Outcomes of pelvic irradiation in normal and tumor-bearing dogs
Date
2013
Authors
Nolan, Michael W., author
LaRue, Susan M., advisor
Biller, Barbara J., committee member
Custis, James T., committee member
Ehrhart, E. J., committee member
Kraft, Susan L., committee member
Marolf, Angela J., committee member
Journal Title
Journal ISSN
Volume Title
Abstract
The purpose of this research was to better understand the effects of abdominopelvic irradiation in dogs. Three studies were performed to that end. The first was a clinical investigation, performed by retrospective data analysis, of safety and activity of intensity-modulated and image-guided radiation therapy (IM-IGRT) for treatment of genitourinary (GU) carcinomas in dogs. The second was a prospective study which developed dogs as a novel animal model for studying radiation-induced erectile dysfunction (RI-ED). The third study reviewed pathological changes associated with unexpected colorectal toxicities encountered in the development of the RI-ED model. As mentioned, the objective of the first study was to assess local tumor control, overall survival and toxicosis following IM/IGRT for treatment of genitourinary carcinomas (CGUC) in dogs. Medical records of patients for which there was intent to treat with a course of definitive-intent IM/IGRT for CGUC were reviewed. Primary tumors were located in the prostate, urinary bladder or urethra of 21 dogs. The total radiation dose ranged from 54-58 Gy, delivered in 20 daily fractions. Grade 1 and 2 acute gastrointestinal toxicoses developed in 33% and 5% of dogs, respectively. Grade 1 and 2 acute genitourinary, and grade 1 acute integumentary toxicoses were documented in 5%, 5% and 20% of dogs, respectively. Four dogs experienced late grade 3 gastrointestinal or genitourinary toxicosis. The subjective response rate was 60%. The median event-free survival was 317 days; the overall median survival time was 654 days. Neither local tumor control nor overall survival were statistically dependent upon location of the primary tumor. In conclusion, IM/IGRT is generally well-tolerated and provides an effective option for locoregional control of CGUC. And, as compared with previous reports in the veterinary literature, inclusion of IM/IGRT in multimodal treatment protocols for CGUC can result in superior survival times. The etiopathology of RI-ED is poorly understood, though this is a common complication of men treated for prostate cancer. Purported mechanisms include cavernosal, arteriogenic and neurogenic injuries. Radiation dose to the posterolateral prostatic neurovascular bundles (NVB) and penile bulb (PB) have been associated with RI-ED. Herein, a canine model is described that has been developed to study the pathogenesis of RI-ED. Stereotactic body radiotherapy (SBRT) was used to irradiate the prostate gland, NVB and/or PB of purpose-bred, intact male dogs. Manual evaluation was used to characterize erectile function and quality. Ultrasound of the internal pudendal arteries, prostate and penis, dynamic contrast-enhanced MRI of the NVB and prostate, and electrophysiology of sensory and motor nerves as well as muscle were performed before and after irradiation. Gross necropsy and histopathology was also performed. Erectile dysfunction was a repeatable finding in subjects for whom the prostate, neurovascular bundles and penile bulb were irradiated with 50 Gy, as documented via subjective and objective manual evaluations following SBRT. Irradiated dogs were found to have a decreased extravascular, extracellular volume in the glans penis, longer systolic rise times in the pudendal artery following papaverine injection, abnormal spontaneous EMG activity in the bulbocavernosus muscle, and slower pudendal nerve motor conduction velocities. Radiation dose-dependent changes in internal pudendal arterial function and dysfunction of the pudendal nerve due to axonal loss may contribute to RI-ED. Measurable endpoints have been developed for evaluation of RI-ED in dogs, that should be used in future studies to refine this novel animal model and perform additional studies aimed at further elucidating the etiopathologic processes underlying RI-ED. The objective of the final study was to describe the dose-response relationship and time-dependency of late radiation-induced colorectal complications endured by dogs in the RI-ED study. The prostates of nineteen intact male mixed breed hounds were irradiated with one of four different dose/fractionation schemes. Subjects were monitored for signs of colorectal toxicosis for up to one year following irradiation. Gross necropsy and histopathology were performed upon euthanasia. All toxicoses were graded according to the RTOG criteria for gastrointestinal toxicity. The frequency and severity of colorectal ulceration were higher in dogs treated 5 fractions of 10 Gy delivered on consecutive days, as compared with those treated on an every other day schedule. The mechanism for this time-dependency is unclear, but likely related to completeness of epithelial regeneration. Vascular sclerosis and serosal thickening occurred in all treatment groups, in a dose-responsive fashion.
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Subject
erectile dysfunction
transitional cell carcinoma
stereotactic body radiation therapy
sexual toxicity
prostate cancer
colorectal toxicity