Cognitive adverse events in patients with lung cancer treated with checkpoint inhibitor monotherapy: a propensity score-matched analysis

Yifei Ma; Nianqi Liu; Yanqi Wang; Ao Zhang; Zirui Zhu; Zhiying Zhang; Yiming Li; Guangmin Jian; Guangzhen Fu; Mingming Dong; Guoxing Zheng; Pengfei Zhu; Guanqing Zhong; Shenrui Bai; Shuqin Chen; Xiaolong Wei; Jifan Tan; Xinjia Wang

doi:10.1016/j.eclinm.2023.101987

Cognitive adverse events in patients with lung cancer treated with checkpoint inhibitor monotherapy: a propensity score-matched analysis

EClinicalMedicine. 2023 Apr 27:59:101987. doi: 10.1016/j.eclinm.2023.101987. eCollection 2023 May.

Authors

Yifei Ma^{1

2}, Nianqi Liu³, Yanqi Wang^{2

4}, Ao Zhang⁵, Zirui Zhu⁶, Zhiying Zhang^{2

4

7}, Yiming Li⁸, Guangmin Jian⁹, Guangzhen Fu⁹, Mingming Dong², Guoxing Zheng¹, Pengfei Zhu⁹, Guanqing Zhong⁵, Shenrui Bai¹⁰, Shuqin Chen¹¹, Xiaolong Wei¹¹, Jifan Tan¹², Xinjia Wang^{1

2}

Affiliations

¹ Department of Orthopedics and Spine Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong Province, China.
² Department of Bone and Soft Tissue Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province, China.
³ Faculty of Psychology, Institute of Educational Science, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
⁴ School of Public Health, Shantou University, Shantou, Guangdong Province, China.
⁵ Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China.
⁶ Department of Thoracic Surgery, Hainan Hospital of People's Liberation Army General Hospital, Sanya, Hainan Province, China.
⁷ Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province, China.
⁸ Department of Neurosurgery, Beijing Tiantan Hospital Capital Medical University, Beijing, China.
⁹ Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Clinical Laboratory of Henan Province, Zhengzhou, Henan Province, China.
¹⁰ Department of Hematological Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China.
¹¹ Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province, China.
¹² Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.

Abstract

Background: Cancer-related cognitive decline is a serious problem in long-term survival but no pivotal study has investigated whether checkpoint inhibitors (ICI) may be associated with cognitive adverse events.

Methods: This propensity score-matched analysis recruited non-small cell lung cancer (NSCLC) patients prescribed with or without ICI monotherapy from three Chinese tertiary hospitals. Patients were excluded from study who developed brain metastasis or had disorders severely affecting cognitive abilities. Primary outcomes were changes in neuropsychological battery test (NBT) at baseline, 6- and 12-month sessions, and any NBT score changes that exceeded 3∗SD of baseline scores would be marked as objective cognitive adverse events (CoAE). Secondary endpoint was the 20-item Perceived Cognitive Impairment (PCI) sub-scale score change in Functional Assessment of Cancer Therapy-Cognitive Function questionnaire, administered at baseline, 3-, 6-, 9-, 12-, and 15-month follow-up session. Per-protocol ICI and control arms were matched with propensity scores that incorporated baseline variables to compare both NBT and PCI assessment results. Patients participating in PCI assessments were analysed in intention-to-treat analysis. Kaplan-Meier survival curves with log-rank tests were adopted to analyse incidence of perceived cognitive decline events (PCDE).

Findings: Between March 12, 2020, and March 28, 2021, 908 participants were enrolled. Compared to control, 3 of 4 subtest of NBT scores in ICI arm showed significant cognitive decline in 6- and 12-month sessions, in which Trail Making Test score change (13.56 ± 11.73) reached threshold of cognitive deficit diagnosis in the 12-month session. In 1:1 matched 292 pairs from 908 patients, PCI score changes in ICI arms were -4.26 ± 8.54 (3rd month), -4.72 ± 11.83 (6th month), -6.16 ± 15.41 (9th month), -6.07 ± 15.71 (12th month), and -7.96 ± 13.97 (15th month). The scores were significantly lower than control arm in 3-, 6-, and 12-session follow-up. The result was validated after adjusting quality of life scores and in intention-to-treat analysis. Mean PCI change exceeded 1/2 SD of baseline PCI score (5.81) in 9-, 12-, and 15-month sessions in ICI arm, but not in control arm. PCDE incidence/prevalence was significantly higher in ICI arm (incidence 26.4% vs. 5.1%, and prevalence 16.2% vs. 1.7%). Immune-related adverse events related to incidence of PCDE after adjusting for baseline variables.

Interpretation: ICI monotherapy seemed to relate to higher cognitive decline represented by score changes and incidence/prevalence rates. The decline deteriorated as treatment progressed, and immune-related adverse events seemed to be associated with higher cognitive adverse events incidence in the ICI treatment.

Funding: The Fellowship of China Postdoctoral Science Foundation and National Natural Science Foundation of China Youth Science Fund Project.

Keywords: Checkpoint inhibitor; Cognitive adverse events; Immune-related adverse events; Minimal clinically important difference; Propensity score matching.