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Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Hepatocellular Carcinoma | Research article

One day versus two days of hepatic arterial infusion with oxaliplatin and fluorouracil for patients with unresectable hepatocellular carcinoma

Authors: Zhicheng Lai, Yexing Huang, Dongsheng Wen, Xuanjia Lin, Anna Kan, Qijiong Li, Wei Wei, Minshan Chen, Li Xu, Minke He, Ming Shi

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin and 5-fluorouracil was effective in unresectable hepatocellular carcinoma (HCC). The program of FOLFOX-HAIC in HCC was performed for 1 day (HAIC 1d) or 2 days (HAIC 2d). We hereby retrospectively compared the efficacy and safety between these two treatment regimens and explored the predictive power of thymidylate synthase (TYMS), an enzyme involved in the DNA synthesis process and metabolism of fluorouracil.

Methods

This study included patients with a primary diagnosis of unresectable HCC. These patients received HAIC for 1 day or 2 days. The overall survival (OS), progression-free survival (PFS), tumor response, and adverse events were compared. The propensity score matching (PSM) was used to reduce bias. Peripheral blood samples before the treatments were collected and used to measure the concentration of TYMS through enzyme-linked immunosorbent assay (ELISA). ELISA was performed according to the manufacturers’ guidelines.

Results

We included 368 patients for this study: 248 in the HAIC 1d group and 120 in the HAIC 2d group. There was no significant difference of OS between the two groups (14.5 for HAIC 1d vs 15.3 months for HAIC 2d, p=0.46). Compared with the HAIC 1d group, the HAIC 2d group did not prolong the PFS (7.3 vs 7.5 months, p=0.91) or elevate the tumor response (42.5% vs 39.1%, p=0.53) per RECIST 1.1. In the PSM cohort, the efficacy between the two groups was similar. The total frequencies of grade 3–4 events were higher with the HAIC 2d group than with the HAIC 1d group, especially in the PSM cohort (p=0.043). Additionally, patients with TYMS low level might benefit longer OS from the HAIC 2d group (18.7 vs 13.6 months, p=0.014).

Conclusions

There was not much of a difference in efficacy between the two groups, but the HAIC for 1 day might be safer, which needed further research. The level of TYMS might be the predictive biomarkers.
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Literature
1.
go back to reference European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L: EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.CrossRef European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L: EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.CrossRef
3.
go back to reference Kim BH, Lim YS, Kim EY, et al. Temporal improvement in survival of patients with hepatocellular carcinoma in a hepatitis B virus-endemic population. J Gastroenterol Hepatol. 2018;33:475–83.CrossRefPubMed Kim BH, Lim YS, Kim EY, et al. Temporal improvement in survival of patients with hepatocellular carcinoma in a hepatitis B virus-endemic population. J Gastroenterol Hepatol. 2018;33:475–83.CrossRefPubMed
4.
go back to reference 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;391:1163–73.CrossRefPubMed 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;391:1163–73.CrossRefPubMed
5.
go back to reference Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.CrossRefPubMed Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.CrossRefPubMed
6.
go back to reference Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMed Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMed
7.
go back to reference Kudo M, Ueshima K, Chan S, et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh A liver function: a proof-of-concept study. Cancers (Basel). 2019;11(8):1084. Kudo M, Ueshima K, Chan S, et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh A liver function: a proof-of-concept study. Cancers (Basel). 2019;11(8):1084.
8.
go back to reference Breder VV, Vogel A, Merle P, et al. IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global Ph III study. J Clin Oncol. 2021;39:4073.CrossRef Breder VV, Vogel A, Merle P, et al. IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global Ph III study. J Clin Oncol. 2021;39:4073.CrossRef
9.
go back to reference Li Q-J, He M-K, Chen H-W, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III trial. J Clin Oncol. 2022;40(2):150–60. Li Q-J, He M-K, Chen H-W, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III trial. J Clin Oncol. 2022;40(2):150–60.
10.
go back to reference He M, Li Q, Zou R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5(7):953–60. He M, Li Q, Zou R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5(7):953–60.
11.
go back to reference He M, Ming S, Lai Z, et al. A phase II trial of lenvatinib plus toripalimab and hepatic arterial infusion chemotherapy as a first-line treatment for advanced hepatocellular carcinoma (LTHAIC study). J Clin Oncol. 2021;39:4083.CrossRef He M, Ming S, Lai Z, et al. A phase II trial of lenvatinib plus toripalimab and hepatic arterial infusion chemotherapy as a first-line treatment for advanced hepatocellular carcinoma (LTHAIC study). J Clin Oncol. 2021;39:4083.CrossRef
12.
go back to reference He MK, Liang RB, Zhao Y, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720.CrossRefPubMedPubMedCentral He MK, Liang RB, Zhao Y, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720.CrossRefPubMedPubMedCentral
13.
go back to reference Xu YJ, Lai ZC, He MK, et al. Toripalimab combined with hepatic arterial infusion chemotherapy versus lenvatinib for advanced hepatocellular carcinoma. Technol Cancer Res Treat. 2021;20:15330338211063848.CrossRefPubMedPubMedCentral Xu YJ, Lai ZC, He MK, et al. Toripalimab combined with hepatic arterial infusion chemotherapy versus lenvatinib for advanced hepatocellular carcinoma. Technol Cancer Res Treat. 2021;20:15330338211063848.CrossRefPubMedPubMedCentral
14.
go back to reference Zhang J, Zhang X, Mu H, et al. Surgical conversion for initially unresectable locally advanced hepatocellular carcinoma using a triple combination of angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy: a retrospective study. Front Oncol. 2021;11:729764.CrossRefPubMedPubMedCentral Zhang J, Zhang X, Mu H, et al. Surgical conversion for initially unresectable locally advanced hepatocellular carcinoma using a triple combination of angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy: a retrospective study. Front Oncol. 2021;11:729764.CrossRefPubMedPubMedCentral
15.
go back to reference Liu BJ, Gao S, Zhu X, et al. Real-world study of hepatic artery infusion chemotherapy combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors for advanced hepatocellular carcinoma. Immunotherapy. 2021;13:1395–405.CrossRefPubMed Liu BJ, Gao S, Zhu X, et al. Real-world study of hepatic artery infusion chemotherapy combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors for advanced hepatocellular carcinoma. Immunotherapy. 2021;13:1395–405.CrossRefPubMed
16.
go back to reference Chen LT, Martinelli E, Cheng AL, et al. Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO. Ann Oncol. 2020;31:334–51.CrossRefPubMed Chen LT, Martinelli E, Cheng AL, et al. Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO. Ann Oncol. 2020;31:334–51.CrossRefPubMed
17.
go back to reference Lyu N, Lin Y, Kong Y, et al. FOXAI: a phase II trial evaluating the efficacy and safety of hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin for advanced hepatocellular carcinoma. Gut. 2018;67:395–6.CrossRefPubMed Lyu N, Lin Y, Kong Y, et al. FOXAI: a phase II trial evaluating the efficacy and safety of hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin for advanced hepatocellular carcinoma. Gut. 2018;67:395–6.CrossRefPubMed
18.
go back to reference Lyu N, Kong Y, Mu L, et al. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018;69:60–9.CrossRefPubMed Lyu N, Kong Y, Mu L, et al. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018;69:60–9.CrossRefPubMed
19.
go back to reference Li S, Zhong C, Li Q, et al. Neoadjuvant transarterial infusion chemotherapy with FOLFOX could improve outcomes of resectable BCLC stage A/B hepatocellular carcinoma patients beyond Milan criteria: an interim analysis of a multi-center, phase 3, randomized, controlled clinical trial. J Clin Oncol. 2021;39:4008.CrossRef Li S, Zhong C, Li Q, et al. Neoadjuvant transarterial infusion chemotherapy with FOLFOX could improve outcomes of resectable BCLC stage A/B hepatocellular carcinoma patients beyond Milan criteria: an interim analysis of a multi-center, phase 3, randomized, controlled clinical trial. J Clin Oncol. 2021;39:4008.CrossRef
20.
go back to reference Lyu N, Wang X, Li J-B, et al. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1). J Clin Oncol. 2021;0:JCO.21.01963. Lyu N, Wang X, Li J-B, et al. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1). J Clin Oncol. 2021;0:JCO.21.01963.
21.
go back to reference Li B, Qiu J, Zheng Y, et al. Conversion to resectability using transarterial chemoembolization combined with hepatic arterial infusion chemotherapy for initially unresectable hepatocellular carcinoma. Ann Surg Open. 2021;2:2691–3593 (Online) Li B, Qiu J, Zheng Y, et al. Conversion to resectability using transarterial chemoembolization combined with hepatic arterial infusion chemotherapy for initially unresectable hepatocellular carcinoma. Ann Surg Open. 2021;2:2691–3593 (Online)
22.
go back to reference Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330–8.CrossRefPubMed Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330–8.CrossRefPubMed
23.
go back to reference Peters G, Backus H, Freemantle S, et al. Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochim Biophys Acta. 2002;1587:194–205.CrossRefPubMed Peters G, Backus H, Freemantle S, et al. Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochim Biophys Acta. 2002;1587:194–205.CrossRefPubMed
24.
go back to reference He MK, Zou RH, Li QJ, et al. Phase II study of sorafenib combined with concurrent hepatic arterial infusion of oxaliplatin, 5-fluorouracil and leucovorin for unresectable hepatocellular carcinoma with major portal vein thrombosis. Cardiovasc Intervent Radiol. 2018;41:734–43.CrossRefPubMed He MK, Zou RH, Li QJ, et al. Phase II study of sorafenib combined with concurrent hepatic arterial infusion of oxaliplatin, 5-fluorouracil and leucovorin for unresectable hepatocellular carcinoma with major portal vein thrombosis. Cardiovasc Intervent Radiol. 2018;41:734–43.CrossRefPubMed
25.
go back to reference He MK, Le Y, Li QJ, et al. Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma: a prospective non-randomized study. Chin J Cancer. 2017;36:83.CrossRefPubMedPubMedCentral He MK, Le Y, Li QJ, et al. Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma: a prospective non-randomized study. Chin J Cancer. 2017;36:83.CrossRefPubMedPubMedCentral
26.
go back to reference Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefPubMed Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefPubMed
27.
go back to reference Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.CrossRefPubMed Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.CrossRefPubMed
28.
go back to reference Sadahiro S, Suzuki T, Ishikawa K, et al. Pharmacokinetics of 5-fluorouracil following hepatic intra-arterial infusion in a VX2 hepatic metastasis model. Jpn J Clin Oncol. 2003;33:377–81.CrossRefPubMed Sadahiro S, Suzuki T, Ishikawa K, et al. Pharmacokinetics of 5-fluorouracil following hepatic intra-arterial infusion in a VX2 hepatic metastasis model. Jpn J Clin Oncol. 2003;33:377–81.CrossRefPubMed
29.
go back to reference De Mattia E, Toffoli G. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur J Cancer. 2009;45:1333–51.CrossRefPubMed De Mattia E, Toffoli G. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur J Cancer. 2009;45:1333–51.CrossRefPubMed
30.
go back to reference Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16:1639–50.CrossRefPubMed Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16:1639–50.CrossRefPubMed
31.
go back to reference Lima A, Azevedo R, Sousa H, et al. Current approaches for TYMS polymorphisms and their importance in molecular epidemiology and pharmacogenetics. Pharmacogenomics. 2013;14:1337–51.CrossRefPubMed Lima A, Azevedo R, Sousa H, et al. Current approaches for TYMS polymorphisms and their importance in molecular epidemiology and pharmacogenetics. Pharmacogenomics. 2013;14:1337–51.CrossRefPubMed
Metadata
Title
One day versus two days of hepatic arterial infusion with oxaliplatin and fluorouracil for patients with unresectable hepatocellular carcinoma
Authors
Zhicheng Lai
Yexing Huang
Dongsheng Wen
Xuanjia Lin
Anna Kan
Qijiong Li
Wei Wei
Minshan Chen
Li Xu
Minke He
Ming Shi
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02608-6

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