PAPER

Chlorambucil and prednisolone

chemotherapy for dogs with
inoperable mast cell tumours:
21 cases
OBJECTIVES: To evaluate the response of measurable canine mast cell
tumours unsuitable for other treatment modalities to
a chemotherapy protocol comprising chlorambucil and prednisolone.
METHODS: Dogs bearing measurable mast cell tumours, unsuitable
for treatment by surgery or radiotherapy, were treated with orally
administered prednisolone and chlorambucil, and their responses
assessed.
RESULTS: Twenty-one dogs were enrolled in the study; 13 had
intermediate-grade mast cell tumour, six were high grade and two
were diagnosed by cytology alone. Eight dogs had multiple tumours
and 13 dogs had single tumours, and six dogs had lymph node
metastases and no dogs had visceral metastases detected. Three
dogs achieved complete remission, ve achieved partial remission
(overall response rate 38 per cent), nine had static disease and four
dogshadprogressivedisease. Medianprogression-freeinterval for the
eight responderswas533days, andmediansurvival timefor all dogsin
thestudywas140days. Progression-freeinterval andmediansurvival
timewerenot inuencedbytheage, sex, weight or neuteringstatusof
thepatient, by thegradeor stageof thetumour or whether thepatient
had single or multiple tumours. No toxicity was detected.
CLINICAL SIGNIFICANCE: Response and survival rates of inoperable
canine MCT to chlorambucil and prednisolone are comparable to
previously described protocols, with no apparent toxicity.
F. TAYLOR, R. GEAR, T. HOATHER AND
J. DOBSON
Journal of Small Animal Practice (2009)
50, 284289
DOI: 10.1111/j.1748-5827.2009.00732.x
Accepted: 18 December 2008
INTRODUCTION
Canine mast cell tumours (MCTs) are
common, comprising seven to 21per cent
of all canine skin tumours (Thamm and
Vail 2007). Tumours are graded on their
histological characteristics, whereby tu-
mours are assigned grades I (low) to III
(high), depending on their morphology,
degree of differentiation and invasiveness
(Patnaik and others 1984). It is well docu-
mented that the majority of dogs affected
by low-grade and mid-grade tumours can
be treated effectively with surgery, and
adjuvant radiotherapy can be used where
complete excision has not been possible
(Turrel and others 1988, Al-Sarraf and
others 1996, Frimberger and others 1997,
LaDue andothers 1998, Dobsonandothers
2004, Hahn and others 2004, Poirier and
others 2006). Unfortunately, a small
proportion of dogs with intermediate-grade
tumours andthe majority of dogs withhigh-
grade tumours can experience aggressive
local tumour recurrence and/or metastatic
disease and thus carry a poor prognosis
(Bostock 1973, Patnaik and others 1984,
Seguin and others 2001, 2006, Michels
and others 2002, Weisse and others 2002,
Murphy and others 2004). In these situa-
tions, chemotherapy could be indicated,
and a variety of drugs and protocols have
been used in an attempt to extend survival
(McCaw and others 1994, 1997, Gerritsen
and others 1998, Rassnick and others 1999,
Thammand others 1999, 2006, Davies and
others 2004). All these studies have included
dogs treatedpostoperatively for microscopic
residual disease as well as those with gross
disease, despite published evidence that
suggests that two thirds to three quarters
of grade II MCTs with microscopic residual
disease following surgery alone do not recur
(Michels and others 2002, Seguin and
others 2006).
The aimof this prospective study was to
evaluate a protocol combining chlorambu-
cil and prednisolone in dogs with measur-
able MCTs that were unsuitable for local
therapies such as surgery and radiotherapy.
MATERIALS AND METHODS
Patient selection and evaluation
Dogs presenting to the Queens Veterinary
School Hospital (QVSH), University of
Cambridge, for management of MCTs
between April 2001 and July 2007
were included in the study if they had
The Queens Veterinary School Hospital,
Department of Veterinary Medicine, University of
Cambridge, Madingley Road, Cambridge CB3OES
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2009 British Small Animal Veterinary Association
measurable MCT deemed unsuitable for
locoregional therapy, such as surgery
and/or radiotherapy. This included dogs
with extensive local disease, multiple
tumours and/or metastatic disease. Dogs
with local lymph node (LN) metastases
suitable for locoregional therapy (surgery
and/or radiotherapy) were not included
in this study. Dogs with suspected residual
disease following surgery were not included.
Dogs were not included if they had had any
prior therapy for their MCT, except for
cases with recurrent MCT that had had
prior surgical treatment only.
All tumourswerehistologicallyorcytolog-
ically conrmed as MCTs by a commercial
laboratory. All the histologically diagnosed
tumours were graded according to the
Patnaiks grading system(Patnaikandothers
1984) by a veterinary histopathologist.
All dogs includedinthestudyunderwent
clinical assessment, includingmeasurement
of gross tumour mass (based on measuring
tumour length and width), palpation and
ne needle aspiration (FNA) of local drain-
ing LNs, thoracic radiography (right and
left lateral views) and ultrasound examina-
tion of abdominal organs and regional LNs
in order to stage the tumour (Owen 1980).
Any lesions deemed to be suspicious for
MCT recurrence or metastasis were inves-
tigatedusingFNAandcytological examina-
tion or tissue biopsy with histopathological
assessment. Multiple cutaneous tumours
were not consideredtobe distant metastatic
diseasefor the purposes of stagingas it is rec-
ognised that some dogs are prone to devel-
opment of more than one MCT, and the
presence of multiple tumours has been
shown not to inuence prognosis (Kiupel
and others 2005, Mullins and others
2006, Murphy and others 2006). Where
multiple tumours occurred, all those that
were excised or biopsied were histologically
graded, and for statistical analyses, patients
were categorised as for the highest grade
tumour. Location of multiple tumours
was categorised for where the majority of
tumours occurred on that patient.
Chemotherapy protocol
The chemotherapy protocol comprised
prednisolone (Prednicare; Animalcare) at
a starting dose of 40mg/m
2
orally once daily
for 14days, reducingto20mg/m
2
dailyevery
other day, combinedwith5mg/m
2
chloram-
bucil (Leukeran; GlaxoSmithKline) orally
every other day. In cases where a sustained
complete remission (CR) occurred, the pro-
tocol was discontinued after six months, and
in all other cases, the protocol was adminis-
tered continuously.
All patients were assessed at the QVSH
after the rst two weeks of treatment.
Revisits were then scheduled on a monthly
basis for as long as the patient survived,
with additional appointments if patients
deteriorated. Where it was not possible
to re-evaluate patients at the QVSH,
follow-up information after the rst two
weeks was obtained from the referring
veterinary surgeon. At each visit, tumour
response was assessed by gross inspection
and physical measurement with radiologi-
cal, ultrasound and cytological examina-
tions at the discretion of oncologists at
the QVSH.
Evaluation of response and
toxicity
Response to treatment was dened as CR:
no clinical evidence of local or distant
MCT, partial remission (PR): greater than
50 per cent reduction in size of tumour (by
length or width measurement), static dis-
ease (SD): no change in MCT size or pro-
gressionof metastatic disease or progressive
disease (PD): increase insize of MCTeither
locally, progression of metastatic disease or
deterioration in associated clinical signs
[World Health Organization (WHO)
1979]. Assessment of response in patients
with multiple tumours was made by sum-
mation of the longest diameter measure-
ment for each tumour. PR in these
patients was dened in a reduction in
greater than 50 per cent of the sum of
the diameters.
A haematology prole was performed
for each patient every four weeks to assess
for myelosuppression; this and any other
toxicities encountered were graded accord-
ing to the Veterinary Comparative Oncol-
ogy Group common terminology criteria
for adverse events (VCOG-CTCAE
2004).
Survival and progression-free
intervals
For each patient, it was recorded if the dog
died of MCT or another cause. The sur-
vival time was calculated from the start
of treatment to the date of death of the
patient because of MCT or other causes.
Patients that were still alive at the end of
the study, died because of other causes or
any that were lost to follow-up were cen-
sored at that point.
The progression-free interval (PFI) was
calculated from the date of start of treat-
ment to the date where the disease pro-
gressed, either as increase in tumour size
or when metastatic spread was docu-
mented. All patients that had stable disease
at the end of the study were censored at this
point.
Where patients that had achieved a CR
and subsequently discontinued the proto-
col at six months, but then restarted che-
motherapy at a later date because of
recurrence, the PFI was extendedtoinclude
the entire treatment period as long as
a response was achieved.
Statistical analysis
Computer software package SPSS15 was
used for statistical analysis. The Kaplan-
Meier product limit method was used to
calculate survival and PFI and to compare
the effect of patient variables onthese. Cox
proportional hazards regression model
was used to determine independent prog-
nostic factors for remission and survival
duration. Dogs were censored if they were
lost to follow-up, alive at the time of data
analysis or if they died of causes unrelated
to their MCT. Where the cause of death
was not clearly dened, it was assumed
that the patient died of MCT-related
causes.
RESULTS
Twenty-one dogs were entered into the
study. Breeds represented included nine
Labrador retrievers, two each of Stafford-
shire bull terrier and crossbred dogs and
one each of greyhound, English springer
spaniel, shar pei, West Highland white ter-
rier, German shepherd dog, Jack Russell
terrier, miniature daschund and boxer.
The mean age was eight years (median
10 years, range four to 130 years), and
mean bodyweight was 255 kg (median
320 kg, range 80 to 388 kg). There were
12 males, of which seven were neutered,
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2009 British Small Animal Veterinary Association 285
Chlorambucil and prednisolone chemotherapy for dogs
and nine females, of which seven were neu-
tered.
Nineteen patients had tumours graded
histologically, and two patients were diag-
nosed on cytology. Of the patients with
histologically graded tumours, 13 had
intermediate-grade (II) and six had high-
grade (III) tumours.
Eight dogs had multiple tumours and 13
hadsinglelesions. Eight dogs hadLNmetas-
tases at the time of diagnosis; no dogs had
distant metastatic disease detected, and no
dogs had signs of systemic effects of MCT
(vomiting, diarrhoea and generalised
oedema). MCTs were in various locations,
including seven dogs with their tumours on
distal limbs, six dogs with tumours on the
head, two dogs withtumours inthe inguinal
region and six dogs with tumours on the
trunk. All the dogs with multiple tumours
had them in the same regional areas (three
dogs with limb tumours and ve with
tumours on the trunk). Eight dogs had
stage I disease, three had stage II disease
and 10 had stage III disease (Appendix
1). Eleven dogs had gross MCT that had
recurred following previous surgery, four
of which also had local LN metastases.
Follow-up was documented in all dogs;
ve were seen monthly at the QVSH until
they died or were euthanased, and the
median number of follow-up appoint-
ments at the QVSHwas two appointments
(range one to seven appointments).
Three dogs achieved CR (14 per cent),
and six dogs achieved a PR (29 per cent),
giving an overall response rate of 38 per
cent. Eight dogs had static disease (SD),
and four dogs showed progression of their
disease (PD). The median PFI for all res-
ponders (CR and PR) was 533 days [SE
446 days, 95 per cent condence interval
(CI) zero to 1407, range 31 to 2283 days]
(Figure 1). Age, sex, weight or neutering
status of the patient, grade, stage, presence
of LN metastases or multiple/single status
of the tumour, tumour site or if the tumour
was recurrent all had no effect on PFI.
At the end of the study, ve dogs were
still alive, 15 dogs died or were euthanased
because of progression of their mast cell
neoplasia, two were euthanased for other
reasons and one dog was lost to follow-
up. Median survival time (MST) of all dogs
in the study was 143 days (SE 71, 95 per
cent CI four to 282, range 16 to 2283 days)
(Figure 2). These results were not inu-
enced by age, sex, weight or neutering sta-
tus of the patient or by grade, stage,
presence of LNmetastases or multiple/sin-
gle status of the tumour or if the tumour
was recurrent. Dogs with tumours on the
head had the longest overall survival
(MST 533 days, range 58 to 2283 days),
dogs with tumours on the distal limbs
had a MST of 143 days (range 59 to 751
days) and dogs with tumours on the trunk
had a MST of 131 days (range 16 to 1481
days). Dogs with tumours in the inguinal
region had poorer survival (MST 61 days,
range 6 to 1631 days) than those with
tumours in other locations, although there
was no statistically signicant difference
between the groups.
No dogs exhibited haematological or
other toxicities.
DISCUSSION
The purpose of this study was to assess the
response to a previously unpublished che-
motherapy protocol for gross MCTindogs
for whom surgery and/or radiotherapy
were not suitable using twoagents that have
shown efcacy against round cell tumours.
Prednisolone is widely used in chemother-
apy regimens for canine MCTs (McCaw
and others 1994, Thamm and others
1999, 2006, Davies and others 2004)
and has been shown to inhibit mast cell
proliferationinvitro(Takahashi andothers
1997); it has also been shown to cause
a reduction of size of gross MCTs before
radiotherapy (Dobson and others 2004)
or surgery (Stanclift and Gilson 2008).
Chlorambucil is an alkylating agent that
has therapeutic indications incanine round
cell tumours, including MCT, lymphoma,
chronic lymphoid leukaemia and some
myelomas (Carberry and others 1987,
Chun and others 2007). It has the advan-
tages of relatively low toxicity, moderate
cost and oral dosing. By selecting only dogs
with measurable tumours unsuitable for
local therapies, the true response to chemo-
therapy alone could be assessed.
Only a small number of studies reporting
results of various chemotherapeutic proto-
cols for treatment of canine MCTs have
actually included dogs with gross disease,
as summarised in Table 1. The most widely
reported and commonly used chemo-
therapy protocol for canine MCT, vin-
blastine and prednisolone, has relatively
low efcacy with less than 50 per cent
response rate in dogs with gross disease
(Thamm and others 1999). The combina-
tion of prednisolone and chlorambucil used
in the present study gave slightly lower
response rates in comparison to other pro-
tocols but comparable survival times when
used for patients with measurable disease.
Prednisolone and chlorambucil can there-
fore be considered an alternative to previ-
ously published chemotherapy protocols
for dogs with inoperable MCTs. The most
effective protocol described to date in terms
of response rate used the combination of an
alkylating agent (cyclophosphamide),
a vinca alkaloid (vinblastine) and predniso-
lone and achieved 63 per cent response rate
in a group of 11 dogs with measurable dis-
ease (Camps-Palau and others 2007). The
PFI for this group of dogs was quite short
(74 days), and there was some haematolog-
ical toxicity; however, this does suggest that
there may be utility in future studies com-
bining chlorambucil with a vinca alkaloid.
Ideally, a randomly assigned control
group of patients should have been
included in the present study and treated
with prednisolone alone. However, this
raises ethical issues because of the poor
response of canine MCT to prednisolone
alone, as previously reported (Table 1)
(McCaw and others 1994). This is likely
to be the reason that none of the previ-
ously reported MCT chemotherapy stud-
ies have included a control group of
animals receiving prednisolone only or
no chemotherapy.
Two studies have reported the use of
prednisolone in a neoadjuvant setting to
reduce MCT mass before radiotherapy
(Dobson and others 2004) and, more
recently, before surgery (Stanclift and
Gilson 2008). Interestingly, both these
studies reported short-term response rates
of measurable tumours to be in the order of
70 to 75 per cent; however, as the tumours
were either surgically removedwithinseven
to 35 days (mean nine days) or irradiated
after 10 to 14 days, these short-term
responses are not directly comparable with
the present or previous studies where
response rates have been reported accord-
ing to WHO criteria, which require the
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F. Taylor and others
response to be maintained for four weeks
(WHO 1979). It is also likely that this
short-term response to prednisolone may
be because of the anti-inammatory effects
rather than antitumour actions.
Follow-up appointments were made
wherever possible at the QVSH. As these
are client-owned patients, this was not
always possible because of owner con-
straints, and inthese cases, follow-up infor-
mation was obtained from the local
veterinary surgeon. Reassessments by differ-
ent individuals, while unavoidable, maylead
to some inter-observer variations and may
have impacted on the results, although this
effect should be minor.
Age, sex, weight or neutering status of
the patient, grade, stage, presence of LN
metastases or multiple/single status of the
tumour, tumour site or if the tumour
was recurrent had no statistically signi-
cant effect on survival time in the dogs
in the present study. It is generally accepted
that tumour grade is a useful prognostic
indicator in canine MCT. The lack of cor-
relation between grade and survival in the
present study may be because of the small
number of patients enrolled and the fact
that by denition of the entry criteria, they
were all patients with poor prognoses at the
outset. Two of the dogs in this study were
diagnosed by cytology, which, although
is considered an adequate method of diag-
nosis, does not allow tumour grading
(Thamm and Vail 2007). These two dogs
therefore could not be included in analysis
of effect of tumour grade on response to
therapy or prognosis. As all the dogs were
referral patients, the histology samples were
not all available for review, and hence, the
grade of the tumours could not be indepen-
dently conrmed.
None of the dogs in this study had evi-
dence of distant metastases at presentation
compared with two dogs with measurable
disease treated with a vinblastine, cyclo-
phosphamide and prednisolone protocol
in another study (Camps-Palau and others
2007). The presence of detected distant
metastatic disease did not inuence sur-
vival in that study, although this is a small
number of individuals and one would gen-
erally expect patients with distant meta-
static disease to have a poorer prognosis;
a larger study group may give a different
result. The number of dogs with visceral
metastases in some of the other studies is
not very well dened (McCaw and others
1997, Thammand others 2006, Hayes and
others 2007), and clearly, it can be very dif-
cult clinically to rule this out. Certainly,
dogs with distant metastatic disease would
be suitable candidates for chemotherapy,
and further studies assessing the impact
of therapy with chlorambucil and prednis-
olone would be of interest.
In the present study, dogs with inguinal
tumours had shorter survival times than
Table 1. Published chemotherapy protocols for canine mast cell tumours that include DWGD
Chemotherapy protocol Total number of
dogs in study
Number of
DWGD
Remission rate for
DWGD (CR1PR) (%)
Median survival
(days) for DWGD
Median PFI
(days) for DWGD
Prednisolone only (McCaw and others 1994) 25 25 20 NA
Prednisolone and vinblastine
(Thamm and others 1999)
41 18 47 NA 154
Prednisolone, vinblastine and cyclophosphamide
(Camps-Palau and others 2007)
35 11 63 145 74
Lomustine (Rassnick and others 1999) 19 19 40 85
Chlorambucil and prednisolone (present study) 21 21 38 143 116
DWGD dogs with gross disease, CR Complete remission, PR Partial remission Remission rates include CR and PR
FIG 1. Kaplan-Meier graph showing progression-free survival for patients that had a clinical
response (complete remission plus partial remission) to chlorambucil and prednisolone
Journal of Small Animal Practice

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2009 British Small Animal Veterinary Association 287
Chlorambucil and prednisolone chemotherapy for dogs
those with tumours in other locations;
however, as there were only two dogs with
inguinal tumours, this result cannot be
viewed as meaningful. Indeed, the small
number of dogs in each site group makes
it difcult to draw any conclusions about
the inuence of tumour site in this study.
Although dogs with MCTs on the head did
not have a prolonged survival overall, three
of the patients within this category each
survived over 1500 days. This included
one dog with a grade III MCT of the muz-
zle, whichhada rst CRperiodof 45years.
The tumour then recurred and was success-
fully treated a second time using the same
chemotherapy protocol; ndings which do
not agree with a previous study that sug-
gested muzzle MCTs tend to behave in
an aggressive fashion (Geiger and others
2003).
Chemotherapy-related toxicity was not
documented in any of the patients in the
current study. All other published MCT
chemotherapy protocols, with the excep-
tion of prednisolone alone (McCaw and
others 1994) recorded patients experienc-
ing side effects. Dogs treated with vinblas-
tine andprednisolone experiencedbetween
12 and 28 per cent toxicity, including cases
of sepsis and treatment-related mortality
(Thamm and others 1999, 2006, Davies
and others 2004, Hayes and others
2007). Other chemotherapy protocols
have resulted in variable toxicity, including
40 per cent grade III or IV neutropenia for
dogs receiving lomustine (Rassnick and
others 1999), 33 per cent discontinuation
of therapy because of toxicity following
vincristine therapy (McCaw and others
1997) and 31 per cent toxicity for vinblas-
tine, prednisolone and cyclophosphamide
therapy, although side effects were gener-
ally mild (Camps-Palau and others 2007).
In conclusion, the combination of pred-
nisolone and chlorambucil used in this
study to treat dogs with gross MCT
resulted in remission and survival rates
comparable withpreviously publishedpro-
tocols for patients with measurable disease.
This protocol has the added advantage of
minimal toxicity with straightforward oral
drug dosing and should be considered for
patients unsuitable for treatment using
more denitive means (surgery and radio-
therapy). Further studies are warranted to
evaluate this protocol in a larger patient
cohort and as an adjunct to surgery for
high-grade MCTs. The authors would like
to stress that this regimen should not be
used indiscriminately in patients for whom
surgical and/or radiotherapy would be
superior.
Acknowledgements
The authors would like to thank Petsavers
for sponsorship of Frances Taylors clinical
training Scholarship in Oncology, all the
staff and students of the QVSH for the care
given to the dogs involved in this study and
the owners and referring vets for their assis-
tance inprovidingfollow-up. Dr FredHeath
assisted with the statistical analyses. This
study has been previously presented at
WORLDvetCANCER, Copenhagen, Feb-
ruary 29, 2008, joint meeting of ESVONC
and VCS.
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APPENDIX 1. CLINICAL
STAGES OF CANINE
MASTOCYTOMA ACCORDING
TO WORLD HEALTH
ORGANIZATION
CLASSIFICATION SYSTEM
(OWEN 1980).
Clinical stage
I: One tumour conned to the dermis
without regional lymph node involve-
ment
Ia without systemic signs
Ib with systemic signs
II: One tumour conned to the dermis,
with regional lymph node involvement
IIa without systemic signs
IIb with systemic signs
III: Multiple dermal nodules or large inl-
trating tumour with or without
regional lymph node involvement
IIIa without systemic signs
IIIb with systemic signs
IV: Any tumour with distant metastasis or
recurrence with metastasis*
*Including blood and/or bone marrow
involvement
Multiple tumours
Tumours occurring simultaneously should
have actual number recorded. The tumour
with the highest T category is selected, and
the number of tumours indicated in paren-
thesis, for example T2(5). Successive
tumours should be classied indepen-
dently.
T classication system using World Health Organization tumour classication system (Owen 1980)
Size T1 T2 T3 T4
Less than 3 cm 3 to 5 cm More than 5 cm More than 5 cm
Skin Minor involvement Major involvement
Fascia, muscle and thoracic wall With or without fascia or muscle xation Thoracic or abdominal wall xation
Journal of Small Animal Practice

Vol 50

June 2009

2009 British Small Animal Veterinary Association 289
Chlorambucil and prednisolone chemotherapy for dogs