toceranib-phosphate and Osteosarcoma

The use of tyrosine kinase inhibitors (TKI) has gained significant importance in veterinary cancer patients over the last decade. Toceranib phosphate has been licensed for the treatment of dogs with mast cell tumours. Its molecular similarity to sunitinib, a TKI used in human medicine, has led many veterinary oncologists to use this agent for multiple neoplastic diseases. The aim of the current study was to perform a systematic review of the evidence for the use of toceranib in dogs with non-mast cell neoplasia. Two electronic databases were searched. Publications were included if toceranib was used as a treatment option in canine patients. Studies and case reports were excluded if toceranib was used as part of a multi-modal treatment plan and response or outcome data related to toceranib therapy were not described. A total of 28 studies were included from 122 references. The most common types of neoplasias identified were neuroendocrine tumours, anal gland sac adenocarcinoma, and osteosarcoma. Multiple other neoplasias had one or two studies identified to describe the use of toceranib. Results of the study support that toceranib phosphate may have efficacy against certain types of neoplasia under certain conditions, such as neuroendocrine tumours, gastrointestinal stromal tumours and anal sac adenocarcinomas, while it is probably not effective for the management of metastatic osteosarcoma based on the findings of the review.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Dog Diseases; Dogs; Humans; Indoles; Osteosarcoma; Pyrroles

Topics: Amputation, Surgical; Animals; Antineoplastic Agents; Carboplatin; Chemotherapy, Adjuvant; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Gene Expression Regulation, Neoplastic; Indoles; Male; Matrix Metalloproteinase 9; Osteosarcoma; Pilot Projects; Pyrroles; Vascular Endothelial Growth Factor A

We hypothesized that the addition of toceranib to metronomic cyclophosphamide/piroxicam therapy would significantly improve disease-free interval (DFI) and overall survival (OS) in dogs with appendicular osteosarcoma (OSA) following amputation and carboplatin chemotherapy.. This was a randomized, prospective clinical trial in which dogs with OSA free of gross metastatic disease (n = 126) received carboplatin chemotherapy (4 doses) following amputation. On study entry, dogs were randomized to receive piroxicam/cyclophosphamide with or without toceranib (n = 63 each) after completing chemotherapy. Patient demographics were not significantly different between both groups. During or immediately following carboplatin chemotherapy, 32 dogs (n = 13 toceranib; n = 19 control) developed metastatic disease, and 13 dogs left the study due to other medical conditions or owner preference. Following carboplatin chemotherapy, 81 dogs (n = 46 toceranib; n = 35 control) received the metronomic treatment; 35 dogs (n = 20 toceranib; n = 15 control) developed metastatic disease during the maintenance therapy, and 26 dogs left the study due to other medical conditions or owner preference. Nine toceranib-treated and 11 control dogs completed the study without evidence of metastatic disease 1-year following amputation. Toceranib-treated dogs experienced more episodes of diarrhea, neutropenia and weight loss than control dogs, although these toxicities were low-grade and typically resolved with supportive care. More toceranib-treated dogs (n = 8) were removed from the study for therapy-associated adverse events compared to control dogs (n = 1). The median DFI for control and toceranib treated dogs was 215 and 233 days, respectively (p = 0.274); the median OS for control and toceranib treated dogs was 242 and 318 days, respectively (p = 0.08). The one year survival rate for control dogs was 35% compared to 38% for dogs receiving toceranib.. The addition of toceranib to metronomic piroxicam/cyclophosphamide therapy following amputation and carboplatin chemotherapy did not improve median DFI, OS or the 1-year survival rate in dogs with OSA.

Topics: Administration, Metronomic; Amputation, Surgical; Animals; Bone Neoplasms; Carboplatin; Cyclophosphamide; Diarrhea; Disease-Free Survival; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Indoles; Kaplan-Meier Estimate; Male; Neutropenia; Osteosarcoma; Piroxicam; Prospective Studies; Pyrroles; Regression Analysis; Treatment Outcome

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.

Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Dogs; Heterografts; In Vitro Techniques; Indoles; Mice; Osteosarcoma; Pyrroles; Treatment Outcome

Efficacious therapies for measurable metastatic canine osteosarcoma (OSA) are generally lacking. Preliminary retrospective studies suggested that approximately 50% of dogs with measurable metastatic OSA experienced clinical benefit (objective response or clinically meaningful disease stabilisation) following toceranib (TOC) treatment. The purpose of this clinical trial was to prospectively evaluate the clinical outcome following TOC treatment in dogs with measurable pulmonary metastatic OSA. A secondary goal was to identify potential biomarkers of clinical benefit by measuring changes in plasma vascular endothelial growth factor (VEGF) and circulating regulatory T-cell (Treg) percentage. Twenty-two dogs with pulmonary metastasis from appendicular OSA having undergone previous amputation were treated prospectively with TOC. Adverse events (AEs) were common but predominantly low grade. Nine patients were withdrawn from the study prior to the week 8 assessment of response either due to progressive disease (PD), decreased quality of life or owner perceived unacceptable AEs. Of the patients evaluable for disease progression at week 8 (or earlier), 3/17 (17.6 %) had stable disease with the remainder having PD. The median progression-free survival time for all patients was 57 days (range 7-176 days) with a median overall survival time of 89 days (range 7-574 days). Plasma VEGF concentrations were significantly elevated in patients after 4 weeks of TOC treatment, but no changes were observed in percentage of Treg in peripheral blood. Overall, the results of this clinical trial do not support the use of TOC as single agent therapy for canine metastatic OSA.

Topics: Animals; Antineoplastic Agents; Biomarkers; Bone Neoplasms; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Indoles; Male; Osteosarcoma; Prospective Studies; Pyrroles; Survival Analysis; T-Lymphocytes, Regulatory; Vascular Endothelial Growth Factor A

This retrospective study evaluated the outcomes of dogs with macroscopic pulmonary metastasis of appendicular osteosarcoma (OSA) treated with toceranib. Medical records of 20 dogs with macroscopic pulmonary metastasis of OSA that received toceranib were reviewed. The median dose and duration of toceranib administration were 2.52 mg/kg (range: 2.12 to 2.72 mg/kg) and 60 days (range: 17 to 231 days). The median progression free survival (PFS) and overall survival (OS) were 36 days (range: 17 to 231 days) and 90 days (range: 17 to 433 days), respectively. The clinical benefit rate was 10% (2/20; 1 partial response and 1 stable disease). The longest length of initial pulmonary nodules had significant impact on both PFS (

Topics: Animals; Bone Neoplasms; Dog Diseases; Dogs; Female; Indoles; Lung Neoplasms; Male; Osteosarcoma; Pyrroles; Retrospective Studies; Treatment Outcome

The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia®, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.

Topics: Adenocarcinoma; Anal Gland Neoplasms; Anal Sacs; Animals; Antineoplastic Agents; Apocrine Glands; Bone Neoplasms; Carcinoma; Dog Diseases; Dogs; Female; Head and Neck Neoplasms; Indoles; Male; Neoplasms; Nose Neoplasms; Osteosarcoma; Pyrroles; Receptor Protein-Tyrosine Kinases; Skin Neoplasms; Thyroid Neoplasms