OBJECTIVE: In order to define the clinical significance of low-volume metastasis, a comprehensive meta-analysis of published data and individual data obtained from articles mentioning micrometastases (MIC) and isolated tumor cells (ITC) in cervical cancer was performed, with a follow up of at least 3 years. METHODS: We performed a systematic literature review and meta-analysis, following Cochrane's review methods guide and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcome was the disease-free survival (DFS), and the secondary outcome was the overall survival (OS). The hazard ratio (HR) was taken as the measure of the association between the low-volume metastases (MIC+ITC and MIC alone) and DFS or OS; it quantified the hazard of an event in the MIC (+/- ITC) group compared to the hazard in node-negative (N0) patients. A random-effect meta-analysis model using the inverse variance method was selected for pooling. Forest plots were used to display the HRs and risk differences within individual trials and overall. RESULTS: Eleven articles were finally retained for the meta-analysis. In the analysis of DFS in patients with low-volume metastasis (MIC + ITC), the HR was increased to 2.60 (1.55-4.34) in the case of low-volume metastasis vs. N0. The presence of MICs had a negative prognostic impact, with an HR of 4.10 (2.71-6.20) compared to N0. Moreover, this impact was worse than that of MIC pooled with ITCs. Concerning OS, the meta-analysis shows an HR of 5.65 (2.81-11.39) in the case of low-volume metastases vs. N0. The presence of MICs alone had a negative effect, with an HR of 6.94 (2.56-18.81). CONCLUSIONS: In conclusion, the presence of MIC seems to be associated with a negative impact on both the DFS and OS and should be treated as MAC.

Breast Gynecology and Reconstructive Surgery Unit Institut Curie Paris France

Breast Gynecology and Reconstructive Surgery Unit Institut Curie Paris France; Faculty of Medicine University of Paris 75006 Paris France

Department of Gynecology and Obstetrics CHUV Lausanne Lausanne Switzerland; Department of Gynecology and Obstetrics FOCH Hospital 92150 Suresnes France

Department of Gynecology and Obstetrics CHUV Lausanne Lausanne Switzerland; Faculty of Medicine and Biology UNIL Lausanne Lausanne Switzerland

Department of Gynecology and Obstetrics CHUV Lausanne Lausanne Switzerland; Faculty of Medicine and Biology UNIL Lausanne Lausanne Switzerland; Department of Gynecology and Obstetrics HFR Fribourg Fribourg Switzerland; Faculty of Medicine University of Fribourg 1700 Fribourg Switzerland

Department of Gynecology and Obstetrics HFR Fribourg Fribourg Switzerland; Faculty of Medicine University of Fribourg 1700 Fribourg Switzerland

Department of Gynecology Gynecologic Oncology and Gynecologic Endocrinology Medical University of Gdansk Poland

Department of Gynecology Oncology Michele e Pietro Ferrero Hospital Verduno Italy

Department of Obstetrics and Gynecology of the 1 Faculty of Medicine General University Hospital Prague Czech Republic

Faculty of Medicine University of Paris 75006 Paris France; Department of Biostatistics Institut Curie Paris France

Stratification of lymph node metastases as macrometastases, micrometastases, or isolated tumor cells has no clinical implication in patients with cervical cancer: Subgroup analysis of the SCCAN project