Treatment-related Lymphopenia Impairs The Treatment Response Of Anti-PD-1 Therapy In Esophageal Squamous Cell Carcinoma

Background:As one of the most common malignant cancers in the world,esophageal carcinoma(EC)is the sixth leading cause of cancer-related mortality worldwide.Esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC)are two predominant histological types of EC.The predominant histological type of EC in China is ESCC,which takes account of 90%EC.At present,surgery is the mainstay of treatment for EC.Due to the atypical clinical symptoms of ESCC,most patients are first diagnosed with late phase,losing the opportunity of radical surgery cure.The 5 years overall survival(OS)rate of EC is only about 15%-25%.At present,concurrent chemoradiotherapy and neoadjuvant chemoradiotherapy have been the standard treatment regimen of locally advanced EC.Immunotherapy combined with chemotherapy is used as first-line treatment in unresectable locally advanced or metastatic EC.Immune checkpoint inhibitors monotherapy has also shown great efficacy in the second-line treatment of unresectable advanced or recurrent EC.Lymphocytes are a vital part of the whole immune system,performing a crucial role in the anti-cancer immune response of the human body.Also,the lymphocytes are a great index for clinical evaluation of the immune status in cancer patients.Many studies have indicated that the level of lymphocytes is associated with clinical prognosis in several cancers.Here in this study,we sought to investigate the significance of treatment-related lymphopenia(TRL)in esophageal squamous cell carcinoma(ESCC)patients receiving anti-PD-1 therapy and the factors associated with TRL,especially RT.Methods:We retrospectively identified 167 patients diagnosed with ESCC in Shandong First Medical University Affiliated Shandong Cancer Hospital from Mar.2019 to Nov.2020.These 167 patients have received anti-PD-1 therapy with or without esophageal local radiotherapy.The following clinical baseline characteristics were collected:age,gender,Karnofsky Performance Status(KPS),clinical stage,tumor location,esophageal surgery history,whether have liver metastasis or not,history of previous esophageal radiotherapy,number of previous chemotherapy lines and treatment regimens.We recorded the absolute value of lymphocytes(ALC)in peripheral blood for every patient.Patients included in this study must have more than nine ALC data.RECIST 1.1 was used to evaluate the treatment effect every two periods of immunotherapy.Through descriptive statistics,we investigated the baseline clinical characteristics of all patients.According to the cut off value of ALC,treatment related lymphopenia(TRL)was defined as ALC ≤0.50 x 109cells/L at the start of immunotherapy and/or during immunotherapy.Depending on the presence of TRL,patients were divided into two groups.Chi-square tests were used for proportional comparison.Survival analyses were performed using the Kaplan-Meier curves and compared using the log-rank test.We used univariate and multivariate Cox proportional hazards model to assess the prognostic factors for PFS.Multivariate analysis was performed including all of the clinically meaningful variables.To determine the factors associated with lymphopenia,logistic regression analysis was performed.The receiver operated characteristics(ROC)curves were performed to determine the optimal cut-off values for a time interval between RT and immunotherapy for PFS prediction.The cut-off value was determined according to the maximum Youden index after considering sensitivity and specificity.We used Kaplan-Meier survival curves to exhibit the relationship between this certain time interval and PFS.Results:According to the cut off value of ALC≤0.5×109/L,167 patients with ESCC that included in this retrospective study were divided into 2 groups.102 patients were diagnosed with TRL while 65 patients were not.At median follow-up of 6.5 months,patients with TRL showed shorter progression-free survival(PFS)compared with patients without TRL(median PFS:4.8 vs.7.0 months,P=0.009).Multivariate analyses confirmed TRL is an independent prognostic factor for poorer PFS(HR,1.855;P=0.008).RT significantly increased the occurrence of TRL(OR=0.502,P=0.035).In the subgroup analysis,patients receiving ICIs<33.5 days after RT showed a poorer PFS compared to that≥33.5 days(median PFS:4.1 vs 7.3 months,P=0.008).The explanation is that patients with shorter time interval had a higher incidence of TRL(P=0.028).Conclusion:TRL was an independent predictor of poor outcomes in ESCC patients receiving anti-PD-1 therapy.RT was a key factor affecting TRL.A shorter time interval of<33.5 days between RT and anti-PD-1 therapy can lead to poor prognosis by increasing the occurrence of TRL.