title: Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes.
abstract: OBJECTIVE
  Radiation therapy (RT) can both suppress and stimulate the immune system. We sought to investigate the mechanisms underlying radiation-induced lymphopenia and its associations with patient outcomes in non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Subjects consisted of 711 patients who had received definitive RT for NSCLC. A lymphocyte nadir was calculated as the minimum lymphocyte value measured during definitive RT. Associations between gross tumor volumes (GTVs) and lung dose-volume histogram (DVH) parameters with lymphocyte nadirs were assessed with Spearman correlation coefficients. Relationships between lymphocyte nadirs with overall survival (OS) and event free survival (EFS) were evaluated with Kaplan-Meier analysis and compared with log-rank test results. Multivariate regressions were conducted with linear and Cox regression analyses. All variables were analyzed as continuous if possible.
  
  
  RESULTS
  Larger GTVs were correlated with lower lymphocyte nadirs regardless of concurrent chemotherapy receipt (with concurrent: r = -0.26, P<.0001; without: r = -0.48, P<.0001). Analyses of lung DVH parameters revealed significant correlations at lower doses (lung V5-V10: P<.0001) that incrementally decreased and became nonsignificant at higher doses (lung V60-V70: P>.05). Of note, no significant associations were detected between GTV and lung DVH parameters with total leukocyte, neutrophil, or monocyte nadirs during RT or with lymphocyte count prior to RT. Multivariate analysis revealed larger GTV (P<.0001), receipt of concurrent chemotherapy (P<.0001), twice-daily radiation fractionation (P=.02), and stage III disease (P=.05) to be associated with lower lymphocyte nadirs. On univariate analysis, patients with higher lymphocyte nadirs exhibited significantly improved OS (hazard ratio [HR] = 0.51 per 10(3) lymphocytes/μL, P=.01) and EFS (HR = 0.46 per 10(3) lymphocytes/μL, P<.0001). These differences held on multivariate analyses, controlling for common disease and treatment characteristics including GTV.
  
  
  CONCLUSIONS
  Lower lymphocyte nadirs during definitive RT were associated with larger GTVs and worse patient outcomes.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chad
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: zliao@mdanderson.org.
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liao
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gomez
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Levy
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rediet A
authors.initials: RA
authors.lastname: Gebremichael
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: James W
authors.initials: JW
authors.lastname: Welsh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy*; D008231:Lymphopenia / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011879:Radiotherapy Dosage; D012044:Regression Analysis; D016896:Treatment Outcome; D047368:Tumor Burden