title: Compensation for changes in dose-rate in radical low-dose-rate brachytherapy: a radiobiological analysis of a randomised clinical trial.
abstract: OBJECTIVE
  This study reanalysed the results of the Cs-137 low-dose-rate brachytherapy trials for stage I and II cervix carcinoma at the Christie Hospital, Manchester, UK, in order to quantify the clinical outcome as a function of dose, and to extract radiobiological parameter values by modelling the data for local control and morbidity.
  
  
  METHODS
  Kaplan-Meier survival curves and Cox regression analyses were used to analyse the time to event data. Linear-quadratic (LQ) analysis was also used in a mixture model, incorporating a half-time for repair, a time factor, and a heterogeneity function between patients. Full 5-year follow-up data were available for 339 patients receiving Cs-137 doses between 60 and 75 Gy delivered at 1.4-1.8 Gy/h, and 178 patients receiving a Ra-226 dose of 75 Gy at 0.5 Gy/h, using two insertions 7-10 days apart.
  
  
  RESULTS
  With the increased dose-rate, a dose reduction between 20 and 25% was required to achieve a similar morbidity rate. This reduction had a detrimental effect on tumour control, by about 15% points. Unexpectedly, this loss in local control did not lead to a decrease in cancer-specific survival. For both tumour control and complications a high alpha/beta and short half-time for repair best fitted the data, suggesting that consequential late reactions may be responsible for much of the bowel and urinary morbidity after these short treatments. The variability in response between patients was greater (CV 40%) for morbidity than for tumour control (CV 17%), probably reflecting the greater variation in dose at the target tissue. There was no significant dependence on overall treatment time detected over the 7-10-day range of these treatments.
  
  
  CONCLUSIONS
  The therapeutic ratio was somewhat less for the higher dose-rate, in agreement with radiobiological expectations, although cancer-specific survival was inexplicably unchanged. The LQ-parameter analysis suggests that high alpha/beta ratios and/or short repair half-times are applicable for both tumour and normal tissue responses in these treatments.
authors.affiliation: Biostatistics Group, School of Epidemiology and Health Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Roberts
authors.forename: Jolyon H
authors.initials: JH
authors.lastname: Hendry
authors.forename: Richard
authors.initials: R
authors.lastname: Swindell
authors.forename: John M
authors.initials: JM
authors.lastname: Wilkinson
authors.forename: Robin D
authors.initials: RD
authors.lastname: Hunter
mesh_terms: D001918:Brachytherapy; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000532:radiotherapy*; D002588:Cesium Radioisotopes / Q000627:therapeutic use; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011879:Radiotherapy Dosage; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000401:mortality / Q000532:radiotherapy*
chemical_list: D002588:Cesium Radioisotopes