Analysis Of Influencing Factors Of PD-1 Inhibitor-related Adverse Thyroid Reactions

Background:Immune checkpoint inhibitors(ICPI)has become a new and effective treatment for malignant tumor of first-line drugs,its antitumor effect for T cell inhibitory receptor monoclonal antibodies including cytotoxic T lymphocyte antigen 4(CTLA4),programmed death 1(PD)and its ligand(PD)-L1,the nonspecific immune enhancement in addition to related antigen against tumor cells,and also against its antigen,and lead to the immune related adverse reactions(IRAEs).IRAEs integrating multiple systems,the total rate range from 15%to 90%,the common endocrine adverse reaction is mainly the pituitary body inflammation(related to CTLA4 antibody)and secondary hyperthyroidism or hypothyroidism(related to PD1,or CTLA4 PDL1 antibody),rare adrenal hypofunction,and type 1 diabetes.PD-1 is the most studied and widely used immunoregulatory factor,and has been applied in the.treatment of many malignant tumors,including melanoma,non-small cell lung cancer,small cell lung cancer,colorectal cancer,renal cell carcinoma,hepatocellular carcinoma,etc,Immune related thyroid adverse reactions are the most common,with hyperthyroidism,hypothyroidism,and autoimmune thyroiditis all reported,of which hypothyroidism is the most common.In a meta-analysis,the overall incidence of PD-1 inhibitor associated hypothyroidism was 7%,and the incidence of hypothyroidism was higher in combination immunotherapy than in monotherapy.The incidence of hyperthyroidism(2.8-3.7%)was significantly lower than that of hypothyroidism,and it was mostly a transient change before hypothyroidism.At present,there are few related clinical studies in China.Objective:This study investigated the occurrence and influencing factors of thyroid related adverse reactions caused by PD-1 inhibitors in the treatment of advanced solid tumor.Objects and Methods:A total of 127 solid tumor patients admitted to the Department of Oncology in the First Affiliated Hospital of Zhengzhou University from September 2019 to September 2020 and receiving PD-1 inhibitor based immunotherapy were collected as the research subjects,including 93 males(73.2%)and 24 females(26.8%),with an average age of(59.84±9.87)years.The thyroid function of 127 patients was normal before the application of PD-1 inhibitor,At the same time,general data of all subjects were collected,including gender,age,course of disease,solid tumor type,diabetes history,type and dose of PD-1 inhibitor,medication cycle,history of surgery before medication,history of chemotherapy,history of radiotherapy,history of tumor metastasis,history of thyroid nodule,etc,collecting peripheral blood testing thyroid hormones level(FT3,FT4 and TSH).Results:(1)Of the 127 patients;47(37%)developed abnormal thyroid function,including 17 cases of hypothyroidism and 10 cases of hyperthyroidism.The median time to TD was 62 days.(2)None of the 47 patients stopped medication due to adverse reactions,and only 3 patients with hypothyroidism were treated with levothyroxine.(3)Thyroid associated antibodies(TPOAb,TgAb,Trab)were negative at baseline in 6 patients in the normal thyroid function group.while thyroid related antibodies(TPOAb,TGAB,Trab)were detected in 8 patients in the thyroid dysfunction group at baseline,and 3 of them were positive for thyroid related antibodies.(4)Of the 127 patients,41 patients were examined by thyroid ultrasound.Among the 19 patients with thyroid dysfunction,10 patients(10/19)showed inhomogeneous internal echo by ultrasound,and 14 patients(14/19)showed no nodules by ultrasound.(5)Multiple stepwise regression analysis showed that women were more likely to have adverse thyroid reactions than men(P<0.05),female and disease duration>1 year were independent risk factors for TD(P<0.05).(6)Baseline thyroidism(FT3,FT4,TSH)and disease course of 127 patients were analyzed by ROC curve.The results showed that baseline thyroid function had no diagnostic value for thyroid dysfunction,while the course of disease has diagnostic value for thyroid dysfunction.(7)Cox regression analysis of course of disease showed that course of disease was an independent influencing factor for thyroid dysfunction(P=0.012),Compared with course of disease<1 year,patients with course of disease>1 year had a higher risk of thyroid dysfunction(HR=2.152(95%CI:1.186-3.904).Conclusion:(1)Hypothyroidism is the most common thyroid adverse reaction of PD-1 inhibitors.(2)Women and patients with disease duration≥1 year were more likely to have adverse thyroid reactions.