Dr Sue Cancer Vet PLLC, Oncology, Tarrytown, NY, USA; Animal Specialty & Emergency Center, Wappinger Falls, NY, USA
Mast cell tumors (MCT) are the most common cutaneous tumor in dogs, accounting for 16 to 21% of skin tumors. While many MCT are often treatable with surgery alone, in some cases surgery may be declined, not an option based on size, or there is advanced (metastatic) disease. Palliative and supportive care is important in these cases.
Dogs with low grade/grade 1 or grade 2 that have low proliferation scores and are c-kit negative can typically be managed with local therapy (surgery +/- radiation). Chemotherapy should be considered for: high grade/grade 3, dogs with distant metastasis, lymph node metastasis, C-kit mutation positive dogs, dogs with high MCT proliferation scores, and for non-resectable MCT in the neo-adjuvant setting. Dogs with multiple MCT in a short time period may also be considered for chemotherapy.
Disease symptoms can be complicated by signs attributable to release of histamine, heparin and other vasoactive amines from the MCT. Darier’s sign refers to the wheal & flare in surrounding tissues following manipulation of the MCT and is caused by mast cell degranulation. GI ulceration is due to histamine stimulation of H receptors on parietal cells that increased HCI. GI ulceration causes vomiting possibly with blood, melena, anorexia, and abdominal pain. GI ulceration is noted in 35–83% necropsy specimens.
Surgery is the ideal treatment in areas amenable to wide resection. The recommendations for margins have historically 3 cm, but 2 cm lateral margins may be adequate for most (Simpson 2004). For small and lower grade, extensive deep margins are just as crucial: 1 fascial plane deep, 4 mm deep margins. The majority of naive dermal MCT are intermediate or low grade will be cured with surgery alone, provided site is amenable.
In some locations, wide margins are often not possible, such as the distal limb. In my opinion, amputation is probably too aggressive. But further therapy will likely be needed after surgery. Post-operative options include external beam RT, scar revision, and chemotherapy. Some tumors are also too large to remove
Radiation therapy (RT) is recommended when wide surgical excision not feasible. Monotherapy has varying control rates with 1 year control rates of 50%. This is in contrast to surgery to achieve clinical stage 0 (microscopic disease) followed by full course RT, (typically 15 treatments over 3 weeks) which has high control rates of 85–95%, 2-year control rates for grade 1 and 2.
For macroscopic MCT, the combo of steroids with palliative radiation have been reported to have an improved overall response rate (ORR) of 75%. Palliative radiation is typically weekly radiation for 4 weeks.
As a single agent in grade 2–3 MCT, overall response rate (ORR) was 20% (5 of 25) (McCaw 1994). But prior to RT for non-resectable grade 1–3, RR was higher at 75% (18/24) (Dobson 2004). When given prior to surgery (neoadjuvant) for grade 1–3 pre-op ORR was 70% (Stanclift 2008).
Chemotherapy can be considered palliative for non-resectable MCT. Single agent chemotherapy has variable response rates, but studies have shown that combination therapies offer improved efficacy. I prefer the combo of vinblastine and prednisone, which has reported efficacy for gross disease of 47%.
Palladia (toceranib phosphate) is an oral tyrosine kinase inhibitors (TKI) that blocks activity of multiple receptors and selectively targets split kinase family of RTKs. It exerts antiangiogenic and antiproliferative effects. The oral bioavailability is 77%. Palladia is labeled for dogs with grade 2 or 3, recurrent cutaneous MCT, + regional LN involvement, and was FDA approved in June 2009. Palladia is the first anti-cancer drug FDA approved for dogs.
In the clinical field study of single agent Palladia (London 2009), this was a multi-center placebo-controlled, double-blinded study looking at the objective response (PR or CR) to single-agent Palladia at 3.25 mg/kg EOD. The biologic response rate was 59.5% for all dogs (blinded + open): CR 16%, PR 31.3%, and SD 12.2%. The odds ratio of OR was 6.5x higher in Palladia-treated patients vs. placebo. Grade 2 MCT had better outcomes than grade 3, and had a significantly longer time to progression (TTP) and significantly longer response duration. Palladia was effective with or without c-Kit mutation (positive: 69% response; negative: 37% response).
Adverse events (AE): GI side effects were most common AES, >10% Palladia dogs (during blinded phase). Neutropenia was the most common lab abnormality.
From the study the recommended dose for MCT is 3.25 mg/kg EOD. It is recommend to give with or without food (I recommend with food), give in evening, and adjust dose based on biweekly assessments for 1st 6 weeks, then every 4 to 6 weeks. Dose reductions of 0.5 mg/kg are recommended with a minimum dose of 2.2 mg/kg EOD. If AE occur, drug holidays for up to 2 weeks. It is important to not be complacent in monitoring. Clients must be educated if any side effects are noted, stop medication, start just-in-case medications, and contact a veterinarian. Early recognition if side effects are critical when using Palladia!
TKI combination protocols are starting to be evaluated. Palladia given with vinblastine caused myelosuppression, and the dose of vinblastine was reduced significantly. The ORR of 71% is encouraging.
Intralesional therapies such as deionized water or corticosteroids may provide temporary shrinkage but unfortunately are rarely effective for long term tumor control.
Any dog that has grossly detectable tumor should have supportive medications, including H1 blocker (diphenhydramine) and a proton pump blocker (omeprazole) or H2 blocker (famotidine).
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2. Geiger T. Mast cell tumors, dog. In: Clinical Veterinary Advisor Dogs and Cats. 3rd ed. St. Louis MO: Elsevier Mosby; 2015:646–648.
3. McCaw DL. Mast cell tumors. In: Cancer Management in Small Animal Practice. Saunders 2010:317–321.