title: Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer--A pooled analysis of PORTEC 1 and 2 trials.
abstract: BACKGROUND
  Lymph-vascular space invasion (LVSI) is an important adverse prognostic factor in endometrial cancer (EC). However, its role in relation to type of recurrence and adjuvant treatment is not well defined, and there is significant interobserver variation. This study aimed to quantify LVSI and correlate this to risk and type of recurrence.
  
  
  METHODS
  In the post operative radiation therapy in endometrial carcinoma (PORTEC)-trials stage I EC patients were randomised to receive external beam radiotherapy (EBRT) versus no additional treatment after surgery (PORTEC-1, n=714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n=427). In tumour samples of 926 (81.2%) patients with endometrioid tumours LVSI was quantified using 2-, 3- and 4-tiered scoring systems. Cox proportional hazard models were used for time-to-event analysis.
  
  
  RESULTS
  Any degree of LVSI was identified in 129 cases (13.9%). Substantial LVSI (n=44, 4.8%) using the 3-tiered approach had the strongest impact on the risk of distant metastasis (hazard ratio (HR) 4.5 confidence interval (CI) 2.4-8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment) substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2 CI 2.4-16), distant metastasis (HR 3.6 CI 1.9-6.8) and overall survival (HR 2.0 CI 1.3-3.1). Only EBRT (HR 0.3 CI 0.1-0.8) reduced the risk of pelvic regional recurrence.
  
  
  CONCLUSIONS
  Substantial LVSI, in contrast to focal or no LVSI, was the strongest independent prognostic factor for pelvic regional recurrence, distant metastasis and overall survival. Therapeutic decisions should be based on the presence of substantial, not 'any' LVSI. Adjuvant EBRT and/or chemotherapy should be considered for stage I EC with substantial LVSI.
authors.affiliation: Department of Pathology, Leiden University Medical Center, The Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Department of Pathology, Leiden University Medical Center, The Netherlands.
authors.forename: Elke E M
authors.initials: EE
authors.lastname: Peters
authors.affiliation: Department of Radiotherapy, Leiden University Medical Center, The Netherlands.
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
authors.affiliation: Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands.
authors.forename: Ina M
authors.initials: IM
authors.lastname: Jürgenliemk-Schulz
authors.affiliation: Department of Radiotherapy, Medisch Spectrum Twente, Enschede, The Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Jobsen
authors.affiliation: Department of Radiation Oncology, Erasmus MC - Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: Jan Willem M
authors.initials: JW
authors.lastname: Mens
authors.affiliation: MAASTtricht Radiation Oncology Clinic, The Netherlands.
authors.forename: Ludy C H W
authors.initials: LC
authors.lastname: Lutgens
authors.affiliation: Arnhems Radiotherapeutisch Instituut, ARTI, Arnhem, The Netherlands.
authors.forename: Elzbieta M
authors.initials: EM
authors.lastname: van der Steen-Banasik
authors.affiliation: Department of Pathology, Leiden University Medical Center, The Netherlands.
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Department of Radiotherapy, Leiden University Medical Center, The Netherlands. Electronic address: r.a.nout@lumc.nl.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001808:Blood Vessels / Q000473:pathology*; D001918:Brachytherapy; D018269:Carcinoma, Endometrioid / Q000378:metabolism / Q000556:secondary* / Q000628:therapy*; D016009:Chi-Square Distribution; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D005260:Female; D006801:Humans; D007044:Hysterectomy; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology*; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D010052:Ovariectomy; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant; D012307:Risk Factors; D058994:Salpingectomy; D013997:Time Factors; D016896:Treatment Outcome
keywords: Endometrial cancer; External beam radiotherapy; Lymph-vascular space invasion; Prognostic factors; Vaginal brachytherapy