6. 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 NCT01774344
7. 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 original article PubMed JapicCTI-090920
8. 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 NCT01755767
9. POLARIS 2009-001: Abou-Alfa GK, Qin S, Ryoo BY, Lu SN, Yen CJ, Feng YH, Lim HY, Izzo F, Colombo M, Sarker D, Bolondi L, Vaccaro G, Harris WP, Chen Z, Hubner RA, Meyer T, Sun W, Harding JJ, Hollywood EM, Ma J, Wan PJ, Ly M, Bomalaski J, Johnston A, Lin CC, Chao Y, Chen LT. Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma. Ann Oncol. 2018 Jun 1;29(6):1402-1408. link to original article PubMed NCT01287585
10. 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 NCT01908426
11. 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 protocol PubMed NCT02435433
12. JET-HCC: Kudo M, Morimoto M, Moriguchi M, Izumi N, Takayama T, Yoshiji H, Hino K, Oikawa T, Chiba T, Motomura K, Kato J, Yasuchika K, Ido A, Sato T, Nakashima D, Ueshima K, Ikeda M, Okusaka T, Tamura K, Furuse J. A randomized, double-blind, placebo-controlled, phase 3 study of tivantinib in Japanese patients with MET-high hepatocellular carcinoma. Cancer Sci. 2020 Oct;111(10):3759-3769. Epub 2020 Aug 26. link to original article link to PMC article PubMed NCT02029157