Retrospective Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jul 24, 2022; 13(7): 641-651
Published online Jul 24, 2022. doi: 10.5306/wjco.v13.i7.641
Necessity of neutrophil-to-lymphocyte ratio monitoring for hypothyroidism using nivolumab in patients with cancer
Ako Gannichida, Yusuke Nakazawa, Akira Kageyama, Hirofumi Utsumi, Kazuyoshi Kuwano, Takashi Kawakubo
Ako Gannichida, Yusuke Nakazawa, Akira Kageyama, Takashi Kawakubo, Department of Pharmacy, The Jikei University Hospital, Tokyo 105-8471, Japan
Hirofumi Utsumi, Kazuyoshi Kuwano, Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
Author contributions: Gannichida A drafted the article and collected the data; Nakazawa Y designed the research; Nakazawa Y and Kageyama A analyzed and interpreted the data; Utsumi H and Kuwano K provided clinical advice; Nakazawa Y, Kageyama A, Utsumi H, Kuwano K, and Kawakubo T contributed to the critical revision of the article for important intellectual content; Kawakubo T provided the final approval for this article.
Institutional review board statement: The study protocol was approved by the Ethics Committee of the Jikei University [No. 31-048 (9547)].
Informed consent statement: This study was a retrospective observational study conducted using the opt-out method. Informed consent for the study was not required because the analysis used anonymous clinical data obtained after each patient had agreed to treatment through written consent. For full disclosure, the details of the study were mentioned in the opt-out document in the Jikei University School of Medicine.
Conflict-of-interest statement: Kazuyoshi Kuwano received study support from Ono Pharmaceutical Co., Ltd., Astellas Pharma Inc., Kyorin Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. These companies did not have a role in conducting this study. All authors have no financial relationships to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Yusuke Nakazawa, MDS, Assistant Lecturer, Department of Pharmacy, The Jikei University Hospital, 3-19-18 Nishi Shimbashi, Minato-ku, Tokyo 105-8471, Japan.
Received: February 5, 2022
Peer-review started: February 5, 2022
First decision: May 12, 2022
Revised: June 1, 2022
Accepted: June 21, 2022
Article in press: June 21, 2022
Published online: July 24, 2022

Low neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with a favorable therapeutic response to nivolumab. The activation of immunocompetent cells such as lymphocytes exhibits an antitumor effect; however, the development of excessive immune responses in autologous organs along with the breakdown of self-tolerance causes immune-related adverse events, including hypothyroidism. Therefore, the possibility that NLR is associated with immune response shows that NLR can be not only a predictive factor for good response to nivolumab but also a predictive factor for the development of hypothyroidism.


To evaluate whether continuous NLR monitoring during nivolumab treatment is useful for predicting the incidence and onset period of hypothyroidism.


This retrospective study comprised patients who received nivolumab for treating all types of cancer at our hospital between January 2015 and December 2019. The NLRs of patients were measured before each administration, and the patients were followed up till the administration of 12 doses. NLR at treatment initiation was compared between patients with and without hypothyroidism. Patients who developed hypothyroidism were categorized into three groups: those with NLR < 3.5, 3.5 to < 5, and ≥ 5 according to their maximum NLR from treatment initiation to hypothyroidism development. Further, the onset periods of hypothyroidism were compared between the groups.


Overall, 104 patients were included in the analysis. Twenty-one patients developed hypothyroidism throughout the observation period. NLR at treatment initiation was significantly lower (2.54 ± 1.21 vs 4.58 ± 4.03; P = 0.017) in patients with hypothyroidism than in those without hypothyroidism, and patients with NLR < 5 had a significantly higher incidence of hypothyroidism than those with NLR ≥ 5 (26%: 20 of 78 patients vs 4%: 1 of 26 patients; P = 0.022). Additionally, treatment continuity in patients with hypothyroidism was significantly longer than in those without hypothyroidism (median not reached vs 7 times administration, P = 0.010). Patients with maximum NLR < 3.5 until the development of hypothyroidism had a significantly earlier onset of hypothyroidism than those with maximum NLR ≥ 5 (hazard ratio for low tertile [NLR < 3.5] vs high tertile [NLR ≥ 5]: 5.33, P = 0.011).


Low NLR at treatment initiation increases the incidence of treatment-induced hypothyroidism. Furthermore, its persistence may be a risk factor for the early onset of hypothyroidism.

Keywords: Nivolumab, Hypothyroidism, Immune checkpoint inhibitors, Immune-related adverse event, Neutrophil-to-lymphocyte ratio

Core Tip: This study evaluated whether continuous monitoring of neutrophil-to-lymphocyte ratio (NLR) during nivolumab treatment is useful for predicting the incidence and onset period of hypothyroidism. Patients with hypothyroidism had a significantly lower NLR at treatment initiation, and hypothyroidism incidence was higher among those with NLR < 5. Patients with persistently low NLR (< 3.5) developed hypothyroidism earlier than those with an NLR of 3.5 to < 5 and ≥ 5. Low NLR at treatment initiation increases the incidence of treatment-induced hypothyroidism. Furthermore, its persistence may be a risk factor for the early onset of hypothyroidism.