title: Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects.
abstract: OBJECTIVE
  Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the dose-limiting toxicity.
  
  
  METHODS
  A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects.
  
  
  RESULTS
  Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD.
  
  
  CONCLUSIONS
  In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Sonja J
authors.initials: SJ
authors.lastname: van der Veen
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hette
authors.initials: H
authors.lastname: Faber
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Ghobadi
authors.affiliation: KVI Center for Advanced Radiation Research, University of Groningen, Groningen, The Netherlands.
authors.forename: Sytze
authors.initials: S
authors.lastname: Brandenburg
authors.affiliation: Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Coppes
authors.affiliation: Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: p.van.luijk@umcg.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: van Luijk
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000473:pathology / Q000528:radiation effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D006984:Hypertrophy / Q000209:etiology / Q000473:pathology; D008168:Lung / Q000098:blood supply* / Q000528:radiation effects*; D008297:Male; D058958:Organs at Risk / Q000098:blood supply / Q000528:radiation effects; D011522:Protons; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000209:etiology / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D056152:Respiratory Rate / Q000528:radiation effects*; D013997:Time Factors
chemical_list: D011522:Protons