Sakakida Tomoki, Ishikawa Takeshi, Uchino Junji, Chihara Yusuke, Komori Satoshi, Asai Jun, Narukawa Tsukasa, Arai Akihito, Kobayashi Tsutomu, Tsunezuka Hiroaki, Kosuga Toshiyuki, Konishi Hirotaka, Hongo Fumiya, Inoue Masayoshi, Hirano Shigeru, Ukimura Osamu, Itoh Yoshito, Taguchi Tetsuya, Takayama Koichi
Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Outpatient Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Oncol Lett. 2019 Aug;18(2):2140-2147. doi: 10.3892/ol.2019.10466. Epub 2019 Jun 12.
Programmed cell death protein-1 (PD-1) blockade therapy has improved outcomes in the treatment of advanced cancers. The therapy is well-tolerated, although it occasionally causes immune-related adverse events (irAEs). Thyroid dysfunction is one of the most common irAEs seen. Our aim was to clarify the clinical characteristics of thyroid dysfunction induced by PD-1 blockade and its association with the therapeutic effect of the treatment in advanced cancers. A total of 174 patients who received nivolumab or pembrolizumab for metastatic or unresectable advanced cancers were included in this retrospective study. The patients were divided into two groups: The thyroid dysfunction group and the euthyroid group. In the present study, the clinical characteristics, the association with anti-thyroid antibodies, as well as the progression-free survival (PFS) and overall survival (OS) were estimated. An adjusted Cox proportional hazard regression model was used to evaluate prognostic factors for OS and PFS. This study showed that 25 out of 150 patients (16.7%) developed immune-related thyroid dysfunction. Hypothyroidism occurred in the early stage of the clinical course (median: 12 weeks); subsequently, 9 of the 25 patients underwent a transient period of hyperthyroidism, all with mild symptoms. The presence of positive anti-thyroid antibodies at baseline was significantly higher in the thyroid dysfunction group (13/22) than in the euthyroid group (18/100, P=0.0002). Moreover, PFS (median: 66 vs. 27 weeks, hazard ratio (HR): 0.50, 95% CI: 0.26-0.89, P=0.02) and OS (median 156 vs. 59 weeks, HR: 0.34, 95% CI: 0.13-0.75, P=0.01) were significantly longer in the thyroid dysfunction group than in the euthyroid group. Multivariable analysis also revealed that thyroid dysfunction was an independent prognostic factor for OS (HR: 0.42, 95% CI: 0.16-0.97, P=0.04). These findings may enable the early recognition and appropriate management of thyroid dysfunction, and help in maximizing the therapeutic effect of PD-1 blockade.
程序性细胞死亡蛋白1（PD-1）阻断疗法改善了晚期癌症的治疗效果。该疗法耐受性良好，尽管偶尔会引起免疫相关不良事件（irAE）。甲状腺功能障碍是最常见的irAE之一。我们的目的是阐明PD-1阻断引起的甲状腺功能障碍的临床特征及其与晚期癌症治疗效果的关联。这项回顾性研究纳入了174例接受纳武单抗或派姆单抗治疗转移性或不可切除晚期癌症的患者。患者被分为两组：甲状腺功能障碍组和甲状腺功能正常组。在本研究中，评估了临床特征、与抗甲状腺抗体的关联以及无进展生存期（PFS）和总生存期（OS）。使用校正后的Cox比例风险回归模型评估OS和PFS的预后因素。本研究显示，150例患者中有25例（16.7%）发生了免疫相关甲状腺功能障碍。甲状腺功能减退发生在临床病程早期（中位时间：12周）；随后，25例患者中有9例经历了短暂的甲状腺功能亢进期，均症状较轻。甲状腺功能障碍组基线时抗甲状腺抗体阳性率（13/22）显著高于甲状腺功能正常组（18/100，P=0.0002）。此外，甲状腺功能障碍组的PFS（中位时间：66周对27周，风险比（HR）：0.50，95%置信区间：0.26-0.89，P=0.02）和OS（中位时间156周对59周，HR：0.34，95%置信区间：0.13-0.75，P=0.01）显著长于甲状腺功能正常组。多变量分析还显示，甲状腺功能障碍是OS的独立预后因素（HR：0.42，95%置信区间：0.16-0.97，P=0.04）。这些发现可能有助于早期识别和适当管理甲状腺功能障碍，并有助于最大化PD-1阻断的治疗效果。
