Management of Unresectable Mast Cell Tumors in Dogs
Sharon Shor, DVM, MS, DACVIM-Oncology
Mast cell tumors are the most common skin tumors in dogs. Their biological behavior is variable; most of the tumors are easily treated with wide-margin surgical removal, but some are more aggressive and carry higher potential for local recurrence and distant spread to the lymphatic system and visceral organs (such as liver and spleen). Local treatment can sometimes be very challenging, especially in situations where the masses are large and locally infiltrative, located at extremities of the body or when there is evidence of tumor spread to local lymph nodes or distant locations. Various forms of treatment have been evaluated for unresectable MCT in dogs including oral prednisone, lomustine (CCNU), Leukeran®, hydroxyurea and intravenous vinblastine (VBL); however, response rates are relatively low (~50% and less), and responses are typically short-lived. The tyrosine kinase inhibitor (TKI), toceranib phosphate (Palladia™), has proven, single-agent activity against canine MCT, but tumor size reduction was found in less than half of the patients treated.
A recent article, “Pulse-Administered Toceranib Phosphate and Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs” (Burton J.H. et al., JVIM 2015; 29:1098-1104) evaluated a new approach for treatment of large mast cell tumors, where surgery was difficult to justify. The theory behind this study came from data supporting a synergistic effect for use of tyrosine kinase inhibitors (such as Palladia and sunitinib) in combination with chemotherapy and/or radiation therapy in different types of human and canine tumors. The combination of VBL and Palladia was already evaluated for dogs with MCT but significant dose reductions were needed in VBL dose due to severe bone marrow suppression. Chronic use of Palladia can also be problematic due to a wide range of complications (diarrhea, vomiting, lethargy, neutropenia, proteinuria and others).
The authors suggested that Palladia will sensitize tumor cells to chemotherapy and that low-frequency use will reduce its costs and side effects. This was a phase I/II, multicenter, prospective clinical trial that evaluated 41 dogs with measurable (>1cm) MCT confirmed by cytology or histology. The phase I CCNU dose-escalation portion of the study determined the maximum tolerated dose of Palladia. In phase II, Palladia was given only on days 1, 3 and 5 of a 21-day cycle, and CCNU was given on day 3 of each cycle. Most dogs treated were of middle to older age (median 8.2y), with a median weight of 28.2kg. Mixed breed and boxers were the most common breeds. The median tumor size was 6.7cm (range 0.84-21.8cm). Local lymph node and distant metastasis were found in 26 and 5 dogs, respectively. Side effects were mostly mild to moderate and included neutropenia (34 dogs), hepatotoxicity (24 dogs) and GI toxicity (vomiting, 15 dogs; diarrhea, 11 dogs). Overall, 16 dogs had CCNU dose reductions and/or treatment delays. The overall response rate was 46% (15 had partial remission, and 4 had complete remission). The median time to maximum response was 21 days, and median overall survival was 131 days. Dogs with tumors <6.7cm had the most benefit with a median survival time (MST) of 264 days. (MST was 89 days for tumors >6.7cm). Patients with no previous chemotherapy also had better MST at 146 days (vs. 50 days with previous treatment).
To summarize, pulse-dosed Palladia in combination with CCNU was well tolerated and caused less GI side effects than with standard frequency use of Palladia. The response rate here (46%) was comparable to other single-agent protocols but superior than reported in a recent multicenter study for use of CCNU as a single agent (23%). This protocol provides a good alternative for treatment of large mast cell tumors, and it may be more appealing to owners who decline parenteral chemotherapy treatment but cannot afford monotherapy with Palladia.