Clinical features of immune‑related thyroid dysfunction and its association with outcomes in patients with advanced malignancies treated by PD‑1 blockade

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

doi:10.3892/ol.2019.10466

Clinical features of immune‑related thyroid dysfunction and its association with outcomes in patients with advanced malignancies treated by PD‑1 blockade

Authors:
- Tomoki Sakakida
- Takeshi Ishikawa
- Junji Uchino
- Yusuke Chihara
- Satoshi Komori
- Jun Asai
- Tsukasa Narukawa
- Akihito Arai
- Tsutomu Kobayashi
- Hiroaki Tsunezuka
- Toshiyuki Kosuga
- Hirotaka Konishi
- Fumiya Hongo
- Masayoshi Inoue
- Shigeru Hirano
- Osamu Ukimura
- Yoshito Itoh
- Tetsuya Taguchi
- Koichi Takayama
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Affiliations: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan, Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan, Outpatient Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan, Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan, Department of Urology, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan, Department of Otolaryngology‑Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan, Department of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan, Division of Thoracic Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan, Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
Published online on: June 12, 2019 https://doi.org/10.3892/ol.2019.10466
Pages: 2140-2147

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Abstract

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.

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