An open-label dose escalation study evaluating tolerability and safety of a single 5-days course of temozolomide in dogs with advanced cancer.

Temozolomide is a novel oral alkylating agent that has schedule-dependent clinical activity in human malignant glioma and metastatic melanoma. Little is known about the efficacy of temozolomide in the treatment of canine solid cancers, where broad range of dosages have been used but no maximally tolerated dose (MTD) had been established. The aim of this this open-label, dose-escalating study was to determine MTD and dose-limiting toxicity (DLT) of a single temozolomide cycle in dogs with advanced solid tumours. Temozolomide was administered as a 5-days course starting at 70 mg/m2 , using escalation of 10 mg/m2 increments with 3 dogs per dose level. MTD was established based on the number of dogs experiencing DLT assessed after 1 cycle. Safety evaluation was performed 10 days after dosing. Thirty-three client-owned dogs were enrolled. MTD was established at 150 mg/m2 and the most frequent adverse events (AEs) were hematologic and hepatic, followed by gastrointestinal, with the majority being self-resolving and of mild grade. VCOG grade 3 hepatic toxicity and grade 4 thrombocytopenia were defined as DLTs at 160 mg/m2 . A subcohort of dogs received multiple temozolomide doses on a 4-week cycle and no cumulative toxicity was documented. Conclusions of this study define temozolomide MTD at 150 mg/m2 when given once daily over 5 days. Future trials on the efficacy of temozolomide administered at its MTD are warranted.

Longitudinal transcriptomic and genetic landscape of radiotherapy response in canine melanoma.

Canine malignant melanoma (MM) is a highly aggressive tumour with a low survival rate and represents an ideal spontaneous model for the human counterpart. Considerable progress has been recently obtained, but the therapeutic success for canine melanoma is still challenging. Little is known about the mechanisms beyond pathogenesis and melanoma development, and the molecular response to radiotherapy has never been explored before. A faster and deeper understanding of cancer mutational processes and developing mechanisms are now possible through next generation sequencing technologies. In this study, we matched whole exome and transcriptome sequencing in four dogs affected by MM at diagnosis and at disease progression to identify possible genetic mechanisms associated with therapy failure. According to previous studies, a genetic similarity between canine MM and its human counterpart was observed. Several somatic mutations were functionally related to MAPK, PI3K/AKT and p53 signalling pathways, but located in genes other than BRAF, RAS and KIT. At disease progression, several mutations were related to therapy effects. Natural killer cell-mediated cytotoxicity and several immune-system-related pathways resulted activated opening a new scenario on the microenvironment in this tumour. In conclusion, this study suggests a potential role of the immune system associated to radiotherapy in canine melanoma, but a larger sample size associated with functional studies are needed.

Comparison of definitive-intent finely fractionated and palliative-intent coarsely fractionated radiotherapy as adjuvant treatment of feline microscopic injection-site sarcoma.

OBJECTIVES: The aim of this retrospective, bi-institutional study was to evaluate the progression-free interval in a cohort of cats with postoperative microscopic injection-site sarcoma (ISS) treated with two different radiotherapy protocols. METHODS: Included in the study were cats with ISSs undergoing macroscopic surgical removal and subsequent electron beam radiotherapy treatment with either a finely fractionated protocol (48 or 52.8 Gy over 4 weeks delivered in 12 or 16 fractions) or a coarsely fractionated protocol (36 Gy over 3 weeks administered in six fractions). Medical records were reviewed and follow-up information was collected. The Kaplan-Meier method and log-rank test were used to compare the progression-free interval (PFI) between the two protocols and to test the influence of many clinical variables. RESULTS: Fifty-nine cats were included; 38 underwent a finely fractionated protocol and 21 a coarsely fractionated protocol. PFI was not significantly different between the two groups. Overall PFI was 2000 days (2000 vs 540 days; P = 0.449). When only first-occurrence cases were included, median PFI was significantly longer in the finely fractionated group compared with the coarsely fractionated group (1430 vs 540 days; P = 0.007). In cats that underwent multiple surgeries PFI was not different between protocols (233 vs 395 days; P = 0.353). CONCLUSIONS AND RELEVANCE: Cats with first-occurrence ISSs appear to benefit from postoperative finely fractionated radiotherapy. The same benefit was not evident in cats that underwent multiple surgeries and we think a coarsely fractionated protocol would be indicated in these cases.

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.

Combination of radiation therapy and firocoxib for the treatment of canine nasal carcinoma.

Carcinomas represent two-thirds of canine nasosinal neoplasms. Although radiation therapy (RT) is the standard of care, the incidence of local recurrence following treatment is high. Cyclooxygenase-isoform-2 (COX-2) is expressed in 71-95% of canine nasal carcinomas and has been implicated in tumor growth and angiogenesis. Accordingly, COX-2 inhibition seems rational to improve outcome. Dogs with histologically confirmed, previously untreated nasal carcinomas were randomized to receive the combination of a selective COX-2 inhibitor (firocoxib) and palliative RT (Group 1) or RT and placebo (Group 2). Patients were regularly monitored with blood tests, urinalysis, and computed tomography. Pet owners were asked to complete monthly a quality-of-life questionnaire. Twenty-four dogs were prospectively enrolled. According to Adams modified system, there were five stage 1, five stage 2, three stage 3, and 11 stage 4 tumors. Two dogs had metastases to regional lymph nodes. Median progression-free interval and overall survival were 228 and 335 days in Group 1 (n = 12) and 234 and 244 days in Group 2 (n = 12). These differences were not statistically significant. The involvement of regional lymph nodes was significantly associated with progression-free interval and overall survival (P = 0.004). Quality of life was significantly improved in Group 1 (P = 0.008). In particular, a significant difference was observed for activity and appetite. Although not providing a significant enhancement of progression-free interval and overall survival, firocoxib in combination with RT is safe and improved life quality in dogs with nasal carcinomas.

Stomach wall evaluation using helical hydro-computed tomography.

In helical hydro-computed tomography (helical hydro-CT), water is used as a neutral luminal contrast medium together with intravenous iodine contrast medium for the diagnosis and staging of human gastric neoplasia. We evaluated the feasibility of helical hydro-CT in 11 healthy animals (nine dogs and two cats). Adequate uniform gastric distension was obtained with 30 ml water/kg body weight. Fourteen client-owned dogs and four cats with suspected or diagnosed gastric neoplasia then underwent helical hydro-CT followed by intravenous contrast medium administration. Focal thickening with moderate contrast enhancement was found in 10 dogs and 3 cats. The extent of the lesion was assessed easily in all these patients. Three dogs and one cat had a normal stomach wall. One dog had multifocal thickening of the antrum but no histopathologic diagnosis was made. Helical hydro-CT, followed by intravenous contrast medium administration, is a simple technique for assessing the stomach wall.