Molecular imaging biomarkers of resistance to radiation therapy for spontaneous nasal tumors in canines.
OBJECTIVE
Imaging biomarkers of resistance to radiation therapy can inform and guide treatment management. Most studies have so far focused on assessing a single imaging biomarker. The goal of this study was to explore a number of different molecular imaging biomarkers as surrogates of resistance to radiation therapy.


METHODS
Twenty-two canine patients with spontaneous sinonasal tumors were treated with accelerated hypofractionated radiation therapy, receiving either 10 fractions of 4.2 Gy each or 10 fractions of 5.0 Gy each to the gross tumor volume. Patients underwent fluorodeoxyglucose (FDG)-, fluorothymidine (FLT)-, and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM)-labeled positron emission tomography/computed tomography (PET/CT) imaging before therapy and FLT and Cu-ATSM PET/CT imaging during therapy. In addition to conventional maximum and mean standardized uptake values (SUV(max); SUV(mean)) measurements, imaging metrics providing response and spatiotemporal information were extracted for each patient. Progression-free survival was assessed according to response evaluation criteria in solid tumor. The prognostic value of each imaging biomarker was evaluated using univariable Cox proportional hazards regression. Multivariable analysis was also performed but was restricted to 2 predictor variables due to the limited number of patients. The best bivariable model was selected according to pseudo-R(2).


RESULTS
The following variables were significantly associated with poor clinical outcome following radiation therapy according to univariable analysis: tumor volume (P=.011), midtreatment FLT SUV(mean) (P=.018), and midtreatment FLT SUV(max) (P=.006). Large decreases in FLT SUV(mean) from pretreatment to midtreatment were associated with worse clinical outcome (P=.013). In the bivariable model, the best 2-variable combination for predicting poor outcome was high midtreatment FLT SUV(max) (P=.022) in combination with large FLT response from pretreatment to midtreatment (P=.041).


CONCLUSIONS
In addition to tumor volume, pronounced tumor proliferative response quantified using FLT PET, especially when associated with high residual FLT PET at midtreatment, is a negative prognostic biomarker of outcome in canine tumors following radiation therapy. Neither FDG PET nor Cu-ATSM PET were predictive of outcome.
Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
Tyler J
TJ
Bradshaw
Departments of Radiation Oncology and Radiology, University of Washington, Seattle, Washington.
Stephen R
SR
Bowen
Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas.
Michael A
MA
Deveau
Angell Animal Medical Center, Boston, Massachusetts.
Lyndsay
L
Kubicek
Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Pamela
P
White
Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center, and Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland.
Søren M
SM
Bentzen
Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
Richard J
RJ
Chappell
Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Lisa J
LJ
Forrest
Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. Electronic address: rjeraj@wisc.edu.
Robert
R
Jeraj
D000230:Adenocarcinoma / Q000662:veterinary; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000662:veterinary; D002813:Chondrosarcoma / Q000662:veterinary; D056831:Coordination Complexes; D004283:Dog Diseases / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D004285:Dogs; D019583:Dose Fractionation, Radiation; D005260:Female; D019788:Fluorodeoxyglucose F18; D008297:Male; D057054:Molecular Imaging / Q000662:veterinary*; D064847:Multimodal Imaging / Q000379:methods / Q000662:veterinary; D009669:Nose Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy / Q000662:veterinary*; D009942:Organometallic Compounds; D012516:Osteosarcoma / Q000662:veterinary; D010255:Paranasal Sinus Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy / Q000662:veterinary; D049268:Positron-Emission Tomography / Q000379:methods / Q000662:veterinary; D011379:Prognosis; D011836:Radiation Tolerance / Q000502:physiology*; D019275:Radiopharmaceuticals; D050397:Radiotherapy, Intensity-Modulated / Q000662:veterinary; D012044:Regression Analysis; D013882:Thiosemicarbazones; D013936:Thymidine; D014057:Tomography, X-Ray Computed / Q000379:methods / Q000662:veterinary; D047368:Tumor Burden
D056831:Coordination Complexes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D019788:Fluorodeoxyglucose F18; D013936:Thymidine