Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib
Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib
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DOI：
10.1177/1758835920922051
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发表时间：
2020-01
影响因子：
4.9
通讯作者：
A. Ono;H. Aikata;M. Yamauchi;Kenichiro Kodama;W. Ohishi;Takeshi Kishi;Kazuki Ohya;Yuji Teraoka;Mitsutaka Osawa;H. Fujino;T. Nakahara;E. Murakami;D. Miki;T. Kawaoka;Hiromi Abe-Chayama;Peiyi Zhang;Songyao Liu;G. N. Makokha;M. Tsuge;M. Imamura;C. N. Hayes;K. Chayama
中科院分区：
文献类型：
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作者：
A. Ono;H. Aikata;M. Yamauchi;Kenichiro Kodama;W. Ohishi;Takeshi Kishi;Kazuki Ohya;Yuji Teraoka;Mitsutaka Osawa;H. Fujino;T. Nakahara;E. Murakami;D. Miki;T. Kawaoka;Hiromi Abe-Chayama;Peiyi Zhang;Songyao Liu;G. N. Makokha;M. Tsuge;M. Imamura;C. N. Hayes;K. Chayama
背景资料：尽管基于III期REFLECT试验，乐伐替尼最近被批准用于治疗晚期不可切除的肝细胞癌（HCC），但尚未建立用于管理乐伐替尼治疗的生物标志物。本研究的目的是确定乐伐替尼治疗晚期HCC患者的预测性生物标志物。方法：回顾性分析41例晚期肝癌患者的临床资料。采用多重Luminex法测定22种循环细胞因子和血管生成因子（CAF）的血清水平。评价CAF、临床化学/血液学参数和临床背景的特征，以探索与临床结局相关的生物标志物。结果如下：相对剂量强度（RDI）在第1-2周和第3-4周之间显著降低（p < 0.001），第3-4周期间的RDI是无进展生存期（PFS）的重要指标。基于与低RDI相关的9种CAF的基线血清水平的特征被确定。在多变量考克斯回归分析中，具有有利的9-CAF特征[风险比（HR）0.42，95%置信区间（CI）0.18-0.96，p = 0.040]的患者风险较低，Child-Pugh分级为B。（HR 1.6，95% CI 1.1-8.3，p = 0.026）和存在大血管浸润（MVI; HR 2.9，95% CI 1.0-8.3，p = 0.045）的患者PFS较短的风险较高。结论：本研究证明RDI是乐伐替尼治疗期间PFS延长的重要预测因素。在这一产生假设的探索性分析中，我们报告了与不良事件和RDI相关的CAF特征可以预测PFS，这可能有助于改善HCC患者中乐伐替尼治疗的管理。
Background: Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients. Methods: A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulating cytokines and angiogenic factors (CAFs) were measured by multiplex Luminex assay. Profiles of CAFs, clinical chemistry/hematology parameters, and clinical background were evaluated to explore biomarkers associated with clinical outcomes. Results: Relative dose intensity (RDI) decreased significantly between weeks 1–2 and 3–4 (p < 0.001), and RDI during weeks 3–4 was a prominent indicator of progression-free survival (PFS). A signature based on baseline serum levels of nine CAFs associated with low RDI was identified. In a multivariate Cox regression analysis, patients with a favorable 9-CAFs signature [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.18–0.96, p = 0.040] had lower risk, and Child-Pugh grade B (HR 1.6, 95% CI 1.1–8.3, p = 0.026) and presence of macrovascular invasion (MVI; HR 2.9, 95% CI 1.0–8.3, p = 0.045) had higher risk of shorter PFS. Conclusion: This study demonstrates that RDI is an important predictive factor for longer PFS during lenvatinib treatment. In this hypothesis-generating exploratory analysis, we report that a CAF-signature associated with adverse events and RDI could predict PFS, which might contribute to improved management of lenvatinib treatment in HCC patients.