Carboplatin versus alternating carboplatin and doxorubicin for the adjuvant treatment of canine appendicular osteosarcoma: a randomized, phase<scp>III</scp>trial

Skorupski, Katherine A; Uhl, Justin M.; Szivek, Anna; Allstadt, Sara D.; Rebhun, Robert B.; Rodríguez, C. O.

doi:10.1111/vco.12069

Cited by 68 publications

(87 citation statements)

References 20 publications

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“…Adjuvant chemotherapy, using doxorubicin and/or either carboplatin or cisplatin can extend survival somewhat. Prescription patterns have shifted over the decades but recent comparisons of chemotherapy regimens concluded that 6 doses of carboplatin was less toxic (and in one study somewhat more effective) than doxorubicin or combination treatments. However, only 15% of canine osteosarcoma patients treated with surgery plus optimal chemotherapy protocols survive for more than 3 years …”

Section: Introductionmentioning

confidence: 99%

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Patatsos

Shekhar

Hawkins

2018

Vet Comparative Oncology

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Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two of the 4 cell lines were somewhat sensitive to the BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected in the bones and lungs of treated rodents. Co-treatment with bortezomib and either doxorubicin or carboplatin was more toxic to canine osteosarcoma cells than each agent alone. Newer proteasome inhibitors carfilzomib, ixazomib, oprozomib and delanzomib manifested similar activities to bortezomib. Human osteosarcoma cells were as sensitive to bortezomib as the canine cells, but slightly less sensitive to the newer drugs. Human osteoblasts were less sensitive to proteasome inhibition than osteosarcoma cells, but physiologically relevant concentrations were toxic. Such toxicity, if replicated in vivo, may impair bone growth and strength in adolescent human osteosarcoma patients, but may be tolerated by canine patients, which are usually diagnosed later in life. Proteasome inhibitors such as bortezomib may be useful for treating canine osteosarcoma, and ultimately may improve outcomes for human patients if their osteoblasts survive exposure in vivo, or if osteoblast toxicity can be managed.

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Section: Introductionmentioning

confidence: 99%

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Patatsos

Shekhar

Hawkins

2018

Vet Comparative Oncology

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“…A thorough understanding of the immune microenvironment in pulmonary metastatic cOSA is necessary to develop immunotherapeutic strategies targeting this site of disease, since the majority of dogs succumb to pulmonary metastases even after amputation and adjuvant cytotoxic chemotherapy . While direct sampling of metastatic lesions would ideally be evaluated to provide the most representative impression of the metastatic immune microenvironment, the invasiveness of collecting cOSA pulmonary metastases from dogs in a clinical setting often precludes this.…”

Section: Discussionmentioning

confidence: 99%

Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma

Withers

York

Choi

et al. 2019

Vet Comparative Oncology

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Our lack of understanding of the immune microenvironment in canine osteosarcoma (cOSA) has limited the identification of potential immunotherapeutic targets. In particular, our ability to utilize readily available tissue from a dog's primary tumour to predict the type and extent of immune response in their pulmonary metastatic lesions is unknown. We, therefore, collected 21 matched pairs of primary tumours and pulmonary metastatic lesions from dogs with OSA and performed immunohistochemistry to quantify T‐lymphocyte (CD3), FOXP3+ cell, B‐lymphocyte (Pax‐5), and CD204+ macrophage infiltration. We found that T‐lymphocytes and FOXP3+ infiltrates in primary tumours positively correlated with that of metastatic lesions (ρ = 0.512, P = 0.038 and ρ = 0.698, P = 0.007, respectively), while a strong trend existed for CD204+ infiltrates (ρ = 0.404, P = 0.087). We also observed T‐ and B‐lymphocytes, and CD204+ macrophages to be significantly higher in a dog's pulmonary metastasis compared to their primary tumour (P = 0.018, P = 0.018, P = 0.016, respectively), while FOXP3+ cells were only significantly higher in metastases when all primary tumour and metastasis lesions were compared without pairing (P = 0.036). Together, these findings suggest that the metastatic immune microenvironment may be influenced by that of the primary cOSA, and that primary tumour immune biomarkers could potentially be applied to predict immunotherapeutic responses in gross metastatic disease. We, therefore, provide a rationale for the treatment of cOSA pulmonary metastases with immunotherapeutics that enhance the anti‐tumour activity of these immune cells, particularly in dogs with moderate to high immune cell infiltration in their primary tumours.

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“…Carboplatin is a platinum chemotherapeutic agent that is used to systemically treat a variety of tumors in companion animals, such as osteosarcoma and apocrine gland adenocarcinoma of the anal sac (AGASACA) (Ross, 1991;Bennett, 2002;Emms, 2005;Saam, 2011; Simcock, 2012;Selmic, 2014;Kozicki, 2015;Skorupski, 2016;Wouda, 2016) and has been shown to be stable in poloxamer carriers (Exner 2005;Hsu, 2014) and fully release carboplatin (Risselada, 2016) however information is not available about the stability of the combination of carboplatin and poloxamer gel in vivo and its release profile.…”

Section: Introductionmentioning

confidence: 99%

Subcutaneous microdialysis in the awake rat.

Risselada

Messenger

2017

Preprint

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Carboplatin versus alternating carboplatin and doxorubicin for the adjuvant treatment of canine appendicular osteosarcoma: a randomized, phaseIIItrial

Cited by 68 publications

References 20 publications

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma

Subcutaneous microdialysis in the awake rat.

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