Hepatocellular carcinoma - historical

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main HCC page for current regimens.

4 regimens on this page 7 variants on this page

First-line therapy for advanced or metastatic disease

Nivolumab monotherapy

Regimen variant #1, weight-based

Study	Years of enrollment	Evidence	Efficacy
El-Khoueiry et al. 2017 (CheckMate 040)	2012-2016	Phase 1/2 (RT)	ORR: 20% (95% CI, 15–26)

This is the dose used in the expansion cohort of this study; patients were required to have ECOG PS 1 or less, and Child-Pugh scores of 6 or less (Child-Pugh A) for the dose expansion. 68% of patients in the dose expansion phase received prior sorafenib therapy.

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycles

Regimen variant #2, flat dosing

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yau et al. 2021 (CheckMate 459)	2016-2017	Phase 3 (E-switch-ooc)	Sorafenib	Might have superior OS Median OS: 16.4 vs 14.7 mo (HR 0.85, 95% CI 0.72-1.02)

Study included patients with Child-Pugh class B (5-9), hepatitis B and C infections. This study was the basis for the withdrawal of FDA approval for this indication.

Immunotherapy

• Nivolumab (Opdivo) 240 mg IV once on day 1

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 3rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. Epub 2017 Apr 20 link to original article contains dosing details in abstract PubMed NCT01658878
2. CheckMate 459: Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Harding JJ, Merle P, Rosmorduc O, Wyrwicz L, Schott E, Choo SP, Kelley RK, Sieghart W, Assenat E, Zaucha R, Furuse J, Abou-Alfa GK, El-Khoueiry AB, Melero I, Begic D, Chen G, Neely J, Wisniewski T, Tschaika M, Sangro B. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022 Jan;23(1):77-90. Epub 2021 Dec 13. link to original article contains dosing details in abstract PubMed NCT02576509

Sunitinib monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Zhu et al. 2009 (DF/HCC 05-348)	2006-NR	Phase 2
Cheng et al. 2013 (SUN 1170)	2008-2010	Phase 3 (E-switch-ic)	Sorafenib	Inferior OS

Early trial termination of the phase III trial occurred for futility and safety reasons; sunitinib treated patients demonstrated inferior OS and more frequent and severe toxicities. Dosing preserved for historical context.

Targeted therapy

• Sunitinib (Sutent) 37.5 mg PO once per day on days 1 to 28
  • Dose can be reduced to 25 and 12.5 mg once per day depending on toxicity

42-day cycles

References

1. DF/HCC 05-348: Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, Bhargava P, Meyerhardt J, Clark JW, Kwak EL, Hezel AF, Miksad R, Abrams TA, Enzinger PC, Fuchs CS, Ryan DP, Jain RK. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol. 2009 Jun 20;27(18):3027-35. Epub 2009 May 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00361309
2. SUN 1170: Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G, Omata M, Pitman Lowenthal S, Lanzalone S, Yang L, Lechuga MJ, Raymond E. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013 Nov 10;31(32):4067-75. Epub 2013 Sep 30. link to original article PubMed NCT00699374

Tamoxifen monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gallo et al. 1998 (CLIP-1)	1995-1997	Phase 3 (E-esc)	Best supportive care	Did not meet primary endpoint of OS
Barbare et al. 2005 (FFCD 9403)	1995-2000	Phase 3 (E-esc)	Best supportive care	Did not meet primary endpoint of OS
Doffoël et al. 2008 (FFCD 9402)	1995-2002	Phase 3 (C)	TACE & Tamoxifen	Did not meet primary endpoint of OS
Chow et al. 2002 (NMRC-AHCC01)	1997-2000	Phase 3 (E-esc)	Placebo	Seems to have inferior OS
Verset et al. 2007	2001-2005	Phase 3 (C)	Octreotide LAR & Tamoxifen	Did not meet primary endpoint of OS

Endocrine therapy

• Tamoxifen (Nolvadex)

References

1. CLIP-1: Gallo C, Daniele B, Gaeta GB, Perrone F, Pignata S; CLIP. Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. Lancet. 1998 Jul 4;352(9121):17-20. link to original article PubMed
2. 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
3. FFCD 9403: Barbare JC, Bouché O, Bonnetain F, Raoul JL, Rougier P, Abergel A, Boige V, Denis B, Blanchi A, Pariente A, Milan C, Bedenne L. Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol. 2005 Jul 1;23(19):4338-46. link to original article PubMed
4. Verset G, Verslype C, Reynaert H, Borbath I, Langlet P, Vandebroek A, Peeters M, Houbiers G, Francque S, Arvanitakis M, Van Laethem JL. Efficacy of the combination of long-acting release octreotide and tamoxifen in patients with advanced hepatocellular carcinoma: a randomised multicentre phase III study. Br J Cancer. 2007 Sep 3;97(5):582-8. Epub 2007 Aug 7. link to original article link to PMC article PubMed
5. FFCD 9402: Doffoël M, Bonnetain F, Bouché O, Vetter D, Abergel A, Fratté S, Grangé JD, Stremsdoerfer N, Blanchi A, Bronowicki JP, Caroli-Bosc FX, Causse X, Masskouri F, Rougier P, Bedenne L; Fédération Francophone de Cancérologie Digestive. Multicentre randomised phase III trial comparing Tamoxifen alone or with transarterial Lipiodol Chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Fédération Francophone de Cancérologie Digestive 9402). Eur J Cancer. 2008 Mar;44(4):528-38. Epub 2008 Jan 31. link to original article PubMed