V. Meier

Outcome in dogs with advanced (stage 3b) anal sac gland carcinoma treated with surgery or hypofractionated radiation therapy

Stage 3b anal sac gland carcinoma (ASGC) can be life-threatening. A surgical approach is not always possible or may be declined. Dogs with stage 3b ASGC treated with surgery or conformal radiation therapy (RT) with 8 × 3.8 Gy (total dose 30.4 Gy, over 2.5 weeks) were retrospectively evaluated. Patient characteristics, median progression-free interval (PFI) and median survival time (MST) were compared. Twenty-eight dogs were included; 15 underwent surgery, 13 underwent RT. At the time of presentation, 21% showed life-threatening obstipation and 25% showed hypercalcaemia. PFI and MST for surgery cases were 159 days (95% CI: 135-184 days) and 182 days (95% CI: 146-218 days), both significantly lower than for RT cases with 347 days (95% CI: 240-454 days) and 447 days (95% CI: 222-672 days), (P = 0.01, P = 0.019). Surgery as well as RT led to a fast relief of symptoms. PFI and survival of surgical patients were significantly inferior to that of a comparable patient group treated with conformal hypofractionated RT.

A complication probability planning study to predict the safety of a new protocol for intracranial tumour radiotherapy in dogs.

Technical advances make it possible to deliver radiation therapy for canine intracranial tumours in fewer fractions, under the assumption of equivalent tumour control. With the aim of estimating the late toxicity risk profile for various tumour sizes and locations, the present paper evaluates the normal tissue complication probability (NTCP) values for the intracranial organs at risk. By making isoeffect calculations, a new 10-fraction radiation protocol was developed with the same tumour control probability (TCP) as a currently used 20-fraction standard protocol, and complication risk profiles for brain, brainstem and optic chiasm were modelled using a representative population of 64 dogs with brain tumours. For >59% of cases, the new 10-fraction protocol yielded an acceptable, low risk estimate of late toxicity (<10%). Our calculations suggest that it may be safe to treat small to intermediate-sized tumours that are neither located near the optic chiasm nor at the brainstem with 10 daily fractions of 4.35 Gy.

Hypoxia-Related Marker GLUT-1, CAIX, Proliferative Index and Microvessel Density in Canine Oral Malignant Neoplasia

For various types of tumor therapy, it is suggested that co-targeting of tumor microenvironment, mainly tumor vasculature, mediates tumor response mechanisms. Immunohistochemistry for glucose transporter-1 (GLUT-1), carbonic anhydrase-IX (CAIX), Ki-67, and von Willebrand factor VIII for microvessel density (MVD) were performed on formalin-fixed paraffin-embedded samples of canine oral malignant neoplasms. Polarographic oxygen measurements (median pO2) and perfusion data via contrast-enhanced power Doppler ultrasound (median vascularity, median blood volume) provided additional information. Ninety-two samples were analyzed: sarcomas (n = 32), carcinomas (n = 30), and malignant melanomas (n = 30). Polarographic oxygen and perfusion data was available in 22.8% (sarcomas n = 9, carcinomas n = 7, melanomas n = 5), and 27.1% (sarcomas n = 10, carcinomas n = 8, melanomas n = 7) of cases, respectively. GLUT-1 expression was detected in 46.7% of all samples, and was generally weak. CAIX expression was found in 34.8% of all samples. Median Ki-67 score and MVD count was 19% and 17, respectively. The evaluation of the GLUT-1 score and continuous data showed significantly lower GLUT-1 levels in sarcomas (mean 5.1%, SD 6.2) versus carcinomas and melanomas (mean 16.5%/ 19.0%, SD 17.3/ 20.9, p = 0.001). The expression of CAIX correlated mildly positively with GLUT-1 (p = 0.018, rho = 0.250) as well as with Ki-67 (p = 0.014, rho = 0.295). MVD showed a significantly lower level in melanomas (mean 12.6, SD 7.7) versus sarcomas and carcinomas (mean 21.8/ 26.9, SD 13.0/20.4, p = 0.001). Median vascularity and blood volume were significantly lower in sarcomas (mean 10.4%, SD 11.0, and mean 6.3%, SD 6.5, respectively) versus carcinomas (mean 39.2%, SD 16.4 and mean 33.0%, SD 25.6, respectively) and melanomas (mean 36.0%, SD 18.3, and 31.5%, SD 24.5). Between the 3 histological groups, there was neither a significant difference in the GLUT-1 and CAIX score and continuous data, nor the Ki67 score, or polarographic oxygen measurements. GLUT-1 continuous data and Ki-67 (p<0.001, rho = 0.403), as well as Ki-67 and MVD (p = 0.029, rho = 0.228) correlated positively and a mild correlation was found between vascularity and GLUT-1 (p = 0.043, rho = 0.408). GLUT-1, CAIX, proliferative index and MVD levels were established as microenvironmental descriptors with the purpose of creating a baseline in order to follow changes seen in the tumor microenvironment after hypofractionated radiation with high doses.

Use of Epothilone B (Patupilone) in Refractory Lymphoma and Advanced Solid Tumors in Dogs

BACKGROUND The epothilones are microtubule-stabilizing agents with promising antitumor effect in refractory and metastatic tumors in humans. The toxicity profile is considered more favorable than in taxanes. The safety of epothilone B (patupilone) has not been evaluated in tumor-bearing dogs. OBJECTIVES To evaluate the inhibition of proliferation in canine tumor cells after patupilone treatment. To assess toxicity profile and maximally tolerated dose of patupilone in dogs with refractory tumors. ANIMALS Twenty client-owned dogs with various malignancies. METHODS Prospective clinical study. The inhibition of proliferation was assessed with a proliferation assay in vitro in canine hemangiosarcoma and lymphoma cell lines. Dogs received patupilone IV once a week for 2 treatments (= 1 treatment cycle). Dose was escalated with 3 dogs per cohort and 20% increments. Adverse effects were graded according to the VCOG-CTCAE v1.0. RESULTS Both canine cell lines were sensitive to patupilone with approximately 50% decrease in proliferative activity at 0.2-1 nM. In vivo, dose-limiting adverse effects occurred at 3.3 mg/m(2); main adverse effects were diarrhea, anorexia, vomiting, and nausea. Neither neutropenia nor peripheral neuropathy was observed. Maximally tolerated dose for 2 patupilone administrations once weekly IV is 2.76 mg/m(2). Three per 11 dogs receiving more than 1 treatment cycle showed partial remission in the short period of observation. CONCLUSIONS AND CLINICAL IMPORTANCE Canine tumor cells show inhibition of proliferation to patupilone in vitro. Clinically, a dose of 2.76 mg/m(2) IV is well tolerated in dogs with spontaneously occurring tumors.

Dosimetric benefit of adaptive radiotherapy in the neoadjuvant management of canine and feline thymoma-An exploratory case series

While surgery is the treatment of choice for thymomas, complete excision is not possible in a significant proportion of cases. For these patients, radiotherapy can be used as neoadjunctive, post-operative adjunctive or sole therapy. During radiotherapy, rapid biological clearance of tumour cells is often observed, requiring adaptation of the treatment plan. Adaptive radiation therapy (RT) is a dynamic process, whereby the treatment plan is altered throughout the treatment course due to changes in morphologic, functional or positioning changes. With the hypothesis, that individually adapted replanning will massively reduce the dose to organs at risk (OAR) in a fast-changing environment such as a rapidly responding thymoma, the dosimetric impact of adaptive treatment planning in 5 patients with large thymoma was measured. In all patients rapid tumour-shrinkage of the gross tumour volume was observed after 1 week of therapy, with a mean shrinkage of 31.0% ± 15.2%, or a tumour regression of 5.2% per day. In consequence, there was a considerable change in position of organs such as heart and lung, both of them moving cranially into the high dose area upon tumour regression. After mid-therapy replanning, the dose to OAR was significantly reduced, with -18.2% in the mean heart dose and -27.9% in the V20 lung dose. Adaptive planning led to a significantly reduced radiation dose and hence protection of OAR for these patients. It can be concluded that adaptive replanning should be considered for canine and feline thymoma patients receiving fractionated RT.

A complication probability study for a definitive-intent, moderately hypofractionated image-guided intensity-modulated radiotherapy protocol for anal sac adenocarcinoma in dogs

Previous trials showed the importance of administering radiation therapy (RT) with small doses per fraction in canine pelvic tumours to maintain acceptable toxicity levels. With increased accuracy/precision of RT, namely intensity-modulated RT (IMRT), this approach might be challenged. Theoretical toxicity calculations for a new definitive-intent moderately hypofractionated RT protocol for canine anal sac adenocarcinomas (ASAC) were performed, focussing on the risk of toxicity in pelvic organs at risk (OAR). Computed tomography datasets of 18 dogs with stage 3b ASAC were included. Re-planning with margins for daily image-guidance/IMRT was performed and a new protocol isoeffective to previously described definitive-intent protocols was computed. Dose-volume information were derived from individual plans and used for normal tissue complication probability (NTCP) computations. A 12 × 3.8 Gy protocol was computed for risk estimation. Tumour volumes ranged from 27.9 to 820.4 cm3 (mean 221.3 cm3 ± 188.9). For late rectal toxicity/bleeding ≥grade 2, median risk probability was 2.3% inter quartile range (IQR: 5.9; 95% confidence interval (CI): 1.2, 8.4) (rho = 0.436) and 3.4% (IQR: 0.96; 95%CI: 3.1, 4.0) (rho = 0.565), respectively. Median late toxicities in urinary bladder, kidneys and small bowel were <1%, except in one kidney. Myelopathy/myelonecrosis had a median risk probability of 4.1% (IQR: 23.5; 95%CI: 2.1, 25.2) (rho = 0.366) and 5.6% (IQR: 13.5; 95%CI: 3.1, 14.1) (rho = 0.363), respectively. However, graded risk showed a probability estimate for late spinal cord toxicity of ≥5% in 8/18 patients. The daily-imaging IMRT 12 × 3.8 Gy protocol for canine ASAC seems tolerable for most cases, even in advanced disease. Theoretical dose computations serve as estimate, but are safe measures before implementing new protocols into clinical use.

A prospective pilot study on early toxicity from a simultaneously integrated boost technique for canine sinonasal tumours using image-guided intensity-modulated radiation therapy

In order to overcome the common local treatment failure of canine sinonasal tumours, integrated boost techniques were tried in the cobalt/orthovoltage era, but dismissed because of unacceptable early (acute) toxicity. Intriguingly, a recent calculation study of a simultaneously integrated boost (SIB) technique for sinonasal irradiation using intensity-modulated radiation therapy (IMRT) predicted theoretical feasibility. In this prospective pilot study we applied a commonly used protocol of 10 × 4.2 Gy to the planning target volume (PTV) with a 20%-SIB dose to the gross tumour volume (GTV). Our hypothesis expected this dose escalation to be clinically tolerable if applied with image-guided IMRT. We included 9 dogs diagnosed with sinonasal tumours without local/distant metastases. For treatment planning, organs at risk were contoured according to strict anatomical guidelines. Planning volume extensions (GTV/CTV/PTV) were standardized to minimize interplanner variability. Treatments were applied with rigid patient positioning and verified daily with image guidance. After radiation therapy, we set focus on early ophthalmologic complications as well as mucosal and cutaneous toxicity. Early toxicity was evaluated at week 1, 2, 3, 8 and 12 after radiotherapy. Only mild ophthalmologic complications were found. Three patients (33%) had self-limiting moderate to severe early toxicity (grade 3 mucositis) which was managed medically. No patient developed ulcerations/haemorrhage/necrosis of skin/mucosa. The SIB protocol applied with image-guided IMRT to treat canine sinonasal tumours led to clinically acceptable side effects. The suspected increased tumour control probability and the risk of late toxicity with the used dose escalation of 20% has to be further investigated.

Safety, tolerability and pharmacokinetic properties of the novel triazene TriN 2755 in tumour bearing dogs – a phase I study†

TriN 2755 is an alkylating antineoplastic agent for intravenous (IV) use, carrying the triazene group as the cytotoxic principal. Using a standard 3 + 3 design, a phase I study was performed in tumour bearing dogs to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and pharmacokinetic (PK) profile of TriN 2755. Thirty dogs were included in the study. TriN 2755 was administered over 20 min on two consecutive weeks per month for a total of three cycles. The starting dose was 25 mg kg-1 and the MTD was 74.6 mg kg-1 . Three dogs experienced DLT, which was characterized by gastrointestinal adverse events. The PKs of TriN 2755 and its main metabolites in plasma and sputum are described in a two-compartment model. The response rate for 19 of 30 dogs was 47.3% (six partial remission, three stable disease) and the median progression-free interval (PFI) for the responders was 47 days (range: 21-450 days).

EP-2103: Margin assessment for feline and canine radiotherapy using a custom cranial immobilisation device

S989 ________________________________________________________________________________ interview technique with an independent interviewer. The focus group was conducted shortly after the completion of the first clinical placement. The themes that came from this were then used to create a survey for group B. This was also completed shortly after their first clinical placement. Additionally this survey was also undertaken by supervising qualified RTs from the clinical placements.

Spindeltoxine als Chemotherapeutika in der Veterinärmedizin Spindle Toxins as Chemotherapeutic Agents in Veterinary Medicine

Spindeltoxine gehoren zu den potentesten Chemotherapeutika im Kampf gegen Krebs, da sie direkt in den Zellzyklus eingreifen. Mikrotubuli, Zielstrukturen der Spindeltoxine, spielen bei vielen verschiedenen physiologischen Vorgangen im Korper eine essentielle Rolle. Mikrotubuli-destabilisierende Substanzen, wie die Vinkaalkaloide und auch Mikrotubuli-stabilisierende Substanzen, wie die Taxane und Epothilone fuhren zu einem Zellzyklusstopp unmittelbar vor der Mitose. Dies fuhrt in der Folge zur Apoptose der Zelle. In der Tiermedizin gehoren Vinkaalkaloide, allen voran das Vincristin, als alleinige Therapie oder in Kombinationsprotokollen zur Standardtherapie gewisser Tumorarten. Vertreter der Taxane konnen bisher nur in beschranktem Umfang bei Tierpatienten angewendet werden, da diese aufgrund moglicher Hypersensitivitatsreaktionen stark pramediziert werden mussen. Uber die neue Substanzgruppe der Epothilone gibt es beim Hund bisher keine klinischen Studien. Da die Epothilone aber uber einige Vorzuge den Taxanen gegenuber verfugen, wird diese Substanzklasse in der Veterinar- und Humanmedizin in Zukunft wohl eine immer grosere Rolle spielen. Wasserlosliche Vertreter der Epothilone losen zum Beispiel keine Hypersensitivitatsreaktionen aus, wirken auch bei chemotherapieresistenten Tumoren und scheinen beim Menschen weniger Nebenwirkungen zu haben als Taxane. Ziel dieses Artikels ist, den Wirkmechanismus der Spindeltoxine zu beschreiben, die Vertreter der einzelnen Substanzklassen vorzustellen und ihre Bedeutung im Bezug auf die Veterinarmedizin darzulegen.