Impact Of Perioperative Administration Of Glucocorti-coids On The Patients With Non-small Cell Lung Cancer

Part I:Impact of Perioperative Administration of Glucocorti-coids on the Peripheral Immune Cells and Inflammatory Cyto-kinesPurpose:Although medical treatment of non-small cell lung cancer is rapidly evolving,surgical resection remains a mainstay in the cure and control of early-stage non-small cell lung cancer.Surgery-induced immunosuppression is associated with infectious complica-tions and cancer recurrence.Glucocorticoids are effective anti-inflammatory drugs com-monly used in non-small cell lung cancer patients to treat a variety of indications.Given the immunosuppressive properties of glucocorticoids,there is understandable concern that the administration of glucocorticoids may deepen already existing injuries by surgical trauma in the immune system.Therefore,this study aimed to assess the effect of perioperative ad-ministration of glucocorticoids on the immune response to surgery in patients with non-small cell lung cancer by comparing lymphocyte subsets,lymphocyte functions,and inflam-matory cytokines between those who did or did not receive glucocorticoids.Methods:105 patients with non-small cell lung cancer who underwent surgical resection were included in the present study.Lymphocyte subsets,lymphocyte functions,and inflam-matory cytokines were prospectively evaluated in peripheral blood before surgery,then on the first day and seventh day postoperatively.Patients were grouped into the no glucocorti-coids group(n=38)and the glucocorticoids group(n=67)according to the use of glucocor-ticoids between the first time and second time of blood sampling.Immune cells and inflam-matory cytokines were compared between different time points and groups.Results:All peripheral immune components included in this study significantly altered in response to surgery,including the reduced absolute number of immune cells and elevated inflammatory cytokines.The recovery was detected at 7 days postoperatively,although still significantly lower than preoperative levels.The absolute numbers of total lymphocytes(P=0.002),T cells(P<0.001),CD4~+T cells(P=0.001),CD8~+T cells(P=0.002),B cells(P=0.002),CD4~+IFN-γ~+T cells(P=0.001),and CD8~+IFN-γ~+T cells(P=0.008)were significantly lower in the glucocorticoids group compared with the no glucocorticoids group at 1 day postoperatively.After propensity score matching immune cells were still lower in the glucocorticoids group compared to the no glucocorticoids group.Then the glucocorti-coids group was divided into the single-dose group and multiple-dose group and immune cells were compared between these three groups.Multiple doses of glucocorticoids were significantly associated with the decreased absolute number of immune cells while a single dose was not.Then the glucocorticoids group was divided into 5-10 mg(dexamethasone equivalent)group and 15-20 mg group,comparison between these three groups showed that immune cells in the 5-10 mg group and 15-20 mg group were both lower than the no gluco-corticoids group.Levels of inflammatory cytokines at 1 day postoperatively were similar between those who did or did not receive glucocorticoids.There were no differences in the incidence of postoperative events between the glucocorticoids group and the no glucocorti-coids group.Conclusions:In summary,thoracic surgery is associated with decreased absolute number of immune cells and impaired function,and perioperative administration of glucocorticoids further reduce the absolute number of immune cells and impair immune cell function.Part II:Impact of Perioperative Administration of Glucocorticoids on the Long-term Prognosis in Patients with Non-Small Cell Lung CancerPurpose: Surgery-induced immunosuppression is associated with poor long-term outcomes in cancer patients.Perioperative administration of glucocorticoids may deepen already existing injuries by surgical resection in the immune system and hence affect the long-term outcomes in cancer patients.The present study aimed to assess the effect of perioperative use of glucocorticoids on the long-term outcomes in patients with non-small cell lung cancer.Methods: 1066 patients with lung cancer who underwent surgical resection and received glucocorticoids during the perioperative periods from May 2015 to December 2016 were included in the study.672 patients received glucocorticoids of <10 mg(dexamethasone equivalent)and 394 patients received glucocorticoids of ≥10 mg.The propensity score matching method was used to achieve a balanced exposure group at baseline variables.Univariable and multivariable analyses were used to analyze the impact of perioperative use of glucocorticoids on overall survival,progression-free survival,and metastasis-free survival.Statistical tests of interaction and subgroup analysis were undertaken to evaluate whether the treatment effect differs across subgroups.Finally,the COX model with restricted cubic splines was used to evaluate the relationship between dose and times of glucocorticoids with overall survival,progression-free survival,and metastasis-free survival.Results: After propensity score matching,the 5-year overall survival in the <10 mg glucocorticoids group and ≥10 mg glucocorticoids group were 72.8% and 68.2% respectively,the 5-year progression-free survival in the <10 mg glucocorticoids group and ≥10 mg glucocorticoids group were 69.5% and 63.7% respectively,the 5-year metastasis-free survival in <10 mg glucocorticoids group and ≥10 mg glucocorticoids group were 77.2% and 70.1% respectively.Multivariable analysis showed that perioperative administration of glucocorticoids was only significantly associated with poor overall survival in the following subgroups of patients: age <65 years(HR:1.559,95%CI: 1.161-2.093,P=0.003),ASA class II (HR:1.419,95% CI:1.068-1.886,P<0.001),open surgery(HR:1.569,95% CI: 1.145-2.150,P=0.005),and patients who did not receive blood transfusion(HR:1.797,95% CI: 1.108-2.913,P=0.016).The multivariable analysis also showed that perioperative administration of glucocorticoids was significantly associated with poor progression-free survival(HR:1.300,95%CI: 1.018-1.650,P=0.035)and poor metastasis-free survival(HR:1.437,95%CI: 1.085-1.903,P=0.012).The COX model with restricted cubic splines of overall survival showed that the mortality risk reach its maximal value when the total dose of glucocorticoids was 20 mg or the total times of glucocorticoids were three.The COX model with restricted cubic splines of progression-free survival and metastasis-free survival showed similar results.Conclusions: For patients with non-small cell lung cancer,perioperative administration of ≥10 mg glucocorticoids is an independent factor of overall survival in the following subgroup patients,age < 65 years,ASA class II,open surgery,and patients who did not receive blood transfusion.Perioperative use of ≥ 10 mg glucocorticoids is an independent factor of progression-free survival and metastasis-free survival.