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Review Article
Review of the Treatment of Canine Cutaneous Mast Cell Tumors
Dank, G.
Koret School of Veterinary Medicine, Hebrew University.
Corresponding author: Dr. Gillian Dank, DVM, D-ACVIM (Oncology), D-ECVIM-Ca (Oncology), Koret School of Veterinary Medicine, Hebrew University.
AB S T RAC T
The most common skin tumor in dogs is the mast cell tumor, with an incidence of close to 20% in the canine
population. The behavior and progression of MCT are highly heterogeneous, and range from relatively benign
to extremely aggressive tumors. There are many treatment options for dogs with mast cell tumors, including
surgery, radiation therapy and chemotherapy. Although surgical excision with or without adjuvant radiation
may cure most patients with low grade mast cell tumors, there are additional options for dogs with aggressive
high grade tumors. The aim of this article is to review the current literature for treatment options for canine
cutaneous mast cell tumors.
REVIEW
Mast cell tumors (MCT) are the second most common malignant tumor in dogs, and the most common canine cutaneous tumor (1, 2). The behavior and progression of MCT are
highly heterogeneous. Some MCT are behaviorally benign,
develop slowly, and persist for years without increasing in
size. Whereas other exhibit aggressive growth and progress
rapidly to a fatal metastatic disease (2). Treatment options
include surgery, radiation therapy and chemotherapy, or a
combination of modalities. The treatment should be based on
the clinical features, clinical stage and grade (3). The aim of
this article is to review the current literature for the treatment
options of canine cutaneous mast cell tumors.
Surgery
Surgery is the treatment of choice in localized, non-metastatic canine MCT (3). If complete margins are achieved
with surgical excision and there is no evidence of metastasis,
surgery is considered curative and no further treatment is
required for all grade 1 tumors and most grade 2 tumors (4,
5). Historically, the recommended margins were 3 cm in all
directions, with at least one fascial plane on the deep margin.
More recent studies have shown that a lateral margin of 2
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cm and a deep margin of one fascial plane is sufficient for
most grade 1 and 2 MCTs (6). Murphy et al. reported 1 year
survival rates of 100%, 92% and 46% for grades 1, 2 and 3 respectively (6). Grade 3 tumors should be excised with lateral
margins of at least 3 centimeters, plus the deep fascial plane.
After resection of grade 2 MCTs, local regrowth rates vary
from 0%-27% have been reported for both completely and
incompletely excised tumors (5, 7-9). Weisse et al., reported
effective local control in 89% of cases in Grade 2 MCT, with
a median survival time of 791 days (4).
In cases when the first surgery has not achieved local
control, a second surgery with wider margins around the
original surgical scar is recommended if feasible. Kry et al.
compared survival times and local recurrence in dogs with
close or incomplete margins treated with primary re-excision
or radiation compared to no additional therapy (10). The
median survival times for the groups with either a second
surgery or radiation therapy were significantly longer that
those that received no additional treatment (2930 and 2194
vs. 710 days) (10). Local recurrence was reported in 13% of
the re-excision group, 8% of the radiation groups and 38% of
the control group. In addition, time to local recurrence was
significantly longer in the treatment groups (10).
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Based on these publications, the goal of successful treatment in dogs with grade 1 and most grade 2 mast cell tumors
should be adequate local control with surgery, which leads to a
median survival of over 2000 days, 1 year survival of 92-100%,
and very low chances of local recurrence (0-27%) (4, 6, 10).
Radiation
When MCT are incompletely excised, and a second surgery
if not feasible, radiation therapy is recommended in order to
provide adequate local control.
One of the earlier studies on radiation for incompletely
resected canine MCT was published in 1998 by LaDue et al.
This retrospective study evaluated 56 dogs with macroscopic
and microscopic disease. The median disease free interval
for dogs with macroscopic disease (21/56 dogs, 38%) was 12
months, compared to 54 months for dogs with microscopic
disease (35/56 dogs, 62%) (11). In addition, dogs with tumors
>10 cm3 had shorter disease free intervals than dogs with
tumors <9 cm3 (11). They concluded that radiation therapy
should be avoided as a sole therapy in cases of macroscopic
disease, due to the risk of radiation induced mast cell granulation, serious systemic effects, and that larger tumors are
more radioresistant, and that cytoreductive surgery should
be performed in dogs with measurable MCT (11). Radiation
therapy was an effective adjuvant therapy to achieve local
control of incompletely excised MCT (microscopic disease)
and to treat local or regional metastasis (11).
Many additional studies have examined the effectiveness of radiation therapy in dogs with MCT, in cases of
incompletely resected tumors, grades 1, 2 and 3 and lymph
node metastasis (10-13). There is a controversy regarding the
treatment of dogs with adjuvant radiation therapy, as some
believe that it is difficult to interpret the added effect, as the
recurrence rate is low with surgery alone, even in the case
of incomplete histological margins (3). On the other hand,
Kry et al. showed that there was a significant improvement
in survival, duration of local control and percent of local recurrence when radiation was performed after incomplete or
close resection compared to dogs that received no additional
treatment (10).
When evaluating adjuvant radiation in 45 dogs with
incompletely excised, stage 0, grade 2 MCTs, Poirier et al.
found that only 3 dogs had local recurrence, 2 developed
metastasis and 14 developed a second cutaneous tumor (12).
They concluded that the adjunctive radiation therapy protocol
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Dank, G.
JUNE 2016.indb 4
was well tolerated and efficacious (12). An additional study
evaluated the efficacy of radiation in 31 dogs with grade
3 MCTs that were incompletely resected, and found that
the median duration of remission was 27.7 months, and
the median survival was 28 months (13). They concluded
that without further treatment, these tumors had high local
regional recurrence rate, and that radiation may effectively be
used to manage them (13).
In conclusion, the need for radiation therapy in grade
1 and most grade 2 MCTs with incomplete margins it is
still controversial. However, one study compared dogs that
received adjunctive radiation to dogs without additional
treatment and found there was a significant improvement
in survival, duration of local control and reduced percent of
local recurrence (10). Additional, larger, prospective studies
are needed in order to reach a better understanding of the
benefit. Grade 3 tumors appear to benefit from the addition
of radiation therapy, as the chances of local recurrence with
incomplete margins are higher (13).
Chemotherapy
Chemotherapy can be used in dogs in three ways.
The first is in the neo-adjuvant setting, to reduce tumor
burden prior to surgery. This may improve the likelihood of
achieving a complete excision, or enable surgery that was not
possible prior to the reduction in the size of the tumor (3).
Neo-adjuvant prednisone has been evaluated (14). Stanclift et
al. treated 49 dogs at two doses, either 1 mg/kg prednisone q 24
hours and 2.2 mg/kg prednisone q 24 hours. In both treatment
groups there was a significant reduction in the tumor burden.
The overall response rate was 70%. There was no significant
difference between the two groups (14). There are no studies accurately evaluating the efficacy of neo-adjuvant chemotherapy.
The second in the adjuvant setting is when chemotherapy
is used to treat residual microscopic disease where further
surgery is not possible and radiation therapy is not available.
Two studies have been done regarding chemotherapy in the
adjuvant setting. Davies et al. looked at 20 dogs with residual
microscopic disease that were treated with vinblastine and
prednisolone. Eighteen dogs did not have local recurrence after 1 year (15). The second study by Hosoya et al. used CCNU
(Lomustine) (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea)
and prednisone in 12 dogs with grade 2 MCT. None of the
dogs developed local recurrence or regional/distant metastasis
(16). Both studies should be interpreted with care, as the
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recurrence rate in grade 1 and 2 tumors with incomplete
margins is low (3).
The third indication is in tumors with a high risk for
metastasis, either high grade tumors (or grade 3) and grade
2 tumors with risk factors associated with reduced survival.
The purpose of the treatment is either to delay or prevent metastasis or to delay progression of existing metastatic disease,
however efficacy studies are lacking (17-19). Many different
drugs, used as both single agents and combinations, have been
studied. The main drugs used include prednisone, vinblastine,
CCNU, and tyrosine kinase inhibitors. However, additional
protocols have been reported. Chlorambucil and prednisone
resulted in an overall response rate of 38% in 21 dogs, and a
median progressive free interval for the 8 responders of 533
days (20). Hydroxyurea was evaluated as a single agent in 46
dogs, with an overall response rate of 28%. Two dogs had a
complete remission (256 and 448 days) and 11 dogs had a
partial remission for a median duration of 46 days (21).
Paclitaxel is part of the taxane family of microtubule inhibitors, paclitaxel suppresses spindle microtubule dynamics.
This results in blockage of metaphase-anaphase transitions, and
ultimately inhibition of mitosis and induction of apoptosis (22,
23). Paccal vet (Oasmia Pharmaceuticals) is a a cremophor-free
formulation of paclitaxel that has been evaluated in two studies,
the first to determine the safety and efficacy and the second
to compare it to CCNU (22, 23). In the first study, Rivera et
al. reported a 59% response rate (either a complete or partial
response), with a time to progression of 247 days and concluded
that the drug appeared safe and effective (22).
The second study was a prospective multicenter randomized double-blind positive-controlled clinical trial in 252
dogs with nonresectable grade 2 or 3 MCTs. The purpose
of the study was to compare the response to paclitaxel and
lomustine. They concluded that paclitaxel’s activity and safety
profile were superior to CCNU (23).
The following is a summary of several studies performed,
evaluating vinblastine, CCNU, and tyrosine kinase inhibitors
(as single agents and combinations) and their effectiveness in
the treatment of canine MCTs.
Vinblastine
Thamm et al. evaluated oral prednisone and vinblastine in
41 dogs with MCTs (23 in the adjuvant setting and 18
with measurable disease) (24). Overall response rate in the
evaluable dogs with gross disease was 47%, consisting of 5
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complete responses and 2 partial responses. Median response
duration was 154 days. As adjuvant therapy to incomplete
surgical resection, prednisone and vinblastine conferred a
57% 1- and 2-year disease-free rate. The median survival time
for the entire patient population was not reached; however,
the mean survival time (MST) for dogs with grade III MCT
was 331 days, with 45% of dogs alive at 1 and 2 years (24).
Three additional studies examining the use of vinblastine
in canine MCTs included two dose escalation studies, an
efficacy study and a study evaluating vinblastine for adjuvant
therapy in high grade tumors (25-27). The dose escalation
studies both concluded that vinblastine may be safe to administer at higher than the traditional 2 mg/m2 dosage. In
addition, Bailey et al. concluded that the maximum tolerated
dose was 3.5 mg/m2 (26, 27). The efficacy trial administered
vinblastine (2 mg/m2 or 3.5 mg/m2) to fifty-one dogs with
non-resectable grade 2 or 3 cutaneous MCTs. The primary
outcome was to measure a reduction in the tumor size. In the
2 mg/m2 group, 3 (12%) had a partial response for a median
of 77 days. In the 3.5 mg/m2 group the overall response rate
was 27%, one dog (4%) had a complete remission and 6 dogs
(23%) had a partial remission for a median of 28 days. They
concluded that when used as a single-agent, vinblastine had
activity against MCTs in dogs (28). Thamm et al. looked at 61
dogs with either grade 3 MCT or grade 2 tumors considered
to be at a high risk for metastasis. They were treated with
vinblastine and prednisone following surgical excision, with
or without radiation therapy. The disease free interval was
1305 days, and the overall survival was not reached. 100% of
the high risk grade 2 dogs were alive at 3 years, the overall
survival for dogs with grade 3 MCT was 1374 days (25). This
study compared favorably with historical data on survival for
patients with grade 3 MCT with surgery alone, where 6-27%
of the patients were alive at 1 year (29, 30).
CCNU- Lomustine
(1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea)
Rassnick et al. evaluated the use of CCNU is the treatment of
canine MCTs in 19 dogs with measurable MCT (31). Dogs
were treated with CCNU at a dosage of 90 mg/m2 every 3
weeks. One dog had a durable complete response for 440
days. Seven dogs had a partial response for a median duration
of 77 days, 6 had stable disease for a median duration of 78
days. The conclusion was that CCNU should be considered
an active agent in the treatment of MCT in dogs (31).
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Combinations of Vinblastine and CCNU
Three articles have evaluated the efficacy of the combination
of vinblastine and CCNU (17, 18, 32). The first was published
in 2009 by Cooper et al. to evaluate the efficacy and toxicity
of CCNU (mean dose of 59 mg/m2) and vinblastine (2 mg/
m2) in 56 dogs (32). Treatment was administered every 2
weeks. Thirty seven dogs had macroscopic disease (12 (32%)
had grade 2 tumors and 17 (46%) had grade 3 tumors) and
20 had microscopic disease. Eight (40%) had grade 2 tumors
and 11 (55%) had grade 3 tumors. A 57% response rate was
seen in dogs with macroscopic disease for a median duration
of 52 weeks. Dogs with macroscopic disease had a median
progression free interval of 30 weeks and a median overall
survival time of 35 weeks. Dogs with microscopic disease
had a median progression interval of 35 weeks and a median
overall survival time of 48 weeks (32). The second was published in 2010 by Rassnick et al. (18). The study examined
the safety and efficacy of a protocol of alternating CCNU
(70 mg/m2) and vinblastine (3.5 mg/m2), and prednisone
(1-2 mg/ kg). Seventeen dogs had macroscopic disease and
35 microscopic disease (either metastatic or grade 3). The
response rate in dogs with non-resectable MCTs was 65%;
five achieved a complete response (median, 141 days) and six
achieved a partial response (median, 66 days). Overall median
progression-free interval in dogs treated in the adjuvant setting was 489 days (18). The third study evaluating the combination of CCNU and vinblastine was performed in dogs with
grade 2, stage 2 MCTs treated with adequate local therapy
and adjuvant systemic therapy (prednisone, vinblastine (2
mg/m2 ) and CCNU (60-80 mg/m2). The results of this study
suggested that, in the presence of loco-regional lymph node
metastasis in grade 2 MCT, the use of prednisone, vinblastine
and CCNU after adequate local-regional therapy can provide
a median survival in excess of 40 months (17).
Tyrosine kinase inhibitors (TKIs)
Receptor tyrosine kinases (RTKs) are an important group
of cell surface receptors that trigger cellular activation resulting in cellular proliferation, differentiation and survival
when stimulated by their ligands. Normal kinase function is
critical to cell growth and differentiation, and dysfunction of
several RTKs has been characterized in canine MCTs (33,
34). RTKs have also been implicated in angiogenesis and the
process of metastasis (3).
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JUNE 2016.indb 6
Specific small-molecule TKIs are able to block the activity of receptors by competitive inhibition of ATP binding.
Two TKIs are approved by the European Medicine Agency
for the use in MCT in dogs - Masitinib (Masivet®, Kinavet
®
AB Science USA, Short Hills, NJ, USA, AB Science
Headquarters, Paris, France) and Toceranib Phosphate
(Palladia® Manufactured by: Pfizer Inc, Ascoli, Italy).
Distributed by: Zoetis Inc., Kalamazoo, MI). Toceranib
Phosphate has been approved for use in the United States.
Masitinib
Three articles have been published to date on the use of
Masitinib in dogs with MCT. The first was a double-blind,
randomized, placebo controlled phase 3 clinical trial in 202
client owned dogs with recurrent or non-resectable grade 2
or 3 non-metastatic MCTs (2). This study found that the
Masitinib increased the overall time to progression from 75
days with the placebo to 118 days. The treatment was found
to be more effective when given as first line (increasing the
time to progression from 75 to 178 days) and was effective in cases with and without a c-kit mutation (2). In the
145 dogs that received the Masitinib, 42.8% experienced
an objective tumor response. The most commonly reported
adverse effects were vomiting, diarrhea and neutropenia, and
the most severe adverse effect reported was proteinuria. They
concluded that masitinib was both safe and effective at delaying tumor progression (2). The second study by Hahn et al.
evaluated the effectiveness of Masitinib for the treatment of
non-resectable MCTs in 132 dogs at 12 and 24 months after
onset of treatment (grade 2 or grade 3 MCTs) (35). The dogs
received either Masitinib (106 dogs) or a placebo (26 dogs).
Masitinib significantly improved the survival rate, compared
with the placebo, with 62.1% vs. 36.0% of the dogs alive at 12
months and 39.8% vs. 15.0% of the dogs alive at 24 months,
respectively. The median overall survival times were 617 and
322 days, respectively. Complete responses at 24 months
were observed in 6 of 67 (9.0%) dogs with non-resectable
MCTs treated with masitinib. They concluded that Masitinib
significantly increased survival rates at 12 and 24 months in
dogs with non-resectable MCTs (35).
The third study, by Smrkovski et al., evaluated the use of
Masitinib as a first-line therapy and rescue agent in 26 dogs
with metastatic and non-metastatic MCTs (36). The overall
response rate was 50% (57% for dogs that received the treatment as first-line therapy and 25% for those that received it
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as a rescue therapy), and the median survival time for dogs
that responded to treatment was 630 days vs. 137 days for
dogs that did not respond. Toxicity was reported in 61.5%
of the treated dogs. The majority of the adverse events were
mild and self limiting, and included liver toxicity, proteinuria, hematologic toxicity and gastrointestinal toxicity. They
concluded that the response to treatment was significantly
associated with increased median survival (36).
Toceranib Phosphate
In 2009 London et al. published the first trial with Toceranib
Phosphate (1). The trial was a multi-center, placebo-controlled, double-blind, randomized study in dogs with recurrent MCT. One hundred and forty nine dogs were included
in the trial; 86 were treated with Toceranib Phosphate and
63 with a placebo. The objective response rate in Toceranib
Phosphate treated dogs was 37.2% (7 complete responses, 25
partial responses) compared with 7.9% in the placebo group
(5 partial responses).
Significantly more placebo-treated dogs showed progressive disease during the 6-week trial compared to the dogs
treated with Toceranib Phosphate. The objective response rate
among Toceranib Phosphate-treated and placebo-escape dogs
was 42.8% (21 complete responses, 41 partial responses). The
observed biological response rate was 59.5% and included
16 dogs with stable disease. The presence of a c-kit mutation and the absence of regional lymph node metastasis were
significantly associated with objective responses (either a
complete or partial response) (1). Among dogs with an objective response (62 dogs) the median time to progression was
18.1 weeks. Dogs with grade 2 tumors had a longer time to
progression compared to those with grade 3 tumors. Adverse
events were generally manageable with dose modification and/
or supportive care. They concluded that Toceranib Phosphate
has biological activity against canine MCTs (1).
Toceranib Phosphate in combination protocols
Although many clinical trials evaluating the use of Toceranib
Phosphate with other chemotherapy agents in canine MCTs
are being performed at this time, only two studies have
been published to date. The first was a Phase 1 study dose
escalation study to evaluate the combination of Toceranib
Phosphate and vinblastine (37). The rational of the study
was that by combining drugs with known single-agent activity that lack overlapping dose-limiting toxicities and exert
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anti-tumor activity through different mechanisms they could
improve the clinical outcome. Fourteen dogs were enrolled
in the trial. The dose limiting toxicity reported in the study
was neutropenia resulting in the maximally tolerated dose
for vinblastine being low, so that the study did not support
this combination. However, evidence of significant activity
(71% objective response) and enhanced myelosuppression
suggested additive or synergistic activity (37).
The second study, published in 2015 by Burton et al.,
evaluated intermittent administration of Toceranib Phosphate
combined with cytotoxic chemotherapy (38). The purpose of
the study was to try to effectively chemosensitize canine MCT
while decreasing cost and adverse effects associated with either agent administered as a monotherapy. They administered
Toceranib Phosphate and Lomustine to 47 client owned dogs
with measurable MCT. The dose limiting toxicity was neutropenia. The overall response rate was 46% (4 complete responses,
15 partial responses) and the overall median progression-free
interval was 53 days with the median overall survival time was
131 days. The progression-free interval for dogs with complete
response was not reached, and for dogs with a partial response
was 131 days. The authors concluded that combined treatment
with pulse-administered Toceranib Phosphate and lomustine
was well tolerated and may be a reasonable treatment option
for dogs with unresectable or metastatic MCT (38).
An additional trial was performed with Toceranib
Phosphate, evaluating the combination with radiation therapy. It was a multicenter, prospective trial of hypofractionated
radiation therapy, Toceranib Phosphate and prednisone by
Carlsten et al. in 17 client owned dogs (39). All dogs received
prednisone, omeprazole, diphenhydramine, and Toceranib
Phosphate. Radiation therapy consisted of 24 Gy delivered
in 3 or 4 fractions. The overall response rate was 76.4%, with
58.8% of dogs achieving a complete response and 17.6% a
partial response. The median time to best response was 32
days, and the median progression-free interval was 316 days.
The overall median survival time was not reached with a
median follow-up of 374 days.
The most common toxicoses were gastrointestinal and
hepatic. The response rates and response durations reported
were higher than those reported for Toceranib Phosphate as
a single-agent treatment for MCT. They concluded that the
combination was a viable treatment option for unresectable
MCT (39).
In summary, the TKIs show a great deal of promise in
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the treatment of canine MCTs. However, severe side effects
have been reported, and hopefully the future trials with combination therapies will show fewer side effects with higher
remission rates and durations. The example by Burton et
al. is considered a step in the right direction, as Toceranib
Phosphate was given only 3 times in a 21 day cycle, instead of
three times a week, with Lomustine. The protocol resulted in
response rates and durations similar to the original Toceranib
Phosphate protocol.
Combination treatment with surgery, chemotherapy
and radiation
Although several studies mentioned above included dogs
with microscopic disease, one recent study evaluated adjuvant
chemotherapy following both surgery and radiation therapy
in dogs with stage 2 MCT (17). Stage 2 was defined as
one tumor confirmed to the dermis with regional lymph
node involvement. All dogs were treated with adequate local control, including surgery of the primary tumor (with
adequate margins) and lymph node excision or incomplete
excision of the primary tumor followed by radiation therapy
plus surgical excision of the lymph node and/or radiation
to the lymph node. All dogs received chemotherapy. Local
relapse occurred in 2/21 dogs in the area of the previous
surgical resection or radiation (17). Four dogs developed de
novo cutaneous MCTs. The overall median survival was 1359
days. The results of this study suggest that dogs with stage 2
MCTs can achieve long-term median survivals when treated
with adequate local control and systemic chemotherapy (17).
CONCLUSIONS
The aim of this article was to review the current literature
for treatment options for canine cutaneous mast cell tumors.
It is clear that there are several treatment options, each with
its advantages and disadvantages, including cost and toxicity.
The most important factor to consider when recommending
treatment options is to look at the individual dog, including
the tumor behavior, clinical signs, histology report, and decide
which (if any) protocol would be most beneficial for that
specific dog. Unfortunately, as animal health insurance is
not common in Israel, the cost of the treatment (including
both the drug and the need for follow up blood work) is very
important to the clients. At the time this article was submitted, the costs for both Masitinib and Toceranib Phosphate
were extremely high and cost prohibitive for many clients.
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Dank, G.
JUNE 2016.indb 8
The purpose in treatment is to choose an appropriate protocol
with the least amount of toxicity and most efficacy and that
is affordable to the client.
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