title: Bone marrow micrometastasis is associated with both disease recurrence and poor survival in surgical patients with node-negative non-small-cell lung cancer: a meta-analysis.
abstract: OBJECTIVE
  We performed a meta-analysis in order to determine whether the molecular tumour cell detection of either micrometastasis or isolated tumour cells in the bone marrow micrometastasis is indicative of a high risk of both disease recurrence and poor survival in the setting of node-negative non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Before beginning this study, a rigorous protocol was established in accordance with the recommendations of the Cochrane Collaboration. A systematic literature search of Medline, EMbase, the Cochrane Library and the Web of Science was conducted in order to identify studies regarding the prognostic value of molecular tumour cell detection in the bone marrow of node-negative NSCLC. Any study describing the use of both immunochemistry and flow cytometry to detect bone marrow metastasis was selected. We extracted the associated 95% confidence intervals (CIs) and hazard ratios (HRs) from the included studies and performed meta-analyses on overall survival and either disease-free survival (DFS) or disease-free recurrence. Meanwhile, we compared the occurrence of bone marrow micrometastasis among different pathological types and different stages of disease.
  
  
  RESULTS
  Eleven studies with a cumulative sample size of 2159 patients were included in our analysis. Our meta-analyses revealed that the occurrence of bone marrow micrometastasis was not related to patient pathological types and stages in cancers ranging from adenocarcinoma and squamous cell carcinoma [relative risk (RR): 0.92; 95% CI: 0.78-1.08; P = 0.29], stages I and II (RR: 0.88; 95% CI: 0.67-1.17; P = 0. 39), stages II and III (RR: 0.98; 95% CI: 0.73-1.31; P = 0.89) and stages I and III (RR: 0.84; 95% CI: 0.68-1.05; P = 0.13). However, molecular tumour cell detection within the bone marrow was associated with both poor OS (HR: 1.84; 95% CI: 1.41-2.40; P < 0.00001) and poor DFS (HR: 1.75; 95% CI: 1.18-2.60; P = 0.005). Our subgroup analyses indicated that the presence of bone marrow micrometastasis was not a significant prognostic factor with respect to DFS at stage I (HR: 2.35; 95% CI: 0.67-8.25; P = 0.18).
  
  
  CONCLUSIONS
  The molecular detection of isolated tumour cell in the bone marrow is associated with both poor survival and an increased rate of recurrence in patients with node-negative NSCLC; this approach may result in the development of a new metastatic cascade concept and the development of novel approaches to cancer therapy.
authors.affiliation: Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xu Feng
authors.initials: XF
authors.lastname: Deng
authors.affiliation: Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Quan Xing
authors.initials: QX
authors.lastname: Liu
authors.affiliation: Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jia Xin
authors.initials: JX
authors.lastname: Min
authors.affiliation: Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China 691057831@qq.com.
authors.forename: Ji Gang
authors.initials: JG
authors.lastname: Dai
mesh_terms: D001856:Bone Marrow Examination; D001859:Bone Neoplasms / Q000401:mortality / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000556:secondary / Q000601:surgery*; D016009:Chi-Square Distribution; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D061206:Neoplasm Micrometastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D016017:Odds Ratio; D011013:Pneumonectomy / Q000009:adverse effects / Q000401:mortality; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
keywords: Bone marrow micrometastasis; Isolated tumour cells; Minimal residual disease; Non-small-cell lung cancer; Occult metastasis; Subclinical metastasis