#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Current treatment options for hepatocellular carcinoma


Authors: MUDr. Kubala Eugen
Authors‘ workplace: Onkologická klinika 1. LF UK a Thomayerovy nemocnice, Praha
Published in: Klin Onkol 2020; 33(Supplementum 3): 20-25
Category: Review
doi: https://doi.org/10.14735/amko20203S20

Overview

Hepatocellular carcinoma remains a serious global disease. Its incidence is increasing. Standard procedures have been developed for each stage. The complexity of this disease shows that the selection of patients in stage 0/A for different types of surgical treatment is very complicated. Treatment methods of stage B, especially locoregional treatment represented by TACE (transarterial chemoembolization or radioembolization of TARE), radiofrequency ablation and others, move freely to lower and higher stages as adjunctive therapy. Lenvatinib can replace TACE with equal efficacy in cases where locoregional treatment cannot be used. Until 2016, the only systemic treatment option for stage C was sorafenib. Lenvatinib became a second-line drug to show non-inferiority to sorafenib in OS. Retrospective analyzes revealed that patients who responded to the treatment with lenvatinib or sorafenib had a median survival of over 22 months. Sequential treatment with sorafenib and regorafenib in the RESOURCE study with a median survival of more than 24 months was similar. Ramucirumab was effective only in patients with high AFP levels. The study demonstrated the importance of selecting patients according to prognostic factors (extrahepatic spread and vascular invasion). Second-line cabozantinib has shown the same benefit as regorafenib. In the second line, immunotherapy represented by anti PD-1 antibodies nivolumab and pembrolizumab was used. Sequential administration after sorafenib prolonged the median overall survival of about 22 months. We currently have sorafenib and lenvatinib in the first line, regorafenib, cabozantinib, ramucirumab (AFP ≥ 400 μg/L), pembrolizumab and nivolumab in the second line. The possibilities of monotherapy have been exhausted. The discovery of a synergistic effect of angiogenesis inhibitors, which convert a cold tumor into a hot one and facilitate the efficacy of anti-PD-1 / anti-PDL-1 antibodies, has led to a highly effective combination therapy. In study IMbrave150, the combination of atezolizumab and bevacizumab was successfully used compared to sorafenib in the first-line treatment. Additional studies are currently underway using other tyrosin kinase inhibitors – regorafenib, lenvatinib and cabozantinib – in combination with nivolumab, ipilimumab and pembrolizumab. This development of treatment at all stages evoked with renewed urgency the need to find a suitable way to search for the early stages of HCC and to create a more effective system for selecting patients for the most appropriate treatment.

Keywords:

hepatocellular carcinoma – disease stages – radical treatment – local treatment – predictors of biological treatment and immunotherapy – systemic treatment


Sources

1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55 (2): 74–108. doi: 10.3322/canjclin.55.2.74.

2. Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61 (2): 69–90. doi: 10.3322/caac.20107.

3. El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol 2001; 96 (8): 2462–2467. doi: 10.1111/j.1572-0241.2001.04054.x.

4. Johnson PJ. How do mechanisms of hepatocarcinogenesis (HBV, HCV, and NASH) affect our understanding and approach to HCC? Am Soc Clin Oncol Educ Book 2013; doi: 10.1200/EdBook_AM.2013.33.e132.

5. Lang H, Sotiropoulos GC, Dömland M et al. Liver resection for hepatocellular carcinoma in non-cirrhotic liver without underlying viral hepatitis. Br J Surg 2005; 92 (2): 198–202. doi: 10.1002/bjs.4763.

6. Belghiti J, Hiramatsu K, Benoist S et al. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000; 191 (1): 38–46. doi: 10.1016/s1072-7515 (00) 00261-1.

7. Livraghi T, Meloni F, Di Stasi M et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 2008; 47 (1): 82–89. doi: 10.1002/hep.21933.

8. Samuel M, Chow PK, Chan Shih-Yen E et al. Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma. Cochrane Database Syst Rev 2009; 1: CD001199. doi: 10.1002/14651858.CD001199.pub2.

9. Bruix J, Takayama T, Mazzaferro V et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): A phase 3, randomised, double-blind, placebo- controlled trial. Lancet Oncol 2015; 16 (13): 1344–1354. doi: 10.1016/S1470-2045 (15) 00198-9.

10. Mazzaferro V, Bhoori S, Sposito C et al. Milan criteria in liver Transplantation for HCC: an evidence-based analysis on 15 years of experience. Liver Transplant 2011; 17 (Suppl 2): S44–S57. doi: 10.1002/lt.22365.

11. Llovest JM, Fuster J, Bruix J. Barcelona approach dia­gnosis, staging and treatment of hepatocellular carcinoma. Liver transplantation 2004; 10 (2 Suppl 1): S115–S120. doi: 10.1002/lt.20034.

12. Sandhu DS, Tharayii VS, Lai J-P et al. Treatment options for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2008; 2 (1): 81–92. doi: 10.1586/17474124.2.1.81.

13. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42 (5): 1208–1236.

14. Llovet JM, Fuster J, Bruix J. Barcelona approach dia­gnosis, staging and treatment of hepatocellular carcinoma. Liver Transplant 2004; 10 (2 Suppl 1): 115–120. doi: 10.1002/lt.20034.

15. Ji SK, Cho YK, Ahn YS et al. Multivariate analysis of the predictors of survival for patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Focusing on superselective chemoembolization. Korean J Radiol 2008; 9 (6): 534–540. doi: 10.3348/kjr.2008.9.6.534.

16. Lencioni R, Llovet JM, Han G et al. Sorefenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beat (DEBOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II randomized, double –blind SPACE trial. J Hepatol 2016; 64 (5): 1090–1098. doi: 10.1016/j.jhep.2016.01.012.

17. Kudo M. Extremely high objective response rate of lenvatinib: its clinical relevance and changing the treatment paradigm in hepatocellular carcinoma. Liver Cancer 2018; 7 (3): 215–224. doi: 10.1159/000492533.

18. Kudo M, Han G, Finn RS et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial. Hepatology 2014; 60 (5): 1697–1707. doi: 10.1002/hep.27290.

19. Lencioni R, Llovet JM, Han G et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol 2016; 64 (5): 1090–1098. doi: 10.1016/j.jhep.2016.01.012.

20. Meyer T, Fox R, Ma YT et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol 2017; 2 (8): 565–575. doi: 10.1016/S2468-1253 (17) 30156-5.

21. Yamashita T, Kudo M, Ikeda K et al. Analysis of Japanese subpopulation form REFLECT trial. The 18th annual meeting of Japan Association of Molecular Targeted Therapy for HCC; 2018 July 14, Tokyo.

22. Vincenzi B, Di Maio M, Silletta M et al. Prognostic relevance of objective response according to EASL criteria and mRECIST criteria in hepatocellular carcinoma patients treated with loco-regional therapies: A literature-based meta-analysis. PLoS One 2015; 10 (7): e0133488. doi: 10.1371/journal.pone.0133488.

23. Sho T, Suda G, Ogawa K et al. Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real-world setting. JGH Open 2020; 4 (1): 54–60. doi: 10.1002/jgh3.12209.

24. Yang Yi, Si T. Yttrium-90 transarterial radioembolization versus conventional transarterial chemoembolization for patients with hepatocellular carcinoma: a systematic review and meta-analysis Cancer Biol Med 2018; 15 (3): 299–310. doi: 10.20892/j.issn.2095-3941.2017.0177.

25. Villanueva A, Newel P, Chiang DY et al. Genomic and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007, 27 (1): 55–76. doi: 10.1055/s-2006-960171.

26. Gherardi E, Birchmeier W, Birchmeier C et al. Targeting MET in cancer: rationale and progress. Nat Rev Cancer 2012; 12 (2): 89–103. doi: 10.1038/nrc3205.

27. Goyal L, Muzumdar MD, Zhu AX. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res 2013; 19 (9): 2310–2318. doi: 10.1158/1078-0432.CCR-12-2791.

28. Lee HJ, Jeng YM, Chen YL et al. Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma. Carcinogenesis 2014; 35 (4): 769–775. doi: 10.1093/carcin/bgt372.

29. Zhou L, Liu XD, Sun M et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2016; 35 (21): 2687–2697. doi: 10.1038/onc.2015.343.

30. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473 (7347): 298–307. doi: 10.1038/nature10144.

31. Schoenleber SJ, Kurtz DM, Talwalkar JA et al. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer 2009; 100 (9): 1385–1392. doi: 10.1038/sj.bjc.6605017.

32. Llovet JM. Ricci S, Mezzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359 (4): 378–390. doi: 10.1056/NEJMoa0708857.

33. Kudo M, Finn RS, Qin S et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391 (10126): 1163–1173. doi: 10.1016/S0140-6736 (18) 30207-1.

34. Bruix J, Qin S, Merle P et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389 (10064): 56– 66. doi: 10.1016/S0140-6736 (16) 32453-9.

35. Zhu AX, Kang YK, Yen CJ et al: Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased a-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20 (2): 282– 296. doi: 10.1016/S1470-2045 (18) 30937-9.

36. Abou-Alfa GK, Meyer T, Cheng AL et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379 (1): 54– 63. doi: 10.1056/NEJMoa1717002.

37. El-Khoueiry AB, Melero I, Cheung Yau T et al. Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): Subanalyses of CheckMate-040. [online]. Available from: https: //ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.475.

38. Kudo M, Finn RS, Edeline J et al. Updated efficacy and safety of KEYNOTE-224: A phase II study of pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC). [online]. Available from: https: //ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.518.

39. Galle PR, Finn RS, Qin S et al. Patient-reported outcomes (PROs) from the Phase III IMbrave150 trial of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). [online]. Available from: https: //ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.476.

40. Yau T, Zagonel V, Santoro A. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. [online]. Available from: https: //ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.478.

41. El-Khoueiry AB, Kim RD, Harris WP et al. Phase Ib study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC). [online]. Available from: https: //ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.564.

42. Ikeda M, Sung MW, Kudo M et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). [online]. Available from: https: //ascopubs.org/doi/abs/10.1200/jco.2018.36.15_suppl.4076

43. Kudo M. Combination cancer immunotherapy in hepatocellular carcinoma. Liver Cancer 2018; 7 (1): 20–27. doi: 10.1159/000486487.

44. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362 (9399): 1907–17. doi: 10.1016/S0140-6736 (03) 14964-1.

45. Modrá kniha české onkologické společnosti [online]. Dostupné z: https: //www.linkos.cz/lekar-a-multidisciplinarni-tym/personalizovana-onkologie/modra-kniha-cos/aktualni-vydani-modre-knihy/.

Labels
Paediatric clinical oncology Surgery Clinical oncology Gastroenterology and hepatology
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#