title: Dose-volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: Results from the prospective multicenter EMBRACE study.
abstract: To establish dose volume-effect relationships predicting late rectal morbidity in cervix cancer patients treated with concomitant chemoradiation and MRI-guided adaptive brachytherapy (IBABT) within the prospective EMBRACE study.
  
  
  
  All patients were treated with curative intent according to institutional protocols with chemoradiation and IGABT. Reporting followed the GEC-ESTRO recommendations ( [Formula: see text] , [Formula: see text] ), applying bioeffect modeling (linear quadratic model) with equieffective doses (EQD23). Morbidity was scored according to the CTC-AE 3.0. Dose-effect relationships were assessed using comparisons of mean doses, the probit model and log rank tests on event-free periods.
  
  
  
  960 patients were included. The median follow-up was 25.4months. Twenty point one percent of the patients had grade 1 events, 6.0% grade 2, 1.6% grade 3 and 0.1%, grade 4. The mean DICRU, [Formula: see text] , and [Formula: see text] were respectively: 66.2±9.1Gy, 72.9±11.9Gy, and 62.8±7.6Gy. Increase of dose was associated with increase in severity of single endpoints and overall rectal morbidity (grade 1-4) (p<0.001-0.026), except for stenosis (p=0.24-0.31). The probit model showed significant relationships between the [Formula: see text] , [Formula: see text] , and DICRUand the probability of grade 1-4, 2-4, and 3-4 rectal events. The equieffective [Formula: see text] for a 10% probability for overall rectal grade⩾2 morbidity was 69.5Gy (p<0.0001). After sorting patients according to 6 [Formula: see text] levels, less favorable outcome was observed in the high dose subgroups, for bleeding, proctitis, fistula, and overall rectal morbidity. A [Formula: see text] ⩾75Gy was associated with a 12.5% risk of fistula at 3years versus 0-2.7% for lower doses (p>0.001). A [Formula: see text] <65Gy was associated with a two times lower risk of proctitis than [Formula: see text] ⩾65Gy.
  
  
  
  Significant correlations were established between late rectal morbidity, overall and single endpoints, and dose-volume ( [Formula: see text] , [Formula: see text] ) and dose-point (DICRU) parameters. A [Formula: see text] ⩽65Gy is associated with more minor and less frequent rectal morbidity, whereas a [Formula: see text] ⩾75Gy is associated with more major and more frequent rectal morbidity.
authors.affiliation: Department of Radiotherapy, Gustave Roussy, University of Paris-Saclay, Villejuif, France. Electronic address: Renaud.mazeron@gustaveroussy.fr.
authors.forename: Renaud
authors.initials: R
authors.lastname: Mazeron
authors.affiliation: Department of Oncology, Aarhus University Hospital, Denmark.
authors.forename: Lars U
authors.initials: LU
authors.lastname: Fokdal
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kirchheiner
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Georg
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria.
authors.forename: Noha
authors.initials: N
authors.lastname: Jastaniyah
authors.affiliation: Department of Radiotherapy, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Šegedin
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, Mount Vernon Cancer Centre, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Hoskin
authors.affiliation: Department of Radiotherapy, University Medical Center Utrecht, The Netherlands.
authors.forename: Ina
authors.initials: I
authors.lastname: Jürgenliemk-Schulz
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 Oncology, Aarhus University Hospital, Denmark.
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Lindegaard
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dörr
authors.affiliation: Department of Radiotherapy, Gustave Roussy, University of Paris-Saclay, Villejuif, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Haie-Meder
authors.affiliation: Department of Oncology, Aarhus University Hospital, Denmark.
authors.forename: Kari
authors.initials: K
authors.lastname: Tanderup
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Pötter
mesh_terms: D001918:Brachytherapy / Q000009:adverse effects* / Q000379:methods; D059248:Chemoradiotherapy / Q000009:adverse effects* / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008875:Middle Aged; D011446:Prospective Studies; D015642:Radiology, Interventional / Q000379:methods*; D011879:Radiotherapy Dosage; D012002:Rectal Diseases / Q000209:etiology*; D012007:Rectum / Q000528:radiation effects; D002583:Uterine Cervical Neoplasms / Q000628:therapy*
keywords: Fistula; Locally advanced cervical cancer; MRI-guided adaptive brachytherapy; Normal tissue complication probability; Proctitis; Rectal bleeding; Rectal morbidity