title: Higher-than-expected severe (Grade 3-4) late urinary toxicity after postprostatectomy hypofractionated radiotherapy: a single-institution analysis of 1176 patients.
abstract: BACKGROUND
  Dose escalation and hypofractionation may have a role in postprostatectomy radiotherapy (RT), but at the risk of increasing urinary toxicity.
  
  
  OBJECTIVE
  To address predictors of severe (Grade ≥3) late urinary toxicities (LGUTOX3) after postoperative irradiation.
  
  
  METHODS
  A single-institution cohort of 1176 patients treated between 1993 and 2010 with adjuvant or salvage RT was analyzed. A total of 929 patients underwent conventionally fractionated (CF) RT (1.8 Gy per fraction; median dose to the prostatic bed: 70.2 Gy) with nonconformal RT (n=169), three-dimensional conformal RT (n=657), or intensity-modulated RT (n=103) technique, while 247 patients received hypofractionated helical TomoTherapy (median: 2.50 Gy per fraction) at the following doses: 117 patients at 65.8 Gy (2.35 Gy in 28 fractions), 80 patients at a median of 71.4 Gy (2.5-2.6 Gy in 28 fractions), and 50 patients at 58 Gy in 20 fractions. Total doses were converted into 2 Gy-equivalent doses (EQD2) following the linear quadratic model taking α/β=5.
  
  
  METHODS
  Univariable and multivariable Cox regression models tested the relationship between clinicodosimetric variables and the risk of LGUTOX3 retrospectively, graded according to Common Terminology Criteria for Adverse Events v.4.0.
  
  
  CONCLUSIONS
  After a median follow-up of 98 mo, the 5-yr risk of LGUTOX3 was 6.9% and 18.1% in the CF and hypofractionated cohorts, respectively. At univariable analysis, the risk of LGUTOX3 was predicted by dose per fraction (hazard ratio [HR]: 2.96), acute Grade ≥2 toxicity (HR: 2.37), EQD2, pT4, and year of irradiation. At multivariable analyses, acute Grade ≥2 toxicity and dose per fraction independently predicted LGUTOX3 in the population, while an interaction analysis indicated a predictive role of hypertension in the hypofractionated cohort only. These findings are limited by their retrospective nature.
  
  
  CONCLUSIONS
  In the postprostatectomy setting, the logistic convenience of hypofractionation should be carefully balanced against the risk of severe late urinary sequelae.
  
  
  RESULTS
  This study investigated the causes of urinary adverse effects after postprostatectomy radiotherapy. Hypofractionation resulted in an increased risk of severe urinary toxicities.
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy. Electronic address: cozzarini.cesare@hsr.it.
authors.forename: Cesare
authors.initials: C
authors.lastname: Cozzarini
authors.affiliation: Department of Medical Physics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiorino
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Deantoni
authors.affiliation: Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Briganti
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrei
authors.initials: A
authors.lastname: Fodor
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: La Macchia
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Noris Chiorda
authors.affiliation: Centre of Statistics for the Biomedical Sciences, Università Vita Salute San Raffaele, Milan, Italy.
authors.forename: Paola Maria Vittoria
authors.initials: PM
authors.lastname: Rancoita
authors.affiliation: Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Nazareno
authors.initials: N
authors.lastname: Suardi
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Zerbetto
authors.affiliation: Department of Medical Physics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Calandrino
authors.affiliation: Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Montorsi
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Di Muzio
mesh_terms: D000368:Aged; D019583:Dose Fractionation, Radiation; D005500:Follow-Up Studies; D006417:Hematuria / Q000209:etiology; D006801:Humans; D006973:Hypertension / Q000150:complications; D008297:Male; D008875:Middle Aged; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000150:complications / Q000532:radiotherapy* / Q000601:surgery; D011832:Radiation Injuries / Q000209:etiology*; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects / Q000379:methods; D050397:Radiotherapy, Intensity-Modulated; D012189:Retrospective Studies; D016879:Salvage Therapy / Q000009:adverse effects* / Q000379:methods; D012720:Severity of Illness Index; D013997:Time Factors; D014521:Urethra / Q000528:radiation effects*; D014525:Urethral Stricture / Q000209:etiology; D001743:Urinary Bladder / Q000528:radiation effects*; D001748:Urinary Bladder Neck Obstruction / Q000209:etiology; D014549:Urinary Incontinence / Q000209:etiology; D014570:Urologic Diseases / Q000209:etiology*
keywords: Dose escalation; Hormonal therapy; Hypertension; Hypofractionation; Late effects; Prostate cancer; Prostatectomy; Radiotherapy; Urinary toxicity; Whole pelvis