title: What hypofractionated protocols should be tested for prostate cancer?
abstract: OBJECTIVE
  Recent analyses of clinical results have suggested that the fractionation sensitivity of prostate tumors is remarkably high; corresponding point estimates of the alpha/beta ratio for prostate cancer are around 1.5 Gy, much lower than the typical value of 10 Gy for many other tumors. This low alpha/beta value is comparable to, and possibly even lower than, that of the surrounding late-responding normal tissue in rectal mucosa (alpha/beta nominally 3 Gy, but also likely to be in the 4-5 Gy range). This lower alpha/beta ratio for prostate cancer than for the surrounding late-responding normal tissue creates the potential for therapeutic gain. We analyze here possible high-gain/low-risk hypofractionated protocols for prostate cancer to test this suggestion.
  
  
  METHODS
  Using standard linear-quadratic (LQ) modeling, a set of hypofractionated protocols can be designed in which a series of dose steps is given, each step of which keeps the late complications constant in rectal tissues. This is done by adjusting the dose per fraction and total dose to maintain a constant level of late effects. The effect on tumor control is then investigated. The resulting estimates are theoretical, although based on the best current modeling with alpha/beta parameters, which are discussed thoroughly.
  
  
  RESULTS
  If the alpha/beta value for prostate is less than that for the surrounding late-responding normal tissue, the clinical gains can be rather large. Appropriately designed schedules using around ten large fractions can result in absolute increases of 15% to 20% in biochemical control with no evidence of disease (bNED), with no increase in late sequelae. Early sequelae are predicted to be decreased, provided that overall times are not shortened drastically because of a possible risk of acute or consequential late reactions in the rectum. An overall time not shorter than 5 weeks appears advisable for the hypofractionation schedules considered, pending further clinical trial results. Even if the prostate tumor alpha/beta ratio turns out to be the same (or even slightly larger than) the surrounding late-responding normal tissue, these hypofractionated regimens are estimated to be very unlikely to result in significantly increased late effects.
  
  
  CONCLUSIONS
  The hypofractionated regimens that we suggest be tested for prostate-cancer radiotherapy show high potential therapeutic gain as well as economic and logistic advantages. They appear to have little potential risk as long as excessively short overall times (<5 weeks) and very small fraction numbers (<5) are avoided. The values of bNED and rectal complications presented are entirely theoretical, being related by LQ modeling to existing clinical data for approximately intermediate-risk prostate cancer patients as discussed in detail.
authors.affiliation: Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA. jffowler@mail.humonc.wisc.edu
authors.forename: Jack F
authors.initials: JF
authors.lastname: Fowler
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ritter
authors.forename: Rick J
authors.initials: RJ
authors.lastname: Chappell
authors.forename: David J
authors.initials: DJ
authors.lastname: Brenner
mesh_terms: D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D016014:Linear Models; D008297:Male; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000209:etiology / Q000517:prevention & control; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods*; D012007:Rectum / Q000528:radiation effects; D012307:Risk Factors; D012680:Sensitivity and Specificity