title: Pre-treatment number of clonogenic cells and their radiosensitivity are major determinants of local tumour control after fractionated irradiation.
abstract: OBJECTIVE
  The response of tumours to fractionated radiotherapy is determined by many factors including repopulation, reoxygenation, the number of clonogenic cells, and their intrinsic radiosensitivity. However, after single radiation doses given under conditions of clamp hypoxia, the dose to control a tumour locally is dependent only on the number of clonogenic cells and their cellular radiosensitivity. Therefore, these parameters were investigated using local control after single doses given under hypoxia, to predict the outcome of fractionated irradiation.
  
  
  METHODS
  Ten hSCC cell lines (FaDu, UT-SCC-15, UT-SCC-14, XF354, UT-SCC-5, UT-SCC-45, SAS, CAL-33, UT-SCC-8, and HSC-4) were transplanted subcutaneously into the right hind-leg of NMRI nude mice. At 7mm in diameter, tumours were irradiated either with graded single doses under clamp blood flow conditions (n=873) or with 30 graded fractions within 6 weeks (n=905) under ambient conditions. Local tumour control was determined 120 days after irradiation. Radiation response was quantified in terms of TCD(50), i.e. the dose required to control 50% of tumours locally.
  
  
  RESULTS
  Ten tumour lines investigated showed a pronounced heterogeneity in both TCD(50(30fx/6w)) after fractionated irradiation and TCD(50(SDclamp)) after single dose irradiation. TCD(50(30fx/6w)) varied between 45Gy for UT-SCC-45 and 127Gy for SAS; TCD(50(SDclamp)) varied between 42Gy for UT-SCC-14 and 66Gy for CAL-33. Two tumours were excluded from further analysis due to immunogenicity or non-defined TCD(50). Linear regression analysis revealed a significant positive correlation between TCD(50(SDclamp)) and TCD(50(30fx/6w)) (R(2)=0.82, p=0.002).
  
  
  CONCLUSIONS
  Significant association between TCD(50(SDclamp)) and TCD(50(30fx/6w)) suggests that the pre-treatment number of clonogenic tumour cells and their cellular radiosensitivity have a major impact on local control after fractionated radiotherapy.
authors.affiliation: OncoRay - Centre for Radiation Research in Oncology, University of Technology Dresden, Germany.
authors.forename: Ala
authors.initials: A
authors.lastname: Yaromina
authors.forename: Marie
authors.initials: M
authors.lastname: Krause
authors.forename: Howard
authors.initials: H
authors.lastname: Thames
authors.forename: Andrea
authors.initials: A
authors.lastname: Rosner
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.forename: Franziska
authors.initials: F
authors.lastname: Hessel
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy*; D002452:Cell Count; D015687:Cell Hypoxia; D002999:Clone Cells / Q000528:radiation effects*; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D011836:Radiation Tolerance; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays