Ito Takanori, Yamamoto Takafumi, Nishida Kazuki, Kobayashi Yumiko, Mizuno Kazuyuki, Suzuki Takaya, Yokoyama Shinya, Yamamoto Kenta, Imai Norihiro, Ishizu Yoji, Honda Takashi, Ishigami Masatoshi, Koya Toshinari, Nakashima Sayori, Naito Takehito, Yasuda Satoshi, Kuzuya Teiji, Toyoda Hidenori, Ando Yuichi, Yoshio Sachiyo, Kawashima Hiroki
Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Division of Biostatistics, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan.
Liver Cancer. 2025 Jun 14. doi: 10.1159/000546967.
INTRODUCTION: Liver injury is a treatment-related adverse event (liver-TRAE), one of the most common complications of atezolizumab plus bevacizumab (Atez/Bev) therapy, when treating unresectable hepatocellular carcinoma (uHCC). Fever following immune checkpoint inhibitor (ICI) therapy may predict ICI-induced liver injury in various malignancy types. However, the association between fever and liver-TRAEs in patients with uHCC treated with Atez/Bev has not been investigated. We prospectively evaluated the relationship between the onset of liver-TRAEs and preceding fever and sought to identify circulating biomarkers that predict liver injury in patients with Atez/Bev-treated uHCC. METHODS: The primary outcome of this prospective, multicenter study was the association between liver-TRAEs (grade ≥2) and the presence of ICI-induced fever before the onset of liver injury. We used a multiplex bead-based immunoassay to evaluate 40 circulating proteins in the serum before and at 1, 3, and 6 weeks after initial Atez/Bev treatment. RESULTS: Among 99 patients receiving Atez/Bev, grade ≥2 liver-TRAEs occurred in 10 (10.1%) during the follow-up period (median, 14.7 months). The incidences of liver-TRAEs associated with fever before liver injury were 27.8% ( = 5/18) and 6.2% ( = 5/81) in the fever and non-fever groups, respectively. Multivariable analysis showed that the presence of fever was a significant risk factor for liver-TRAEs (odds ratio 7.57; 95% confidence interval, 1.83-33.89; = 0.006). Furthermore, the prognosis was worse in the liver-TRAE (grade ≥2) group ( = 0.065 for progression-free survival and = 0.074 for overall survival). Among patients with preceding fever, the liver-TRAE group had significantly lower CXCL-5 levels before treatment, higher IL-6 levels at 1 and 3 weeks, and lower CXCL-5, IFN-γ, and IL-10 levels at 6 weeks ( < 0.05). CONCLUSION: Fever during Atez/Bev treatment may predict liver-TRAEs, which leads to poor prognosis in patients with uHCC. Altered inflammatory cytokine and chemokine levels may help predict liver-TRAEs in patients with fever after Atez/Bev therapy.
引言：肝损伤是一种与治疗相关的不良事件（肝脏治疗相关不良事件），是阿替利珠单抗联合贝伐单抗（阿替利珠单抗/贝伐单抗）治疗不可切除肝细胞癌（uHCC）时最常见的并发症之一。免疫检查点抑制剂（ICI）治疗后发热可能预示着多种恶性肿瘤类型中ICI诱导的肝损伤。然而，接受阿替利珠单抗/贝伐单抗治疗的uHCC患者发热与肝脏治疗相关不良事件之间的关联尚未得到研究。我们前瞻性地评估了肝脏治疗相关不良事件的发生与先前发热之间的关系，并试图确定可预测接受阿替利珠单抗/贝伐单抗治疗的uHCC患者肝损伤的循环生物标志物。 方法：这项前瞻性多中心研究的主要结局是肝脏治疗相关不良事件（≥2级）与肝损伤发生前ICI诱导的发热之间的关联。我们使用基于多重珠的免疫测定法在初始阿替利珠单抗/贝伐单抗治疗前以及治疗后1、3和6周评估血清中的40种循环蛋白。 结果：在99例接受阿替利珠单抗/贝伐单抗治疗的患者中，随访期间有10例（10.1%）发生了≥2级肝脏治疗相关不良事件（中位时间为14.7个月）。肝损伤前伴有发热的肝脏治疗相关不良事件的发生率在发热组和非发热组中分别为27.8%（n = 5/18）和6.2%（n = 5/81）。多变量分析显示，发热是肝脏治疗相关不良事件的一个重要危险因素（优势比7.57；95%置信区间，1.83 - 33.89；P = 0.006）。此外，肝脏治疗相关不良事件（≥2级）组的预后较差（无进展生存期P = 0.065，总生存期P = 0.074）。在先前有发热的患者中，肝脏治疗相关不良事件组在治疗前CXCL - 5水平显著较低，在1周和3周时IL - 6水平较高，在6周时CXCL - 5、IFN - γ和IL - 10水平较低（P < 0.05）。 结论：阿替利珠单抗/贝伐单抗治疗期间发热可能预示肝脏治疗相关不良事件，这会导致uHCC患者预后不良。炎症细胞因子和趋化因子水平的改变可能有助于预测阿替利珠单抗/贝伐单抗治疗后发热患者的肝脏治疗相关不良事件。
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