title: Modelling the impact of fractionation on late urinary toxicity after postprostatectomy radiation therapy.
abstract: OBJECTIVE
  To fit urinary toxicity data of patients treated with postprostatectomy radiation therapy with the linear quadratic (LQ) model with/without introducing a time factor.
  
  
  METHODS
  Between 1993 and 2010, 1176 patients were treated with conventional fractionation (1.8 Gy per fraction, median 70.2 Gy, n=929) or hypofractionation (2.35-2.90 Gy per fraction, n=247). Data referred to 2004-2010 (when all schemes were in use, n=563; conventional fractionation: 316; hypofractionation: 247) were fitted as a logit function of biological equivalent dose (BED), according to the LQ model with/without including a time factor γ (fixing α/β = 5 Gy). The 3-year risks of severe urethral stenosis, incontinence, and hematuria were considered as endpoints. Best-fit parameters were derived, and the resulting BEDs were taken in multivariable backward logistic models, including relevant clinical variables, considering the whole population.
  
  
  RESULTS
  The 3-year incidences of severe stenosis, incontinence, and hematuria were, respectively, 6.6%, 4.8%, and 3.3% in the group treated in 2004-2010. The best-fitted α/β values were 0.81 Gy and 0.74 Gy for incontinence and hematuria, respectively, with the classic LQ formula. When fixing α/β = 5 Gy, best-fit values for γ were, respectively, 0.66 Gy/d and 0.85 Gy/d. Sensitivity analyses showed reasonable values for γ (0.6-1.0 Gy/d), with comparable goodness of fit for α/β values between 3.5 and 6.5 Gy. Likelihood ratio tests showed that the fits with/without including γ were equivalent. The resulting multivariable backward logistic models in the whole population included BED, pT4, and use of antihypertensives (area under the curve [AUC] = 0.72) for incontinence and BED, pT4, and year of surgery (AUC = 0.80) for hematuria. Stenosis data could not be fitted: a 4-variable model including only clinical factors (acute urinary toxicity, pT4, year of surgery, and use of antihypertensives) was suggested (AUC = 0.73).
  
  
  CONCLUSIONS
  The unexpected impact of moderate hypofractionation on severe incontinence and hematuria after postprostatectomy radiation therapy may be explained by a bladder α/β value <1 Gy or, radiobiologically more plausible, by introducing a time factor likely to represent a previously hypothesized consequential component of late effect.
authors.affiliation: Department of Medical Physics, San Raffaele Scientific Institute, Milan, Italy. Electronic address: fiorino.claudio@hsr.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiorino
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Cozzarini
authors.affiliation: Prostate Cancer Program, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rancati
authors.affiliation: Department of Urology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Briganti
authors.affiliation: Department of Medical Physics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giovanni Mauro
authors.initials: GM
authors.lastname: Cattaneo
authors.affiliation: Department of Medical Physics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Mangili
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Nadia Gisella
authors.initials: NG
authors.lastname: Di Muzio
authors.affiliation: Department of Medical Physics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Calandrino
mesh_terms: D000368:Aged; D019540:Area Under Curve; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D006417:Hematuria / Q000453:epidemiology*; D006801:Humans; D015994:Incidence; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000532:radiotherapy* / Q000601:surgery; D011832:Radiation Injuries / Q000150:complications* / Q000453:epidemiology; D012062:Relative Biological Effectiveness; D012680:Sensitivity and Specificity; D013997:Time Factors; D014525:Urethral Stricture / Q000453:epidemiology*; D014549:Urinary Incontinence / Q000453:epidemiology*