title: Dose painting based on tumor uptake of Cu-ATSM and FDG: a comparative study.
abstract: BACKGROUND
  Hypoxia and increased glycolytic activity of tumors are associated with poor prognosis. The purpose of this study was to investigate differences in radiotherapy (RT) dose painting based on the uptake of 2-deoxy-2-[(18) F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer, copper(II)diacetyl-bis(N(4))-methylsemithiocarbazone (Cu-ATSM) using spontaneous clinical canine tumor models.
  
  
  METHODS
  Positron emission tomography/computed tomography scans of five spontaneous canine sarcomas and carcinomas were obtained; FDG on day 1 and (64)Cu-ATSM on day 2 and 3 (approx. 3 and 24 hours pi.). Sub-volumes for dose escalation were defined by a threshold-based method for both tracers and five dose escalation levels were formed in each sub-volume. Volumetric modulated arc therapy plans were optimized based on the dose escalation regions for each scan for a total of three dose plans for each dog. The prescription dose for the GTV was 45 Gy (100%) and it was linearly escalated to a maximum of 150%. The correlations between dose painting plans were analyzed with construction of dose distribution density maps and quality volume histograms (QVH). Correlation between high-dose regions was investigated with Dice correlation coefficients.
  
  
  RESULTS
  Comparison of dose plans revealed varying degree of correlation between cases. Some cases displayed a separation of high-dose regions in the comparison of FDG vs. (64)Cu-ATSM dose plans at both time points. Among the Dice correlation coefficients, the high dose regions showed the lowest degree of agreement, indicating potential benefit of using multiple tracers for dose painting. QVH analysis revealed that FDG-based dose painting plans adequately covered approximately 50% of the hypoxic regions.
  
  
  CONCLUSIONS
  Radiotherapy plans optimized with the current approach for cut-off values and dose region definitions based on FDG, (64)Cu-ATSM 3 h and 24 h uptake in canine tumors had different localization of the regional dose escalation levels. This indicates that (64)Cu-ATSM at two different time-points and FDG provide different biological information that has to be taken into account when using the dose painting strategy in radiotherapy treatment planning.
authors.affiliation: Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. mmc@sund.ku.dk.|Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. mmc@sund.ku.dk.|Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark. mmc@sund.ku.dk.
authors.forename: Malene Martini
authors.initials: MM
authors.lastname: Clausen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. aeha@sund.ku.dk.|Technical University of Denmark, DTU Nanotech, Center of Nanomedicine and theranostics, Lyngby, Denmark. aeha@sund.ku.dk.
authors.forename: Anders Elias
authors.initials: AE
authors.lastname: Hansen
authors.affiliation: Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. michael.lundemann.jensen@regionh.dk.
authors.forename: Michael
authors.initials: M
authors.lastname: Lundemann
authors.affiliation: Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. christianhollensen@gmail.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Hollensen
authors.affiliation: Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. leif.tobias.pommer@regionh.dk.|Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark. leif.tobias.pommer@regionh.dk.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pommer
authors.affiliation: Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. per.munck@regionh.dk.|Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark. per.munck@regionh.dk.
authors.forename: Per
authors.initials: P
authors.lastname: Munck Af Rosenschöld
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark. atk@sund.ku.dk.
authors.forename: Annemarie Thuri
authors.initials: AT
authors.lastname: Kristensen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. akjaer@sund.ku.dk.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjær
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark. fme@sund.ku.dk.
authors.forename: Fintan J
authors.initials: FJ
authors.lastname: McEvoy
authors.affiliation: Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. svend.aage.engelholm@regionh.dk.
authors.forename: Svend Aage
authors.initials: SA
authors.lastname: Engelholm
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D015687:Cell Hypoxia; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000493:pharmacokinetics*; D004283:Dog Diseases / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D004285:Dogs; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006019:Glycolysis; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted; D050397:Radiotherapy, Intensity-Modulated; D012513:Sarcoma, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D013882:Thiosemicarbazones / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D019788:Fluorodeoxyglucose F18