title: Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling.
abstract: OBJECTIVE
  For prostate cancer that is thought to be locally recurrent after prostatectomy, the optimal timing, dose and techniques for salvage radiotherapy (SRT) have not been established. Here we perform a systematic review of published reports including regression meta-analysis and radiobiologic modelling to identify predictors of biochemical disease control and late toxicity.
  
  
  METHODS
  We performed a review of published series reporting treatment outcomes following SRT. Studies with at least 30 patients, median PSA before SRT of less than 2.0 ng/mL, and median follow-up of greater than 36 months were identified. Univariate and multivariate analyses were performed to test Gleason Score, SRT dose, SRT timing, pre-SRT PSA, whole pelvic irradiation and androgen deprivation therapy as predictors of 5-year biochemical progression-free survival (bPFS) and severe (grade≥3) late GI and GU toxicity. bPFS and toxicity data were fit to tumour control probability and normal tissue complication probability models, respectively.
  
  
  RESULTS
  Twenty-five articles met the inclusion criteria for this analysis. Five-year bPFS ranged from 25% to 70%. Severe late GI toxicity rates were 0% to 9%, and severe late GU toxicity rates were 1-11%. On multivariate analysis, bPFS increased with SRT dose by 2.5% per Gy and decreased with pre-SRT PSA by 18.3% per ng/mL (p<0.001). Late GI and GU toxicity increased with SRT dose by 1.2% per Gy (p=0.012) and 0.7% per Gy (p=0.010), respectively. Radiobiological models demonstrate the interaction between pre-SRT PSA, SRT dose and bPFS. For example, an increase in pre-SRT PSA from 0.4 to 1.0 ng/mL increases the SRT dose required to achieve a 50% bPFS rate from 60 to 70Gy. This could increase the rate of severe late toxicity by approximately 10%.
  
  
  CONCLUSIONS
  Biochemical control rates following SRT increase with SRT dose and decrease with pre-SRT PSA. Severe late GI and GU toxicity rates also increase with SRT dose. Radiobiological models suggest that the therapeutic ratio of SRT may be improved by initiating treatment at low PSA levels.
authors.affiliation: Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA. ohri.nitin@gmail.com
authors.forename: Nitin
authors.initials: N
authors.lastname: Ohri
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.forename: Edouard J
authors.initials: EJ
authors.lastname: Trabulsi
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Showalter
mesh_terms: D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D008954:Models, Biological; D015999:Multivariate Analysis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000532:radiotherapy*; D011879:Radiotherapy Dosage; D012044:Regression Analysis; D016879:Salvage Therapy / Q000379:methods*
chemical_list: D017430:Prostate-Specific Antigen