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Objectives: Mammary tumours in cats are biologically aggressive. The standard of care relies upon wide surgical resection. Chemotherapy has been described in the macroscopic disease setting; however, limited efficacy has been shown. The aim of this study was to assess the efficacy of toceranib phosphate in macroscopic feline mammary tumours (FMTs). Methods: A total of 17 cats with cytologically or histopathologically confirmed mammary adenocarcinoma (gross disease) were prospectively enrolled. Toceranib phosphate was administered at a median dose of 2.77 mg/kg (range 2.3–3.2) PO q48 h. No corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) were administered. Toxicity was graded according to Veterinary Cooperative Oncology Group–Common Terminology Criteria for Adverse Events (VCOG-CTCAE) v1.1 criteria. The response was assessed after 1 month, following Response Evaluation Criteria In Solid Tumours (RECIST) criteria. Results: Toxicity was observed in eight cats, with most instances being grade 1 or 2, which were managed with supportive care. Only one cat experienced grade 3 toxicity (anorexia), which resolved after a dose reduction. Clinical benefit was seen in 12 (64.7%) cats and an objective response was seen in six (35.2%) cats. One cat experienced complete response, five had partial response, six had stable disease and five had progressive disease. One cat showed distant progression (malignant pleural effusion) despite continued partial remission of the primary tumour. The median progression-free survival and median overall survival time were 91 days (range 30–158) and 145 days (range 31–234), respectively. Conclusions and relevance: Toceranib phosphate showed clinical benefit and a good safety profile in advanced or recurrent FMTs, offering a new alternative in the treatment of this disease; however, further prospective and randomised studies are required to further assess its efficacy. Interestingly, one cat developed distant metastases while the primary tumour showed partial response, suggesting that primary tumour and metastatic disease may not sustain the same sensitivity to toceranib. [ABSTRACT FROM AUTHOR]

Canine carcinomatosis (CC) and mesothelioma (CM) are rare but aggressive neoplasms that historically have been associated with poor prognoses. There is limited information regarding treatment for CC and CM. The purpose of this retrospective study was to evaluate the efficacy and tolerability of toceranib phosphate (Palladia) in dogs with CC and CM. Cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv and retrospectively reviewed. For eligibility, a cytologic and/or histopathologic diagnosis of CC or CM was required. A total of 23 cases were included (CC = 14, CM = 8, both = 1). Eighty‐two percent (19/23) of dogs presented with effusion. The best overall response rate (BORR) was 30.4% (13% complete response [CR], 17.3% partial response [PR]). Stable disease (SD) was appreciated in 14 dogs (60.8%) including the four dogs without effusion. The most common toceranib‐related adverse events were either Grade 1 and 2 diarrhea or hyporexia. The median progression‐free survival (PFS) was 171 days (range, 7–519 days) and overall median survival time (MST) was 301 days (range, 49–875 days) for all dogs. When evaluating dogs solely with effusion, the median PFS and overall MST were 171 days (range, 7–519 days) and 285 days (range, 49–875 days), respectively. This report demonstrates that toceranib is both well tolerated and a potential treatment for CC and CM. A randomised, controlled, prospective study would be needed to objectively assess the survival benefit of toceranib in the management of CC and CM, with and without effusion. [ABSTRACT FROM AUTHOR]

Simple Summary: Oncology is a rapidly advancing field in small-animal medicine, underscoring the importance of innovative therapeutic approaches. Tyrosine kinase inhibitors (TKIs) are drugs that block various important cellular functions and play an important role in treating cancer in people and dogs. However, their role in feline oncology is less established. This comprehensive review surveys the existing literature on tyrosine kinases (TKs) and the use of TKIs in cats, aiming to identify knowledge gaps, speculate on potential indications and lay the groundwork for future investigations. Diverse feline tissues have been examined for various TK expressions. However, although limited evidence exists on the use of TKIs in specific feline tumors, it trails behind progress in human and canine oncology. We believe additional research could identify new uses for these drugs and improve therapeutic options for cats with cancer in the future. Tyrosine kinase inhibitors (TKIs) have become invaluable in the treatment of human and canine malignancies, but their role in feline oncology is less defined. While toceranib phosphate and masitinib mesylate are licensed for use in dogs, no TKI is yet approved for cats. This review systematically maps the research conducted on the expression of tyrosine kinases in neoplastic and non-neoplastic domestic feline tissues, as well as the in vitro/in vivo use of TKIs in domestic cats. We identify and discuss knowledge gaps and speculate on the further research and potential indications for TKI use in cats. A comprehensive search of three electronic databases and relevant paper reference lists identified 139 studies meeting the inclusion criteria. The most commonly identified tumors were mast cell tumors (MCTs), mammary and squamous cell carcinomas and injection-site sarcomas. Based on the current literature, toceranib phosphate appears to be the most efficacious TKI in cats, especially against MCTs. Exploring the clinical use of TKIs in mammary carcinomas holds promise. Despite the progress, currently, the evidence falls short, underscoring the need for further research to discover new indications in feline oncology and to bridge the knowledge gaps between human and feline medicine. [ABSTRACT FROM AUTHOR]

Primary renal neoplasia is rare in humans and dogs, with renal cell carcinoma (RCC) being the most common form of this cancer. As RCC is often diagnosed at an advanced stage, pulmonary metastasis is frequently observed. Tyrosine kinase inhibitors (TKIs) are the standard adjuvant treatments for metastatic RCC in humans. Similarly, in veterinary medicine, recent trials have employed TKIs for early-stage RCC patients who underwent complete surgical resection and showed no distant metastasis. However, the use of TKIs has not yet been reported commonly in cases of advanced RCC with metastasis. This case study presents the first clinical outcomes of TKI therapy in a dog with incompletely resected RCC and metastasis. A 5-year-old spayed female Chihuahua was referred to our hospital with a right renal mass and multiple pulmonary nodules suspected to be metastases. A portion of the renal mass was surgically removed, and histopathological examination revealed RCC with a high mitotic index. Adjuvant chemotherapy was administered, owing to incomplete resection with suspected pulmonary metastasis. An anticancer drug response prediction test was conducted using patient tissues. Since toceranib showed the most favorable responsiveness, it was selected as a therapeutic agent. Toceranib was orally administered at a dosage of 2.27 mg/kg every 48 h. Regular medical records for potential adverse effects were obtained, including systemic blood pressure, complete blood count, serum biochemical examination, and urinalysis. After 2 weeks of toceranib therapy, partial remission of pulmonary nodules continued for 2 months. The patient did not experience any adverse effects of the anticancer drug during the 4-month follow-up period. However, the patient died from an unidentified cause 6 months after the initial detection of the renal mass. This report describes the use of toceranib in dogs with RCC. In the present case, the patient showed an initial response to chemotherapy, and despite the presence of several poor prognostic factors, the dog survived beyond the expected 3-month lifespan to 6 months. Notably, no adverse events were observed during treatment.

A nine-year-old, castrated male mixed-breed dog presented with a three-month history of sneezing and stertorous breathing. Computed tomography revealed a soft tissue mass in the left nasal cavity with lysis of the cribriform plate. The mass was diagnosed as intranasal sarcoma based on histopathological analysis. The tumor cells were immunohistochemically positive for KIT and platelet-derived growth factor receptor a/ß and negative for vascular endothelial growth factor receptor 2 and cyclooxygenase-2. Treatment with toceranib phosphate (TOC) and firocoxib reduced the tumor size, which was defined as partial response (PR). After PR induction, TOC alone mediated survival for 205 days. This case report suggests that the combination of TOC and possibly firocoxib may be a therapeutic option for canine intranasal sarcoma. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This is the first case report of treatment with toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS. This reported case highlights the need for further studies on the efficacy of toceranib phosphate as adjuvant chemotherapy for FROMS. Feline restrictive orbital myofibroblastic sarcoma (FROMS) is a rare aggressive tumor in cats. We explored the effectiveness of using toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS in a 7‐year‐old cat. Despite treatment, the cat died 4 months after surgery. This report highlights the need for further studies on the efficacy of toceranib phosphate as adjuvant chemotherapy for FROMS. [ABSTRACT FROM AUTHOR]

Background and Aims: Human hepatocellular carcinoma (HCC) is an aggressive malignancy with poor clinical outcomes. There are limited therapeutic options for those diagnosed with terminal HCC and therefore incorporating novel agents into standard‐of‐care regimens is urgently needed. In contrast to de novo drug discovery, the strategy of repurposing compounds initially designed to treat animals might yield substantial advantages in terms of efficacy and safety. Given the evidence for the clinical efficacy of toceranib phosphate (TOC) against canine carcinomas, we aimed to investigate its therapeutic effect on human HCC. Methods: The antitumor effects of TOC were evaluated using human HCC cell lines and cell‐line‐derived xenograft models. Changes in autophagic response upon TOC exposure were quantified through immunoblotting and immunofluorescence analysis. The role of TOC‐triggered autophagy was addressed via pharmacological and genetic inhibition. Results: We demonstrated TOC exhibited potent antitumor activity against human HCC cells by stimulating apoptosis in vitro and in vivo by a concomitant increase in autophagic flux. Blocking the TOC‐triggered autophagy inhibited cellular proliferation and decreased tumour burden, indicating a protective role of autophagy against TOC‐mediated HCC cell death. This role played by TOC‐induced autophagy was further linked to the inactivation of the Akt/mTOR pathway that could be attributed to the upregulation of Cyr61. Moreover, treatment with sorafenib plus TOC resulted in pronounced synergistic effects on HCC cells. Conclusion: Our results elucidate a newly identified therapeutic potential of TOC in treating HCC, sparking a growing interest in repurposing such canine drugs for human use. [ABSTRACT FROM AUTHOR]

Key Clinical Message This is the first case report of treatment with toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS. This reported case highlights the need for further studies on the efficacy of toceranib phosphate as adjuvant chemotherapy for FROMS. Abstract Feline restrictive orbital myofibroblastic sarcoma (FROMS) is a rare aggressive tumor in cats. We explored the effectiveness of using toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS in a 7‐year‐old cat. Despite treatment, the cat died 4 months after surgery. This report highlights the need for further studies on the efficacy of toceranib phosphate as adjuvant chemotherapy for FROMS.

Intranasal tumors in dogs are malignant solid tumors that are primarily treated with radiotherapy and often recur post-treatment. Combination therapy is pivotal in cancer therapy. Effective drugs include fluoropyrimidine 5-fluorouracil (5-FU) and toceranib phosphate. TS-1, an oral formulation containing the 5-FU prodrug tegafur and enzyme modulators gimeracil and oteracil, is proven to be safe in dogs with solid tumors. While the oral drug toceranib phosphate (Palladia ® ) is safely administered, the combined toxicity with TS-1 is unknown. We aimed to determine the dosage of this combination in dogs. In the preclinical/clinical trials conducted here, we used a standard 3+3 cohort design with fixed doses of toceranib phosphate (2.4 mg/kg) administered thrice weekly. TS-1 administration was initiated at a dose of 0.5 mg/kg (upper limit 2.0 mg/kg) thrice weekly. Four cohorts were included to confirm the safety of TS-1 and toceranib phosphate. Each cohort was followed up for 1 month. The intranasal tumor types included in the clinical trial (n=13) were adenocarcinoma (n=7), squamous cell carcinoma (n=1), non-epithelial malignancy (n=2), undifferentiated carcinoma (n=1), and transitional carcinoma (n=2). The TS-1 dosage could be increased up to its dose limit in the preclinical/clinical trials. The TS-1 dose to combine with toceranib phosphate thrice weekly was 2.0 mg/kg. This regimen was well-tolerated in dogs. Thus, combined TS-1 and toceranib phosphate therapy is safe for dogs with intranasal tumors.

Abstract Background Urothelial carcinoma (UC) accounts for > 90% of canine tumors occurring in the urinary bladder. Toceranib phosphate (TOC) is a multi-target receptor tyrosine kinase (RTK) inhibitor that exhibits activity against members of the split kinase family of RTKs. The purpose of this study was to evaluate primary UC tumors and UC cell lines for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, and KIT to assess whether dysregulation of these RTKs may contribute to the observed biological activity of TOC. Results Transcript for VEGFR2, PDGFRα, PDGFRβ, and KIT was detected in all UC tissue samples and UC cell lines. The Proteome Profiler™ Human Phospho-RTK Array Kit (R & D Systems) provided a platform to assess phosphorylation of 42 different RTKs in primary UC tumors and UC cell lines. Evidence of PDGFRα and PDGFRβ phosphorylation was present in only 11% or 33% of UC tumors, respectively, and 25% of UC cell lines. Treatment of UC cell lines with TOC had no significant impact on cell proliferation, including UC cell lines with evidence of PDGFRβ phosphorylation. Conclusions Phosphorylation of several key RTKs targeted by TOC is present in a small subset of primary UC tumors and UC cell lines, suggesting that these RTKs do not exist in a state of continuous activation. These data suggest that activation of RTKs targeted by TOC is present in a small subset of UC tumors and UC cell lines and that treatment with TOC at physiologically relevant concentrations has no direct anti-proliferative effect on UC cells.

Tyrosine kinase inhibitors (TKIs) have become invaluable in the treatment of human and canine malignancies, but their role in feline oncology is less defined. While toceranib phosphate and masitinib mesylate are licensed for use in dogs, no TKI is yet approved for cats. This review systematically maps the research conducted on the expression of tyrosine kinases in neoplastic and non-neoplastic domestic feline tissues, as well as the in vitro/in vivo use of TKIs in domestic cats. We identify and discuss knowledge gaps and speculate on the further research and potential indications for TKI use in cats. A comprehensive search of three electronic databases and relevant paper reference lists identified 139 studies meeting the inclusion criteria. The most commonly identified tumors were mast cell tumors (MCTs), mammary and squamous cell carcinomas and injection-site sarcomas. Based on the current literature, toceranib phosphate appears to be the most efficacious TKI in cats, especially against MCTs. Exploring the clinical use of TKIs in mammary carcinomas holds promise. Despite the progress, currently, the evidence falls short, underscoring the need for further research to discover new indications in feline oncology and to bridge the knowledge gaps between human and feline medicine.

Case summary: An 11-year-old male neutered domestic shorthair cat was presented with a 4-week history of an intermittent cough and dyspnoea. A pleural effusion was identified, which was confirmed as chyle. Echocardiography and CT revealed a 16 mm mass cranial to the heart, which was invading the cranial vena cava. Because of the location of the mass, it was assumed that chylothorax had developed as a result of direct disruption of the thoracic duct by the tumour or secondarily to central venous hypertension. An exploratory thoracotomy was performed, and the mass, which originated within the wall of the cranial vena cava, was excised with narrow gross margins. Histopathology and immunohistochemistry were consistent with a chemodectoma with residual tumour cells at the surgical margin. Given the residual microscopic disease, adjuvant treatment with toceranib phosphate was initiated. The cat remained well for the duration of treatment and was euthanased 31 months after diagnosis when CT identified recurrent pleural effusion, a heart base mass with cranial vena cava and azygos vein invasion. Relevance and novel information: Chemodectomas are rare in cats, with only 13 cases reported in the literature to date, and all were located in either the aortic or carotid body. The reported survival with partial resection and/or subtotal pericardiectomy was 13–19 months. Treatment of feline chemodectomas with toceranib phosphate has not been previously reported. To our knowledge, this is the first description of the surgical management of a feline vena cava chemodectoma, combined with adjuvant toceranib phosphate, resulting in a prolonged survival. [ABSTRACT FROM AUTHOR]

A three-year-old male neutered Norwegian Forest cat was referred for bilateral ambulatory paraparesis and spinal pain. On magnetic resonance imaging (MRI), a mass involving the right epaxial muscles with vertebral canal invasion and causing marked extradural spinal cord compression was identified. At surgery, the mass was debulked and a right hemilaminectomy was performed. Histopathology was diagnostic of fibroblastic osteosarcoma. Residual osteolytic lesions of the osteosarcoma were present at the level of the spinous process of the second lumbar vertebra. Four cycles of adjuvant doxorubicin chemotherapy were administered followed by oral toceranib phosphate. Neurological signs improved gradually over weeks to months and the lesion in the spinous process was no longer visible on radiographs. At one year from diagnosis, an MRI of the T3-L3 (3rd thoracic vertebra to the 3rd lumbar vertebra) spinal region and a whole-body computer tomography (CT) scan found no evidence of the osteosarcoma in the spine or of any metastasis. All medications were stopped and, at the time of writing 16 months later, the patient is neurologically normal with no signs of cancer recurrence. This is the first case report documenting the complete resolution of vertebral osteosarcoma lesions after treatment with doxorubicin followed by toceranib phosphate. The treatment also prevented tumor recurrence and was associated with an exceptionally long-term survival time. [ABSTRACT FROM AUTHOR]

Abstract Background Nephrotic syndrome (NS) is rare in dogs and is characterized by concurrent clinical findings of proteinuria, hyperlipidemia, hypoalbuminemia, and edema. NS has been reported in humans receiving tyrosine kinase inhibitors (TKI) and in dogs receiving masitinib. This is the first report of NS in a dog receiving toceranib phosphate. Case presentation An 8-year-old, female, spayed Labrador retriever was diagnosed with a 10 cm mast cell tumor on the left lateral abdomen. After completion of a 12-week vinblastine and prednisone protocol, she began treatment with toceranib phosphate (2.6 mg/kg by mouth, every other day). Proteinuria was documented prior to starting toceranib. On day 426 after diagnosis (day 328 of toceranib phosphate treatment), the dog was evaluated for diarrhea, lethargy and anorexia. On physical examination, dependent edema was noted on the ventral chest and abdomen, and sterile neutrophilic inflammation was aspirated from a 2.3 cm splenic nodule. The following laboratory values were reported: albumin

Radiation is the standard of care for dogs with nasal tumours. The addition of another therapy that could improve outcome without increasing toxicity is attractive. Medical therapy that could offer better outcome than maximally tolerated dose chemotherapy when radiation therapy (RT) is not possible or is declined is also attractive. This article reports the findings from a prospective, multi‐centre, non‐randomized, Veterinary Radiation Therapy Oncology Group clinical trial designed to evaluate whether toceranib phosphate (toceranib) has primary activity and if the addition of toceranib to RT could positively impact outcome. Owner's discretion determined enrolment in toceranib alone or toceranib + RT arm. Historical controls for radiation alone were selected from patients treated with identical RT and imaging protocols. Responses were evaluated with pre‐treatment and week‐16 CT scans. RT total dose of 42 Gy was completed in 10 fractions. Sixty‐three dogs enrolled from 10 study sites. Overall response rates (CR + PR) were significantly improved in the toceranib + RT (79.4%) and RT alone (68.9%) arms over toceranib alone (22%) (p =.011). Clinical benefit rates (CR + PR + SD) were significantly improved in the toceranib + RT arm over the RT alone arm at 97.3% and 79.2% respectively (p =.036). Treatment with toceranib alone, toceranib + RT and RT alone resulted in median survival times of 298, 615 and 368 days respectively, but were not statistically significantly different (p =.0502). Adverse events associated with toceranib administration did not potentiate the RT side effect profile. Toceranib appears to have primary activity against nasal carcinoma. [ABSTRACT FROM AUTHOR]

Abstract Background Toceranib phosphate (TOC) could be made widely available for treating tumors in dogs if evidence shows that TOC inhibits recurrence after surgery. Objectives To investigate how postoperative adjuvant treatment with TOC modulates the tumor microenvironment (TME), by assessing effects on angiogenic activity, tumor‐infiltrating regulatory T cells (Tregs), and intratumoral hypoxia. Animals Ninety‐two client‐owned dogs were included: 28 with apocrine gland anal sac adenocarcinoma, 24 with small intestinal adenocarcinoma, 22 with lung adenocarcinoma, and 18 with renal cell carcinoma. Methods Retrospective, multicenter study comparing time to progression (TTP) between 42 dogs treated by surgery and TOC and 50 dogs treated by surgery alone. Differences were analyzed in the expression of vascular endothelial growth factor receptor‐2 (VEGFR2) and the number of Foxp3+ Tregs and hypoxia‐inducible factor (HIF)‐1α+ cells in tumor tissues sampled at the first and second (recurrence) surgeries. Results Median TTP for dogs treated by surgery and TOC (360 days) was higher than that for dogs treated by surgery alone (298 days; hazard ratio, 0.82; 95% confidence interval [CI], 0.65‐0.96; P = .02). In dogs treated by surgery and TOC, VEGFR2 expression and the number of Tregs and HIF‐1α+ cells were significantly lower in tissues sampled at the second surgery than in those sampled after the first surgery. In dogs treated by surgery alone, significant differences were found between samples from the 2 surgeries. Conclusions and Clinical Importance Toceranib phosphate could prove to be a useful postoperative adjuvant treatment because of its modulation of the TME.

Background: Urothelial carcinoma (UC) accounts for > 90% of canine tumors occurring in the urinary bladder. Toceranib phosphate (TOC) is a multi-target receptor tyrosine kinase (RTK) inhibitor that exhibits activity against members of the split kinase family of RTKs. The purpose of this study was to evaluate primary UC tumors and UC cell lines for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, and KIT to assess whether dysregulation of these RTKs may contribute to the observed biological activity of TOC. Results: Transcript for VEGFR2, PDGFRα, PDGFRβ, and KIT was detected in all UC tissue samples and UC cell lines. The Proteome Profiler™ Human Phospho-RTK Array Kit (R & D Systems) provided a platform to assess phosphorylation of 42 different RTKs in primary UC tumors and UC cell lines. Evidence of PDGFRα and PDGFRβ phosphorylation was present in only 11% or 33% of UC tumors, respectively, and 25% of UC cell lines. Treatment of UC cell lines with TOC had no significant impact on cell proliferation, including UC cell lines with evidence of PDGFRβ phosphorylation. Conclusions: Phosphorylation of several key RTKs targeted by TOC is present in a small subset of primary UC tumors and UC cell lines, suggesting that these RTKs do not exist in a state of continuous activation. These data suggest that activation of RTKs targeted by TOC is present in a small subset of UC tumors and UC cell lines and that treatment with TOC at physiologically relevant concentrations has no direct anti-proliferative effect on UC cells. [ABSTRACT FROM AUTHOR]

Objectives: Although feline mammary carcinomas (FMCs) are highly metastatic, the literature and treatment options pertaining to advanced tumours are scarce. This study aimed to investigate the clinical outcome of metastatic FMC with or without adjuvant treatment. Methods: The medical records of 73 cats with metastatic FMC (stage IV) were reviewed and included in this study. Metastatic disease was detected by distinct imaging techniques (radiography, ultrasound and CT) and confirmed by cytology and/or histopathology. Cats with adjuvant chemotherapy treatment (n = 34) were divided into three groups: group 1 (n = 9) cats receiving maximum tolerated dose chemotherapy; group 2 (n = 15) cats receiving metronomic chemotherapy; and group 3 (n = 10) cats treated with toceranib phosphate. The study endpoints were time to progression (TTP) and tumour-specific survival (TSS). Treatment-related toxicity was evaluated according to the Veterinary Co-operative Oncology Group's Common Terminology Criteria for Adverse Events version 1.1 (VCOG-CTCAE). Results: Overall mean TTP and TSS were 23 and 44 days, respectively. Cats with clinical signs at the time of diagnosis had a lower TSS (14 days) than asymptomatic cats (128 days; P <0.001). Cats with pleural effusion had a lower TSS (16 days) than cats without (P <0.001). Median TSS was 58, 75 and 63 days in groups 1, 2 and 3, respectively (P = 0.197). Toxicity was observed in 66.7%, 20% and 30% of cats in groups 1, 2 and 3, respectively. Conclusions and relevance: To the best of our knowledge, this study includes the highest number of patients with metastatic FMC assessed. Despite the overall poor prognosis, some cats survived >6 months, indicating that adjuvant treatment may be an option to consider in metastatic disease. More studies are warranted for better understanding and management of stage IV patients. [ABSTRACT FROM AUTHOR]

Background: Nephrotic syndrome (NS) is rare in dogs and is characterized by concurrent clinical findings of proteinuria, hyperlipidemia, hypoalbuminemia, and edema. NS has been reported in humans receiving tyrosine kinase inhibitors (TKI) and in dogs receiving masitinib. This is the first report of NS in a dog receiving toceranib phosphate. Case presentation: An 8-year-old, female, spayed Labrador retriever was diagnosed with a 10 cm mast cell tumor on the left lateral abdomen. After completion of a 12-week vinblastine and prednisone protocol, she began treatment with toceranib phosphate (2.6 mg/kg by mouth, every other day). Proteinuria was documented prior to starting toceranib. On day 426 after diagnosis (day 328 of toceranib phosphate treatment), the dog was evaluated for diarrhea, lethargy and anorexia. On physical examination, dependent edema was noted on the ventral chest and abdomen, and sterile neutrophilic inflammation was aspirated from a 2.3 cm splenic nodule. The following laboratory values were reported: albumin < 1.5 g/dL; cholesterol 378 mg/dl and urine protein to creatinine ratio of 3.79. The patient was diagnosed with NS, and treatment with toceranib phosphate was discontinued. Low-dose aspirin was started in addition to an increased dosage of enalapril (0.47 mg/kg q12hr). No other therapy was instituted. The dog improved clinically, and laboratory values returned to near normal over the 8-week follow-up. She was euthanized 1399 days after discontinuing toceranib phosphate with progressive disease. Conclusions: Nephrotic syndrome is a potential adverse event associated with the drug toceranib phosphate which may be reversible with discontinuation of treatment. Careful monitoring of urine protein, serum biochemistry, blood pressure and patient weight is advisable during treatment with toceranib phosphate. [ABSTRACT FROM AUTHOR]

A three-year-old male neutered Norwegian Forest cat was referred for bilateral ambulatory paraparesis and spinal pain. On magnetic resonance imaging (MRI), a mass involving the right epaxial muscles with vertebral canal invasion and causing marked extradural spinal cord compression was identified. At surgery, the mass was debulked and a right hemilaminectomy was performed. Histopathology was diagnostic of fibroblastic osteosarcoma. Residual osteolytic lesions of the osteosarcoma were present at the level of the spinous process of the second lumbar vertebra. Four cycles of adjuvant doxorubicin chemotherapy were administered followed by oral toceranib phosphate. Neurological signs improved gradually over weeks to months and the lesion in the spinous process was no longer visible on radiographs. At one year from diagnosis, an MRI of the T3-L3 (3rd thoracic vertebra to the 3rd lumbar vertebra) spinal region and a whole-body computer tomography (CT) scan found no evidence of the osteosarcoma in the spine or of any metastasis. All medications were stopped and, at the time of writing 16 months later, the patient is neurologically normal with no signs of cancer recurrence. This is the first case report documenting the complete resolution of vertebral osteosarcoma lesions after treatment with doxorubicin followed by toceranib phosphate. The treatment also prevented tumor recurrence and was associated with an exceptionally long-term survival time.

The purpose of this retrospective study was to provide additional data on the use of toceranib in a wide variety of tumor types in small breed dogs, especially < 8 kg (except 5 dogs). This was a retrospective study of 31 dogs with malignant tumors treated with a 2.5 mg/kg median dose of toceranib (Palladia; Zoetis, USA) on a Monday– Wednesday–Friday schedule. Clinical benefit was observed in 13 of 15 dogs (86.7%, 3 with complete response, 4 with partial response, 6 with stable disease) with gross disease. Distant metastasis, response to treatment, and treatment setting were significantly associated with survival time. Negative prognostic factors were multiple chemotherapy and distant metastasis (affecting progression-free survival [PFS]), surgery, regional enlarged lymph nodes, underlying disease, and toxicity (affecting median survival time [MST]). Positive prognostic factors were epithelial and round cell tumor (affecting PFS), epithelial tumor, microscopic disease, no evidence of disease response, and stable disease (MST). In conclusion, a clinical benefit from toceranib treatment was noted in most of the dogs with gross disease in our study. This study suggested that the toceranib is probably selective treatment to various tumor types in small breed dogs. [ABSTRACT FROM AUTHOR]

In humans, contrast‐enhanced CT (CECT) has been used to indirectly assess the antiangiogenic effects demonstrated by a number of tyrosine kinase inhibitors. This retrospective, cross‐sectional study aimed to quantitatively evaluate changes in tumor contrast‐enhancement (CE) using CECT in solid tumor‐bearing dogs treated with toceranib phosphate (TOC). The changes in tumor size and CE were measured using the Hounsfield unit (HU) scale in CECT images before TOC treatment and between 30 and 90 days after initiating the treatment. Among the 36 dogs treated with TOC, eight (22.2%) showed a partial response, 22 (61.1%) showed stable disease, and six (16.7%) showed progressive disease. Thirty (83.3%) of 36 dogs showed a decrease in tumor CE (median: −20%, range: −1% to −48%) after initiating the treatment. The results indicated that tumor CE and size changes were observed in tumor‐bearing dogs that were treated with TOC; however, tumor CE was not significantly correlated with tumor regression. We suggest that these results could serve as pilot data to evaluate the antiangiogenic effects associated with TOC. [ABSTRACT FROM AUTHOR]

Background: Toceranib phosphate (TOC) could be made widely available for treating tumors in dogs if evidence shows that TOC inhibits recurrence after surgery. Objectives: To investigate how postoperative adjuvant treatment with TOC modulates the tumor microenvironment (TME), by assessing effects on angiogenic activity, tumor‐infiltrating regulatory T cells (Tregs), and intratumoral hypoxia. Animals Ninety‐two client‐owned dogs were included: 28 with apocrine gland anal sac adenocarcinoma, 24 with small intestinal adenocarcinoma, 22 with lung adenocarcinoma, and 18 with renal cell carcinoma. Methods: Retrospective, multicenter study comparing time to progression (TTP) between 42 dogs treated by surgery and TOC and 50 dogs treated by surgery alone. Differences were analyzed in the expression of vascular endothelial growth factor receptor‐2 (VEGFR2) and the number of Foxp3+ Tregs and hypoxia‐inducible factor (HIF)‐1α+ cells in tumor tissues sampled at the first and second (recurrence) surgeries. Results: Median TTP for dogs treated by surgery and TOC (360 days) was higher than that for dogs treated by surgery alone (298 days; hazard ratio, 0.82; 95% confidence interval [CI], 0.65‐0.96; P =.02). In dogs treated by surgery and TOC, VEGFR2 expression and the number of Tregs and HIF‐1α+ cells were significantly lower in tissues sampled at the second surgery than in those sampled after the first surgery. In dogs treated by surgery alone, significant differences were found between samples from the 2 surgeries. Conclusions and Clinical Importance: Toceranib phosphate could prove to be a useful postoperative adjuvant treatment because of its modulation of the TME. [ABSTRACT FROM AUTHOR]

Canine osteosarcoma (OSA) is the most common primary malignant bone tumour in dogs, and it has a high metastatic rate and poor prognosis. Toceranib phosphate (TOC; Palladia, Zoetis) is a veterinary tyrosine kinase inhibitor that selectively inhibits VEGFR‐2, PDGFRs and c‐Kit, but its efficacy is not yet fully understood in the treatment of canine OSA. Here, we evaluated the functional effects of TOC on six OSA cell lines by transwell, wound healing and colony formation assays. Subsequently, two cell lines (Wall and Penny) were selected and were inoculated in mice by intrafemoral injection to develop an orthotopic xenograft model of canine OSA. For each cell line, 30 mice were xenografted; half of them were used as controls, and the other half were treated with TOC at 40 mg/kg body weight for 20 days. TOC inhibited cell growth of all cell lines, but reduced invasion and migration was only observed in Penny and Wall cell lines. In mice engrafted with Penny cells and subjected to TOC treatment, decreased tumour growth was observed, and PDGFRs and c‐Kit mRNA were downregulated. Immunohistochemical analyses demonstrated a significant reduction of Ki67 staining in treated mice when compared to controls. The results obtained here demonstrate that TOC is able to slightly inhibit cell growth in vitro, while its effect is evident only in a Penny cell xenograft model, in which TOC significantly reduced tumour size and the Ki67 index without modifying apoptosis markers. [ABSTRACT FROM AUTHOR]

Heart base tumours (HBT) occur commonly in older, brachycephalic dogs. A presumptive diagnosis is made based on location and appearance of the tumour via echocardiogram. Effective treatment options are limited to surgery (when feasible) or radiation therapy. Benefit of medical management is presently unknown. The goal of this retrospective study was to assess the efficacy and tolerability of toceranib phosphate for dogs with HBT. Twenty‐eight dogs with histologically, cytologically confirmed or presumed HBT were evaluated retrospectively. Twenty‐seven dogs were treated with single agent toceranib. One dog received combination therapy with concurrent metronomic chemotherapy. This dog was not included in response or survival analysis. Factors assessed included clinical signs, hematologic/biochemical parameters and response to treatment. For the 27 dogs receiving single agent toceranib, an overall response rate of 10% was found. Overall median survival time was 823 days (range, 68‐1190 days). The overall response rate for the dogs presenting with metastasis was 28.5%, with a median survival time of 532 days (range, 77‐679 days). This was not significantly different than the median survival time of 796 days for dogs who did not present with metastasis. Of the dogs displaying clinical signs at the time of diagnosis, 90% had improvement and 81% had complete resolution of signs after starting toceranib. Toxicity was seen in 54% of dogs with gastrointestinal distress as the most common toxicity but dose reductions were infrequent required. Results demonstrate that toceranib phosphate is a well‐tolerated and effective treatment for inoperable canine heart base tumours including dogs with advanced or metastatic disease. [ABSTRACT FROM AUTHOR]

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with lowdose metronomic and/or anti-angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose-finding clinical trial assumed an openlabel 3 + 3 cohort design. Client-owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg−1 by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m−2. A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m−2. AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG-CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose-limiting. Response to therapy was evaluated according to the VCOG’s revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m−2 IV every 21 days and approximately 2.75 mg kg−1 PO EOD, respectively. The dose-limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well-tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials. [ABSTRACT FROM AUTHOR]

We examined whether multidrug resistant (MDR) canine lymphoma increases gene expression for platelet-derived growth factor receptor α (PDGFRα), vascular endothelial growth factor receptor 2 (VEGFR2), and c-KIT, and whether toceranib phosphate (TOC) has potential as a treatment for MDR canine lymphoma. The clinical data showed that PDGFRα expression was higher in canine subjects with MDR T-cell lymphoma than in those with untreated T-cell lymphoma, and that c-KIT expression was greater in subjects with T-cell lymphoma than in those with B-cell lymphoma. TOC monotherapy was well tolerated without serious adverse effects, and two of the five subjects that received TOC exhibited partial responses. The data presented here could contribute to the assessment of TOC-based therapy for dogs with MDR or T-cell lymphoma. [ABSTRACT FROM AUTHOR]

A nine-year-old, castrated male mixed-breed dog presented with a three-month history of sneezing and stertorous breathing. Computed tomography revealed a soft tissue mass in the left nasal cavity with lysis of the cribriform plate. The mass was diagnosed as intranasal sarcoma based on histopathological analysis. The tumor cells were immunohistochemically positive for KIT and platelet-derived growth factor receptor α/β and negative for vascular endothelial growth factor receptor 2 and cyclooxygenase-2. Treatment with toceranib phosphate (TOC) and firocoxib reduced the tumor size, which was defined as partial response (PR). After PR induction, TOC alone mediated survival for 205 days. This case report suggests that the combination of TOC and possibly firocoxib may be a therapeutic option for canine intranasal sarcoma.

A 13-yr-old female binturong ( Arctictis binturong) presented with a 1 wk history of decreased appetite. The animal was thin, with hypercalcemia (calcium 12.2 mg/dl). A right renal mass was identified on ultrasound and removed via nephrectomy. Histopathology indicated a renal adenocarcinoma. Treatment with toceranib phosphate, a tyrosine-kinase inhibitor, was initiated and well tolerated by the animal. Four months after initial diagnosis radiographs indicated metastases to the lungs and the animal was euthanized. Necropsy revealed disseminated adenocarcinoma. Although treatment did not prevent metastasis, it was minimally invasive and well tolerated by the animal with minimal side effects. Review of records at the institution revealed that the cause of death for the primary case's dam and sire was disseminated renal carcinoma. These cases suggest that there may be a hereditary component to development of renal neoplasia in binturongs. Renal carcinoma should be considered an aggressive neoplasia in binturongs with a poor prognosis. [ABSTRACT FROM AUTHOR]

Background: The receptor kinase inhibitor toceranib phosphate (Palladia) was approved for use in dogs in 2009 using a dose of 3.25 mg/kg administered every other day. Preliminary data suggests that lower doses of toeceranib may be associated with a reduced adverse event profile while maintaining sufficient drug exposure to provide biologic activity. The purpose of this study was to determine the Cmax of toceranib in dogs with solid tumors receiving 2.5-2.75 mg/kg every other day and to document the adverse events associated with this dose rate. Secondary objectives included determination of plasma VEGF concentrations in treated dogs and response to therapy. Results: Dogs with solid tumors were administered toceranib at an intended target dose ranging from 2.5-2.75 mg/kg every other day and plasma samples were obtained for analysis of toceranib and VEGF plasma concentrations on days 0, 7, 14 and 30 of the study at 6 and 8 hours post drug administration. Additionally, plasma samples were obtained at 0, 1, 2, 6, 8, and 12 hours from dogs on day 30 for confirmation of Cmax. Response to therapy was assessed using standard RECIST criteria and adverse events were characterized using the VCOG-CTCAE. Toceranib administered at doses between 2.4-2.9 mg/kg every other day resulted in an average 6-8 hr plasma concentration ranging from 100-120 ng/ml, well above the 40 ng/ml concentration associated with target inhibition. Plasma VEGF concentrations increased significantly over the 30 day treatment period indicating that VEGFR2 inhibition was likely achieved in the majority of dogs. The lower doses of toceranib used in this study were associated with a substantially reduced adverse event profile compared to the established label dose of 3.25 mg/kg EOD. Conclusions: Doses of toceranib ranging from 2.4-2.9 mg/kg every other day provide drug exposure considered sufficient for target inhibition while resulting in an adverse event profile substantially reduced from that associated with the label dose of toceranib. This lower dose range of toceranib should be considered for future use in dogs with cancer. [ABSTRACT FROM AUTHOR]