The future of radiotherapy in small animals - should the fractions be coarse or fine?

Radiation therapy has been used to treat animal cancers for more than 100 years. Clinical experiences and experimental results have been widely published and provide a basis for the recognition of radiation therapy as an integral component of multimodal cancer management in veterinary oncology. As the expectations of pet owners and the demand for treatment of companion animals with cancer have increased, veterinary oncology itself has undergone dramatic advances in the past several decades both in terms of improved diagnostics and treatments, including increased accessibility of radiation therapy. Synchronous with development of the specialism of veterinary radiation oncology, confusion and controversy have arisen with regard to distinguishing between different types of radiotherapy and methods of treatment delivery. Importantly, the confusion extends beyond semantics, and includes opinionated debate about defining which forms of therapy (if any at all) are optimal for a given patient. This exemplifies how, despite marks of maturity including age and a robust publication history, the field of veterinary radiation oncology is in some ways still in its infancy. The purpose of this article is to review the evidence base for daily (fine) fractionation versus weekly (coarse) hypofractionation in veterinary oncology, using selected tumour types as examples.

Stereotactic body radiation therapy for heart-base tumors in six dogs.

INTRODUCTION: Heart-base tumors are increasingly treated with radiotherapy, yet safety and efficacy are incompletely understood. This case series describes outcomes after stereotactic body radiation therapy (SBRT) for presumed chemodectoma. ANIMALS: Six pet dogs. METHODS: A retrospective study was performed, including dogs with a clinical diagnosis of chemodectoma and treatment with three-fraction SBRT (30 Gy total). RESULTS: Heart-base tumors, presumed or confirmed to be chemodectomas, were diagnosed via histopathology or imaging. Treatment was delivered with intensity modulation and cone-beam computed tomography-based image guidance, using a linear accelerator and robotic couchtop. Intrafraction respiratory motion was managed with either neuromuscular blockade and breath-holding (n = 3) or high-frequency jet ventilation (n = 3); mean total anesthesia times for each technique were 165 and 91 min per fraction, respectively. Four tumors were assessed after SBRT; tumor volume decreased by 30-76%. Possible treatment-related complications included cough, tachyarrhythmias, and congestive heart failure. Two dogs experienced sudden death 150 and 294 days after SBRT. Three dogs are alive 408-751 days after SBRT, and one dog died of unrelated disease 1,228 days after SBRT. CONCLUSIONS: This SBRT protocol resulted in rapid tumor volume reduction, and jet ventilation effectively reduced treatment delivery times. However, cardiac arrhythmias (presumably tumor or treatment associated) and sudden death were common after SBRT. Therefore, SBRT is a potentially useful treatment but may not be appropriate for dogs with incidentally diagnosed, slowly growing tumors, which are not causing cardiovascular disturbances. Longer follow-up and larger case numbers are needed to more completely define safety and impact of treatment on long-term survivability.

Linac-based stereotactic radiation therapy for canine non-lymphomatous nasal tumours: 29 cases (2013-2016).

Twenty-nine dogs were treated with linac-based stereotactic radiation therapy (SRT) for non-lymphomatous nasal tumours. Only dogs with a follow-up time >365 days were included in this retrospective analysis. No dogs had evidence of distant metastasis at diagnosis. Treatment was planned and a total of 30 Gy in 3 daily 10 Gy fractions was delivered using intensity-modulation, cone-beam CT-based image guidance and a robotic treatment couch. Clinical signs improved in all cases. Nineteen dogs had CT scans 3-4 months post-SRT and all had partial or complete tumour response. Minimal acute toxicities were detected. Clinically significant late toxicities included oronasal or nasocutaneous fistulas (N = 3) and biopsy-confirmed fungal rhinitis with no evidence of tumour progression (N = 2). The median progression-free survival (PFS) was 354 days, with 49% and 39% progression-free at 1 and 2 years post-SRT, respectively. The median survival time (ST) was 586 days, with 69% and 22% alive 1 and 2 years post-SRT, respectively. Neither the clinical parameters evaluated (modified Adams' stage, histopathology, presence of intracranial extension of the tumour) nor dosimetric data were predictive for PFS or ST. This SRT protocol appears to be well tolerated, and PFI and ST are comparable or superior to those reported in other definitive-intent radiotherapy protocols.

Pilot study to determine the feasibility of radiation therapy for dogs with right atrial masses and hemorrhagic pericardial effusion.

OBJECTIVES: To determine the short-term safety and biologic activity of radiation therapy (RT) for presumptive cardiac hemangiosarcoma in pet dogs. ANIMALS: Six dogs with echocardiographic evidence of a right atrial/auricular mass, and hemorrhagic pericardial effusion, were enrolled in a prospective, single-arm clinical trial. METHODS: A single fraction of 12 Gy was delivered using conformal external beam irradiation. Serum cardiac troponin I and plasma concentrations of vascular endothelial growth factor were quantified before, 4 and 24 h after RT. The frequency of required pericardiocenteses (quantified as the number of pericardiocenteses per week) before RT was compared to that after treatment. Overall survival time was determined. RESULTS: No treatment-related complications were observed. Pericardiocentesis was performed an average of 0.91 times per week before RT, and an average of 0.21 times per week after RT; this difference was statistically significant (p=0.03, as compared using a Wilcoxon signed-rank test of paired data). Pre- and post-treatment plasma vascular endothelial growth factor concentrations were not significantly different at any time point; there was a statistically significant (p=0.04; Friedman's test for non-parametric repeated measures) increase in cardiac troponin concentrations 4 h after irradiation. Median overall survival time was 79 days. CONCLUSIONS: In this population of dogs, RT was delivered without complication, and appears to have reduced the frequency of periacardial tamponade that necessitated pericardiocentesis. Serum cardiac troponin levels are altered after RT. RT alone, or in combination with chemotherapy, may provide clinical benefit to dogs with presumptive diagnoses of cardiac hemangiosarcoma.

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.

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.

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.

Pharmacokinetics of oxytetracycline in the American horseshoe crab, Limulus polyphemus.

The American horseshoe crab, Limulus polyphemus, is regularly cultured and maintained in research laboratories and public aquaria. Rising concerns over the health of these captive animals makes the diagnosis and treatment of pathological conditions in L. polyphemus essential. This study investigated the kinetics of oxytetracyline following either intravascular or oral dosing. Oxytetracylcine is a broad-spectrum antibiotic used in the treatment of various bacterial diseases of aquatic animals. A noncompartmental model was developed to describe the pharmacokinetics of oxytetracycline (OTC) in the horseshoe crab. The following parameters were determined for a single intravascular bolus of 25 mg/kg OTC: AUC = 9524.60 microg.h/mL, MRT = 443.65 h, Clb = 0.044 mL/min/kg, Vd(ss) = 1.164 L/kg, t(1/2) = 128.3 h, Cmax = 55.90 microg/mL, C(ave) = 27.39 microg/mL. Following a single oral bolus of 25 mg/kg, these parameters were calculated: AUC = 5861.81 microg.h/mL, MRT = 395.89 h, Clb = 0.071 mL/min/kg, Vd(ss) = 1.688 L/kg, t(1/2) = 210.0 h, Cmax = 7.83 microg/mL, C(ave) = 2.89 microg/mL, F = 61.56%.

The treatment of resistant warts with intralesional bleomycin: a controlled clinical trial.

A controlled double-blind trial was carried out on fifty-nine matched pairs of hand warts in a group of twenty-four patients, with proven resistance to treatment, to study the effectiveness of the intralesional injection of 0.1% solution of bleomycin sulphate in normal saline, compared with a normal saline placebo injected into the paired warts in the same patient. We found that 87.5% of patients showed a more favourable response to bleomycin (P less than 0.001); 76% of the fifty-nine warts treated with bleomycin were cured by one to three injections of up to 0.2 ml of solution. Subsequently 75% of thirty-two patients with resistant hand warts and 66% of fifteen patients with mosaic plantar warts were cured of all their warts. No patient received more than 4 mg of bleomycin. No toxicity was experienced. Local pain was on the whole well tolerated. This form of treatment for resistant warts is reliable, safe and acceptable to patients.

An assessment of methods of treating viral warts by comparative treatment trials based on a standard design.

A series of eleven comparative wart treatment trials undertaken between 1969 and 1975 and involving 1802 patients is described. A method of coding provided groups of patients matched for age, type, number and duration of warts, within which treatments could be randomized. The variation in response to treatment was shown to be influenced significantly by these factors and the level of cure to depend on the proportions of the various response groups within the population under consideration. These proportions were found to vary geographically and at different periods. In all the trials the results were assessed at 12 weeks. In the treatment of hand warts, the percentage cure of patients treated with liquid nitrogen fell significantly from 75 to 40% when the interval between freezings was increased from 3 to 4 weeks. The average number of freezings required for a cure was 3-1 amongst all patients cured by 6 or less freezings at intervals of 2 or 3 weeks. In a two-centre trial there was no significant difference between the percentage cure of patients with hand warts treated with liquid nitrogen (69%) and of those applying a paint containing salicylic and lactic acids (SAL) (67%). Patients receiving both treatments concurrently did better (78%) but the difference was not found to be statistically significant. In the treatment of simple plantar warts the percentage cure for the SAL paint (84%) was found to compare favourably with that for a podophyllin treatment (81%). Only one of the patients cured by the paint in that trial was found to have had a recurrence after 6 months. The paint was found to be satisfactory for use under general practice conditions. Additions to the formula did not alter its effectiveness. In the treatment of mosaic plantar warts the overall percentage cure for the SAL paint in a series of comparative trials (1969-75) was 45%. In these trials it was compared directly with one or more other preparations. No differences were found between its efficacy and that of 10% buffered gluteraldehyde (47%), 40% benzalkonium chloride dibromide (Callusolve 40) (30%) and 5% 5-fluorouracil in dimethyl sulphoxide (53%). Only 25% of thirty-six patients treated with 5% idoxuridine in dimethylsulphoxide were cured. Throughout the trials approximately 30% of patients with hand warts, 20% of those with simple plantar warts and 50% of those with mosaic plantar warts were found to be resistant to treatment. The adoption of treatment with SAL paint for hand warts and simple plantar warts by the general practitioners in the Edinburgh area has proved satisfactory. Only resistant cases are now referred to hospital and these can be treated within a few weeks instead of 4-5 months as was the case in 1969.