Clinical Rounds: Recurrent mast cell tumors in a boxer - Veterinary Medicine
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Clinical Rounds: Recurrent mast cell tumors in a boxer
Make the rounds with these veterinary specialists and residents and see how various combinations of therapy eventually produced a good outcome in this case.


VETERINARY MEDICINE


SURGICAL PERSPECTIVE


Dr. Karen M. Tobias
Karen M. Tobias, DVM, MS, DACVS


Table 2: Patnaik Grading System for Canine Cutaneous Mast Cell Tumors*
Surgical resection is the treatment of choice for mast cell tumors amenable to wide excision. Margins required for complete resection depend on the tumor grade. Patnaik19 Grade I mast cell tumors are completely excised with margins 1 cm wide and one fascial plane deep (Table 2). Complete excision of Patnaik Grade II mast cell tumors may require margins 2 cm wide and one fascial plane deep; however, complete excision is possible with 1-cm-wide margins in up to 75% of dogs.21,22 Since tumor grade is usually unknown before surgery, clinicians will usually attempt to achieve 2-cm margins.

Remarkably, local recurrence rates after incomplete resection of Patnaik Grade II mast cell tumors is 5% to 23%,23 suggesting that mast cells found along margins of some samples are likely recruited healthy cells rather than neoplastic ones.

If the ability to attain adequate surgical margins is questionable because of peritumoral edema or ill-defined borders, use of preoperative glucocorticoids can be considered. In one study, 70% of dogs showed a reduction in tumor size when treated with prednisone for a median of 10 days before surgery.24 Mean tumor volume and maximal diameter decreased 53% and 35%, respectively, in dogs receiving low-dose prednisone (1 mg/kg [0.45 mg/lb] orally ever 24 hours) and 78% and 49%, respectively, in dogs receiving high-dose prednisone (2.2 mg/kg [1 mg/lb] orally every 24 hours). The difference in response based on dose was not significantly different.24 The effect of preoperative corticosteroid administration on tumor grade has not been determined.

MEDICAL ONCOLOGY PERSPECTIVE


Dr. Richard A. Chetney, Jr.
Richard A. Chetney, Jr., DVM


Table 3: Cytotoxic Chemotherapy Drugs with Documented Clinical Efficacy Against Canine Mast Cell Tumors
The two most common chemotherapy options we use for canine cutaneous mast cell tumors include combination oral prednisone and injectable vinblastine25 or oral lomustine.4 However, other cytotoxic chemotherapies have been shown to have efficacy against mast cell tumors (Table 3).

A recent study demonstrated that a new water-soluble (micellar) formulation of paclitaxel (1 mg/ml; Paccal Vet—Oasmia Pharmaceutical AB) was safe and had a higher confirmed overall response rate than lomustine in dogs with advanced nonresectable mast cell tumors.26 The biologic overall response rate to lomustine in this study (10%) was much lower than in previous reports, but the endpoint for assessment of response to the micellar paclitaxel was 14 weeks vs. six weeks for the lomustine.4,26

Tyrosine kinase inhibitors

Oral small molecule tyrosine kinase inhibitors toceranib phosphate and masitinib mesylate are two novel FDA-approved drugs for treating canine mast cell tumors. They competitively inhibit the ATP-binding site of the various members of the split-kinase receptor family, preventing receptor phosphorylation and downstream cell signaling.27 Toceranib targets primarily Kit, VEGF, and PDGFR.5,27 Masitinib's targets include Kit, PDGFR, and EGFR.3

In a study of 145 dogs with recurrent and nonresectable cutaneous mast cell tumors, the overall response rate to toceranib was 43% (21 dogs had a complete response, 41 had a partial response).5 In a double-blind, randomized, placebo-controlled phase III clinical trial of dogs with gross mast cell tumor disease, masitinib significantly increased time to tumor progression compared with placebo, especially when masitinib was used as the initial therapy.3

Prognostic factors

Prognostic indicators for mast cell tumors include histologic grade, mitotic index, tumor characteristics such as growth rate and ulceration, the tumor's location, the patient's breed, the clinical stage of disease, tumor-related clinical signs, and tumor recurrence after surgical excision.1,28 The presence of c-kit gene mutation, Kit protein localization status, and cellular proliferation indices (Ki67, AgNOR, PCNA) also carry prognostic significance.23,29

The Kit receptor tyrosine kinase plays an important role in mast cell tumor pathogenesis. Several studies have shown that 20% to 30% of canine mast cell tumors carry a Kit mutation, which results in constitutive activation of this receptor.30,31 Kit mutations were found more frequently in higher Patnaik grade mast cell tumors and were associated with increased risk of local tumor recurrence and metastasis.29,32

This case

The status of Kit mutation was unknown in the dog in this case. The fact that the disease originally progressed in face of masitinib followed by complete response to the drug is difficult to explain and would be interesting to investigate. A recent report demonstrated that combinations of two tyrosine kinase inhibitors can produce synergistic inhibition of growth and proliferation of canine C2 mastocytoma cell line in vitro.33 Tyrosine kinases inhibitors have also been reported to produce synergism in people with myeloid malignancies.33 It is unknown what effect the exposure to toceranib before reinstitution of masitinib therapy had on this dog's mast cell tumors.


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Source: VETERINARY MEDICINE,
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