title: Acute radiation reactions in oral and pharyngeal mucosa: tolerable levels in altered fractionation schedules.
abstract: OBJECTIVE
  To investigate whether a predictive estimate can be obtained for a 'tolerance level' of acute oral and pharyngeal mucosal reactions in patients receiving head and neck radiotherapy, using an objective set of dose and time data.
  
  
  METHODS
  Several dozen radiotherapy schedules for treating head and neck cancer have been reviewed, together with published estimates of whether they were tolerated or (in a number of schedules) not. Those closest to the borderline were given detailed analysis. Total doses and biologically effective doses (BED or ERD) were calculated for a range of starting times of cellular repopulation and rates of daily proliferation. Starting times of proliferation from 5 to 10 days and daily cellular doubling rates of 1-3 days were considered. The standard published form of BED with its linear overall time factor was used: BED=nd(1 + d/(alpha/beta) - Ln2(T - T(k))/alpha T(p) (see text for parameters).
  
  
  RESULTS
  A clear progression from acceptable to intolerable mucosal reactions was found, which correlated with total biologically effective dose (BED in our published modeling), for all the head and neck cancer radiotherapy schedules available for study, when ranked into categories of 'intolerable' or 'tolerable'. A review of published mechanisms for mucosal reactions suggested that practical schedules used for treatment caused stimulated compensatory proliferation to start at about 7 days. The starting time of compensatory proliferation had little predictive value in our listing, so we chose the starting time of 7 days. Very short and very long daily doubling rates also had little reliability, so we suggest choosing a doubling time of 2.5 days as a datum. With these parameters a 'tolerance zone of uncertainty' could be identified which predicted acute-reaction acceptability or not of a schedule within a range of about 2-10 Gy in total BED. If concurrent chemoradiotherapy is used, our provisional suggestion is that this zone should be reduced by up to roughly 3-5 Gy10 in BED, with a request for further evidence.
  
  
  CONCLUSIONS
  It is suggested that total BED should be used, as specified above. Parameters of alpha=0.35 Gy-(1), alpha/beta=10 Gy, Tk=7 days and Tp=2.5 days are suggested. The 'acute/ tolerance zone' then turns out to be 59-61 Gy10 for radiation-only treatments. Further information about the decrement caused by concurrent head-and-neck cancer chemoradiotherapy, possibly 3-5 Gy10, is required.
authors.affiliation: Department of Human Oncology K4/316, University of Wisconsin, 600 Highland Ave., Madison, WI 53792, USA.
authors.forename: Jack F
authors.initials: JF
authors.lastname: Fowler
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
authors.forename: Felix
authors.initials: F
authors.lastname: Leborgne
authors.forename: José H
authors.initials: JH
authors.lastname: Leborgne
mesh_terms: D019583:Dose Fractionation, Radiation; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D009061:Mouth Mucosa / Q000473:pathology / Q000528:radiation effects; D009960:Oropharynx / Q000473:pathology / Q000528:radiation effects*; D011832:Radiation Injuries / Q000209:etiology; D011836:Radiation Tolerance; D011878:Radiotherapy / Q000009:adverse effects; D011879:Radiotherapy Dosage