Page 415 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 21 Mast Cell Tumors 393

reported after initiation of TOC therapy in dogs and blood pres- cimetidine (4–5.5 mg/kg PO q8hrs), famotidine (0.5–1 mg/kg
sure monitoring and intervention is advised. 208 Other adverse q12hrs), or ranitidine (2 mg/kg q12hrs). Omeprazole (0.5–1 mg/
kg q12–24hrs), a proton pump inhibitor, may be more effective,
effects reported include mild to moderate leukopenia, proteinuria
VetBooks.ir (with or without hypertension), and muscle pain. 206,208 Recent particularly in the setting of bulky MC disease. These agents are
generally used in the setting of gross disease, particularly those
clinical experience with TOC suggests that equivalent antitumor
activity and reduced adverse effects may be observed if dosages cases in which (1) systemic signs are present; (2) the tumor is
lower than the label dosage are employed. A dosage of 2.5 to 2.75 likely to be entered or manipulated at surgery (i.e., cytoreductive
mg/kg every other day or 3 days per week (Monday, Wednesday, surgery); or (3) treatment is undertaken where gross disease will
Friday) is currently used by many oncologists. 209 remain and degranulation is likely to occur in situ (e.g., RT or
A clinical trial of similar design was completed with MAS in medical therapy for tumors that are not surgically cytoreduced).
dogs with recurrent or unresectable MCT. 210 This study dem- For cases with active evidence of GI ulceration, the addition of
onstrated significantly improved time to progression in MAS- sucralfate (0.5–1.0 g PO q8hrs) and occasionally misoprostol
treated dogs versus placebo-treated dogs, and, again, outcome was (2–4 μg/kg PO q8hrs) to histamine blockers is prudent. Some
improved in dogs with MCT harboring activating c-kit muta- experimental data suggest that the use of H and H blockers
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tions. Subsequent follow-up of patients treated with long-term could also be beneficial for the prevention or resolution of hista-
MAS identified an increased number of patients with long-term mine-mediated wound breakdown, 232–234 but this has not been
disease control compared with those treated with placebo (40% systematically evaluated. The use of protamine sulfate, a heparin
vs 15% alive at 2 years), 211 underscoring the potential for long- antagonist, has been mentioned by some for use in cases of severe
term disease stabilization with TKIs. GI adverse effects (vomiting hemorrhage. 128
or diarrhea) were most common but were mild and self-limiting
in the majority of cases. Myelosuppression was also observed and Feline Mast Cell Tumors
was mild in most cases. A small percentage of dogs developed a
protein-losing nephropathy leading to edema. Increases in urea Unlike MCTs in the dog, which are primarily cutaneous/subcuta-
and creatinine were observed in some dogs, and hemolytic anemia neous in nature, MCTs in the cat typically occur in three distinct
was also observed rarely. 210 syndromes, although there is some overlap among them. These
Lastly, small studies have evaluated the efficacy of imatinib for are cutaneous MCT, splenic/visceral MC disease, and intestinal
the treatment of measurable canine MCT. 212–214 Imatinib was well MCT. The etiology of feline MCT is currently unknown and
tolerated and objective antitumor responses were observed in dogs appears unrelated to viral infection 235 ; however, it is now evident
with both c-kit mutant and wild-type MCTs. It is important to that feline MCTs also possess somatic activating mutations in
note that no studies have yet been performed in dogs with MCTs c-kit. 175,236–238 In one study, 42 of 62 (67%) of cutaneous and
to assess the pharmacokinetics of imatinib, and thus current dos- splenic/visceral MCT had c-kit mutations that were primarily
ing recommendations are based on observed clinical activity, not present in exons 8 (28/62) and 9 (15/62), both of which encode
pharmacokinetic and pharmacodynamic relationships. the fifth immunoglobulin domain of KIT. 239 Similar to the canine
There are now several published studies regarding the safety juxtamembrane domain mutations, these feline c-kit mutations
and efficacy of combination therapy with KIT inhibitors and induce ligand independent activation of KIT, which can be inhib-
standard forms of therapy, such as RT or cytotoxic chemotherapy; ited by imatinib in vitro. 238
however, evidence of benefit when used in the postoperative set- The granules present in feline MCTs stain blue with Giemsa
ting has yet to be demonstrated. Combinations of continuously or and purple with toluidine blue. 1,2,4 As in the dog, granules pres-
intermittently administered TOC with lomustine and VBL have ent in feline MCs contain vasoactive substances such as heparin
been evaluated. 215–218 In all of these studies, significant reductions and histamine. 2,240 In culture, feline MCs express surface-bound
in chemotherapy drug dosage and/or frequency were required immunoglobulins and are capable of secreting histamine, heparin,
to avoid additive myelosuppression. Another study investigated and probably other vasoactive compounds when appropriately
the combination of TOC, prednisone, and hypofractionated RT stimulated. 240 Feline MCs also have phagocytic capability and can
in dogs with unresectable and/or metastatic MCTs. The overall endocytose erythrocytes in both experimental models and in clini-
response rate was 76.4%, with 58.8% of dogs achieving CRs and cal samples. 241 Complications associated with degranulation of
17.6% PRs. The overall MST was not reached with a median MCTs can also occur in the cat, including coagulation disorders,
follow-up of 374 days. The combination of hypofractionated RT GI ulceration, and anaphylactoid reactions. 2,242,243 Given that the
and TOC was well tolerated and demonstrated efficacy in the biologic behaviors of the three feline MCT syndromes are differ-
majority of dogs, indicating that this may be a viable treatment ent, they will be described individually.
option for dogs with unresectable MCTs. 219
Novel medical approaches that may hold promise for the Cutaneous Feline Mast Cell Tumors
future treatment of MCT include JAK2/STAT5 inhibitors, 220
histone deacetylase inhibitors, 221–223 HSP90 inhibitors, 224,225 MCTs represent the second most common cutaneous tumors in
retinoids, 226–228 TRAIL, 229 and polo-like kinase-1 inhibitors. 230 A the cat, accounting for approximately 20% of cutaneous tumors
recent study evaluated a KIT-targeting monoclonal antibody for in cats in the United States. 2,4,12 The incidence of MCTs in cats
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the treatment of canine MCT; KIT protein activation was blocked appears to have increased dramatically since 1950. Interestingly,
in vivo and multiple objective responses were observed. 231 MCTs appear to occur much less frequently in the United King-
Ancillary therapy to address the systemic effects of MC media- dom than in the United States, accounting for only 8% of all cuta-
tors is sometimes warranted in dogs with MCT. Minimizing the neous tumors. The typical feline cutaneous MCT is a solitary,
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effects of histamine release can be accomplished by administer- raised, firm, well-circumscribed, hairless, dermal nodule between
ing the H blockers diphenhydramine (2–4 mg/kg PO q12hrs) or 0.5 and 3.0 cm in diameter. 2,4,244,245 They are often white in
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chlorpheniramine (0.22–0.5 mg/kg q8hrs) and the H blockers appearance, although a pink erythematous form is occasionally
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