Dose-escalated simultaneously integrated boost radiation protocol fails to result in a survival advantage for sinonasal tumors in dogs.

The prognosis for canine sinonasal tumors remains rather poor despite definitive-intent radiotherapy (RT). Theoretical calculations predicted improved outcomes with simultaneously integrated boost (SIB) protocols. With the hypothesis of clinically detectable differences in outcome between groups, our retrospective study evaluated prognostic variables and outcome in dogs treated with regular versus SIB RT. Dogs with sinonasal tumors treated with either a regular (10 × 4.2 Gy) or new SIB protocol (10 × 4.83 Gy to macroscopic tumor) were included. Information regarding signalment, tumor stage, type, clinical signs, radiation toxicity, response, and outcome was collected. Forty-nine dogs were included: 27 treated regularly and 22 treated with SIB RT. A total of 69.4% showed epistaxis, 6.1% showed epileptic seizures, 46.9% showed stage IV tumors, and 6.1% showed lymph node metastases. Early toxicity was mostly mild. Late grade 1 skin toxicity (alopecia/leucotrichia) was seen in 72.1% of dogs, and a possible grade 3 ocular toxicity (blindness) was seen in one dog. Complete/partial resolution of clinical signs was seen in 95.9% of patients as best clinical response and partial remission was seen as best imaging response in 34.7%. The median progression-free survival (PFS) was 274 days (95% CI: 117-383) for regular and 300 days (95% CI: 143-451) for SIB RT, which was not significantly different (P = 0.42). Similarly, the median overall survival (OS) was 348 days (95% CI: 121-500) for regular and 381 days (95% CI: 295-634) for the SIB RT (P = 0.18). Stratified by protocol, the hazard ratio of stage IV versus stage I-III tumors was 2.29 (95% CI: 1.156-4.551, P = 0.02) for OS but not PFS. All dogs showed acceptable toxicity. In contrast to theoretical predictions, however, we could not show a statistically significant better outcome with the new protocol.

Minimal late radiation toxicity and transient early toxicity following postoperative definitive intent conformal radiation therapy (20 × 2.5 Gy) for canine apocrine gland anal sac adenocarcinoma.

Postoperative radiation therapy (RT) may be beneficial for dogs with anal sac apocrine gland adenocarcinoma (ASAC). Clinically significant late toxicities have been reported in up to 65% of dogs with perianal tumors following non-conformal definitive RT, particularly when fractions of 3 Gy or higher are prescribed. The primary objective of this prospective, descriptive study was to evaluate tolerability of a novel 3D conformal RT (3DCRT) protocol in a group of dogs. Dogs with ASAC were prospectively enrolled if clients elected RT following surgery. The planning target volume was prescribed 50 Gy in 2.5 Gy fractions using 6 MV photons and administered over 26 days. Early and late radiation toxicities were graded according to standardized criteria. Thirteen dogs were initially enrolled but 1 was excluded due to a high risk of anesthesia-related mortality. Seven dogs presented with early stage disease. Median follow up time was 771 days (91-2223). Transient grade 3 dermatitis and anusitis developed in all dogs, with resolution within 4 weeks. Two dogs developed transient grade 2 late colitis. Locoregional failure in the irradiated field was documented in one dog at 738 days. All-cause median survival time was 771 days (95% confidence interval: 510 â†’ 2223 days). Findings indicated that this fractionation may be safely administered to the canine anus and pelvic canal using 3DCRT, although acute toxicity should be anticipated. Further prospective studies are needed in order to confirm long-term tolerability and efficacy.

Changes in the gut microbiome community of nonhuman primates following radiation injury.

BACKGROUND: Composition and maintenance of the microbiome is vital to gut homeostasis. However, there is limited knowledge regarding the impact of high doses of radiation, which can occur as a result of cancer radiation therapy, nuclear accidents or intentional release of a nuclear or radioactive weapon, on the composition of the gut microbiome. Therefore, we sought to analyze alterations to the gut microbiome of nonhuman primates (NHPs) exposed to high doses of radiation. Fecal samples were collected from 19 NHPs (Chinese rhesus macaques, Macaca mulatta) 1 day prior and 1 and 4 days after exposure to 7.4 Gy cobalt-60 gamma-radiation (LD70-80/60). The 16S V4 rRNA sequences were extracted from each sample, followed by bioinformatics analysis using the QIIME platform. RESULTS: Alpha Diversity (Shannon Diversity Index), revealed no major difference between pre- and post-irradiation, whereas Beta diversity analysis showed significant differences in the microbiome after irradiation (day + 4) compared to baseline (pre-irradiation). The Firmicutes/Bacteriodetes ratio, a factor known to be associated with disruption of metabolic homeostasis, decreased from 1.2 to less than 1 post-radiation exposure. Actinobacillus, Bacteroides, Prevotella (Paraprevotellaceae family) and Veillonella genera were significantly increased by more than 2-fold and Acinetobacter and Aerococcus genus were decreased by more than 10-fold post-irradiation. Fifty-two percent (10/19) of animals exposed to radiation demonstrated diarrhea at day 4 post-irradiation. Comparison of microbiome composition of feces from animals with and without diarrhea at day 4 post-irradiation revealed an increase in Lactobacillus reuteri associated with diarrhea and a decrease of Lentisphaerae and Verrucomicrobioa phyla and Bacteroides in animals exhibiting diarrhea. Animals with diarrhea at day 4 post-irradiation, had significantly lower levels of Lentisphaere and Verrucomicrobia phyla and Bacteroides genus at baseline before irradiation, suggesting a potential association between the prevalence of microbiomes and differential susceptibility to radiation-induced diarrhea. CONCLUSIONS: Our findings demonstrate that substantial alterations in the microbiome composition of NHPs occur following radiation injury and provide insight into early changes with high-dose, whole-body radiation exposure. Future studies will help identify microbiome biomarkers of radiation exposure and develop effective therapeutic intervention to mitigate the radiation injury.

Ocular and periocular radiation toxicity in dogs treated for sinonasal tumors: A critical review.

Visual impairment from radiation-induced damage can be painful, disabling, and reduces the patient's quality of life. Ocular tissue damage can result from the proximity of ocular organs at risk to irradiated sinonasal target volumes. As toxicity depends on the radiation dose delivered to a certain volume, dose-volume constraints for organs at risk should ideally be known during treatment planning in order to reduce toxicity. Herein, we summarize published ocular toxicity data of dogs irradiated for sinonasal tumors from 36 publications (1976-2018). In particular, we tried to extract a dose guideline for a clinically acceptable rate of ocular toxicity. The side effects to ocular and periocular tissues were reported in 26/36 studies (72%) and graded according to scoring systems (10/26; 39%). With most scoring systems, however, toxicities of different ocular and periocular tissues are summed into one score. Further, the scores were mostly applied in retrospect and lack volume- and dose-data. This incomplete information reflects the crux of the matter for radiation dose tolerance in canine ocular tissues: The published information of the last three decades does not allow formulating dose-volume guidelines. As a start, we can only state that a mean dose of 39 Gy (given in 10 x 4.2 Gy fractions) will lead to loss of vision by one or both eyes, while mean doses of <30 Gy seem to preserve functionality. With a future goal to define tolerated doses and volumes of ocular and periocular tissues at risk, we propose the use of combined ocular toxicity scoring systems.

Outcome of a dog undergoing definitive-intent intensity-modulated radiation therapy for an intranasal ganglioneuroma.

An 11-year-old intact male Shiloh Shepherd was presented for evaluation of epistaxis, decreased nasal airflow, and destructive caudal nasal lesion identified using CT. Histopathologic evaluation of the nasal mass was consistent with a ganglioneuroma. The dog was treated with 10 × 4.2 Gy using IMRT technique. Post radiation therapy (RT), improvement in clinical signs were noted. Tumor progressed in size based on CT evaluation at 49 days, 3, and 6 months post-treatment. A grade 2 oral mucositis was the only RT side effect noted. Radiation therapy as described above was completed without evidence of high-grade radiation toxicities and has potential to improve clinical signs but failed to induce tumor response.

Using biologically based objectives to optimize boost intensity-modulated radiation therapy planning for brainstem tumors in dogs.

Irradiated brain tumors commonly progress at the primary site, generating interest in focal dose escalation. The aim of this retrospective observational study was to use biological optimization objectives for a modeling exercise with simultaneously-integrated boost IMRT (SIB-IMRT) to generate a dose-escalated protocol with acceptable late radiation toxicity risk estimate and improve tumor control for brainstem tumors in dogs safely. We re-planned 20 dog brainstem tumor datasets with SIB-IMRT, prescribing 20 × 2.81 Gy to the gross tumor volume (GTV) and 20 × 2.5 Gy to the planning target volume. During the optimization process, we used biologically equivalent generalized equivalent uniform doses (gEUD) as planning aids. These were derived from human data, calculated to adhere to normal tissue complication probability (NTCP) ≤5%, and converted to the herein used fractionation schedule. We extracted the absolute organ at risk dose-volume histograms to calculate NTCP of each individual plan. For planning optimization, gEUD(a = 4)  = 39.8 Gy for brain and gEUD(a = 6.3)  = 43.8 Gy for brainstem were applied. Mean brain NTCP was low with 0.43% (SD ±0.49%, range 0.01-2.04%); mean brainstem NTCP was higher with 7.18% (SD ±4.29%, range 2.87-20.72%). Nevertheless, NTCP of < 10% in brainstem was achievable in 80% (16/20) of dogs. Spearman's correlation between relative GTV and NTCP was high (ρ = 0.798, P < .001), emphasizing increased risk with relative size even with subvolume-boost. Including biologically based gEUD values into optimization allowed estimating NTCP during the planning process. In conclusion, gEUD-based SIB-IMRT planning resulted in dose-escalated treatment plans with acceptable risk estimate of NTCP < 10% in the majority of dogs with brainstem tumors. Risk was correlated with relative tumor size.

Hypofractionated radiotherapy in nine dogs with unresectable solitary lung adenocarcinoma.

Although lung lobectomy is the most common treatment option for dogs with solitary lung tumors, surgery often cannot be performed at the time of diagnosis. In this retrospective, case series study, we described the effects of hypofractionated radiotherapy for tumor mass reduction in nine dogs with solitary lung adenocarcinoma that were later considered for surgical resection, and we assessed the tolerability of the radiation protocol. Tumors were deemed unresectable by the attending veterinarian. The dose prescription was 7.0-12.0 Gy/fraction in four to seven fractions, administered weekly for a total dose of 40-50 Gy. Treatment planning prioritized normal tissue dose constraints. The median interval between the last radiotherapy session and maximum tumor size reduction was 56 (range: 26-196) days, with six and three dogs exhibiting a partial response and stable disease, respectively. Although acute and late radiation-induced toxicity to the skin and/or lungs developed in all nine dogs, it was self-limiting or improved with short-term anti-inflammatory treatment. Tumor progression after initial size reduction was confirmed in three dogs at 62, 126, and 175 days, respectively, after the last radiotherapy session. Seven of the nine dogs underwent lobectomy a median of 68 days after radiotherapy when tumors were in partial response or stable disease or at the time of progression, and five received systemic chemotherapy concurrent with or after radiotherapy. These findings suggest that hypofractionated radiotherapy for canine solitary lung adenocarcinoma is useful when the tumor is large or when surgery cannot be performed immediately after diagnosis.

Proposed expansion margins for planning organ at risk volume for lenses during radiation therapy of the nasal cavity in dogs and cats.

Radiation therapy protocols for the feline or canine nasal cavity can damage epithelial cells of the posterior pole of the lens and lead to the development of cataracts. Aims of this retrospective, descriptive study were to calculate movements of the lens during radiation therapy of the nasal cavity in a sample of cats and dogs, and to propose species-specific expansion margins for planning organ at risk volume (PRV) to minimize radiation doses to the lens. All included patients were immobilized with an indexed bite block and positioned in a vacuum positioning cushion for head irradiation. On-board cone beam CT (CBCT) imaging was used for patient alignment. Both ocular lenses were contoured on the therapeutic CBCTs. Coregistration (fusion) between the planning CT and CBCTs was used to measure the movements of the lens. Two measurements were made: the differences between the centroid point of each lens as well as the displacement of the coregistrations. A total of 496 different observations were recorded from 14 cats and 52 dogs. Using the displacement results, we calculated how often the lens would be within the lens-PRV contour. We proposed that an optimal expansion margin from the lens volume of 2 mm in cats and 3 mm in dogs may be necessary in generating PRV expansion for the lens. From our results, we expect the lens would therefore be within these proposed PRV expansions in 92% of the feline measurements and 95% of the canine measurements.

Necrotizing fasciitis caused by methicillin-resistant Staphylococcus pseudintermedius at a previously irradiated site in a dog.

A great Dane dog was presented with a small, superficial wound on the left tarsus that rapidly progressed to a large necrotic area. The dog had undergone radiation therapy in the left tarsal region 33 months previously. Necrotizing fasciitis was diagnosed on histopathological examination, and bacterial culture revealed methicillin-resistant Staphylococcus pseudintermedius.

Fasciite nécrosante causée parStaphylococcus pseudintermediusrésistant à la méthicilline à un site antérieurement irradié chez un chien. Un chien Grand danois a été présenté avec une petite blessure superficielle sur le tarse gauche qui a rapidement progressé pour devenir une grande région nécrotique. Le chien avait subi de la radiothérapie dans la région du tarse gauche 33 mois auparavant. La fasciite nécrosante a été diagnostiquée à l'examen histopathologique et la culture bactérienne a révélé Staphylococcus pseudintermedius résistant à la méthicilline.(Traduit par Isabelle Vallières).

Retrospective assessment of radiation toxicity from a definitive-intent, moderately hypofractionated image-guided intensity-modulated protocol for anal sac adenocarcinoma in dogs.

A recent calculation study predicted acceptable toxicity in pelvic organs at risk for a new definitive-intent, moderately hypofractionated radiation therapy (RT) protocol (12 x 3.8 Gy), when used with image-guided intensity-modulated radiation therapy (IG-IMRT). We hypothesized this protocol to result in clinically acceptable radiation toxicities. Dogs diagnosed with and irradiated for anal sac adenocarcinoma (ASAC) were retrospectively assessed. Eleven dogs were included, six had prior surgery. Before any therapy, staging according to Polton et al. resulted in the following distribution: stage 1 (n = 1), stage 2 (n = 1), stage 3a (n = 6), stage 3b (n = 3). We scored radiation toxicities at the end of therapy, at weeks 1, 3 and every 3 months after RT according to Veterinary Radiation Therapy Oncology Group radiation toxicity criteria. Clinical follow-up was maintained on regular intervals combined with computed tomography (n = 3). Median follow-up time for dogs still alive was 594 days (range: 224-972 days). Within 1 week post treatment, eight dogs (73%) developed grade 2 and four dogs (36%) grade 1 acute toxicity in the perianal region. All acute toxicities resolved or improved to grade 1 within 3 weeks after treatment. Late toxicity, for example, chronic colitis/diarrhoea, ulcerations, strictures or myelopathies was not observed in any patient. Five dogs were euthanized 105, 196, 401, 508 and 908 days after RT and six dogs were still alive, one in spite of progressive disease. The median progression-free survival was 908 days (95%CI: 215; 1602). The previous theoretically described definitive-intent, moderately hypofractionated protocol using IG-IMRT for the treatment of advanced ASAC showed clinically acceptable acute and late toxicities.

Outcomes of dogs with thymoma treated with intensity modulated stereotactic body radiation therapy or non-modulated hypofractionated radiation therapy.

Canine thymomas are routinely treated with radiotherapy (RT). In this study, we investigate the response and toxicity of canine thymoma treated with intensity-modulated stereotactic body radiation therapy (SBRT) relative to dogs treated with hypofractionated non-modulated radiation therapy (NMRT). A retrospective study was performed of dogs with thymoma treated with RT (total: n = 15; SBRT: n = 8, NMRT: n = 7). Tumour response was evaluated in six dogs (40%); following SBRT, three dogs (100%) experienced stable disease (SD); following NMRT, one dog (33%) had a PR, and two dogs (67%) had SD. Median PFS was 116 days (range 66-727 days) for the SBRT group and 134 days (range 10-405 days) for the NMRT group. The MST for the SBRT group was 250 days (range 1-727 days) and 155 days (range 10-405 days) for NMRT. Median disease-specific survival was 250 days (range 1-727 days) for the SBRT group and 169 days (range 20-405 days) for the NMRT group. No significant differences in survival data were found between the treatment groups, however the results from the small number of dogs analysed are likely underpowered for statistical comparisons. Reported acute and late side effects were limited to the lungs and heart and were statistically significantly more common in the NMRT (71%) compared to the SBRT group (25%) (p = .04). We suggest similar treatment efficacy may be provided for canine thymoma treated with either approach, but SBRT could provide the clinical benefit of reduced incidence of radiation-induced toxicity and completion of RT in a shorter time frame.

Assessment of risk to wildlife from ionising radiation: can initial screening tiers be used with a high level of confidence?

A number of models are being used to assess the potential environmental impact of releases of radioactivity. These often use a tiered assessment structure whose first tier is designed to be highly conservative and simple to use. An aim of using this initial tier is to identify sites of negligible concern and to remove them from further consideration with a high degree of confidence. In this paper we compare the screening assessment outputs of three freely available models. The outputs of these models varied considerably in terms of estimated risk quotient (RQ) and the radionuclide-organism combinations identified as being the most limiting. A number of factors are identified as contributing to this variability: values of transfer parameters (concentration ratios and K(d)) used; organisms considered; different input options and how these are utilised in the assessment; assumptions as regards secular equilibrium; geometries and exposure scenarios. This large variation in RQ values between models means that the level of confidence required by users is not achieved. We recommend that the factors contributing to the variation in screening assessments be subjected to further investigation so that they can be more fully understood and assessors (and those reviewing assessment outputs) can better justify and evaluate the results obtained.

Considerations for the integration of human and wildlife radiological assessments.

A number of tools and approaches have been developed recently to allow assessments of the environmental impact of radiation on wildlife to be undertaken. The International Commission on Radiological Protection (ICRP) has stated an intention to provide a more inclusive protection framework for humans and the environment. Using scenarios, which are loosely based on real or predicted discharge data, we investigate how radiological assessments of humans and wildlife can be integrated with special consideration given to the recent outputs of the ICRP. We highlight how assumptions about the location of the exposed population of humans and wildlife, and the selection of appropriate benchmarks for determining potential risks can influence the outcome of the assessments. A number of issues associated with the transfer component and numeric benchmarks were identified, which need to be addressed in order to fully integrate the assessment approaches. A particular issue was the lack of comparable benchmark values for humans and wildlife. In part this may be addressed via the ICRP's recommended derived consideration reference levels for their 12 Reference Animals and Plants.

A multi-criteria weight of evidence approach for deriving ecological benchmarks for radioactive substances.

Dose rate benchmarks are required in the tiered approaches used to screen out benign exposure scenarios in radiological ecological risk assessment. Such screening benchmarks, namely the predicted no-effect dose rates (PNEDR), have been derived by applying, as far as possible, the European guidance developed for chemicals. To derive the ecosystem level (or generic) PNEDR, radiotoxicity EDR(10) data (dose rates giving a 10% effect in comparison with the control) were used to fit a species sensitivity distribution (SSD) and estimate the HDR(5) (the hazardous dose rate affecting 5% of species with a 10% effect). Then, a multi-criteria approach was developed to justify using an assessment factor (AF) to apply to the HDR(5) for estimating a PNEDR value. Several different statistical data treatments were considered which all gave reasonably similar results. The suggested generic screening value of 10 microGy h(-1) (incremental dose rate) was derived using the lowest available EDR(10) value per species, an unweighted SSD, and an AF of 2 applied to the estimated HDR(5). Consideration was also given to deriving screening benchmark values for organism groups but this was not thought to be currently appropriate due to few relevant data being currently available.

Protection of the environment from ionising radiation in a regulatory context--an overview of the PROTECT coordinated action project.

The outcome of the PROTECT project (Protection of the Environment from Ionising Radiation in a Regulatory Context) is summarised, focusing on the protection goal and derivation of dose rates which may detrimentally affect wildlife populations. To carry out an impact assessment for radioactive substances, the estimated dose rates produced by assessment tools need to be compared with some form of criteria to judge the level of risk. To do this, appropriate protection goals need to be defined and associated predefined dose rate values, or benchmarks, derived and agreed upon. Previous approaches used to estimate dose rates at which there may be observable changes in populations or individuals are described and discussed, as are more recent derivations of screening benchmarks for use in regulatory frameworks. We have adopted guidance and procedures used for assessment and regulation of other chemical stressors to derive benchmarks. On the basis of consultation with many relevant experts, PROTECT has derived a benchmark screening dose rate, using data on largely reproductive effects to derive species sensitivity distributions, of 10 microGy h(-1) which can be used to identify situations which are below regulatory concern with a high degree of confidence.

Protective effects of dietary antioxidants on proton total-body irradiation-mediated hematopoietic cell and animal survival.

Abstract Dietary antioxidants have radioprotective effects after gamma-radiation exposure that limit hematopoietic cell depletion and improve animal survival. The purpose of this study was to determine whether a dietary supplement consisting of l-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve survival of mice after proton total-body irradiation (TBI). Antioxidants significantly increased 30-day survival of mice only when given after irradiation at a dose less than the calculated LD(50/30); for these data, the dose-modifying factor (DMF) was 1.6. Pretreatment of animals with antioxidants resulted in significantly higher serum total white blood cell, polymorphonuclear cell and lymphocyte cell counts at 4 h after 1 Gy but not 7.2 Gy proton TBI. Antioxidants significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGFbeta1 and increased bone marrow cell counts and spleen mass after TBI. Maintenance of the antioxidant diet resulted in improved recovery of peripheral leukocytes and platelets after sublethal and potentially lethal TBI. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival after proton TBI.

Tolerance doses of cutaneous and mucosal tissues in ring-necked parakeets (Psittacula krameri) for external beam megavoltage radiation.

Currently used dosages for external-beam megavoltage radiation therapy in birds have been extrapolated from mammalian patients and often appear to provide inadequate doses of radiation for effective tumor control. To determine the tolerance doses of cutaneous and mucosal tissues of normal birds in order to provide more effective radiation treatment for tumors that have been shown to be radiation responsive in other species, ingluvial mucosa and the skin over the ingluvies of 9 ring-necked parakeets (Psittacula krameri) were irradiated in 4-Gy fractions to a total dose of either 48, 60, or 72 Gy using an isocentric cobalt-60 teletherapy unit. Minimal radiation-induced epidermal changes were present in the high-dose group histologically. Neither dose-related acute nor chronic radiation effects could be detected in any group grossly in cutaneous or mucosal tissue over a 9-month period. Radiation doses of 72 Gy in 4-Gy fractions were well tolerated in the small number of ring-necked parakeets in this initial tolerance dose study.

Outcomes and adverse effects associated with stereotactic body radiation therapy in dogs with nasal tumors: 28 cases (2011-2016).

OBJECTIVE To assess outcomes, factors associated with survival time, and radiation-induced toxicoses in dogs treated for nasal tumors with curative-intent stereotactic body radiation therapy (SBRT). DESIGN Retrospective case series. ANIMALS 28 client-owned dogs. PROCEDURES By use of a 6-MV linear accelerator, dogs were treated with SBRT (3 consecutive-day fractions of 9 or 10 Gy or once with 1 fraction of 20 Gy). Data regarding adverse effects, outcomes, and survival times were obtained from the medical records. RESULTS The median survival time to death due to any cause was 388 days. Of the 24 dogs known to be dead, 14 (58%) died or were euthanized because of local disease progression. Acute radiation-induced adverse effects developed in the skin (excluding alopecia) in 26% (6/23) of dogs and in the oral cavity in 30% (7/23) of dogs. Acute ocular adverse effects included discharge in 26% (6/23) of dogs and keratoconjunctivitis sicca in 4% (1/23) of dogs. Among the 22 dogs alive at > 6 months after SBRT, 4 (18%) developed a unilateral cataract; 4 (18%) developed other complications that may have been late-onset radiation toxicoses (excluding leukotrichia and skin hyperpigmentation). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that dogs treated with SBRT had outcomes comparable to those reported for dogs with nasal carcinomas and sarcomas that undergo conventionally fractionated radiation therapy. Administration of SBRT was associated with a comparatively lower frequency of acute radiation-induced adverse effects. For SBRT and conventionally fractionated radiation therapy, the frequencies of serious late-onset adverse effects appear similar.