title: The relationship of local and distant failure from endometrial cancer: defining a clinical paradigm.
abstract: OBJECTIVE
  Recently, statistical methods have been developed to rigorously assess the relationship between local and distant failures. Such methodology has successfully been applied to a variety of tumors including those arising in the prostate, breast, and cervix. To date, no published data are available to generate a hypothesis to characterize the relationship between local and distant failure for endometrial cancer. The present analysis was undertaken to determine the effect of locoregional control on subsequent metastatic dissemination among women with pathologically staged endometrial cancer treated by hysterectomy followed by adjuvant radiotherapy.
  
  
  METHODS
  The series consisted of 394 patients with FIGO stages I-III endometrial cancer who were surgically staged prior to irradiation [median external beam dose 45 Gy +/- brachytherapy (median vaginal surface dose, 30 Gy)]. The duration of follow-up ranged from 2 to 151 months, with a median of 62 months. Multiple factors were evaluated to determine the associations with distant relapse including FIGO pathological stage, grade, histopathologic subtype (adeno vs papillary/papillary-serous/clear cell), depth of myometrial penetration, age, and local disease status. Time-dependent survival models were generated to assess the influence of local failure on distant metastases.
  
  
  RESULTS
  For the entire series, the 5-year actuarial rates of local and distant failures were 9 and 20%, respectively. Women who failed locally had nearly a fourfold risk of failing distantly compared to those who remained locally controlled (P = 0.02). Moreover, the earlier a local failure developed (e.g., within 1 year vs within 3 years), the more likely it was to be associated with distant metastases (P < 0. 05). The univariate correlations of other factors with the 5-year rate of freedom from distant relapse also disclosed significant associations for grade, histology (adenoca vs papillary/papillary-serous/clear cell), and FIGO path stage. In multivariate analysis, only local control, low grade (grade 1 and 2), and early pathological stage were independently related to the likelihood of achieving freedom from distant relapse.
  
  
  CONCLUSIONS
  Distant dissemination of endometrial cancer may develop secondary to local failure. Optimization of local control is therefore necessary if long-term cure is to be achieved. The limits of the current database cannot establish whether local failure is a cause of distant spread or a high-risk marker for metastases; however, ongoing national cooperative trials may resolve this controversy.
authors.affiliation: Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, USA.
authors.forename: B W
authors.initials: BW
authors.lastname: Corn
authors.forename: R M
authors.initials: RM
authors.lastname: Lanciano
authors.forename: R
authors.initials: R
authors.lastname: D'agostino
authors.forename: E
authors.initials: E
authors.lastname: Kiggundu
authors.forename: C J
authors.initials: CJ
authors.lastname: Dunton
authors.forename: P
authors.initials: P
authors.lastname: Purser
authors.forename: K M
authors.initials: KM
authors.lastname: Greven
mesh_terms: D000206:Actuarial Analysis; D003131:Combined Modality Therapy; D016889:Endometrial Neoplasms / Q000473:pathology* / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D012307:Risk Factors; D016019:Survival Analysis