title: Equivalence of hyperfractionated and continuous brachytherapy in a rat tumor model and remarkable effectiveness when preceded by external irradiation.
abstract: OBJECTIVE
  In clinical brachytherapy, there is a tendency to replace continuous low-dose-rate (LDR) irradiation by either single-dose or fractionated high-dose-rate (HDR) irradiation. In this study, the equivalence of LDR treatments and fractionated HDR (2 fractions/day) or pulsed-dose-rate (PDR, 4 fractions/day) schedules in terms of tumor cure was investigated in an experimental tumor model.
  
  
  METHODS
  Tumors (rat rhabdomyosarcoma R1M) were grown s.c. in the flank of rats and implanted with 4 catheters guided by a template. All interstitial radiation treatment (IRT) schedules were given in the same geometry. HDR was given using an (192)Ir single-stepping source. To investigate small fraction sizes, part of the fractionated HDR and PDR schedules were applied after an external irradiation (ERT) top-up dose. The endpoint was the probability of tumor control at 150 days after treatment. Cell survival was estimated by excision assay.
  
  
  RESULTS
  Although there was no fractionation effect for fractionated HDR given in 1 or 2 fractions per day, TCD(50)-values were substantially lower than that for LDR. A PDR schedule with an interfraction interval of 3 h (4 fractions/day), however, was equivalent to LDR. The combination of ERT and IRT resulted in a remarkably increased tumor control probability in all top-up regimens, but no difference was found between 2 or 4 fractions/day. Catheter implantation alone decreased the TCD(50) for single-dose ERT already by 17.4 Gy. Cell viability assessed at 24 h after treatment demonstrated an increased effectiveness of interstitial treatment, but, after 10 Gy ERT followed by 10 Gy IRT (24-h interval), it was not less than that calculated for the combined effect of these treatments given separately.
  
  
  CONCLUSIONS
  In full fractionation schedules employing large fractions and long intervals, the sparing effect of sublethal damage repair may be significantly counteracted by reoxygenation. During 3-h intervals, however, repair may be largely completed with only partial reoxygenation causing PDR schedules to be less effective than fractionated HDR, and equivalent to LDR. Brachytherapy with clinically sized fractions after a large external top-up dose showed a remarkable increase in tumor control rate with no effect of fractionation (up to 4 fractions/day), which could not be fully explained by differences in dose distribution or in the cell viability assessed after treatment. This suggests a longer lasting effect on cell survival or radiosensitivity associated with catheter implantation shortly after the top-up dose.
authors: Department of Radiation Oncology, University Hospital Rotterdam--Daniel, Rotterdam, The Netherlands.
authors: T
authors: T
authors: Veninga
authors: A G
authors: AG
authors: Visser
authors: A P
authors: AP
authors: van den Berg
authors: C M
authors: CM
authors: van Hooije
authors: C A
authors: CA
authors: van Geel
authors: P C
authors: PC
authors: Levendag
mesh_terms: D000818:Animals; D001918:Brachytherapy / Q000379:methods*; D002470:Cell Survival; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D016015:Logistic Models; D023421:Models, Animal; D009368:Neoplasm Transplantation; D011853:Radiobiology; D051381:Rats; D012208:Rhabdomyosarcoma / Q000532:radiotherapy*; D013997:Time Factors