to approximately 90% with surgery alone (Seguin et al. 2001; Weisse et al. 2002b). If margins are found to be incomplete or close, additional local therapy with primary re‐excision or radiation therapy improves survival and local control (Kry and Boston 2014). However, another study found the outcome of dogs with incompletely excised grade II MCTs was not affected by adjuvant treatments (surgery, radiation therapy, chemotherapy, or combination), suggesting attentive monitoring and action upon uncommon recurrence (Vincenti and Findji 2017). Assessing the proliferation activity of incompletely excised grade II MCTs may assist in determining the need for ancillary therapy, however, even those with low proliferation activity can recur (Smith et al. 2017). Using the Patnaik system, 93% with Grade I MCT, 44% with Grade II and 6% with Grade III tumors survived 4 years after surgery (Patnaik et al. 1984). Similarly, 100% of dogs with grade I, 44% with grade II, and 7% with grade III MCT were alive at 24 months after surgery (Abadie et al. 1999). However, in other studies, 5–22% of grade II MCTs metastasized (Seguin et al. 2001; Michels et al. 2002; Weisse et al. 2002b; Cahalane et al. 2004; Murphy et al. 2004). The need for adjuvant chemotherapy for completely excised grade II tumors (when not in a poor prognostic location) is unpredictable; close monitoring is advisable (Seguin et al. 2001); and determining mitotic and Ki67 indices may help identify which subset of grade II MCTs may benefit from chemotherapy (Abadie et al. 1999; Scase et al. 2006; Romansik et al. 2007; Webster et al. 2007; Maglennon et al. 2008; Elston et al. 2009; Kiupel et al. 2011; Thompson et al. 2011a, 2011b; O'Connell and Thomson 2013; van Lelyveld et al. 2015), with clinical staging being important regardless of histologic grade (Stefanello et al. 2015). Dogs with stage 2 (loco‐regional lymph node metastasis) grade II MCT, the use of prednisone, vinblastine, and lomustine after adequate local‐regional therapy can provide a median survival in excess of 40 months (Lejeune et al. 2015). In another paper, for dogs with grade 2, stage II MCTs, there was no significant difference in survival times between dogs with and without LN metastasis; however, removal of the metastatic LN may prolong survival (Baginski et al. 2014). Vinblastine‐prednisolone chemotherapy is given as adjuvant to surgery for high‐risk MCT (mucous membrane origin, node‐positive, high‐grade) (Thamm et al. 2006). Vinblastine‐prednisolone chemotherapy increased survival significantly compared to the tyrosine kinase inhibitor masitinib as adjuvant to high‐risk MCTs in another study (Miller et al. 2014). Another approach is marginal surgery with adjuvant chemotherapy (vinblastine and prednisolone) (Davies et al. 2004). In a study of dogs with a median number of 4 MCTs at presentation, 90% of dogs were treated with surgery, and 40% of dogs were treated with only surgery as the sole form of treatment, and 60% of dogs received chemotherapy. There was no significant difference in progression‐free survival or MST in those dogs that received chemotherapy compared to those dogs that did not. Incomplete surgical margins were not associated with decreased survival times (O'Connell and Thomson 2013). Chemotherapy may also be used for dogs with multiple cutaneous mast cell tumors or unresectable/metastatic disease. Multiple cutaneous MCTs may represent multiple de novo events rather than metastatic disease, with a disease‐free survival time of >5 years in 54 dogs reported (Mullins et al. 2006), and no difference in outcome compared to stage 1 dogs in another study (Murphy et al. 2006). However in another study, if any one of multiple cutaneous MCTs was identified as high grade, then there was a worse prognosis (O'Connell and Thomson 2013), and Kiupel et al.(2005) found that dogs presenting with multiple synchronous MCTs had a significant decrease in survival time (Kiupel et al. 2005). In another paper, 23 dogs with MCTs treated with incomplete resection and adjuvant prednisolone and vinblastine chemotherapy, there was a 57% 1‐ and 2‐year disease‐free rate, and some of these dogs had multiple MCTs (Thamm et al. 1999). Other chemotherapy agents include lomustine, vincristine, prednisolone/cyclophosphamide/vinblastine, cyclophosphamide/vincristine/prednisolone/hydroxyurea, lomustine/vinblastine, chlorambucil/prednisolone (McCaw et al. 1997; Elmslie 1997; Gerritsen et al. 1998; Rassnick et al. 1999; Thamm et al. 1999; Davies et al. 2004; Taylor et al. 2009; Cooper et al. 2009), vinorelbine (Grant et al. 2008; Wouda et al. 2015), and inhibitors of tyrosine kinase toceranib phosphate which possess both direct anti‐tumor and anti‐angiogenic activity (Liao et al. 2002; London et al. 2003). Dogs with grade II or III MCTs treated with the tyrosine kinase inhibitor masitinib had a longer time to disease progression (178 days) vs dogs receiving placebo (75 days), although MST was only improved in dogs with KIT mutations (417 days vs 182 days with placebo) (Hahn et al. 2008). In a subsequent study, the MSTs of dogs treated with masitinib or placebo were not significantly different (Hahn et al. 2010). The tyrosine kinase inhibitor Toceranib phosphate (Palladia®) was used to treat bulky (non‐resectable) grade II or III MCTs with an overall 43% partial or complete response rate, and 12% stable disease, with 82% of dogs with KIT mutations responding compared to 54% for those without (London et al. 2009). Vinblastine – toceranib phosphate combination showed a 71% objective response rate in one study (Robat et al. 2012). Water‐soluble micellar paclitaxel was safer with 30% biologic response rate compared to lomustine (11% biologic response rate) in the treatment of non‐resectable grade II or III MCTs (Vail et al. 2012). In another study of non‐resectable MCT, treated with toceranib phosphate‐lomustine‐prednisone resulted in a response rate of 46% and a median progression‐free survival of 53 days (Burton et al. 2015). Non‐resectable MCT can also be treated with radiation therapy combined with chemotherapy (toceranib‐prednisolone), MST was not reached at a median follow‐up of 374 days (Carlsten et al. 2012). Other adjunctive medical therapies include H1 blocker, H2 blocker, omeprazole, sucralfate, and misoprostol. Pretreatment with prednisone prior to surgery (neoadjuvant) can reduce the size of mast cell tumors, facilitating resection with adequate margins in situations where margins cannot be confidently attained because of mass location or size or both (Stanclift and Gilson 2008). ECT with cisplatin administered intratumorally was used to treat 12 cutaneous MCT nodules in dogs. Electrical pulses were delivered to the tumor and surrounding margin. If the tumor did not respond completely to the first session, additional sessions were performed at 2‐ to 4‐week intervals. The median tumor size was 2.9 cm3, there was a 62.5% complete response with a median follow‐up time of 26 months. Tumors >8 cm3 did not respond. Tumor grade prior to treatment was unknown (Kodre et al. 2009). ECT with bleomycin injected into peritumoral tissue has also been reported as adjuvant treatment for incompletely resected MCT in dogs. The overall response rate was 85% with a mean time to recurrence of 53 ± 6.5 months (Spugnini et al. 2006b) Electrogene therapy with IL‐12 was used in 11 canine cutaneous MCTs, resulting in a 13–83% reduction (median 50%) of the original tumor volume (Pavlin et al. 2011). ECT with cisplatin and peritumoral IL‐12 gene electrotransfer was used to treat 18 dogs with canine MCT. Eleven of 18 dogs had pre‐treatment punch biopsies, and all were grade I or II and the median volume of treated tumors was 2.1 cm3. At a median of 40 months, a complete response was achieved in 72% (Cemezar et al. 2017).
