Hepatocellular carcinoma – prognostic criteria of individualized treatment

Česká verzia

Authors: P. Kysela ¹; Z. Kala ¹; M. Zatloukal ¹; M. Raudenská ²; D. Brančíková ³
Authors place of work: Chirurgická klinika LF MU a FN Brno ¹; Fyziologický ústav, LF MU Brno ²; Interní hematologická a onkologická klinika LF MU a FN Brno ³
Published in the journal: Klin Onkol 2022; 35(2): 100-113
Category: Review
doi: https://doi.org/10.48095/ccko2022100

Summary

Background: Though the sixth most frequent malignancy, hepatocellular carcinoma (HCC) is the third most common cause of death amongst solid tumours. Only surgery in the early stages may provide the cure; however, HCC still has a high recurrence rate. Non-surgical treatment lacks comparable efficacy. It was not sooner than in 2017 that the therapy galore started to extend. Thus prognostic factors driving the therapy have been gaining importance. Material and methods: All relevant literature was checked for aetiology, epidemiology, diagnostic means, and individualised treatment of HCC. Cytochrome P-450 expression data from 22 patients operated in the University Hospital Brno in the period 2017–2020 were included. Results: Screening the population at risk (presence of cirrhosis) with the transabdominal ultrasound lies at the centre of the diagnostic algorithm. Making the diagnosis does not require a biopsy in most cases. Only a few parameters are thus known before the treatment – a size and number of lesions, and AFP level. These drive the indication to surgery. Relapses after surgery and response to palliative treatment depend on the expression of MET and AXL that directly affect anti-VEGF therapy. High AFP predicts a good response to regorafenib but early relapse after surgery. The pattern of P450 expression was found linked with tumour differentiation. The differentiation correlates with the size and number of lesions. We also found a link between the P450 expression and some mi-RNAs possibly detectable using liquid biopsy techniques. Conclusion: The share of deaths from HCC overweighs its incidence. The risk population to screen is well-defined (cirrhosis). The BCLC staging system probably gives the best complication/efficacy results. This system does not require any biopsy and does not comprise all predictive factors important in the expanding targeted molecular therapy. According to our results, small molecules to treat HCC should work better in poorly differentiated tumours. Surgery is more effective in those well-differentiated. It isn‘t easy to get all relevant information before therapy. Some factors need macrobiopsy (surgical). The pretreatment workup will probably require a mandatory biopsy in BCLC B and C stages to get the information. This opens up a way for the liquid biopsy that could use some specific mi RNAs.

Keywords:

Biopsy – drug resistance – hepatocellular carcinoma – predictive oncology – tailored treatment – P-450 cytochrome – isoform

Zdroje

1. Perz JF, Armstrong GL, Farrington LA et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45 (4): 529–538. doi: 10.1016/j.jhep.2006.05. 013.

2. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132 (7): 2557–2576. doi: 10.1053/j.gastro.2007.04.061.

3. Law MG, Roberts SK, Dore GJ et al. Primary hepatocellular carcinoma in Australia, 1978–1997: increasing incidence and mortality. Med J Aust 2000; 173 (8): 403–405. doi: 10.5694/j.1326-5377.2000.tb139267.x.

4. Benhamiche AM, Faivre C, Minello A et al. Time trends and age-period-cohort effects on the incidence of primary liver cancer in a well-defined French population: 1976–1995. J Hepatol 1998; 29 (5): 802–806. doi: 10.1016/s0168-8278 (98) 80262-6.

5. Cancer today. [online]. Available from: https: //gco.iarc.fr/today/home.

6. 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.

7. SVOD. Epidemiologie zhoubných nádorů v České republice. [online]. Dostupné z: https: //www.svod.cz/.

8. Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (3): 209–249. doi: 10.3322/caac.21660.

9. Llovet JM, Bustamante J, Castells A et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 1999; 29 (1): 62–67. doi: 10.1002/hep.510290145.

10. Lee D, Choi SW, Kim M et al. Discovery of differentially expressed genes related to histological subtype of hepatocellular carcinoma. Biotechnol Prog 2003; 19 (3): 1011–1015. doi: 10.1021/bp025746a.

11. Rivenbark AG, Coleman WB. The use of epigenetic biomarkers for preclinical detection of hepatocellular carcinoma: potential for noninvasive screening of high-risk populations. Clin Cancer Res 2007; 13 (8): 2309–2312. doi: 10.1158/1078-0432.CCR-07-0086.

12. Wang XW, Hussain SP, Huo TI et al. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology 2002; 181–182: 43–47. doi: 10.1016/s0300-483x (02) 00253-6.

13. Nakanuma Y, Terada T, Ueda K et al. Adenomatous hyperplasia of the liver as a precancerous lesion. Liver 1993; 13 (1): 1–9. doi: 10.1111/j.1600-0676.1993.tb00597.x.

14. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362 (9399): 1907–1917. doi: 10.1016/S0140-6736 (03) 14964-1.

15. 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.

16. Vescovo T, Refolo G, Vitagliano G et al. Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma. Clin Microbiol Infect 2016; 22 (10): 853–861. doi: 10.1016/j.cmi.2016.07.019.

17. Tarocchi M, Polvani S, Marroncini G et al. Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis. World J Gastroenterol 2014; 20 (33): 11630–11640. doi: 10.3748/wjg.v20.i33.11630.

18. Wang B, Majumder S, Nuovo G et al. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology 2009; 50 (4): 1152–1161. doi: 10.1002/hep.23100.

19. Majumder M, Ghosh AK, Steele R et al. Hepatitis C virus NS5A physically associates with p53 and regulates p21/waf1 gene expression in a p53-dependent manner. J Virol 2001; 75 (3): 1401–1407. doi: 10.1128/JVI.75.3.1401-1407.2001.

20. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J Carcinog 2017; 16: 1. doi: 10.4103/jcar.JCar_9_16.

21. Thorgeirsson SS, Lee JS, Grisham JW. Functional genomics of hepatocellular carcinoma. Hepatology 2006; 43 (2 Suppl 1): S145–S150. doi: 10.1002/hep.21063.

22. Chang MH, Chen CJ, Lai MS et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997; 336 (26): 1855–1859. doi: 10.1056/NEJM199706263362602.

23. Sung JJ, Tsoi KK, Wong VW et al. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008; 28 (9): 1067–1077. doi: 10.1111/j.1365-2036.2008.03816.x.

24. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Dig Dis 2016; 34 (4): 382–386. doi: 10.1159/000444551.

25. Fattovich G, Stroffolini T, Zagni I et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127 (5 Suppl 1): S35–S50. doi: 10.1053/ j.gastro.2004.09.014.

26. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53 (3): 1020–1022. doi: 10.1002/hep.24199.

27. Vauthey JN, Lauwers GY, Esnaola NF et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002; 20 (6): 1527–1536. doi: 10.1200/JCO.2002.20.6.1527.

28. Okuda K, Ohtsuki T, Obata H et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985; 56 (4): 918–928. doi: 10.1002/1097-0142 (19850815) 56: 4<918:: aid-cncr2820560437>3.0.co; 2-e.

29. Kudo M, Kitano M, Sakurai T et al. General rules for the clinical and pathological study of primary liver cancer, nationwide follow-up survey and clinical practice guidelines: the outstanding achievements of the liver cancer study group of Japan. Dig Dis 2015; 33 (6): 765–770. doi: 10.1159/000439101.

30. Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) Investigators. Hepatology 2000; 31 (4): 840–845. doi: 10.1053/he.2000.5628.

31. Leung TW, Tang AM, Zee B et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 2002; 94 (6): 1760–1769. doi: 10.1002/cncr.10384.

32. Chevret S, Trinchet JC, Mathieu D et al. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d‘Etude et de Traitement du Carcinome Hépatocellulaire. J Hepatol 1999; 31 (1): 133–141. doi: 10.1016/s0168-8278 (99) 80173-1.

33. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19 (3): 329–338. doi: 10.1055/s-2007-1007122.

34. Vogel A, Cervantes A, Chau I et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29 (Suppl 4): iv238–iv255. doi: 10.1093/annonc/mdy308.

35. Urbánek P, Hříbek P. Hepatocelulární karcinom z pohledu gastroenterologa/hepatologa. Klin Onkol 2020; 33 (Suppl 3): 34–44. doi: 10.14735/amko20203S34.

36. Třeška V. Chirurgická léčba hepatocelulárního karcinomu. Klin Onkol 2020; 33 (Suppl 3): 30–33. doi: 10.14735/amko20203S30.

37. Tokarčík J, Slížová D, Andrašina I et al. Systemic treatment for hepatocellular carcinoma. Klin Onkol 2020; 33 (5): 356–361. doi: 10.14735/amko2020356.

38. National Comprehensive Cancer Network. Guidelines. [online]. Available from: https: //www.nccn.org/.

39. ESMO guidelines. [online]. Available from: https: //www.esmo.org/guidelines.

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

41. Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334 (11): 693–699. doi: 10.1056/NEJM199603143341104.

42. Mazzaferro V, Llovet JM, Miceli R et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009; 10 (1): 35–43. doi: 10.1016/S1470-2045 (08) 70284-5

43. Decaens T, Roudot-Thoraval F, Hadni-Bresson S et al. Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time. Liver Transpl 2006; 12 (12): 1761–1769. doi: 10.1002/lt.20884.

44. Mazzaferro V, Bhoori S, Sposito C et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011; 17 (Suppl 2): S44–57. doi: 10.1002/lt.22365.

45. Yao FY, Ferrell L, Bass NM et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33 (6): 1394–1403. doi: 10.1053/jhep.2001.24563.

46. Liver Transplantation for hepatocellular carcinoma. The metroticket project. [online]. Available from: http: //www.hcc-olt-metroticket.org/

47. Marsh JW, Finkelstein SD, Demetris AJ et al. Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. Liver Transpl 2003; 9 (7): 664–671. doi: 10.1053/jlts.2003.50144.

48. Merani S, Majno P, Kneteman NM et al. The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma. J Hepatol 2011; 55 (4): 814–819. doi: 10.1016/j.jhep.2010.12.040.

49. Toso C, Asthana S, Bigam DL et al. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipients database. Hepatology 2009; 49 (3): 832–838. doi: 10.1002/hep.22693.

50. Citores MJ, Lucena JL, de la Fuente S et al. Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation. World J Hepatol 2019; 11 (1): 50–64. doi: 10.4254/wjh.v11.i1.50.

51. Abreu P, Gorgen A, Oldani G et al. Recent advances in liver transplantation for cancer: the future of transplant oncology. JHEP Rep 2019; 1 (5): 377–391. doi: 10.1016/j.jhepr.2019.07.004.

52. Zhou L, Xu Y, Guo Z et al. Perioperative circulating tumor DNA analysis to predict patient prognosis in liver cancer. J Clin Oncol 2020; 38 (15 suppl): 4593–4593. doi: 10.1200/JCO.2020.38.15_suppl.4593.

53. Ravaioli M, Grazi GL, Pisciglia F et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patiants initially outside of the Milan selection criterie. Am J Transplant 2008; 8 (12): 254–757. doi: 10.1111/j.1600-6143.2008.02409.x.

54. Sapisochin G, Goldaracena N, Laurence JM et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology 2016; 64 (6): 2077–2088. doi: 10.1002/hep.28643.

55. Sun DW, An L, Wei F et al. Prognostic significance of parameters from pretreatment (18) F-FDG PET in hepatocellular carcinoma: a meta-analysis. Abdom Radiol (NY) 2016; 41 (1): 33–41. doi: 10.1007/s00261-015- 0603-9.

56. Pomfret EA, Washburn K, Wald C et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 2010; 16 (3): 262–278. doi: 10.1002/lt.21999.

57. Bhoori S, Sposito C, Germini A et al. The challenges of liver transplantation for hepatocellular carcinoma on cirrhosis. Transpl Int 2010; 23 (7): 712–722. doi: 10.1111/j.1432-2277.2010.01111.x.

58. Vitale A, Volk ML, Pastorelli D et al. Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation: a cost-benefit analysis while awaiting data on sorafenib safety. Hepatology 2010; 51 (1): 165–173. doi: 10.1002/hep.23260.

59. Oliverius M, Studeník P. Transplantace jater pro hepatocelulární karcinom. Folia Gastroenterol Hepatol 2005; 3 (Suppl 1): 69–77.

60. Belghiti J, Fuks D. Liver resection and transplantation in hepatocellular carcinoma. Liver Cancer 2012; 1 (2): 71–82. doi: 10.1159/000342403.

61. Cherqui D, Laurent A, Mocellin N et al. Liver resection for transplantable hepatocellular carcinoma: long-term survival and role of secondary liver transplantation. Ann Surg 2009; 250 (5): 738–746. doi: 10.1097/SLA.0b013e3181bd582b.

62. Wang HL, Mo DC, Zhong JH et al. Systematic review of treatment strategy for recurrent hepatocellular carcinoma: salvage liver transplantation or curative locoregional therapy. Medicine (Baltimore) 2019; 98 (8): e14498. doi: 10.1097/MD.0000000000014498.

63. Miyagawa S, Makuuchi M, Kawasaki S et al. Criteria for safe hepatic resection. Am J Surg 1995; 169 (6): 589–594. doi: 10.1016/s0002-9610 (99) 80227-x.

64. Válek V, Kala Z, Kiss I et al. Maligní ložiskové procesy jater. Diagnostika a léčba včetně minimálně invazivních metod. Praha: Grada Publishing 2006.

65. Marelli L, Stigliano R, Triantos C et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007; 30 (1): 6–25. doi: 10.1007/s00270-006-0062-3.

66. Meyers MA. Neoplasms of the digestive tract: imaging, staging, and management. Philadelphia: Lippincot Raven 1998.

67. Dodd GD 3rd, Soulen MC, Kane RA et al. Minimally invasive treatment of malignant hepatic tumors: at the threshold of a major breakthrough. Radiographics 2000; 20 (1): 9–27. doi: 10.1148/radiographics.20.1.g00ja019.

68. Dawson SL, Lee MJ, Mueller PR. Nonsurgical treatment of liver tumors: seminars in interventional radiology. Radiology 1993; 10: 2.

69. Kemeny N, Huang Y, Cohen AM et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341 (27): 2039–2048. doi: 10.1056/NEJM199912303412702.

70. 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.

71. 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.

72. Lencioni RA, Allgaier HP, Cioni D et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003; 228 (1): 235–240. doi: 10.1148/radiol.2281020718.

73. Salmi A, Turrini R, Lanzani G et al. Efficacy of radiofrequency ablation of hepatocellular carcinoma associated with chronic liver disease without cirhosis. Int J Med Sci 2008; 5 (6): 327–332. doi: 10.7150/ijms.5.327.

74. Wilhelm SM, Carter C, Tang L et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrozine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64 (19): 7099–7109. doi: 10.1158/0008-5472.CAN-04-1443.

75. Abou-Alfa GK, Johnson P, Knox JJ et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010; 304 (19): 2154–2160. doi: 10.1001/jama.2010.1672.

76. Hu B, Yang XB, Sang XT. Liver graft rejection following immune checkpoint inhibitors treatment: a review. Med Oncol 2019; 36 (11): 94. doi: 10.1007/s12032-019-1316-7.

77. Choi BO, Jang HS, Kang KM et al. Fractionated stereotactic radiotherapy in patients with primary hepatocellular carcinoma. Jpn J Clin Oncol 2006; 36 (3): 154–158. doi: 10.1093/jjco/hyi236.

78. Cárdenes HR, Price TR, Perkins SM et al. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol 2010; 12 (3): 218–225. doi: 10.1007/s12094-010-0492-x.

79. Chen H, Shen ZY, Xu W et al. Expression of P450 and nuclear receptors in normal and end-stage Chinese livers. World J Gastroenterol 2014; 20 (26): 8681–8690. doi: 10.3748/wjg.v20.i26.8681

80. Nekvindova J, Mrkvicova A, Zubanova V et al. Hepatocellular carcinoma: gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450. Biochem Pharmacol 2020; 177: 113912. doi: 10.1016/j.bcp.2020.113912.

81. Zhu AX, Kang YK, Yen CJ et al. 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; 20 (2): 282–296. doi: 10.1016/S1470-2045 (18) 30937-9.

82. Flem-Karlsen K, Nyakas M, Farstad IN et al. Soluble AXL as a marker of disease progression and survival in melanoma. PLoS One 2020; 15 (1): e0227187. doi: 10.1371/journal.pone.0227187.

83. Reichl P, Fang M, Starlinger P at al. Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma. Int J Cancer 2015; 137 (2): 385–394. doi: 10.1002/ijc.29394.

84. Brychtova V, Zampachova V, Hrstka R et al. Differential expression of anterior gradient protein 3 in intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Exp Mol Pathol 2014; 96 (3): 375–381. doi: 10.1016/j.yexmp.2014.04.002.

85. Cohen JD, Javed AA, Thoburn C et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc Natl Acad Sci U S A 2017; 114 (38): 10202–10207. doi: 10.1073/pnas.1704961114.