Changes in plasma interleukin-8 and tumor necrosis factor-α levels during the early treatment period as a predictor of the response to sorafenib in patients with unresectable hepatocellular carcinoma
- 77 Downloads
This study aimed to identify a biomarker for predicting the response to sorafenib in patients with hepatocellular carcinoma (HCC).
Of 100 patients with unresectable HCC who received sorafenib treatment in our institute (Cohort A), 48 had stored plasma samples collected within 28 days before the start of treatment (Cohort B). Concentrations of 18 plasma cytokines were measured in plasma samples using a sandwich immunoassay with multiplexed fluorescent bead-based technology. Among 27 patients with follow-up plasma samples taken at 5–10 days of treatment (Cohort C), changes in the 18 cytokines were also evaluated.
In Cohort A, progressive disease (PD) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) was associated with poor overall survival by multivariate analysis (p = 0.024). In Cohort B, no significant differences in baseline concentrations of α-fetoprotein, des-γ-carboxy prothrombin, or the 18 cytokines were found between patients with PD and those with stable disease (SD) or partial response (PR). In Cohort C, the increase in interleukin-8 and tumor necrosis factor-α (TNF-α) was significant in the PD group (p = 0.0063 and p < 0.001, respectively) but not in the SD + PR group (p = 0.67 and p = 0.15, respectively). In addition, the fold changes in interleukin-8 and in TNF-α were correlated (p < 0.001, r = 0.67).
Changes in plasma interleukin-8 and TNF-α levels during the first few days could predict the response to sorafenib therapy in HCC patients.
KeywordsBiomarker HCC IL-8 Prediction Sorafenib TNF-α
The authors are grateful to Ms. Yoko Yasuhara, Ms. Sanae Deguchi, and Ms. Ayano Fujikawa for her technical assistance and to Dr. Misako Sato-Matsubara for her valuable comments on this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
- 3.Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390CrossRefGoogle Scholar
- 4.Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10(1):25–34CrossRefGoogle Scholar
- 5.Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G, RESORCE Investigators (2017) Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389(10064):56–66CrossRefGoogle Scholar
- 6.Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng ALK (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. https://doi.org/10.1016/S0140-6736(18)30207-1 CrossRefPubMedGoogle Scholar
- 7.Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK (2018) Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379(1):54–63CrossRefGoogle Scholar
- 8.El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH, Rd Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088):2492–2502CrossRefGoogle Scholar
- 10.Miyahara K, Nouso K, Tomoda T, Kobayashi S, Hagihara H, Kuwaki K, Toshimori J, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Yamamoto K (2011) Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 26(11):1604–1611CrossRefGoogle Scholar
- 11.Miyahara K, Nouso K, Morimoto Y, Takeuchi Y, Hagihara H, Kuwaki K, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Honda M, Kaneko S, Sato T, Sato S, Obi S, Iwadou S, Kobayashi Y, Takaguchi K, Kariyama K, Takuma Y, Takabatake H, Yamamoto K, Okayama Liver Cancer Group (2013) Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma. Br J Cancer 109(8):2072–2078CrossRefGoogle Scholar
- 15.Kaneko S, Furuse J, Kudo M, Ikeda K, Honda M, Nakamoto Y, Onchi M, Shiota G, Yokosuka O, Sakaida I, Takehara T, Ueno Y, Hiroishi K, Nishiguchi S, Moriwaki H, Yamamoto K, Sata M, Obi S, Miyayama S, Imai Y (2012) Guideline on the use of new anticancer drugs for the treatment of Hepatocellular Carcinoma 2010 update. Hepatol Res 42(6):523–542CrossRefGoogle Scholar
- 19.Lencioni R, Montal R, Torres F, Park JW, Decaens T, Raoul JL, Kudo M, Chang C, Ríos J, Boige V, Assenat E, Kang YK, Lim HY, Walters I, Llovet JM (2017) Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC. J Hepatol 66(6):1166–1172CrossRefGoogle Scholar
- 26.Ueshima K, Kudo M, Takita M, Nagai T, Tatsumi C, Ueda T, Kitai S, Ishikawa E, Yada N, Inoue T, Hagiwara S, Minami Y, Chung H, Sakurai T (2011) Des-γ-carboxyprothrombin may be a promising biomarker to determine the therapeutic efficacy of sorafenib for hepatocellular carcinoma. Dig Dis 29(3):321–325CrossRefGoogle Scholar