title: Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.
abstract: BACKGROUND
  After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life.
  
  
  METHODS
  In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756.
  
  
  RESULTS
  At median follow-up of 45 months (range 18-78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1.8% (95% CI 0.6-5.9) for VBT and 1.6% (0.5-4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17-3.49; p=0.74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% (2.8-9.6) for VBT and 2.1% (0.8-5.8) for EBRT (HR 2.08, 0.71-6.09; p=0.17). 1.5% (0.5-4.5) versus 0.5% (0.1-3.4) of patients presented with isolated pelvic recurrence (HR 3.10, 0.32-29.9; p=0.30), and rates of distant metastases were similar (8.3% [5.1-13.4] vs 5.7% [3.3-9.9]; HR 1.32, 0.63-2.74; p=0.46). We recorded no differences in overall (84.8% [95% CI 79.3-90.3] vs 79.6% [71.2-88.0]; HR 1.17, 0.69-1.98; p=0.57) or disease-free survival (82.7% [76.9-88.6] vs 78.1% [69.7-86.5]; HR 1.09, 0.66-1.78; p=0.74). Rates of acute grade 1-2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12.6% [27/215] vs 53.8% [112/208]).
  
  
  CONCLUSIONS
  VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk.
  
  
  BACKGROUND
  Dutch Cancer Society.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, Netherlands. r.a.nout@lumc.nl
authors.forename: R A
authors.initials: RA
authors.lastname: Nout
authors.forename: V T H B M
authors.initials: VT
authors.lastname: Smit
authors.forename: H
authors.initials: H
authors.lastname: Putter
authors.forename: I M
authors.initials: IM
authors.lastname: Jürgenliemk-Schulz
authors.forename: J J
authors.initials: JJ
authors.lastname: Jobsen
authors.forename: L C H W
authors.initials: LC
authors.lastname: Lutgens
authors.forename: E M
authors.initials: EM
authors.lastname: van der Steen-Banasik
authors.forename: J W M
authors.initials: JW
authors.lastname: Mens
authors.forename: A
authors.initials: A
authors.lastname: Slot
authors.forename: M C Stenfert
authors.initials: MC
authors.lastname: Kroese
authors.forename: B N F M
authors.initials: BN
authors.lastname: van Bunningen
authors.forename: A C
authors.initials: AC
authors.lastname: Ansink
authors.forename: W L J
authors.initials: WL
authors.lastname: van Putten
authors.forename: C L
authors.initials: CL
authors.lastname: Creutzberg
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary; D000368:Aged; D001918:Brachytherapy; D016889:Endometrial Neoplasms / Q000401:mortality / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D011879:Radiotherapy Dosage; D012307:Risk Factors; D015996:Survival Rate; D014621:Vagina / Q000528:radiation effects; D014625:Vaginal Neoplasms / Q000517:prevention & control