title: Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers.
abstract: OBJECTIVE
  The dose distributions of intensity-modulated radiotherapy (IMRT) treatment plans can be shown to be significantly superior in terms of higher conformality if designed to simultaneously deliver high dose to the primary disease and lower dose to the subclinical disease or electively treated regions. We use the term "simultaneous integrated boost" (SIB) to define such a treatment. The purpose of this paper is to develop suitable fractionation strategies based on radiobiological principles for clinical trials and routine use of IMRT of head and neck (HN) cancers. The fractionation strategies are intended to allow escalation of tumor dose while adequately sparing normal tissues outside the target volume and considering the tolerances of normal tissues embedded within the primary target volume.
  
  
  METHODS
  IMRT fractionation regimens are specified in terms of "normalized total dose" (NTD), i.e., the biologically equivalent dose given in 2 Gy/fx. A linear-quadratic isoeffect formula is applied to convert NTDs into "nominal" prescription doses. Nominal prescription doses for a high dose to the primary disease, an intermediate dose to regional microscopic disease, and lower dose to electively treated nodes are used for optimizing IMRT plans. The resulting nominal dose distributions are converted back into NTD distributions for the evaluation of treatment plans. Similar calculations for critical normal tissues are also performed. Methods developed were applied for the intercomparison of several HN treatment regimens, including conventional regimens used currently and in the past, as well as SIB strategies. This was accomplished by comparing the biologically equivalent NTD values for the gross tumor and regional disease, and bone, muscle, and mucosa embedded in the gross tumor volume.
  
  
  RESULTS
  (1) A schematic HN example was used to demonstrate that dose distributions for SIB IMRT are more conformal compared to dose distributions when IMRT is divided into a large-field phase and a boost phase. Both were shown to be significantly superior compared to dose distributions obtained using conventional beams for the large-field phase followed by IMRT for the boost phase. (2) The relationship between NTD and nominal dose for HN tumors was found to be quite sensitive to the choice of tumor clonogen doubling time but relatively insensitive to other parameters. (3) For late effect normal tissues embedded in the tumor volume and assumed to receive the same dose as the tumor, the biologically equivalent NTD for the SIB IMRT may be significantly higher. (4) Normal tissues outside the target volume receive lower dose due to the higher conformality of the IMRT plans. The biologically equivalent NTDs are even lower due to the lower dose per fraction in the SIB strategy.
  
  
  CONCLUSIONS
  IMRT dose distributions are most conformal when designed to be delivered as SIB. Using isoeffect radiobiological relationships and published HN data, fractionation strategies can be designed in which the nominal dose levels to the primary, regional disease and electively treated volumes are appropriately adjusted, each receiving different dose/fx. Normal tissues outside the treated volumes are at reduced risk in such strategies since they receive lower total dose as well as lower dose/fx. However, the late effect toxicities of tissues embedded within the primary target volume and assumed to receive the same dose as the primary may pose a problem. The efficacy and safety of the proposed fractionation strategies will need to be evaluated with careful clinical trials.
authors.affiliation: Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University and McGuire VA Hospital, Richmond 23298, USA. rmohan@hsc.vcu.edu
authors.forename: R
authors.initials: R
authors.lastname: Mohan
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Manning
authors.forename: R
authors.initials: R
authors.lastname: Schmidt-Ullrich
mesh_terms: D019583:Dose Fractionation, Radiation; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D008198:Lymph Nodes; D008954:Models, Biological; D010282:Parathyroid Neoplasms / Q000532:radiotherapy; D019047:Phantoms, Imaging; D011853:Radiobiology; D012062:Relative Biological Effectiveness