Prognostic Analysis Of Inflammatory Immune-related Indexes In Patients With Esophageal Cancer Before Chemoradiotherapy

Objective:Many studies have shown that inflammatory immune indexes of the body are of certain significance in the assessment of the development of malignant tumors and prediction of their prognosis.Moreover,it is easy to obtain data in clinical work,and the detection cost is low,and the clinical reference value is high.Although many hematological and immunological markers have been found and used to predict the prognosis of patients with solid malignancies,there is no consensus on the relationship between these markers and the prognosis of esophageal cancer.In addition,for patients with non-surgical esophageal cancer,no studies have reported the relationship between pre-treatment blood indicators and immune parameters and prognosis.The purpose of this study was to observe the relationship between immune parameters,peripheral blood cell ratio and overall survival（OS）in patients with esophageal cancer after non-operative chemoradiotherapy,and to analyze the relevant clinical prognostic factors.Methods:A total of 610 non-surgical radiotherapy and chemotherapy patients who received initial treatment in Shanxi Cancer Hospital and were pathologically diagnosed with esophageal cancer from January 2015 to January 2020 were collected.The blood routine data and immune function index data were collected within one week before initial treatment.According to different treatment methods,the patients were divided into four groups for analysis:114 patients with radiotherapy only,143 patients with chemotherapy only,343 patients with radiotherapy and chemotherapy,and 10 other patients.Among 343patients,297 patients with esophageal cancer with radiotherapy dose between 50 and70Gy were selected and analyzed.Data collection includes general information（age and gender,KPS,body mass index,smoking history,family history of cancer）,diagnostic information（histological pathology type,clinical staging,the location of the lesion illustrated by gastroscopy）,the treatment of related information（radiation dose,frequency of radiotherapy segmentation,chemotherapy cycle）,hematology data（white lymphocytes neutrophils mononuclear cells,and platelets）,immune function data（proportion of CD3+,CD4+,CD8+T cells and CD4+CD8+and CD4+/CD8+double positive cells,NK cells,NKT cells,regulatory T cells and total number of B cells）.All data were within 1week before treatment.For 610 patients:optimal boundary values for each continuous variable were determined by ROC curves（including hematological data and immunological function data）,and patients were stratified based on optimal boundary values for baseline hematological and immunological markers.Univariate and multivariate Cox proportional regression models were used to determine independent prognostic factors for OS.The 0.05 variable was analyzed.For independent predictors selected by multivariate analysis,the mean and median of OS were obtained by Kaplan-Meier survival analysis.For 297 cases of patients,according to the ROC curve from the peripheral blood T lymphocyte subsets in screening diagnosis value of the highest regulatory T cells in detail analysis:according to the proportion of regulatory T cells all patients were divided into two groups,by chi-square analysis of regulatory T cells proportion clinicopathologic correlation,Kaplan-Meier method using univariate survival analysis,and through the log rank test evaluation of survival curves.All analyses were conducted by bilateral analysis,with P value set at 0.05,and SPSS 26 was used for statistical analysis.Results:A total of 610 patients with non-surgical EC were included in the analysis（Table 1）.The median age of the patients was 63 years[range 34-80],including 411 males and 199females.For 114 patients treated with radiotherapy only,eight factors were found to be associated with better OS on univariate analysis:low clinical staging,radiotherapy mode of IMRT,radiotherapy dose of≥60Gy（≥60 vs.≥50 but<60Gy）,radiotherapy dose of≥60Gy（≥60 vs.<60Gy）,radiotherapy dose of≥50Gy（≥50 vs.<50Gy）,radiotherapy dose of≥40Gy（≥40 vs.<40Gy）,ANC≤3.9 and NLR≤2（P<0.05）.The final multivariate analysis indicated that low NLR of≤2（HR 4.710,95%CI1.036-21.406,P=0.045）,IMRT（intensity modulated radiation therapy）subgroup of radiotherapy mode（HR 3.037,95%CI 1.018-9.062,P=0.046）,high dose（≥60Gy）subgroup of the first kind radiotherapy dose grouping（HR 3.320,95%CI 1.264-8.721,P=0.015）were independent predictors of better survival.For 143 patients treated with chemotherapy only,seven factors were found to be associated with better OS on univariate analysis:chemotherapy cycles of≥4（<4 vs.≥4）,white blood cells of≤5.2（≤5.2 vs>5.2）,absolute count of neutrophils of≤3.4（≤3.4 vs>3.4）,NLR of≤2.0（≤2.0 vs>2.0）,absolute count of monocytes of≤0.4（≤0.4 vs>0.4）,PLR of≤161.1（≤161.1 vs>161.1）and CD4+CD8+of≤1.7（≤1.7 vs>1.7）（P<0.05）.The final multivariate analysis indicated that chemotherapy cycles of≥4（HR 2.532,95%CI1.594-4.021,P=0.000）,ANC≤3.4（HR 1.669,95%CI 1.085-2.568,P=0.020）,PLR≤161.1（HR 1.975,95%CI 1.291-3.022,P=0.002）and CD4+CD8+≤1.7%（HR 2.345,95%CI 1.506-3.651,P=0.000）were independent predictors of better survival.For 343patients treated with chemoradiotherapy,about half of the patients（166,48.4%）received concurrent chemoradiotherapy,and the chemotherapy regimen mainly included DP regimen and TP regimen.In univariate analysis,for 343 patients treated with chemoradiotherapy,there was no statistical difference between the concurrent chemoradiotherapy group and the asynchronous chemoradiotherapy group.For the 343chemoradiotherapy patients,patients with 4 cycles or more had a better prognosis than those with less than 4 cycles.But for 166 patients with concurrent chemoradiotherapy,there was no statistical difference between patients treated with 4 cycles or more and patients treated with 4 cycles or less.In contrast,for 177 patients with asynchronous chemoradiotherapy,patients with 4 cycles or more had a better prognosis than those with less than 4 cycles.For 329 patients with radiation dose of 45Gy or greater,patients with 4cycles or more had a better prognosis than those with less than 4 cycles.The dose of radiation for all patients receiving chemoradiotherapy was divided into two groups respectively to compare prognosis,radiotherapy dose（≥60 vs.≥50 but<60Gy）,radiotherapy dose（≥60 vs.<60Gy）,radiotherapy dose（≥50 vs.<50Gy）,radiotherapy dose（≥40 vs.<40Gy）.There was no statistical significance in radiotherapy dose（≥60vs≥50 but<60Gy）or radiotherapy dose（≥60 vs<60Gy）（P>0.05）.Radiotherapy dose of≥50Gy or radiotherapy dose of≥40Gy were found to be associated with better OS.Additionally,NLR≤1.6,PLT≤215.5,PLRof≤146.9,CD45+CD4+CD25^HICD127^LOW≤5.2%and CD4+CD8+>3.5%（P<0.05）were found to be associated with better OS.The final multivariate analysis indicated that chemotherapy cycles of≥4 for 177 patients with asynchronous chemoradiotherapy（HR1.688,95%CI 1.108-2.572,P=0.015）,radiotherapy dose of≥50Gy（HR 2.192,95%CI1.228-3.915,P=0.008）and CD4+CD8+>3.5%（HR 2.175,95%CI 1.208-3.917,P=0.010）were independent predictors of better survival.The Kaplan-Meier analysis showed that the mean values of the chemoradiotherapy group,radiotherapy group,and chemotherapy group were 31.00 months,27.71 months,and 20.14 months.Median values were 20.63 months,17.87 months,and 10.87 months,respectively.Among 343 patients,297 patients with radiotherapy dose of 50-70Gy were selected as regulatory T cells with the highest diagnostic value for detailed analysis:The mean pretreatment proportion of regulatory T cells（%）in the 297 patients was 5.47%±1.91%,with a median of 5.20%（range,1.30–13.80%）.We set 5.15%as the cutoff value and divided the patients into a high-regulatory T cell group（>5.15%;n=152,51.2%）and a low-regulatory T cell group（≤5.15%;n=145,48.8%）to predict prognosis.Of the clinicopathological features analyzed,the proportion of pretreatment regulatory T cells were significantly associated with tumor location and the proportion of CD4+CD8+double-positive cells.Patients with a high proportion of regulatory T cells had a significantly worse OS than patients with a low proportion of regulatory T cells.Furthermore,the OS of patients with a low proportion of CD4+CD8+double-positive cells was lower than that of patients with a high proportion of CD4+CD8+double-positive cells.Two factors were found to be associated with better OS on univariate analysis:CD4+CD8+double-positive cell proportion>3.45%（P<0.05）and CD45+CD4+CD25^HICD127^LOWregulatory T cell proportion≤5.15%（P<0.05）.Conversely,multivariate analysis indicated that KPS,tumor location,and proportion of CD4+CD8+double-positive and proportion of regulatory T cells,were independent risk factors for poor OS.Conclusion:1.Pretreatment NLR was associated with OS of three treatment groups（only radiotherapy,only chemotherapy,chemoradiotherapy）,and patients with low NLR in non-surgical esophageal cancer can predict better OS.Pretreatment CD4+CD8+T cell is an independent prognostic indicator for patients with esophageal cancer who have not received surgical treatment with chemotherapy only or chemoradiotherapy.The survival benefit of the three treatments was ranked as the chemoradiotherapy group>radiotherapy alone group>chemotherapy alone group.2.Regulatory T cells play a role in predicting the prognosis of patients with EC before chemoradiotherapy,and a low proportion of pretreatment regulatory T cells were demonstrated to independently predict a better OS.