Hepatocellular carcinoma - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only.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

Capecitabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Abdel-Rahman et al. 2013 2010-2011 Randomized Phase 2 (E-switch-ooc) Sorafenib Inferior PFS (primary endpoint)

Note: 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

Nivolumab monotherapy

Regimen variant #1, weight-based

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

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

Immunotherapy

14-day cycles


Regimen variant #2, flat dosing

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yau et al. 2021 (CheckMate 459) 2016-01-11 to 2017-05-24 Phase 3 (E-switch-ooc) Sorafenib Might have superior OS (primary endpoint)
Median OS: 16.4 vs 14.7 mo
(HR 0.85, 95% CI 0.72-1.02)

Note: 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

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
    1. Update: El-Khoueiry AB, Trojan J, Meyer T, Yau T, Melero I, Kudo M, Hsu C, Kim TY, Choo SP, Kang YK, Yeo W, Chopra A, Soleymani S, Yao J, Neely J, Tschaika M, Welling TH, Sangro B. Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040. Ann Oncol. 2023 Dec 25:S0923-7534(23)05115-3. Epub ahead of print. link to original article PubMed
  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 variant #1, interrupted sunitinib

Study Dates of enrollment Evidence
Zhu et al. 2009 (DF/HCC 05-348) 2006-NR Phase 2

Targeted therapy

42-day cycles


Regimen variant #2, continuous sunitinib

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cheng et al. 2013 (SUN 1170) 2008-2010 Phase 3 (E-switch-ic) Sorafenib Inferior OS (primary endpoint)
Median OS: 7.9 vs 10.2 mo
(HR 1.30, 95% CI 1.13-1.50)

Note: Early trial termination of SUN 1170 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

28-day cycles

Dose and schedule modifications

  • Dose can be reduced to 25 and 12.5 mg once per day depending on toxicity

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 variant #1, 20 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
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
Verset et al. 2007 2001-2005 Phase 3 (C) Octreotide LAR & Tamoxifen Did not meet primary endpoint of OS

Endocrine therapy

Continued indefinitely


Regimen variant #2, 40 mg/day

Study Dates 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

Endocrine therapy

Continued indefinitely

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 contains dosing details in abstract PubMed
  2. 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 contains dosing details in abstract PubMed
  3. 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 contains dosing details in manuscript PubMed
  4. 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 contains dosing details in manuscript PubMed
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