Is Postoperative Adjuvant Transcatheter Arterial Infusion Therapy Effective for Patients with Hepatocellular Carcinoma who Underwent Hepatectomy? A Prospective Randomized Controlled Trial

Abstract

Background

The effectiveness of adjuvant transcatheter arterial chemo- or/and chemoembolization therapy after curative hepatectomy of initial hepatocellular carcinoma (HCC) is controversial. This study aimed to evaluate whether hepatectomy combined with adjuvant transcatheter arterial infusion therapy (TAI) for initial HCC has better long-term survival outcomes than hepatectomy alone.

Methods

From January 2012 to December 2014, a prospective randomized controlled trial of patients with initial HCC was conducted. Then, 114 initial HCC patients were recruited to undergo hepatectomy with adjuvant TAI (TAI group, n = 55) or hepatectomy alone (control group, n = 59) at our institution. The TAI therapy was performed twice, at 3 and 6 months after curative hepatectomy (UMIN 000011900).

Results

The patients treated with TAI had no serious side effects, and operative outcomes did not differ between the two groups. No significant differences were found in the pattern of intrahepatic recurrence or time until recurrence between the two groups. Moreover, no significant differences were found in the relapse-free survival or overall survival. Low cholinesterase level (< 200) had been identified as a risk factor affecting relapse-free survival. Furthermore, compared with surgery alone, adjuvant TAI with hepatectomy improved the overall survival for lower-cholinesterase patients.

Conclusions

Adjuvant TAI is safe and feasible, but it cannot reduce the incidence of postoperative recurrence or prolong survival for patients who underwent curative hepatectomy for initial HCC.

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References

  1. 1.

    Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50.

    PubMed  Article  Google Scholar 

  2. 2.

    Lau WY, Lai EC, Leung TW, Yu SC. Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial-update on 5-year and 10-year survival. Ann Surg. 2008;247:43–8.

    PubMed  Article  Google Scholar 

  3. 3.

    Lai EC, Lo CM, Fan ST, Liu CL, Wong J. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Arch Surg. 1998;133:183–8.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Cheng HY, Wang X, Chen D, Xu AM, Jia YC. The value and limitation of transcatheter arterial chemoembolization in preventing recurrence of resected hepatocellular carcinoma. World J Gastroenterol. 2005;11:3644–6.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Ueno S, Tanabe G, Yoshida A, Yoshidome S, Takao S, Aikou, T. Postoperative prediction of and strategy for metastatic recurrent hepatocellular carcinoma according to histologic activity of hepatitis. Cancer. 1999;86:248–54.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Boucher E, Corbinais S, Rolland Y, et al. Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology. 2003;38:1237–41.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356:802–7.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Kinoshita, H. Randomized clinical trial of long-term outcome after resection of hepatitis C virus-related hepatocellular carcinoma by postoperative interferon therapy. Br J Surg. 2002;89:418–22.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Sun HC, Tang ZY, Wang L, et al. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol. 2006;132:458–65.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Peng BG, Liang LJ, He Q, et al. Tumor vaccine against recurrence of hepatocellular carcinoma. World J Gastroenterol. 2005;11:700–4.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med. 1996;334:1561–1567.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Cammà C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 2002;224:47–54.

    PubMed  Article  Google Scholar 

  13. 13.

    Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429–42.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Ramsey DE, Geschwind JF. Chemoembolization of hepatocellular carcinoma: what to tell the skeptics: review and meta-analysis. Tech Vasc Interv Radiol. 2002;5:122–6.

    PubMed  Article  Google Scholar 

  15. 15.

    Shin SW. The current practice of transarterial chemoembolization for the treatment of hepatocellular carcinoma. Korean J Radiol. 2009;10:425–34.

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Timm S, Sotiropoulos GC, Draier M, Knüpffer J, Steger U, Lang, H. Selective transarterial chemoembolization of advanced hepatocellular carcinomas: a reasonable palliative option. Transplant Proc. 2008;40:3179–81.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Liu Y, Yang R. Preoperative combined with postoperative chemoembolization can improve survival in patients with hepatocellular carcinoma: a single-center study. J Vasc Interv Radiol. 2009;20:472–83.

    PubMed  Article  Google Scholar 

  18. 18.

    Ren ZG, Lin ZY, Xia JL, et al. Postoperative adjuvant arterial chemoembolization improves survival of hepatocellular carcinoma patients with risk factors for residual tumor: a retrospective control study. World J Gastroenterol. 2004;10:2791–4.

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Shimoda M, Bando T, Nagata T, Shirosaki I, Sakamoto T, Tsukada, K. Prophylactic chemolipiodolization for postoperative hepatoma patients. Hepatogastroenterology. 2001;48:493–7.

    CAS  PubMed  Google Scholar 

  20. 20.

    Shuqun C, Mengchao W, Han C, et al. Combination transcatheter hepatic arterial chemoembolization with thymosin alpha1 on recurrence prevention of hepatocellular carcinoma. Hepatogastroenterology. 2004;51:1445–7.

    PubMed  Google Scholar 

  21. 21.

    Izumi R, Shimizu K, Iyobe T, et al. Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology. 1994;20:295–301.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Li JQ, Zhang YQ, Zhang WZ, Yuan YF, Li GH. Randomized study of chemoembolization as an adjuvant therapy for primary liver carcinoma after hepatectomy. J Cancer Res Clin Oncol. 1995;121:364–6.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Li Q, Wang J, Sun Y, et al. Postoperative transhepatic arterial chemoembolization and portal vein chemotherapy for patients with hepatocellular carcinoma: a randomized study with 131 cases. Dig Surg. 2006;23:235–40.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Peng BG, He Q, Li JP, Zhou F. Adjuvant transcatheter arterial chemoembolization improves efficacy of hepatectomy for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Surg. 2009;198:313–8.

    PubMed  Article  Google Scholar 

  25. 25.

    Zhong C, Guo RP, Li JQ, et al. A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for stage III A hepatocellular carcinoma. J Cancer Res Clin Oncol. 2009;135:1437–45.

    PubMed  Article  Google Scholar 

  26. 26.

    Lau WY, Lai EC, Lau SH. The current role of neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for hepatocellular carcinoma: a systematic review. Hepatobil Pancreat Dis Int. 2009;8:124–133.

    CAS  Google Scholar 

  27. 27.

    Marelli L, Stigliano R, Triantos C, et al. Treatment outcomes for hepatocellular carcinoma using chemoembolization in combination with other therapies. Cancer Treat Rev. 2006;32:594–606.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Mathurin P, Raynard B, Dharancy S, et al. Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma. Aliment Pharmacol Ther. 2003;17:1247–61.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    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;2009:CD001199. https://doi.org/10.1002/14651858.CD001199.pub2.

    Article  PubMed Central  PubMed  Google Scholar 

  30. 30.

    Schwartz JD, Schwartz M, Mandeli J, Sung M. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol. 2002;3:593–603.

    PubMed  Article  Google Scholar 

  31. 31.

    Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early- and late-phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–7.

    PubMed  Article  Google Scholar 

  32. 32.

    Ishikawa T, Higuchi K, Kubota T, et al. Prevention of intrahepatic distant recurrence by transcatheter arterial infusion chemotherapy with platinum agents for stage I/II hepatocellular carcinoma. Cancer. 2011;117:4018–25.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Fan J, Zhou J, Wu ZQ, et al. Efficacy of different treatment strategies for hepatocellular carcinoma with portal vein tumor thrombosis. World J Gastroenterol. 2005;11:1215–9.

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Asahara T, Itamoto T, Katayama K, et al. Adjuvant hepatic arterial infusion chemotherapy after radical hepatectomy for hepatocellular carcinoma: results of long-term follow-up. Hepatogastroenterology. 1999;46:1042–8.

    CAS  PubMed  Google Scholar 

  35. 35.

    Feng AL, Zhu JK, Yang Y, et al. Repeated postoperative adjuvant TACE after curative hepatectomy improves outcomes of patients with HCC. Minim Invasive Ther Allied Technol. 2019. https://doi.org/10.1080/13645706.2019.1707689.

    Article  PubMed  Google Scholar 

  36. 36.

    Chen H, Hu N, Chang P. et al. Modified Glasgow prognostic score might be a prognostic factor for hepatocellular carcinoma: a meta-analysis. Panminerva Med. 2017;59:302–7.

    PubMed  Google Scholar 

  37. 37.

    Fujiwara Y, Shiba H, Furukawa K, et al. Glasgow prognostic score is related to blood transfusion requirements and postoperative complications in hepatic resection for hepatocellular carcinoma. Anticancer Res. 2010;30:5129–36.

    CAS  PubMed  Google Scholar 

  38. 38.

    Glen P, Jamieson NB, McMillan DC, et al. Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer. Pancreatology. 2006;6:450–3.

    PubMed  Article  Google Scholar 

  39. 39.

    Kobayashi T, Teruya M, Kishiki T, et al. Inflammation-based prognostic score and number of lymph node metastases are independent prognostic factors in esophageal squamous cell carcinoma. Dig Surg. 2010;27:232–7.

    PubMed  Article  Google Scholar 

  40. 40.

    Neofytou K, Smyth EC, Giakoustidis A, et al. The preoperative lymphocyte-to-monocyte ratio is prognostic of clinical outcomes for patients with liver-only colorectal metastases in the neoadjuvant setting. Ann Surg Oncol. 2015;22:4353–62.

    PubMed  Article  Google Scholar 

  41. 41.

    Donadon M, Cimino M, Procopio F, et al. Potential role of cholinesterases to predict short-term outcome after hepatic resection for hepatocellular carcinoma. Updates Surg. 2013;65:11–8.

    PubMed  Article  Google Scholar 

  42. 42.

    Donadon M, Costa G, Cimino M, et al. Safe hepatectomy selection criteria for hepatocellular carcinoma patients: a validation of 336 consecutive hepatectomies. The BILCHE score. World J Surg. 2015;39:237–43.

    PubMed  Article  Google Scholar 

  43. 43.

    Takaki S, Fukuhara T, Mori N, Tsuji K. High cholinesterase predicts tolerance to sorafenib treatment and improved prognosis in patients with transarterial chemoembolization refractory intermediate stage hepatocellular carcinoma. Mol Clin Oncol. 2020;12:60–8.

    CAS  PubMed  Google Scholar 

  44. 44.

    Barquero-Quirós M, Dominguez-Renedo O, Alonso-Lomillo MA, Arcos-Martinez MJ. Acetylcholinesterase inhibition-based biosensor for aluminum(III) chronoamperometric determination in aqueous media. Sensors Basel. 2014;14:8203–16.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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Acknowledgments

We thank Editage (www.editage.com) for English language editing.

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Correspondence to Fumitoshi Hirokawa MD, PhD.

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Hirokawa, F., Komeda, K., Taniguchi, K. et al. Is Postoperative Adjuvant Transcatheter Arterial Infusion Therapy Effective for Patients with Hepatocellular Carcinoma who Underwent Hepatectomy? A Prospective Randomized Controlled Trial. Ann Surg Oncol 27, 4143–4152 (2020). https://doi.org/10.1245/s10434-020-08699-w

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