Douglas H. Thamm, VMD, DACVIM (Oncology)
Animal Emergency Center
There are some canine MCT where appropriately aggressive surgery is either not
possible or necessitates a disfiguring procedure that may be declined by the owner.
Additionally, 20 to 40% of canine MCT may also have a high potential for eventual metastasis.
Radiotherapy and chemotherapy are the treatment options designed to best address the
potential for recurrence and metastasis, respectively.
Incompletely excised MCT of any grade have a high likelihood for local recurrence. As
was discussed in the second part of this series, recurrent MCT have a much worse prognosis,
even with aggressive therapy. For those tumors where appropriate aggressive surgery is not
possible, several other local therapeutic modalities have been investigated for the adjuvant
treatment of canine MCT. Radiotherapy (RT) has proven to be a very effective local treatment
modality when utilized after incomplete surgical excision. Two-year control rates of 85 to 90%
can be expected when incompletely excised low- or intermediate-grade MCT are treated with
RT. Radiotherapy to bulky tumors is consistently less effective than RT to microscopic disease,
with a one-year control rate of approximately 50%. Alternative local therapies that have been
reported include hyperthermia, interstitial RT, photodynamic therapy, intralesional
corticosteroids, cryotherapy, and intralesional deionized water injection. None are as thoroughly
investigated, clinically effective, or practical for achieving long-term local control as are
appropriately aggressive surgery or cytoreduction and RT.
The RT protocol currently in use at UW-Madison for incompletely resected, low-or
intermediate-grade MCT consists of a total of 15 treatments, given Monday through Friday for 3
weeks. Each treatment requires a very brief general anesthesia, which is typically very well
tolerated. As a local form of therapy, there are no systemic side effects from RT. However,
pets can develop varying degrees of acute hyperemia, pruritus and moist dermatitis at the RT
site. This typically starts the third week of treatment, and resolves within 2-4 weeks. The RT
site may be permanently alopecic, or may have hair of a different color. Overall, RT is
exceptionally well tolerated by most animals.
MCT of low or intermediate histologic grade (Histologic Grade I or II) comprise 60 to
80% of all cutaneous MCT in the dog. These tumors exhibit quite aggressive local tissue
invasion, necessitating aggressive local therapy to prevent recurrence. However, their
metastatic rate is relatively low. High-grade or undifferentiated MCT (Grade III), in addition to
being very locally infiltrative, have a considerably higher metastatic rate. Thus, aggressive
surgery or other local therapies, while still necessary, are considered insufficient for optimum
control. The presence of these highly metastatic undifferentiated tumors, and their high
potential for metastasis, have prompted the search for other effective treatment modalities.
Animals with undifferentiated MCT, MCT that have metastasized, or tumors in a
historically unfavorable location may benefit from the addition of some form of systemic therapy
to appropriate local therapy. In addition, aggressive surgery or RT may be cosmetically
unappealing or financially impossible for some owners. Recently, several studies have been
published investigating various systemic therapies for measurable canine MCT, the results of
which are summarized in Table 1.
|Response to Chemotherapy in Dogs with Mast Cell Tumors.|
|Drug(s)||%CR||%PR||ORR||Median Resp. Dur.||Comments|
|Vincristine||0%||7%||7%||NR||32% severe toxicity (?)|
|CCNU (Lomustine)||6%||38%||44%||79 days*||Cum. Thrombocytopenia|
CR: Complete Response. PR: Partial (>50%) Response. ORR: Overall Response Rate. P/C/V: Prednisone/Cyclophosphamide/Vinblastine.
COP-HU: Cyclophosphamide/Vincristine/Prednisone/Hydroxyurea. NR: Not Reported.
*Excludes patient that experienced CR – Euth. without evidence of disease after 440 days.
Only one study has been published evaluating the efficacy of chemotherapy in the prevention of
recurrence or metastasis in the post-surgical setting. This utilized oral prednisone and
Prednisone and vinblastine administration – Prednisone is administered orally at an initial dose
of 2 mg/kg SID, and this dose is tapered and discontinued over approximately 3 months. VBL is
given as a rapid intravenous bolus at 2 mg/m2 every 1-2 weeks. The standard protocol consists
of weekly injections for 4 weeks, followed by 4 biweekly injections.
Side Effects – Adverse effects are noted in approximately 20% of patients, usually after the first
dose of VBL. These are mild in most. Mild side effects include self-limiting vomiting,
neutropenia without evidence of sepsis (7-day neutrophil count less than 1,000/μL), or
lethargy/soft stool. Severe side effects occur in only approximately 5% of patients.
Efficacy – As an adjuvant therapy to incomplete surgical resection (“microscopic disease”), VBL
and prednisone treatment conferred a 57% one and two-year disease free rate. Although this is
less than the 85 to 90% two-year disease free rate conferred by surgery plus RT, it is our feeling
that this number represents a significant improvement over incomplete resection alone. It
should be pointed out that this represents a small case number, and results may vary with a
larger sampling of “microscopic disease” patients.
As adjuvant therapy to prevent metastasis in patients with “high-risk” disease (i.e. high
grade tumor, lymph node metastasis, historically unfavorable location), prednisone and
vinblastine results in 2-year disease-free survivals of 60%. Interestingly, there seems to be a
profound difference between the outcome of a high-grade tumor and an intermediate-grade
tumor with lymph node metastasis. Despite the presence of lymph node metastasis, 90% of
patients with grade II tumors with positive lymph nodes are disease-free at two years. Patients
with grade III tumors treated in the adjuvant setting have 2-year survival rates of 60%. This
appears to be a significant improvement over historical data employing surgery alone, which
report 2-year survivals of less than 15%.
Perhaps the most important recent finding with potential to translate into new and exciting forms
of therapy is the discovery that the majority of canine (and human) mast cell neoplasms express
alterations in the expression of, or genetic mutations within, the gene that encodes the tyrosine
kinase growth factor receptor c-kit. This gene codes for a transmembrane protein that serves
as the receptor for the hormone stem cell factor, important in the maturation of normal mast
cells and other hematopoietic cells. It has been shown that the majority of canine MCT either
aberrantly express c-kit or contain mutations that render c-kit constitutively active in the absence
of bound stem cell factor. In other words, these mutations mean that the cells are receiving
signals to proliferate and survive when they normally would not, leading to unchecked growth.
New molecules have been developed that inhibit signaling through the c-kit tyrosine kinase, and
there is now information that some of these compounds are able to interfere with the
proliferation of canine MCT in vitro, and have shown great promise in preliminary evaluation in
canine patients with MCT.
Combination chemotherapy with prednisone and vinblastine appears to be an effective therapy
for canine MCT. In addition to apparently increasing the survival time of high-risk (grade III)
patients after surgery, it may also be beneficial for animals with incompletely resected
intermediate grade tumors where aggressive local therapy (surgery, RT) is not possible or has
been declined. The cost of these drugs is relatively low, particularly in comparison to RT, and
they appear to be well tolerated by the majority of canine patients.
It is important to remember that, while radiotherapy and chemotherapy are potentially
very useful adjuvant forms of therapy, aggressive surgery remains the mainstay of treatment for
canine MCT, and is sufficient to successfully treat the majority of MCT encountered in practice.