Impact of Toceranib/Piroxicam/Cyclophosphamide Maintenance Therapy on Outcome of Dogs with Appendicular Osteosarcoma following Amputation and Carboplatin Chemotherapy: A Multi-Institutional Study

Abstract

BackgroundWe 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.Methods and FindingsThis 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.ConclusionsThe 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.

In vitro and in vivo effects of toceranib phosphate on canine osteosarcoma cell lines and xenograft orthotopic models

“…Today, clear indications for using TOC in canine OS treatment are not available, and recent clinical trials did not support the use of TOC as a single agent or in combination with other commonly used therapies . In conclusion, our results demonstrate that TOC is able to mildly inhibit cell growth in vitro, while its effect is more relevant in xenograft models.…”

“…However, there is increasing evidence that other solid tumours, such as anal sac, head‐neck and thyroid carcinomas, and OSA can be successfully treated with TOC . Clinical trials performed on canine OSA patients showed controversial results when using Palladia as a single agent in canine metastatic OSA or in combination with other drugs, suggesting that more data are needed to clarify its benefit . Xenograft mouse models represent important tools for investigating the in vivo response to cancer therapeutic interventions.…”

Palliative care in small animal oncology

“…Metronomic chemotherapy is the administration of daily or every other day low-dose alkylating agents in combination with NSAIDs and has been evaluated in both the adjunctive and gross disease setting for various canine and feline neoplasms (Lana and others 2007, Burton and others 2011, Tripp and others 2011, Marchetti and others 2012, Leo and others 2014, London and others 2015). …”

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

“…However, other studies have failed to show a clear clinical benefit. A randomized, prospective clinical trial of dogs with appendicular osteosarcoma in which dogs received metronomic cyclophosphamide/piroxicam with or without toceranib following standard of care therapy (amputation and carboplatin chemotherapy) found no significant difference in disease‐free interval, OS or 1‐year survival rate . In a subsequent pilot study, a similar conclusion was reached and toceranib alone following amputation and carboplatin yielded a median survival of 253 days in 10 dogs .…”