title: Dose-effect relationship and risk factors for vaginal stenosis after definitive radio(chemo)therapy with image-guided brachytherapy for locally advanced cervical cancer in the EMBRACE study.
abstract: OBJECTIVE
  To identify risk factors for vaginal stenosis and to establish a dose-effect relationship for image-guided brachytherapy in locally advanced cervical cancer.
  
  
  METHODS
  Patients from the ongoing EMBRACE study with prospectively assessed morbidity (CTCAEv3.0) at baseline and at least one follow-up were selected. Patient-, disease- and treatment characteristics were tested as risk factors for vaginal stenosis G ⩾ 2 in univariate and multivariable analyses (Cox proportional hazards model) and a dose-effect curve was deduced from the estimates. The ICRU rectum point was used to derive the recto-vaginal reference point dose.
  
  
  RESULTS
  In 630 patients included (median follow-up 24months), 2-year actuarial estimate for vaginal stenosis G ⩾ 2 was 21%. Recto-vaginal reference point dose (HR=1.025, p=0.029), external beam radiotherapy (EBRT) dose >45 Gy/25 fractions (HR=1.770, p=0.056) and tumor extension in the vagina (HR=2.259, p ⩽ 0.001) were risk factors for vaginal stenosis, adjusted for center reporting effects. Based on the model curve, the risk was 20% at 65 Gy, 27% at 75 Gy and 34% at 85 Gy (recto-vaginal reference point dose).
  
  
  CONCLUSIONS
  Keeping the EBRT dose at 45 Gy/25 fractions and decreasing the dose contribution of brachytherapy to the vagina decrease the risk of stenosis. A planning aim of ⩽65 Gy EQD2 (EBRT+brachytherapy dose) to the recto-vaginal reference point is therefore proposed.
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria. Electronic address: kathrin.kirchheiner@meduniwien.ac.at.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kirchheiner
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, The Netherlands.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Department of Oncology, Aarhus University Hospital, Denmark.
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Lindegaard
authors.affiliation: Department of Radiotherapy, Gustave-Roussy, Villejuif, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Haie-Meder
authors.affiliation: Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India.
authors.forename: Umesh
authors.initials: U
authors.lastname: Mahantshetty
authors.affiliation: Department of Radiotherapy, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Segedin
authors.affiliation: Department of Radiation Oncology, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Ina M
authors.initials: IM
authors.lastname: Jürgenliemk-Schulz
authors.affiliation: Cancer Centre, Mount Vernon Hospital, London, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hoskin
authors.affiliation: Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Rai
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria; Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dörr
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Kirisits
authors.affiliation: Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, USA.
authors.forename: Søren M
authors.initials: SM
authors.lastname: Bentzen
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria; Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Pötter
authors.affiliation: Department of Oncology, Aarhus University Hospital, Denmark.
authors.forename: Kari
authors.initials: K
authors.lastname: Tanderup
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001918:Brachytherapy / Q000009:adverse effects*; D059248:Chemoradiotherapy; D003251:Constriction, Pathologic; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011832:Radiation Injuries; D011879:Radiotherapy Dosage; D061089:Radiotherapy, Image-Guided; D012307:Risk Factors; D002583:Uterine Cervical Neoplasms / Q000532:radiotherapy*; D014621:Vagina / Q000528:radiation effects*
keywords: ICRU recto-vaginal point; Image-guided brachytherapy; Radiotherapy; Vaginal morbidity; Vaginal shortening/narrowing