Effects Of Antibiotics And Immune-related Adverse Events On The Efficacy In Esophageal Cancer

Esophageal cancer(EC)is one of the common malignant tumors of the digestive system,accounting for approximately 3.2% of global cancer cases and 5.3% of mortality,with a 5-year survival rate of less than 20%,making it the sixth leading cause of cancer-related death.Esophageal cancer is composed of two main pathological types: esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC).In eastern developing countries,ESCC is the predominant subtype with the main treatment including surgery,radiotherapy,chemotherapy,targeted therapy and immunotherapy.Although many advances have been made in recent decades in the diagnosis and treatment of ESCC,these methods prolonged the ESCC lifespan with a limited increase.The rates of recurrence and metastasis in esophageal cancer remain high due to the histological,molecular and etiological heterogeneity.The gut microbiota which can modulate the efficacy and toxicity of oncology treatments has been influenced by many factors such as antibiotic(ATB),dietary habits and environment.In addition,the microbiota is still involved in human metabolism,immune regulation,neurodevelopment and maintenance of the intestinal mucosal barrier,disease development and other processes.A series of evidence suggested that the transformations in the abundance or diversity of microorganisms may lead to the changes in disease pathology.ATB can alter the gastrointestinal microbiota and also cause changes in bacterial metabolites,disrupt bacterial signaling thereby leading to intestinal immune cell dysregulation and systemic immune dysfunction,and even cause changes in different pathogens and tumor microenvironments by inducing microbiota dysregulation.ATB has been associated with reduced efficacy and poor prognosis of chemotherapy in a variety of tumors including urothelial carcinoma and non-small cell lung cancer.In this study,we investigated the correlation between ATB or immune-related adverse event(ir AE)and the efficacy of combined antitumor therapy including chemotherapy and immunotherapy in ESCC,which will provide a basis for whether to apply antibiotics and probiotics during antitumor therapy,with a view to improving the prognosis in these patients.Immune checkpoint inhibitor(ICI)have recently been a source of promising new cancer treatments in ESCC that increase the cytotoxicity of T cells by blocking intrinsic downregulators of immunity such as cytotoxic Tlymphocyte antigen 4(CTLA-4)and programmed cell death protein1(PD-1)so as to enhance antitumor activity.ir AE,a type of inflammatory side effect which caused by ICI,can affect almost every organ of the body and observed most commonly in the skin,gastrointestinal tract,lung,endocrine,and musculoskeletal.These ir AEs can be serious and sometimes fatal.In the human immune system,T cell activation is regulated by stimulatory and inhibitory ligand-receptor interactions between T cells,dendritic cells,macrophages and tumor cells in the tumor microenvironment and is involved in immune defense against cancer.These ligand-receptor pairs that negatively regulate T cell activation are known as immune checkpoints.ICIs can block the binding of these ligand-receptor pairs,thereby increasing T cell clones and thus triggering their antitumor effects in the tumor microenvironment.PD-1has changed the treatment paradigm and improved survival in many tumor types,but almost 25% of cancer patients treated with ICIs will experience any grade ir AEs.we investigated the correlation between ir AEs and anti-PD-1antibody efficacy in ESCC patients.Ir AEs were associated with better treatment efficacy of anti-PD-1 antibody in ESCC patients referring to higher disease control rate(DCR),longer progression-free survival(PFS)and better overall survival(OS).Ir AEs are better biomarkers to predict the outcomes of ICIs treatment in ECSS.Part One Antibiotics Modulate Chemotherapy Efficacy in Patients withEsophageal CancerObjective: Accumulating evidence suggests that microbiota dysbiosis induced by antibiotic administration plays a crucial role in regulating the efficacy and toxicity of cancer therapy.We explored the influence of antibiotic administration on the efficacy of chemotherapy in patients with esophageal cancer(EC).Methods: 108 EC patients were stratified into two groups: ATB-treated group and control group.The ATB-treated group included patients who received ATB within 60 days before or after chemotherapy initiation,and the control group included patients who did not receive ATB within 60 days before or after chemotherapy initiation.PFS and OS curves were constructed using the Kaplan-Meier method.The Cox proportional hazards model was used for univariate and multivariate analyses.Results: The rate of primary progressive disease in the ATB-treated group was significantly higher than that in the control group(36.58% vs10.45%,P=0.002)as calculated using the Chi-square test.Further,ATB administration was associated with shorter PFS [6.7 vs 14.6 months,hazard ratio(HR): 2.545,95% confidence interval(CI): 1.554-4.168,P<0.001] and reduced OS(15.0 vs 21.0 months,HR: 2.007,95% CI: 1.213-3.319,P=0.007)in univariate analysis.Subsequent multivariate analysis indicated that ATB administration was a significant independent prognostic factor for PFS(HR:2.350,95% CI: 1.423-3.882,P=0.001)and OS(HR:1.900,95% CI: 1.140-3.167,P = 0.014).。Summary: Antibiotic administration was associated with reduced chemotherapy efficacy and poor prognosis in patients with EC.Part Two Correlations Between the Immune-related Adverse Events andTreatment Efficacy of Anti-PD1 Immunotherapy inEsophageal Squamous Cell Carcinoma PateintsObjective: Ir AEs caused by ICIs seem to be associated with better treatment efficacy for some tumors including lung cancer,melanoma and hepatocellular carcinoma.Whereas few reports focus on the correlation between ir AEs and treatment efficiency of ICIs in ESCC patients.we evaluate the correlation between ir AEs and ICIs efficacy in present study.Methods: We divided the 54 esophageal squamous cell carcinoma(ESCC)patients who received anti PD-1 antibody into two groups as ir AEs group and non-ir AE group.Objective response rate(ORR),DCR,PFS and OS were used to evaluate the treatment efficacy of ICIs.Results: Fifteens cases developed ir AEs in 54 ICIs treated ESCC patients.The median OS and PFS was 600 days and 210 days for overall ESCC patients.The median OS(P=0.038)and median PFS(P=0.001)in the ir AE group were better than those in the non-ir AE group.In addition,the DCR of the ir AE group was superior to that in the non-ir AE group(P=0.016).Furthermore,the non-ir AE group was associated with both shorter PFS at statistical levels(HR=4.604,95% CI: 1.709-12.407,P=0.003)and shorter OS at borderline statistical levels(HR=4.192,95% CI:0.952-18.454,P=0.058)by univariate analysis,the multifactorial analysis demonstrated that ir AEs status was independent predictor for PFS(HR=7.604,95% CI: 2.212-26.138,P=0.001)and OS(HR=4.604,95% CI: 1.709-12.407,P=0.030)in ESCC patients treated by ICIs.Summary: Our study confirmed that occurrence of ir AEs predicted the better ICI treatment efficacy for ESCC patients.Conclusions: Antibiotic is associated with reduced chemotherapy efficacy and poor prognosis in patients with metastatic EC.ATB identified as an important independent influencing factor which affects the prognosis of EC patients.Ir AEs were associated with better treatment efficacy of anti-PD-1antibody in ESCC patients referring to higher DCR,longer PFS and better OS.Ir AEs are better biomarkers to predict the outcomes of ICIs treatment in ECSS.