Comparison of alfaxalone and propofol on haematological and serum biochemical variables in cats undergoing radiotherapy with sevoflurane maintenance.

OBJECTIVE: To evaluate effects of repeated alfaxalone or propofol administration on haematological and serum biochemical variables in cats undergoing radiotherapy. STUDY DESIGN: Prospective, block-randomized, clinical trial. ANIMALS: A group of 39 client-owned cats. METHODS: After butorphanol (0.2 mg kg-1) and midazolam (0.1 mg kg-1) sedation, cats were randomly assigned to receive either alfaxalone or propofol for induction of anaesthesia and sevoflurane maintenance. Cats were anaesthetized daily with the same induction agent for 10-12 days. Complete blood counts, reticulocytes, Heinz body score and serum biochemistry were performed before the first treatment (T1), at T6, T10 and 3 weeks after the final treatment (T21). Cumulative induction agent dose for each cat at each time point was evaluated for an effect on Heinz body score. Data are shown as mean ± standard deviation; p < 0.05. RESULTS: At baseline there were no significant differences in signalment or blood variables between groups. A significant decrease in haematocrit of 2.3% ± 0.77 (p = 0.02) between T1-T6 and T1-T10 [mean 4.1% (± 0.78, p < 0.0001)] was detected, with a significant increase in haematocrit of 2.1% ± 0.80 (p = 0.046) between T6-T21 and 4.0% ± 0.8 (p < 0.001) between T10-T21. Heinz body score significantly increased by 1.86 ± 0.616 (p = 0.013) between T1-T10. In the propofol group, reticulocytes increased significantly between T1-T6 [mean 23,090 µL-1 ± 7670 (p = 0.02)] and T1-T10 [mean 27,440 µL-1 ± 7990 (p = 0.007)]. Mean cumulative dose at T10 was 19.65 mg kg-1 ± 5.3 and 43.4 mg kg-1 ± 14.4 for alfaxalone and propofol, respectively, with no significant effect on Heinz body formation at any time point. CONCLUSIONS AND CLINICAL RELEVANCE: Haematocrit decreased in both groups with recovery after 3 weeks. Repeated alfaxalone and propofol administration was not associated with marked haematological or serum biochemistry changes.

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.

Estimation of planning organ at risk volumes for ocular structures in dogs undergoing three-dimensional image-guided periocular radiotherapy with rigid bite block immobilization.

Planning organ at risk volume (PRV) estimates have been reported as methods for sparing organs at risk (OARs) during radiation therapy, especially for hypofractioned and/or dose-escalated protocols. The objectives of this retrospective, analytical, observational study were to evaluate peri-ocular OAR shifts and derive PRVs in a sample of dogs undergoing radiation therapy for periocular tumors. Inclusion criteria were as follows: dogs irradiated for periocular tumors, with 3D-image-guidance and at least four cone-beam CTs (CBCTs) used for position verification, and positioning in a rigid bite block immobilization device. Peri-ocular OARs were contoured on each CBCT and the systematic and random error of the shifts in relation to the planning CT position computed. The formula 1.3×Σ+0.5xσ was used to generate a PRV of each OAR in the dorsoventral, mediolateral, and craniocaudal axis. A total of 30 dogs were sampled, with 450 OARs contoured, and 2145 shifts assessed. The PRV expansion was qualitatively different for each organ (1-4 mm for the dorsoventral and 1-2 mm for the mediolateral and craniocaudal axes). Maximal PRV expansion was ≤4 mm and directional for the majority; most pronounced for corneas and retinas. Findings from the current study may help improve awareness of and minimization of radiation dose in peri-ocular OARs for future canine patients. Because some OARs were difficult to visualize on CBCTs and/ or to delineate on the planning CT, authors recommend that PRV estimates be institution-specific and applied with caution.

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.

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.

Definitive-intent intensity-modulated radiation therapy provides similar outcomes to those previously published for definitive-intent three-dimensional conformal radiation therapy in dogs with primary brain tumors: A multi-institutional retrospective study.

Radiotherapy with or without surgery is a common choice for brain tumors in dogs. Although numerous studies have evaluated use of three-dimensional conformal radiotherapy, reports of definitive-intent, IMRT for canine intracranial tumors are lacking. Intensity-modulated radiation therapy has the benefit of decreasing dose to nearby organs at risk and may aid in reducing toxicity. However, increasing dose conformity with IMRT calls for accurate target delineation and daily patient positioning, in order to decrease the risk of a geographic miss. To determine survival outcome and toxicity, we performed a multi-institutional retrospective observational study evaluating dogs with brain tumors treated with IMRT. Fifty-two dogs treated with fractionated, definitive-intent IMRT at four academic radiotherapy facilities were included. All dogs presented with neurologic signs and were diagnosed via MRI. Presumed radiological diagnoses included 37 meningiomas, 12 gliomas, and one peripheral nerve sheath tumor. One dog had two presumed meningiomas and one dog had either a glioma or meningioma. All dogs were treated in the macroscopic disease setting and were prescribed a total dose of 45-50 Gy (2.25-2.5 Gy per fraction in 18-20 daily fractions). Median survival time for all patients, including seven cases treated with a second course of therapy was 18.1 months (95% confidence of interval 12.3-26.6 months). As previously described for brain tumors, increasing severity of neurologic signs at diagnosis was associated with a worse outcome. Intensity-modulated radiation therapy was well tolerated with few reported acute, acute delayed, or late side effects.

Intensity-modulated radiation therapy dose prescription and reporting: Sum and substance of the International Commission on Radiation Units and Measurements Report 83 for veterinary medicine.

Institutions' adherence to protocol, quality assurance, and radiation parameter reporting are key to adequately interpret and compare treatment outcomes in radiation oncology. In 2017, the editorial board for Veterinary Radiology & Ultrasound adapted author guidelines on "technical information for radiation therapy (RT)". These guidelines provide a framework to report the RT treatment process in manuscripts resulting from veterinary clinical trials. In spite of this framework, however, in implementing IMRT, we have identified different "interpretations" of the extended prescription and reporting recommendations of the International Commission on Radiation Units and Measurements (ICRU 83), even within our small team. In the following commentary review, we provide a short summary of various detailed aspects of the ICRU 83 recommended (IMRT) prescription and reporting, including (a) absorbed target dose specification and prescription, (b) homogeneity and conformity, and (c) reporting of absorbed dose in organs at risk. In particular, we want to share our thoughts on possible dangers of noncompliance in adhering to protocol, prescription, and reporting. As veterinary IMRT publications still sparsely adhere to the recommendations of the ICRU, we were motivated to summarize the recommendations to facilitate appropriate reporting for IMRT in future veterinary studies.

Computed tomographic-lymphography as a complementary technique for lymph node staging in dogs with malignant tumors of various sites.

Locoregional lymph nodes are routinely examined in order to define the spatial extent of neoplastic disease. As draining patterns of certain tumor types can be divergent from expected anatomical distribution, it is critical to sample the lymph nodes truly representing the draining area. The aim of this bicenter prospective pilot study was to describe the technique of computed tomographic (CT)-lymphography for primary draining lymph node mapping in tumor staging in dogs. Forty-five dogs with macro- or microscopic tumors in specified localizations were evaluated. Depending on body weight, 0.8-2 ml contrast agent (iohexol) was injected into four quadrants around the tumor, and CT-images were obtained at 1, 3, 6, 9, and 12 minutes post-injection. Attenuation of chosen regions of interest (Hounsfield units (HU)) and patterns of enhancement were assessed for 284 lymph nodes in the precontrast study with median HUs of 31.1 (Interquartile range (IQR) = 18.4) and for 275 in the intravenous postcontrast study with 104.3 HU (IQR = 31.2) (paired Wilcoxon test, P < 0.001). In the CT-lymphography study, 45 primary draining lymph nodes with a significantly higher median HU value of 348.5 (IQR = 591.4) (one-sample t-test, P < 0.001) were identified. Primary draining lymph nodes were found to be clearly visible after 1-3 minutes after local injection, often concurrent with a good visibility of the lymphatic vessel system. The herein described technique of peritumorally injected CT-contrast agent followed by subsequent CT-lymphography for primary draining lymph node mapping works well in a majority of cases in all investigated sites and warrants further validation for different tumor entities.

Retrospective clinical study on outcome in cats with nasal planum squamous cell carcinoma treated with an accelerated radiation protocol.

BACKGROUND: Cutaneous squamous cell carcinoma of the nasal planum in cats is a common indication for antitumor treatment such as external beam radiation therapy. Curative-intent radiation therapy has been described as a valuable treatment option, resulting in long and stable tumor control in these patients. The aim of the current study was to evaluate outcome and toxicity, as well as possible prognostic factors using an accelerated hypofractionated radiation therapy protocol. Cats with squamous cell carcinoma of the nasal planum treated with an accelerated radiation protocol (10 × 4.8 Gy, over one week) were retrospectively evaluated. Tumor- and treatment-associated variables were evaluated in respect to local control and survival. RESULTS: Forty-four cats met the inclusion criteria for this study. All cats showed complete response to therapy. Median disease-free interval (DFI) for all cases was 916 days (95% CI: 456-1377). One- and two-year DFIs were 71% (95% CI: 56-86%) and 60% (95% CI: 43-77%). Of the tested variables, only tumor volume showed a tendency to influence DFI, with larger tumors having a 5.4 times greater risk of recurrence than the smaller ones (HR 1.33 (95% CI: 0.99-1.79), p = 0.054). Median overall survival (OS) was 902 days (95% CI: 862-942). One- and 2-year OSs were 79.3% (95% CI: 67.3-91.3) and 58.4% (95% CI: 42.8-74). Of the tested variables, again, only tumor volume influenced OS with larger tumors having a 6.3 times greater risk of dying than the smaller ones (HR 1.36 (95% CI: 1.07-1.73), p = 0.010). The acute and late toxicity profile was low and hence clinically acceptable. CONCLUSIONS: Curative-intent radiation therapy with an accelerated fractionation schedule can be considered a safe, cosmetically superior treatment option for cutaneous squamous cell carcinomas of the nasal planum in cats, resulting in long and stable tumor control.

HYPOFRACTIONATED RADIOTHERAPY FOR MACROSCOPIC CANINE SOFT TISSUE SARCOMA: A RETROSPECTIVE STUDY OF 50 CASES TREATED WITH A 5 × 6 GY PROTOCOL WITH OR WITHOUT METRONOMIC CHEMOTHERAPY.

Wide surgical resection or a marginal/incomplete resection followed by full-course radiation therapy is the current standard of care for canine soft tissue sarcoma. The purpose of this retrospective, descriptive, bi-institutional study was to determine the effectiveness and toxicity of a hypofractionated 5 × 6 Gy protocol on macroscopic canine soft tissue sarcoma in terms of progression-free interval (PFI) and overall survival (OS), and to identify prognostic factors for patient outcome. Dogs with macroscopic soft tissue sarcoma irradiated with 5 × 6 Gy were eligible for the study. Progression-free interval and OS were compared with respect to different tumor and patient characteristics by the Kaplan-Meier method and multivariable Cox regression analysis. Fifty dogs with macroscopic disease were included. All dogs received the same radiation therapy protocol; part of the group (n = 20) received postradiation metronomic chemotherapy. Median PFI for all cases was 419 days (95% confidence interval (CI): 287-551) and median OS was 513 days (95% CI: 368-658). Dogs with tumors on the limbs had significantly longer PFI and OS, compared with head or trunk. Increasing tumor burden decreased OS. The addition of metronomic chemotherapy yielded a significantly longer OS (757 days (95% CI: 570-944) compared with dogs that did not receive systemic treatment (286 days (95% CI: 0-518), (P = 0.023)), but did not influence progression-free interval. Toxicity was low throughout all treatments. The 5 × 6 Gy radiation therapy protocol was well tolerated and provided long PFI and OS in dogs with macroscopic soft tissue sarcoma.

Radiation toxicity grading after chemoradiotherapy of canine urinary tract carcinomas: Comparing VRTOG to VRTOG_v2.0.

Radiation toxicities may be underestimated after treatment of transitional cell carcinoma in dogs' lower urinary tract. Assessing acute and late toxicities and differentiating them from progressive disease (PD) impacts further therapeutic approach. We retrospectively assessed dogs treated with definitive-intent chemoradiotherapy (12 × 3.8 Gy, various first-line chemotherapeutics). Local tumour control, radiation toxicities and survival were evaluated. We classified radiation toxicities according to the previously published radiation toxicity scheme "VRTOG" as well as the updated version, "VRTOG_v2.0". Fourteen dogs with transitional cell carcinoma of bladder ± urethra (n = 8), +prostate (n = 3) or solely urethra (n = 3), were included. Median follow-up was 298 days (range 185-1798 days), median overall survival 305 days (95%CI = 209;402) and 28.6% deaths were tumour-progression-related. Acute radiation toxicity was mild and self-limiting with both classification systems: In VRTOG, 5 dogs showed grade 1, and 1 dog grade 2 toxicity. In VRTOG_v2.0, 2 dogs showed grade 1, 3 dogs grade 2, and 3 dogs grade 3 toxicity. Late toxicity was noted in 14.2% of dogs (2/14) with the VRTOG, both with grade 3 toxicity. With VRTOG_v2.0, a larger proportion of 42.9% of dogs (6/14) showed late toxicities: Four dogs grade 3 (persistent incontinence), 2 dogs grade 5 (urethral obstructions without PD resulting in euthanasia). At time of death, 5 dogs underwent further workup and only 3 were confirmed to have PD. With the updated VRTOG_v2.0 classification system, more dogs with probable late toxicity are registered, but it is ultimately difficult to distinguish these from disease progression as restaging remains to be the most robust determinant.

Risk adaptive planning with biology-based constraints may lead to higher tumor control probability in tumors of the canine brain: A planning study.

BACKGROUND: Classical radiation protocols are guided by physical dose delivered homogeneously over the target. Protocols are chosen to keep normal tissue complication probability (NTCP) at an acceptable level. Organs at risk (OAR) adjacent to the target volume could lead to underdosage of the tumor and a decrease of tumor control probability (TCP). The intent of our study was to explore a biology-based dose escalation: by keeping NTCP for OAR constant, radiation dose was to be maximized, allowing to result in heterogeneous dose distributions. METHODS: We used computed tomography datasets of 25 dogs with brain tumors, previously treated with 10x4 Gy (40 Gy to PTV D50). We generated 3 plans for each patient: A) original treatment plan with homogeneous dose distribution, B) heterogeneous dose distribution with strict adherence to the same NTCPs as in A), and C) heterogeneous dose distribution with adherence to NTCP <5%. For plan comparison, TCPs and TCP equivalent doses (homogenous target dose which results in the same TCP) were calculated. To enable the use of the generalized equivalent uniform dose (gEUD) metric of the tumor target in plan optimization, the calculated TCP values were used to obtain the volume effect parameter a. RESULTS: As intended, NTCPs for all OARs did not differ from plan A) to B). In plan C), however, NTCPs were significantly higher for brain (mean 2.5% (SD±1.9, 95%CI: 1.7,3.3), p<0.001), optic chiasm (mean 2.0% (SD±2.2, 95%CI: 1.0,2.8), p=0.010) compared to plan A), but no significant increase was found for the brainstem. For 24 of 25 of the evaluated patients, the heterogenous plans B) and C) led to an increase in target dose and projected increase in TCP compared to the homogenous plan A). Furthermore, the distribution of the projected individual TCP values as a function of the dose was found to be in good agreement with the population TCP model. CONCLUSION: Our study is a first step towards risk-adaptive radiation dose optimization. This strategy utilizes a biologic objective function based on TCP and NTCP instead of an objective function based on physical dose constraints.

Solitary intraventricular tumors in dogs and cats treated with radiotherapy alone or combined with ventriculoperitoneal shunts: A retrospective descriptive case series.

BACKGROUND: Intraventricular tumors are rare, optimal treatment is not defined. Symptomatic patients often exhibit life-threatening hydrocephalus. With several months time-to-effect after radiotherapy (RT), increased intracranial pressure is concerning. This increase in pressure can be overcome by ventriculoperitoneal shunting (VPS). OBJECTIVES: Retrospective evaluation of outcome and complications in dogs and cats with intracranial tumors treated with either RT or VPS/RT. ANIMALS: Twelve client-owned cats and dogs. METHODS: Dogs and cats with symptomatic intraventricular tumors treated with definitive-intent RT or VPS/RT were included in a retrospective, descriptive case series. Complications, tumor volume evolution, time-to-progression, and survival time were determined. RESULTS: Twelve animals were included: 1 cat and 5 dogs treated with single-modality RT and 4 cats and 2 dogs treated with VPS/RT. Neurological worsening seen in 4/6 animals during single-modality RT and 2/6 died during RT (suspected brain herniation). All dogs with VPS normalized clinically by the end of RT or earlier. Complications occurred in 4/6 animals, all but 1 were successfully managed surgically. Imaging follow-up in 8 animals surviving RT showed a marked decrease in tumor volume. Median survival time was 162 days (95% confidence interval [CI]: 16; infinity) for animals treated with RT and 1103 days (95%CI: 752; infinity) for animals treated with VPS/RT. Median time-to-progression was 71 days (95%CI: 7; infinity) and 895 days (95%CI: 704; infinity) for each group, respectively. Two dogs died because of intraventricular metastasis 427 and 461 days after single-modality RT. CONCLUSIONS AND CLINICAL IMPORTANCE: Ventriculoperitoneal shunting led to rapid normalization of neurological signs and RT had a measurable effect on tumor volume. Combination of VPS/RT seems to be beneficial.

Lymph node metastasis in feline cutaneous low-grade mast cell tumours.

OBJECTIVES: This retrospective study aimed to determine the incidence of nodal metastatic disease in cats affected by low-grade cutaneous mast cell tumours (MCTs) in our study population. METHODS: The clinical records of two centres were retrospectively searched for cats with cutaneous MCTs that had undergone lymphadenectomy of enlarged and non-enlarged lymph nodes. All primary tumours were histologically reviewed by two experienced pathologists and graded as high- or low-grade based on the grading system for feline cutaneous MCT. We graded the lymph nodes based on the grading scheme used for canine MCTs and considered HN2 and HN3 nodes to be metastatic. The number of patients with nodal metastasis was calculated. RESULTS: We identified 17 cats with cutaneous MCT resection and concurrent lymphadenectomy. All 21 MCTs were graded as low grade and 30 nodes were removed, with 12 being considered early or overtly metastatic (HN2 or HN3, respectively). Based on nodal status, 10/17 (59%) cats were affected by nodal metastasis in our population. CONCLUSIONS AND RELEVANCE: In contrast to previous reports, high percentage of cats with cutaneous MCTs in which lymphadenectomy was performed were presented with metastatic lymph nodes. The clinical relevance of this finding and a potential benefit of lymphadenectomy must be determined in future studies.

Relative tumor volume has prognostic relevance in canine sinonasal tumors treated with radiation therapy: A retrospective study.

Tumor volume is controversially discussed as a prognostic factor in dogs treated with radiation therapy for sinonasal tumors. Dogs' body sizes vary widely and relative rather than absolute tumor volume might provide better prognostic information. Our hypothesis was that relative rather than absolute tumor volume (gross tumor volume, GTV) influences time to progression (TTP) and that a larger tumor volume is correlated with a higher tumor stage. We retrospectively investigated possible correlations of initial GTV to weight, body surface area (BSA), nasal cavity size and the tumor stage in 49 dogs with sinonasal tumors. Here, also presumed sinonasal tumors, esthesioneuroblastomas and histologically benign tumors were included. The possible impact of absolute and relative GTV on response and outcome were assessed according to imaging findings in 34 dogs with available follow-up computed tomographies (CTs) after definitive-intent radiation therapy with either a regular (10x4.2 Gy) or a simultaneously- integrated boost protocol (SIB; GTV boosted to 10x4.83 Gy). In contrast to absolute GTV (p<0.001), the relative GTVs were not correlated with dogs' body sizes. Absolute GTV, GTV relative to weight and BSA were not associated with TTP based on CT imaging. However, GTV relative to nasal cavity showed a prognostic influence with a hazard ratio of 10.97 (95%CI:1.25-96.06). When looking at GTV relative to nasal cavity, stage 3 and 4 tumors were significantly larger than stage 1 and 2 tumors (p = 0.005). Our results suggest that GTV relative to nasal cavity could be prognostic for TTP and a larger tumor volume relative to nasal cavity is correlated with a higher tumor stage.

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.

Treatment of intracranial neoplasia in dogs using higher doses: A randomized controlled trial comparing a boosted to a conventional radiation protocol.

BACKGROUND: Local progression of intracranial tumors can be the consequence of insufficient radiation dose delivered. Dose increases in the brain must be made carefully so as not to risk debilitating adverse effects such as radiation necrosis. HYPOTHESIS: A new protocol with 10 × 4 Gy + 11% physical dose increase limited to the macroscopic tumor volume results in a clinically better outcome compared to a 10 × 4 Gy protocol. ANIMALS: Fifty-seven client-owned dogs with primary intracranial neoplasia. METHODS: Randomized controlled trial. Twenty-eight dogs were assigned to the control protocol (10 × 4 Gy) and 29 to the simultaneous integrated boost (SIB) protocol with 4.45 Gy dose increase. Treatment groups were compared for outcome and signs of toxicity. RESULTS: Mild, transient acute or early-delayed adverse radiation effects were observed in 5 dogs. Severe late adverse effects were not seen. Between the protocols, no significant differences were found for outcome (intention-to-treat analysis): overall time to progression (TTP) was 708 days (95% confidence interval (95% CI) [545,872]), in the control group it was 828 days (95% CI [401,1256]), and in the SIB group 627 days (95% CI [282,973]; P = .07). Median overall survival (OS) was 684 days (95% CI [516,853]), in the control group it was 724 days (95% CI [623,826]), and in the SIB group 557 days (95% CI [95,1020]; P = .47). None of the tested variables was prognostic in terms of outcome. CONCLUSION AND CLINICAL IMPORTANCE: The dose escalation used with an 11% physical dose increase did not result in better outcome.

Indocyanine-based near-infrared lymphography for real-time detection of lymphatics in a cat with multiple mast cell tumours.

CASE SUMMARY: An 11-year-old female domestic shorthair cat was presented with cutaneous mast cell tumours (MCTs) localised at the right temporal region, the left buccal region and on the third digit of the right thoracic limb. Staging was negative and locoregional lymph nodes appeared normal, based on clinical findings. During surgery, real-time indocyanine green (ICG)-based lymphography was performed to detect the cutaneous draining pattern of all the primary MCTs. ICG was injected intracutaneously in four quadrants around each tumour, and a clear lymphogram was visible shortly after injection. Using near-infrared lymphography (NIR-L) for guidance, all lymphadenectomies were performed in 12 mins or less, with a maximal incision length of 3.5 cm. The smallest resected node was 0.9 cm in diameter. All MCTs were classified as low-grade cutaneous MCT. All four ICG-positive lymph nodes were considered premetastatic or metastatic. The only ICG-negative resected node was also negative for tumour cells. No complications related to NIR-L were recorded. RELEVANCE AND NOVEL INFORMATION: This is the first description of NIR-L in a cat with MCT. Application was straightforward and ICG enrichment only occurred in the metastatic nodes, suggesting correct identification of lymphatic draining patterns. Of note, as previously described in dogs, we did detect nodal metastasis, despite low-grade primary tumours. The clinical relevance should be evaluated in future studies.

A concept for anisotropic PTV margins including rotational setup uncertainties and its impact on the tumor control probability in canine brain tumors.

Objective.In this modelling study, we pursued two main goals. The first was to establish a new CTV-to-PTV expansion which considers the closest and most critical organ at risk (OAR). The second goal was to investigate the impact of the planning target volume (PTV) margin size on the tumor control probability (TCP) and its dependence on the geometrical setup uncertainties. The aim was to achieve a smaller margin expansion close to the OAR while allowing a moderately larger expansion in less critical areas further away from the OAR and whilst maintaining the TCP.Approach.Imaging data of radiation therapy plans from pet dogs which had undergone radiation therapy for brain tumor were used to estimate the clinic specific rotational setup uncertainties. A Monte-Carlo methodology using a voxel-based TCP model was used to quantify the implications of rotational setup uncertainties on the TCP. A combination of algorithms was utilized to establish a computational CTV-to-PTV expansion method based on probability density. This was achieved by choosing a center of rotation close to an OAR. All required software modules were developed and integrated into a software package that directly interacts with the Varian Eclipse treatment planning system.Main results.Several uniform and non-isotropic PTVs were created. To ensure comparability and consistency, standardized RT plans with equal optimization constraints were defined, automatically applied and calculated on these targets. The resulting TCPs were then computed, evaluated and compared.Significance.The non-isotropic margins were found to result in larger TCPs with smaller margin excess volume. Further, we presented an additional application of the newly established CTV-to-PTV expansion method for radiation therapy of the spinal axis of human patients.

Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs.

PURPOSE: The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results, we designed a randomized phase III trial to investigate the FLASH effect in cat patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-radiotherapy was studied on mini pigs by using large field irradiation. EXPERIMENTAL DESIGN: Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to two arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10 × 4.8 Gy (90% isodose); arm 2 used 1 × 30 Gy (90% isodose) FLASH. Mini pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH. RESULTS: In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis, which occurred 9 to 15 months after radiotherapy in 3 of 7 cats treated with FLASH-radiotherapy (43%), as compared with 0 of 9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded, but severe late skin necrosis occurred in a volume-dependent manner (7-9 months), which later resolved. CONCLUSIONS: The reported outcomes point to the caveats of translating single-high-dose FLASH-radiotherapy and emphasizes the need for caution and further investigations. See related commentary by Maity and Koumenis, p. 3636.