Michael W. Nolan

Intensity-Modulated and Image-Guided Radiation Therapy for Treatment of Genitourinary Carcinomas in Dogs

BACKGROUND External beam radiation therapy can be used to treat pelvic tumors in dogs, but its utility is limited by lack of efficacy data and associated late complications. HYPOTHESIS/OBJECTIVES The objective of this study was to assess local tumor control, overall survival, and toxicosis after intensity-modulated and image-guided radiation therapy (IM/IGRT) for treatment of genitourinary carcinomas (CGUC) in dogs. ANIMALS 21 client-owned dogs. METHODS A retrospective study was performed. Medical records of dogs for which there was intent to treat with a course of definitive-intent IM/IGRT for CGUC between 2008 and 2011 were reviewed. Descriptive and actuarial statistics comprised the data analysis. RESULTS Primary tumors were located in the prostate (10), urinary bladder (9), or urethra (2). 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 was statistically dependent upon location of the primary tumor. CONCLUSIONS AND CLINICAL IMPORTANCE IM/IGRT is generally well-tolerated and provides an effective option for locoregional control of CGUC. 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; controlled prospective evaluation is warranted.

Chemical Carcinogenesis of the Gastrointestinal Tract in Rodents: An Overview with Emphasis on NTP Carcinogenesis Bioassays

Cancers of the stomach and large intestine (LI) are the second and fourth leading causes of human cancer mortality. A review of the National Toxicology Program (NTP) database and the Carcinogenic Potency Database (CPDB) reveals that chemically induced neoplasms of the gastrointestinal tract (GIT) are relatively common. Within the GIT, epithelial tumors of the forestomach in mice and rats and LI of the rat are most common. Generally, there is a high species concordance for forestomach with at least 26 chemicals inducing tumors in both species. Glandular stomach tumors are rare, and the few reported are usually neuroendocrine tumors (carcinoids) originating from the enterochromaffin-like (ECL) cells. Of 290 carcinogenic agents identified by the NTP, 19 (7%) caused intestinal neoplasia, 14 in the rat and 5 in the mouse. Neoplasms occurred in both males and females, exclusively in the small intestine (SI) of the mouse and in the LI or both SI and LI in the rat. Enteric carcinogens (NTP) frequently induced neoplasms at other alimentary sites (oral cavity, esophagus, and stomach). In conclusion, the most common induced GIT tumors are squamous neoplasms of the forestomach, glandular neoplasms of the stomach are rare, and rats appear more prone to developing LI (colorectal) cancer compared to mice.

Stereotactic radiation therapy for treatment of canine intracranial meningiomas.

The objective of this study is to determine the rate of toxicity, median survival time (MST) and prognostic factors in dogs with presumed intracranial meningiomas that were treated with stereotactic radiation therapy (SRT). Patient demographics, neurological history, details of SRT plans and response to treatment (including toxicity and survival times) were examined for potential prognostic factors. Overall MST (MST) due to death for any cause was 561 days. There was a mild to moderate exacerbation of neurological symptoms 3-16 weeks following SRT treatments in 11/30 (36.7%) of dogs. This presumed adverse event was treated with corticosteroids, and improvement was seen in most of these dogs. Death within 6 months of treatment as a result of worsening neurologic signs was seen in 4/30 (13.3%) of dogs. Volume of normal brain that received full dose at a prescription of 8Gy × 3 fractions was predictive of death due to neurological problems within this 6-month period.

Stereotactic body radiation therapy for treatment of injection-site sarcomas in cats: 11 cases (2008–2012)

OBJECTIVE To evaluate outcomes of stereotactic body radiation therapy (SBRT) in cats with injection-site sarcomas (ISS) via assessment of local responses and recurrences, survival times, and complications. DESIGN Retrospective case series. ANIMALS 11 cats with ISS. PROCEDURES Medical records of cats that were treated with SBRT for ISS between June 2008 and July 2012 were reviewed; information on patient demographics (age, sex, and breed), oncological histories (including prior treatment and histologic grade), details of SBRT plans (tumor volume, treatment field sizes, and prescription), response to treatment (including toxicoses), progression-free intervals, and survival times were extracted. RESULTS Acute radiation-associated toxicoses were infrequent and limited to mild, self-limiting dermatitis and colitis in 2 and 1 of the 11 cats, respectively. No late radiation-associated toxicoses were observed. The objective response rate was 8 of 11 cats; these patients either had a partial or complete response as determined on the basis of CT or physical examination findings. The median progression-free interval was 242 days, and the median overall survival time was 301 days; median follow-up time of censored subjects was 173 days. CONCLUSIONS AND CLINICAL RELEVANCE SBRT was completed in 3 to 5 days and was well tolerated when used to treat cats with ISS. Measurable tumor responses were achieved in most cats in this study. Stereotactic body radiation therapy provided a means for palliation of ISS; further investigation is required to determine whether SBRT is a valid treatment option for downstaging disease prior to definitive surgery.

Surface Characterization of Gallium Nitride Modified with Peptides before and after Exposure to Ionizing Radiation in Solution

An aqueous surface modification of gallium nitride was employed to attach biomolecules to the surface. The modification was a simple two-step process using a single linker molecule and mild temperatures. The presence of the peptide on the surface was confirmed with X-ray photoelectron spectroscopy. Subsequently, the samples were placed in water baths and exposed to ionizing radiation to examine the effects of the radiation on the material in an environment similar to the body. Surface analysis confirmed degradation of the surface of GaN after radiation exposure in water; however, the peptide molecules successfully remained on the surface following exposure to ionizing radiation. We hypothesize that during radiation exposure of the samples, the radiolysis of water produces peroxide and other reactive species on the sample surface. Peroxide exposure promotes the formation of a more stable layer of gallium oxyhydroxide which passivates the surface better than other oxide species.

Pudendal Nerve and Internal Pudendal Artery Damage May Contribute to Radiation-Induced Erectile Dysfunction

PURPOSE/OBJECTIVES Erectile dysfunction is common after radiation therapy for prostate cancer; yet, the etiopathology of radiation-induced erectile dysfunction (RI-ED) remains poorly understood. A novel animal model was developed to study RI-ED, wherein stereotactic body radiation therapy (SBRT) was used to irradiate the prostate, neurovascular bundles (NVB), and penile bulb (PB) of dogs. The purpose was to describe vascular and neurogenic injuries after the irradiation of only the NVB or the PB, and after irradiation of all 3 sites (prostate, NVB, and PB) with varying doses of radiation. METHODS AND MATERIALS Dogs were treated with 50, 40, or 30 Gy to the prostate, NVB, and PB, or 50 Gy to either the NVB or the PB, by 5-fraction SBRT. Electrophysiologic studies of the pudendal nerve and bulbospongiosus muscles and ultrasound studies of pelvic perfusion were performed before and after SBRT. The results of these bioassays were correlated with histopathologic changes. RESULTS SBRT caused slowing of the systolic rise time, which corresponded to decreased arterial patency. Alterations in the response of the internal pudendal artery to vasoactive drugs were observed, wherein SBRT caused a paradoxical response to papaverine, slowing the systolic rise time after 40 and 50 Gy; these changes appeared to have some dose dependency. The neurofilament content of penile nerves was also decreased at high doses and was more profound when the PB was irradiated than when the NVB was irradiated. These findings are coincident with slowing of motor nerve conduction velocities in the pudendal nerve after SBRT. CONCLUSIONS This is the first report in which prostatic irradiation was shown to cause morphologic arterial damage that was coincident with altered internal pudendal arterial tone, and in which decreased motor function in the pudendal nerve was attributed to axonal degeneration and loss. Further investigation of the role played by damage to these structures in RI-ED is warranted.

Management of transitional cell carcinoma of the urinary bladder in dogs: Important challenges to consider

Our understanding of the natural history, as well as techniques for diagnosis, staging and restaging, and therapy for dogs afflicted by urothelial carcinomas, has greatly expanded in the past couple of decades. And yet, as outlined in the review by Christopher Fulkerson and Deborah Knapp from the Department of Veterinary Clinical Sciences at Purdue University in this Special Issue of The Veterinary Journal, there are plenty of remaining unknowns about the management of dogs with transitional cell carcinoma (TCC) of the lower urinary tract (Fulkerson and Knapp, 2015). Some of the most common questions we ponder, or are asked to comment on by fellow clinicians, relate to diagnosis and staging of bladder and prostate tumors. The focus of this editorial is to share our opinions on diagnosis and staging of TCC, and how these may impact on treatment decisions. As mentioned by Fulkerson and Knapp (2015), many practitioners recommend that percutaneous aspirates and biopsies of suspected TCC lesions be avoided due to the risk of tumor seeding along the needle tract. Nevertheless, a growing number of radiologists, internists and oncologists consider fine needle aspiration (FNA) and cytology of the bladder and/or prostate to be an acceptable (and perhaps preferred) first-line diagnostic. The underlying rationale relates to the perception that FNA is the most efficient means for acquisition of a diagnostic sample, and that the risk for seeding is low. This notion is supported by a recent study, in which only 24/544 (4.4%) of dogs with TCC evaluated at a single institution had histopathological evidence of TCC in the abdominal wall (Higuchi et al., 2013). In most cases (18/20 cases in which the inciting cause was known), the event thought to incite seeding was a transabdominal surgical procedure, rather than an FNA (Higuchi et al., 2013). Furthermore, the incidence rate for development of body wall TCC was only 1.6% in dogs not having undergone cystotomy. While 1.6% and even 4.4% seem to be relatively low incidence rates, we agree with the authors that the data must be interpreted with caution. Of the 367 dogs that did not undergo cystotomy in that study, the total number that had transabdominal FNA of the urinary tract was unknown (Higuchi et al., 2013); therefore, the reported incidence rates may not reflect the true risk of seeding after such a procedure. In addition, since many dogs with TCC also have concurrent urinary tract infections (and clinical signs can be identical), it is possible that multiple cystocenteses were performed to diagnose and monitor urinary tract infections prior to diagnosis of a TCC, further confounding the true incidence of bladder wall puncture in dogs with TCC resulting in abdominal wall tumor seeding. Because there are several simple, low cost and high yield alternatives to FNA, our clinical practice centers around the philosophy that diagnostic tests involving transabdominal sampling of bladder and prostate masses are the last diagnostic option, when all other tests have failed to yield a diagnosis, and when the owner has provided informed consent for FNA, acknowledging the risk for potential seeding. Instead, our diagnostic workup often starts with cytological evaluation (performed by a clinical pathologist) of urine sediment prepared using a cytospin protocol. If that is unrewarding, we often proceed with cystoscopic biopsies. Cytological samples obtained from flushing through the endoscope at the end of the procedure are often the most diagnostic of cytology samples obtained in the workup of these cases. Cystoscopy has the advantage of allowing for direct visualization and evaluation of the urothelium. Cystoscopy is not widely available in general practice, and not all clients will pursue referral for such a procedure. A very reasonable alternative is traumatic catheterization. This simple procedure involves sedation or light anesthesia, and gentle passage of a firm plastic urinary catheter (which has been fenestrated on the sides, at the distal end) into the urinary bladder, emptying the bladder, then passing the catheter back and forth over the lesion using a sawing motion. To avoid pieces of catheter breaking off into cavities, it is important that the structural integrity of the catheter be maintained by limiting the fenestrations (typically made by the clinician using a scalpel blade), such that they do not exceed a third of the circumference of the catheter and are longitudinally non-overlapping. A few milliliters of sterile saline are then instilled into and subsequently recovered from the bladder. In our hands, the procedure is of highest yield when performed with ultrasound guidance; the resultant sample is a bloody fluid, which can be submitted for cytology. Alternatively, if visible pieces of tissue are retrieved, they can be submitted for histological evaluation. When these pieces are small, clinicians are encouraged to converse with their laboratory to determine whether the pathologist would prefer the sample be evaluated using routine histopathology (with paraffin embedding) or prepared in an agar block (noting that cell block preparations are not available through all laboratories). Traumatic catheterization should be performed with care, as iatrogenic rupture of the urinary bladder and/or urethra is possible. If these procedures have failed to yield a cytological diagnosis, we will consider FNA after consultation with the owner about the risks of abdominal wall seeding. Because of the known risks, and the availability of alternative diagnostic procedures thought to be associated with a lower risk of seeding, performing transabdominal

Misadministration of radiation therapy in veterinary medicine: a case report and literature review

Recent technical advancements in radiation therapy have allowed for improved targeting of tumours and sparing nearby normal tissues, while simultaneously decreasing the risk for medical errors by incorporating additional safety checks into electronic medical record keeping systems. The benefits of these new technologies, however, depends on their proper integration and use in the oncology clinic. Despite the advancement of technology for treatment delivery and medical record keeping, misadministration errors have a significant impact on patient care in veterinary oncology. The first part of this manuscript describes a medical incident that occurred at an academic veterinary referral hospital, in a dog receiving a combination of stereotactic radiation therapy and full-course intensity-modulated, image-guided radiation therapy. The second part of the report is a literature review, which explores misadministration errors and novel challenges which arise with the implementation of advancing technologies in veterinary radiation oncology.

Clinical and imaging findings, treatments, and outcomes in 27 dogs with imaging diagnosed trigeminal nerve sheath tumors: A multi‐center study

The clinical behavior of canine trigeminal nerve sheath tumors and benefits of previously reported treatments are incompletely defined. Aims of this retrospective, multicenter, observational study were to describe clinical signs, tumor localization characteristics, treatments, and clinical outcomes in a group of dogs with this neoplasm. Databases at four hospitals were reviewed for dogs with a trigeminal nerve sheath tumor diagnosis, magnetic resonance imaging (MRI) studies, and presentation between 2004 and 2014. A single observer recorded medical record findings and two observers recorded MRI characteristics by consensus. A total of 27 dogs met inclusion criteria (15 treated with stereotactic radiation therapy and 12 unirradiated). Two unirradiated dogs were excluded from outcome analyses. The most common presenting signs were masticatory muscle atrophy (26 dogs), neurologic signs referable to intracranial disease (13), and ocular disease (12). Based on MRI findings, all dogs had disease extending centrally at the level of the brainstem. The most commonly affected trigeminal nerve branches were the mandibular (26 dogs), maxillary (22), and ophthalmic (10). Of 15 dogs treated with stereotactic radiation therapy, one had improved muscle atrophy, and six had poor ocular health after treatment. Neurologic signs improved in 4/5 dogs with intracranial signs. Overall median survival time for the 10 unirradiated dogs with available follow-up was 12 days and 441 days for the 15 stereotactic radiation therapy dogs. Mean survival times between these groups were not significantly different (mean 95% CI for unirradiated dogs was 44-424 days and mean 95% CI for stereotactic radiation therapy dogs was 260-518 days).

SU-C-204-06: Monte Carlo Dose Calculation for Kilovoltage X-Ray-Psoralen Activated Cancer Therapy (X-PACT): Preliminary Results

PURPOSE X-PACT is an experimental cancer therapy where kV x-rays are used to photo-activate anti-cancer therapeutics through phosphor intermediaries (phosphors that absorb x-rays and re-radiate as UV light). Clinical trials in pet dogs are currently underway (NC State College of Veterinary Medicine) and an essential component is the ability to model the kV dose in these dogs. Here we report the commissioning and characterization of a Monte Carlo (MC) treatment planning simulation tool to calculate X-PACT radiation doses in canine trials. METHODS FLUKA multi-particle MC simulation package was used to simulate a standard X-PACT radiation treatment beam of 80kVp with the Varian OBI x-ray source geometry. The beam quality was verified by comparing measured and simulated attenuation of the beam by various thicknesses of aluminum (2-4.6 mm) under narrow beam conditions (HVL). The beam parameters at commissioning were then corroborated using MC, characterized and verified with empirically collected commissioning data, including: percent depth dose curves (PDD), back-scatter factors (BSF), collimator scatter factor(s), and heel effect, etc. All simulations were conducted for N=30M histories at M=100 iterations. RESULTS HVL and PDD simulation data agreed with an average percent error of 2.42%±0.33 and 6.03%±1.58, respectively. The mean square error (MSE) values for HVL and PDD (0.07% and 0.50%) were low, as expected; however, longer simulations are required to validate convergence to the expected values. Qualitatively, pre- and post-filtration source spectra matched well with 80kVp references generated via SPEKTR software. Further validation of commissioning data simulation is underway in preparation for first-time 3D dose calculations with canine CBCT data. CONCLUSION We have prepared a Monte Carlo simulation capable of accurate dose calculation for use with ongoing X-PACT canine clinical trials. Preliminary results show good agreement with measured data and hold promise for accurate quantification of dose for this novel psoralen X-ray therapy. Funding Support, Disclosures, & Conflict of Interest: The Monte Carlo simulation work was not funded; Drs. Adamson & Oldham have received funding from Immunolight LLC for X-PACT research.