a comparison of the survival times of dogs treated with mitotane or trilostane for...
TRANSCRIPT
-
8/4/2019 A Comparison of the Survival Times of Dogs Treated With Mitotane or Trilostane for Pituitary-Dependent Hyperadre
1/6
J Vet Intern Med2005;19:810815
A Comparison of the Survival Times of Dogs Treated with Mitotaneor Trilostane for Pituitary-Dependent Hyperadrenocorticism
E.N. Barker, S. Campbell, A.J. Tebb, R. Neiger, M.E. Herrtage, S.W.J. Reid, and I.K. Ramsey
The survival times of 148 dogs treated for pituitary-dependent hyperadrenocorticism were studied using clinical records from 3
UK veterinary centers between 1998 and 2003. Of these animals, 123 (83.1%) were treated with trilostane, while 25 (16.9%) were
treated with mitotane. Treatment groups were compared using t-tests and analysis of variance (or their nonparametric equivalents)
and chi-square tests. Survival data were analyzed using Kaplan-Meier survival plots and Cox proportional hazard methods. There
was no significant difference between the population attributes from each center or between treatment groups. The median survival
time for animals treated with trilostane was 662 days (range 81,971) and for mitotane it was 708 days (range 331,399). There
were no significant differences between the survival times for animals treated with trilostane and those treated with mitotane. In
the multivariable model (including drug, center, breed group, weight, diagnostic group, and age at diagnosis), only age at diagnosis
and weight were significantly negatively associated with survival. Importantly, there was no significant effect of drug choice on
survival.
Key words: Canine; Cushings disease; Endocrine; Prognosis; Therapy.
Spontaneous hyperadrenocorticism (HAC) is one of themost common endocrine diseases of the dog. It resultsfrom the overproduction of steroid hormones from the ad-
renal cortex. The most common cause is a functional pi-
tuitary neoplasm, which secretes excessive adrenocortico-
tropic hormone (ACTH) resulting in overstimulation of the
adrenal glands. Pituitary-dependent hyperadrenocorticism
(PDH) accounts for approximately 8085% of cases.1,2 The
majority of the remaining dogs have functional adrenocor-
tical neoplasms leading to adrenal-dependent hyperadre-
nocorticism (ADH).
The excess adrenocortical hormones can result in a num-
ber of nonspecific clinical signs, which are reviewed else-
where.1 The majority of the clinical signs, while not im-
mediately life threatening, have a considerable impact on
the animals quality of life. Therefore, this condition is usu-
ally treated and there are no studies on the causes of death
in a large series of untreated cases.
PDH is mostly treated medically, although surgical op-
tions have been described.3 In North America and, until
recently, in Europe, HAC is usually treated with mitotane
(o,pDDD), an adrenocorticolytic drug. Recent studies fromEurope have found trilostane, a competitive 3-hydroxy-steroid dehydrogenase inhibitor, to be an effective alterna-
tive in the treatment of canine PDH.4,5 In addition, there
have been reports of the treatment of HAC using ketoco-
nazole, selegiline hydrochloride, and aminoglutethimide.68
From the Department of Veterinary Clinical Studies, University of
Glasgow, Bearsden Road, Bearsden, Glasgow G61 1QH Scotland
(Barker, Campbell, Tebb, Reid, Ramsey); Small Animal Clinic (Inter-
nal Medicine), Justus-Liebig Universitat Giessen, Giessen, Germany
(Neiger); Department of Clinical Veterinary Medicine, University ofCambridge, Cambridge CB3 0ES, UK (Herrtage). This study was pre-
viously presented in abstract form at the 47th British Small Animal
Veterinary Association Annual Congress, April 14, 2004, Birming-
ham, UK.
Reprint requests: Ian K. Ramsey, Veterinary Clinical Sciences, Uni-
versity of Glasgow Veterinary School, Bearsden Road, Bearsden G61
1QH, UK; e-mail: [email protected].
Received September 20, 2004; Revised March 16, 2005; Accepted
June 21, 2005.
Copyright 2005 by the American College of Veterinary Internal
Medicine
0891-6640/05/1906-0004/$3.00/0
Mitotane binds covalently to adrenal proteins before be-
ing converted to a reactive metabolite, resulting in the de-
struction of adrenal tissue. Destruction of the adrenal cor-
tices can be partial or complete, depending on dose and
frequency of administration. Complete destruction results
in hypoadrenocorticism requiring long-term steroid replace-
ment therapy.9 Partial destruction involves induction and
maintenance periods.10 Trilostane is an orally active steroid
analogue that acts as a competitive inhibitor of 3-hydroxy-steroid dehydrogenase, interrupting the synthesis of several
steroids, including cortisol.
To date, there have been no studies published that di-
rectly compare the use of mitotane to trilostane in the treat-
ment of canine PDH. The hypothesis of this study was that
there was no significant difference between the survival
times of dogs with PDH that had been treated with trilos-
tane and those that had been treated with mitotane.
Materials and Methods
Clinical Cases
The medical records of all dogs that were diagnosed with PDH at
three referral-only hospitals, from January 1, 1998, to July 7, 2003, were
reviewed. The centers involved were the Queens Veterinary School Hos-
pital of the University of Cambridge (center 1), the Small Animal Hos-
pital of the University of Glasgow (center 2), and the Queen Mother
Hospital for Small Animals of the Royal Veterinary College (center 3).
A small number of the cases in all the centers were referred from 1st
opinion charity practices associated with these institutions; however,
their investigation and treatment protocols were no different from other
cases referred from private practitioners. These cases included some
dogs that had been evaluated in a previous study into the efficacy of
trilostane in the treatment of PDH.4 Only animals that had been treatedmedically for PDH with either mitotane or trilostane and that had suf-
ficient case records available were included. Animals that had not been
treated, had been managed surgically, or had been given more than 1
drug for the treatment of HAC were excluded.
Data obtained from the records included breed, sex, weight at di-
agnosis, age at diagnosis, date of diagnosis, treatment given, and date
of treatment initiation where recorded. Date of death, date at which
point they were lost to follow-up or survival to July 7, 2003, were
also recorded. When needed, referring veterinarians and owners were
contacted. The results of pretreatment ACTH stimulation tests, low-
and high-dose dexamethasone suppression tests (LDDSTs, HDDSTs),
endogenous ACTH plasma concentration assays, and abdominal ultra-
-
8/4/2019 A Comparison of the Survival Times of Dogs Treated With Mitotane or Trilostane for Pituitary-Dependent Hyperadre
2/6
811Canine Hyperadrenocorticism
sonographies were also recorded where these were performed. Ani-
mals were grouped into breed categories as defined by the Kennel Club
of the United Kingdom (1996): gun dog, hounds, pastoral, terrier, toy,
utility, working, and mixed breeds. The numbers of dogs is each group
were then directly compared with the registration statistics for 1990
(the median year of birth for the dogs). No comparison was made with
the referral populations of the centers, as this was felt to be biased by
the activities of other clinic services within the centers. Breed crosses
were included into the breed category that was known. Jack RussellTerriers were included in the terrier group.
Diagnosis
A similar diagnostic protocol was used in each center. Suspicion of
HAC was based on history, clinical examination, and routine blood
analysis. An ACTH stimulation test was performed as described else-
where.11 HAC was confirmed by the demonstration of an exaggerated
increase in circulating cortisol concentration (600 nmol/L, 21.6 g/
dL) 1 hour postintravenous administration of tetracosactide.a A small
number of cases were included that had unequivocal clinical signs,
biochemical markers, and a 1-hour post-ACTH cortisol concentration
575 nmol/L (20.7 g/dL). In animals with clinical signs and bio-
chemical markers of HAC but without a positive ACTH stimulation
test, the diagnosis was confirmed by a more sensitive but less specific
test, either by an LDDST that demonstrated an inadequate suppression
(40 nmol/L, 1.44 g/dL) of cortisol concentration 8 hours after in-
travenous administration of a low-dose of dexamethasone,b or by an
exaggerated increase (8.5 nmol/L, 2.83 ng/mL) in circulating 17-
hydroxyprogesterone (17-OHP) 1 hour postintravenous administration
of tetracosactide.12,13 The test that confirmed the diagnosis was record-
ed for each case for later analysis.
PDH was diagnosed by a combination of LDDST, HDDST, endog-
enous ACTH concentration, and abdominal imaging as previously de-
scribed elsewhere.2,4,14,15
Treatment Regimen
The same treatment protocol was used for each drug in each center.
Mitotane therapy involved an induction period followed by a main-
tenance dose.11
In the induction period, mitotanec
was administered ata dose of 50 mg/kg, up to a limit of 1,000 mg/dog, until polyphagia
or polydipsia resolved and the post-ACTH cortisol concentration was
less than 120 mmol/L (4.32 g/dL). Following successful induction,
a maintenance dose of mitotane was given (initially 50 mg/kg/week).
The aim of the therapy was to achieve a postmedication post-ACTH
cortisol concentration of 120 mmol/L (4.32 g/dL) at the end of
induction and during the maintenance phase, and good clinical re-
sponse to treatment, ie, reduction/elimination of polyphagia and poly-
dipsia, return of normal coat quality with minimal side effects. The
maintenance dose of mitotane was adjusted in frequency or amount to
achieve these aims in individual animals.
In contrast, trilostane therapy did not involve an induction period.
The initial doses of trilostaned were based on body weight and given
PO q24h: 520 kg, 60 mg: 2140 kg, 120 mg: 40 kg, 120240 mg.4
The aim of the therapy was to achieve a 4-hour postmedication post-
ACTH cortisol concentration of 40120 mmol/L (1.444.32 g/dL)
with good clinical control of the HAC. The initial dose and dose fre-
quency were adjusted accordingly. Dogs that had a postmedication
post-ACTH cortisol concentration of 120200 mmol/L (4.327.2 g/
dL) but were responding well to either treatment did not necessarily
have their doses adjusted.
Statistics
Population attributes (age at diagnosis and weight) of the 3 centers
were compared using analysis of variance (ANOVA) techniques for
parametric data, or Kruskal-Wallis for nonparametric data, as appro-
priate. Categorical data were compared using a chi-square test. Two-
tailed t-tests were used to compare the population attributes of the
animals on the 2 drug regimens.
Survival analysis was performed using a Kaplan-Meier product limit
method supplemented by a Cox proportional hazard model to include
drug, center, breed group, diagnostic test group, and age and weight
at diagnosis as covariates. All analysis was carried out using statistical
software.e Significance was set at the 5% level for all tests.
The power of the study to detect a clinically significant difference
between survival rates was calculated using a difference in survivalof 90 days (or about 15% of the previously reported median survival
time for dogs treated with mitotane).10
Results
One hundred forty-eight dogs were identified that fitted
the inclusion criteria. A number of additional animals that
had been identified as having received mitotane or trilostane
were excluded due to multidrug therapy (n 8), concurrentradiotherapy (n 3), insufficient data (n 8), and equiv-
ocal adrenal function results (n 5).There was a marked difference in the treatment regimens
preferred by the different centers. Center 1 treated 20 pa-
tients (57.1%) with mitotane and 15 patients (42.9%) withtrilostane. Center 2 treated 5 patients (9.4%) with mitotane
and 48 patients (90.6%) with trilostane. Center 3 treated 60
patients (100%) with trilostane and none with mitotane.
Center 1 treated HAC in 24 patients (68.6%) where it
had been confirmed using ACTH stimulation test, 5 patients
(14.3%) using LDDST, and 6 patients (17.1%) with 17-
OHP assays. Center 2 confirmed HAC in 44 patients
(83.0%) using ACTH stimulation test, 7 patients (13.2%)
with LDDST, and 2 patients (3.8%) with 17-OHP assays.
Center 3 confirmed HAC in 50 patients (83.3%) using
ACTH stimulation test and 10 patients (16.6%) using
LDDST.
There were no statistical differences between the dogs
seen by each veterinary center when age at diagnosis (P
.71), weight at diagnosis (P .29), and reproductive status
(P .25) were compared. There were no statistical differ-ences between the populations of dogs in each treatment
group when age at diagnosis (P .30), weight at diagnosis
(P .57), and reproductive status (P .27) were com-pared. The number of animals in some of the breed groups
was too small to allow meaningful comparison between
centers or treatment groups.
The median age at diagnosis was 10 years (mean 9.6
years; SD 2.3; range 3.515.2 years). The median weight
was 14.45 kg (mean 19.0 kg; SD 12.4; range 358.5 kg).
Seventy-five dogs were male (45 entire, 30 castrated), and
73 dogs were female (20 entire, 53 spayed). Forty-fourbreeds were represented (the breed group distribution and
most frequently seen breeds are listed in Table 1). When
breed was recorded (90.5%), there was a higher prevalence
of animals in the toy (26.1%) and terrier (21.6%) groups
when compared with national registration statistics for 1990
for the toy (20.3%) and terrier (16%) groups. In contrast,
gun dogs were relatively underrepresented, with a preva-
lence of 20.1%, compared with 28.2% of registrations.
Yorkshire Terriers and their crosses were the most frequent-
ly encountered breed type (20/148; 13.5%). However, in
1990, Yorkshire Terriers were also the most frequently reg-
-
8/4/2019 A Comparison of the Survival Times of Dogs Treated With Mitotane or Trilostane for Pituitary-Dependent Hyperadre
3/6
812 Barker et al
Table 1. Breed group distribution for all centers. The
numbers of the most common breeds within each group are
shown.
Breed Group Number
Gun dog,
including
27
Labrador 9
Irish Setter 7
English Springer Spaniel 5
Hound,
including
8
Dachshund 4
Pastoral,
including
11
Collie 7
Terrier,
including
29
Jack Russell Terrier 7
Staffordshire Bull Terrier 5
Cairn Terrier 4
Toy,
including
35
Yorkshire Terrier 20
Cavalier King Charles Spaniel 6
Bichon Frise 5
Utility,including
10Poodle 3
Miniature Schnauzer 3
Working,
including
14
Boxer 9
Rottweiler 3
Mixed breed 14
Fig 1. Kaplan-Meier survival curve for both mitotane- and trilostane-treated animals. Dogs alive at the completion of the study and those lost
to follow-up were censored.
istered breed in the UK, accounting for 9.5% of all dogs
registered that year.16
Mitotane was administered to 25 animals (16.9% of those
treated). At date of censorship, 17 were dead, 5 were alive,
and 3 had been lost to follow-up. The median survival time
for animals treated with mitotane was 708 days (range 33
1,399). Trilostane was administered to 123 animals (83.1%
of those treated). At date of censorship, 65 were dead, 54
were alive, and 4 had been lost to follow-up. The median
survival time for animals treated with trilostane was 662
days (range 81,971). There was no significant difference
between the survival times for animals treated with trilos-
tane and those treated with mitotane when compared usinglog rank (P .62) and Wilcoxon (P .81) methods (Fig
1).
In the multivariable model (starting with center, breed
group, weight, treatment group, diagnostic test group, and
age at diagnosis), only the age at diagnosis (hazard ratio
0.81 [confidence limits 0.73, 0.90] P .001) and weight
(hazard ratio 0.78 [confidence limits 0.77, 0.80] P
.015) were significantly negatively associated with survival
in the final model. The 1-year survival fraction for animals
on mitotane was 62% and the 2-year survival fraction was
48%. The 1-year survival fraction for animals on trilostane
was 68% and the 2-year survival fraction was 47%. The
study was, however, underpowered. On the basis of our
assumption regarding the effect size and assuming 5% levelof significance and 80% power, over 200 dogs would have
been required in each group to state confidently that the
choice of therapy had no effect on survival.
Of the 82 animals that were dead at date of censorship,
the cause of death or reason for euthanasia were recorded
where possible (Table 2). Of these animals, 9/82 (11.0%)
died of causes that were felt to be probably due to the PDH
or its treatment. These included signs of space-occupying
cranial lesions, confirmed pulmonary embolism (a reported
complication of PDH), or suspected hypoadrenocorticism
(a reported adverse effect of both mitotane and trilostane
therapy). A further 14 (17.0%) died of causes that were felt
could have been due to the PDH or its treatment. These
-
8/4/2019 A Comparison of the Survival Times of Dogs Treated With Mitotane or Trilostane for Pituitary-Dependent Hyperadre
4/6
813Canine Hyperadrenocorticism
Table 2. Reason for death/euthanasia for all 82 dogs that
had died by the time of censorship.
Reason for Death/Euthanasia
Number
Recorded
No cause recorded Total 28
Specific cause recorded that is not directly attributable
to pituitary-dependent hyperadrenocorticism (PDH)or its treatment Total 31
Respiratory disease (including dyspnea, tracheal
collapse) 7
Heart disease (including congestive heart failure,
atrial fibrillation) 6
Renal failure
Gastric dilation and volvulus
5
3
Neoplasia (not central nervous system) 3
Orthopedic disease (including pressure point ulcers,
osteo) 2
Pyometritis
Diabetes mellitus
Pancreatitis
1
1
1
Cer vical degenerative radiculomyelopathy 1
Anesthetic complication 1Vague cause recorded that might be attributable to
PDH or its treatment Total 14
Progressive deterioration
Old age
Collapse
7
4
3
Specific cause recorded that is likely attributable to
PDH or its treatment Total 9
Neurological signs
Suspected hypoadrenocorticism
Pulmonary thromboembolism
7
1
1
included signs of collapse, progressive deterioration, poor
quality of life, and what was described as old age. A further31 (37.8%) dogs died of causes that could not be directly
attributable to PDH or its treatment. There are, however, a
number of limitations when interpreting cause of death in
this study group: 28 (34.1%) of the animals that were dead
at censorship did not have a recorded cause of death or
reason for euthanasia. Even in those cases where a reason
was recorded, it was usually not supported by postmortem
examination results. It was felt that there was insufficient
reliable data to compare the causes of death between the
treatment groups or with the length of survival. However,
no trends were apparent on visual inspection of the data.
Discussion
There was a marked difference in the treatment regimen
preferred by each center, with one center using trilostane
for all of its cases, while another center used mitotane until
trilostane became licensed for the treatment of HAC in the
UK. However, as there was no geographical variation found
when age at diagnosis, weight at diagnosis, and reproduc-
tive status were compared, it was concluded that the dogs
from each center were derived from the same population
and could therefore be combined for further analysis. There
was no difference found between each treatment group
when age at diagnosis, weight at diagnosis, and reproduc-
tive status were compared. From this, it was concluded that
the dogs from each treatment group were derived from the
same population. This meant that treatment regimens could
be compared in terms of survival parameters. Comparisons
between centers and treatment groups in terms of breed
were not possible due to the small numbers of animals with-
in some of the breed categories.
The dogs in this study tended to be middle to older aged,of medium to small size, although there was a wide weight
range. These results agree with previous studies of popu-
lations of dogs with PDH. One study reported a mean age
of 10.2 years and median weight of 10.3 kg (mean 12.4 8.2 kg; range 1.546.8 kg),10 while another reported a me-
dian age of 9 years and a median weight of 12 kg (range
251 kg).9 The same studies also found no sex predispo-
sition. A high incidence of poodles, Dachshunds, and York-
shire Terriers has been previously reported.9,10 In our study,
when the breed group distribution was compared with na-
tional registration statistics for 1990 for the toy, terrier, and
gun dog groups, it suggested an overrepresentation of toy
and terrier breeds, with an underrepresentation of gun
dogs.16
In particular, the Yorkshire Terrier was frequentlyencountered. In 1990, poodles and Dachshunds only com-
prised 2.7 and 1.9%, respectively, of the dogs registered
that year in the UK, while Yorkshire Terriers were most
popular (9.5%).17 The differences between study popula-
tions are therefore likely to be explained by national vari-
ation in breed popularity. No comparison was made with
the hospital populations, as these records might be influ-
enced by referral rates for other conditions.
As some animals were alive at the time of censorship for
both treatment groups, an element of error is introduced
into the median survival times of both mitotane- and tri-
lostane-treated animals. As a greater proportion of animals
in the mitotane group (68%) were dead at censorship com-
pared with trilostane (53%), the median survival time formitotane-treated animals is likely to be a more accurate
reflection of the true value. However, as the survival times
to the date of censorship of the surviving dogs are evenly
distributed, it is unlikely that the mean survival figure will
change. The power of the study was found to be inadequate
to confirm the null hypothesis because the number of mi-
totane-treated dogs was too low. However, it should be
stressed that the median survival time (708 days) and 2-
year survival fraction (48%) of animals treated with mito-
tane in this study was found to be similar to previously
published results. In a study of 200 dogs with PDH treated
with mitotane using a similar protocol, the median survival
time was 1.7 years (mean 2.2; range 10 days to 8.2 years)
with a 2-year survival of 47%.10 The median survival time(662 days) and 2-year survival fraction (47%) of animals
treated with trilostane in this study was found to be greater
than previously published results. A previous study had
found a median survival time of 549 days for dogs with
PDH treated with trilostane.4 However, they noted that this
figure was unreliable as very few of their dogs had died at
the completion of the study.
The retrospective study design was chosen as it was able
to encompass the period of time that both trilostane and
mitotane were available as the 1st-line treatment for PDH.
Due to changes in the prescription regulations in the UK
-
8/4/2019 A Comparison of the Survival Times of Dogs Treated With Mitotane or Trilostane for Pituitary-Dependent Hyperadre
5/6
814 Barker et al
around the time of censoring, trilostane is now the sole
product licensed for the treatment of PDH in the UK. It
therefore has to be used as the 1st-line medical treatment
for PDH. Mitotane can only be dispensed following treat-
ment failure with trilostane. A prospective study was there-
fore not possible. In addition, it would not be possible to
do a blinded trial, as the treatment protocols are so differ-
ent. It was also not possible to compare survival times oftreated animals with a no-treatment control group, as it
would be unethical to withhold treatment for this disease.
There are no published reports by other authors describing
the survival parameters of a large population of dogs with
PDH that did not undergo any form of therapy. The clinical
implications of this study should be assessed by comparison
with previous reports.
This study used mitotane-induced selective adrenocorti-
colysis, while others have used nonselective adrenocorti-
colysis for the treatment of PDH. One study of nonselective
adrenocorticolysis with mitotane, where a state of hypo-
adrenocorticism was induced, reported a 2-year survival
fraction of 69%.9 However, they also reported a loss of
11.6% animals (15/129) during the induction period, whiledeath from overdosage for selective adrenocorticolysis was
reported to occur in less than 2% of cases.18 Another study
reported a median survival time of 30 months for animals
with HAC treated with mitotane.19 When those animals that
had developed permanent iatrogenic hypoadrenocorticism
were excluded from this calculation, the median survival
time was reduced to 27 months, suggesting nonselective
adrenocorticolysis confers a longer survival time compared
with selective adrenocorticolysis. However, while the ma-
jority of animals in that study had PDH, animals with ADH
were not excluded.19
Surgical treatment for PDH, in the form of hypophysec-
tomy, has been reported in the literature.3 A 2-year survival
fraction of 82% for dogs that had undergone hypophysec-tomy for PDH has been reported, along with a reduction in
the recurrence rate of HAC when compared with results
obtained following mitotane therapy in the same institu-
tion.3 While hypophysectomy can offer a cure for PDH and
avoids the potential adverse effects of medical therapy, such
as development of signs of cranial-space occupying lesion
or iatrogenic hypoadrenocorticism, it does require access to
advanced imaging techniques (computer axial tomography,
magnetic resonance imaging) and surgical expertise.
It was noted in this study that age at diagnosis influences
survival time; the older the animal at diagnosis, the shorter
its survival time tended to be. A previously published study
found that the majority of animals with PDH did not die
because of diseases associated with PDH or its treatmentbut rather failure of other organs (heart, liver, kidneys, etc),
unrelated neoplasia, or geriatric diseases (eg, gradual de-
terioration, incontinence).10 Another study found that, of the
27 animals that had died by date of censorship, 22.2% had
died of causes attributable to HAC or its treatment (n 6),while a further 66.6% could possibly be attributed to HAC
(n 18).19 However, the group for which signs could pos-sibly be attributed to HAC included those animals where a
reason of euthanasia/death was not recorded, those who
died of congestive heart failure, and 2 large-breed dogs with
hind-limb weakness. In our study, 11% of animals died or
were euthanatized as a result of clinical signs that were
considered likely to be a result of HAC or its treatment and
a further 17% may also have been euthanatized as a result
of HAC or its treatment. This data must be interpreted with
caution, as the assessment of these cases both before eu-
thanasia and at postmortem was very variable.
Multivariable analysis in this study also found that
weight at survival was significantly negatively correlatedwith survival, although to a lesser extent than age at diag-
nosis. This has not been reported elsewhere in animals
treated for PDH medically. Our finding is not surprising, as
smaller dogs have been shown to have longer life spans
when looking at a general population of dogs.20
As this was a retrospective study, it did not encompass
the quality of life of the animals in either treatment group,
their response to treatment was not assessed, nor did it as-
sess owner compliance. Previous studies have assessed re-
sponse to medical therapy.4,10 A total resolution of clinical
signs and decrease in pre- and post-ACTH cortisol values
to within the normal resting range occurred in 83% of cases
of PDH treated with mitotane,10 while in over 70% of dogs
with PDH treated with trilostane, their polydipsia/polyuriaor polyphagia resolved within the 1st month of treatment,
and many of the remaining dogs had a reduction in the
severity of clinical signs with dosage adjustment.4 This sug-
gests a comparable efficacy between mitotane and trilo-
stane.
Conclusion
The hypothesis that there was no significant difference
between the survival times of dogs with PDH that had been
treated with trilostane and those that had been treated with
mitotane could not be rejected. Although the power of this
study was limited, by taking previously published survival
studies into account, it is unlikely that the choice of therapy
(mitotane or trilostane) has a major effect on survival times
in dogs with PDH.
Footnotes
a Synacthen, Alliance Pharmaceuticals, Chippenham, UKb Dexadresson, Intervet UK Ltd, Milton Keynes, UKc Lysodren, Bristol-Myers, Canadad Vetoryl, Arnolds Veterinary Products, Shrewsbury, UKe Minitab; Minitab Inc, State College, PA
Acknowledgments
The authors would like to thank their veterinary and
nursing colleagues at the Universities of Cambridge, Glas-
gow, and London for the dedicated care and management
of these cases. Arnolds Veterinary Products partly funded
the treatment of some of the trilostane-treated patients.
References
1. Guptill L, Scott-Moncrieff JC, Widmer WR. Diagnosis of canine
hyperadrenocorticism. Vet Clin North Am Small Anim Pract 1997;27:
215235.
2. Gould SM, Baines EA, Mannion PA, et al. Use of endogenous
-
8/4/2019 A Comparison of the Survival Times of Dogs Treated With Mitotane or Trilostane for Pituitary-Dependent Hyperadre
6/6
815Canine Hyperadrenocorticism
ACTH concentration and adrenal ultrasonography to distinguish the
cause of canine hyperadrenocorticism. J Small Anim Pract 2001;42:
113121.
3. Meij B, Voorhout G, Rijnberk A. Progress in transsphenoidal
hypophysectomy for treatment of pituitary-dependent hyperadrenocor-
ticism in dogs and cats. Mol Cell Endo 2002;197:8996.
4. Neiger R, Ramsey IK, OConnor J, et al. Trilostane treatment of
78 dogs with pituitary dependent hyperadrenocorticism. Vet Rec 2002;
150:799804.5. Ruckstuhl NS, Nett CS, Reusch CE. Results of clinical exami-
nations, laboratory tests, and ultrasonography in dogs with pituitary-
dependent hyperadrenocorticism treated with trilostane. Am J Vet Res
2002;63:506512.
6. Feldman EC, Bruyette DS, Nelson RW, Farver TB. Plasma cor-
tisol response to ketoconazole administration in dogs with hyperad-
renocorticism. J Am Vet Med Assoc 1990;197:7178.
7. Bruyette DS, Ruehl WW. CVT update: L-deprenyl in the treat-
ment of canine pituitary-dependent hyperadrenocorticism. In: Bona-
gura JD, ed. Current Veterinary Therapy XIII: Small Animal Practice.
Philadelphia, PA: WB Saunders; 2000: 364366
8. Perez Alenza MD, Guerrero B, Melian C, et al. Use of amino-
glutethimide in the treatment of pituitary-dependent hyperadrenocor-
ticism in the dog. J Small Anim Pract 2002;43:104108.
9. Den Hertog E, Braakman JCA, Teske E, et al. Results of non-selective adrenocorticolysis by o,p-DDD in 129 dogs with pituitary
dependent hyperadrenocorticism. Vet Rec 1999;144:1217.
10. Kintzer PP, Peterson ME. Mitotane (o,p-DDD) treatment of
200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Int
Med 1991;5:182190.
11. Herrtage ME. Canine Hyperadrenocorticism. In: Torrance AG,
Mooney CT, eds. Manual of Small Animal Endocrinology, 2nd ed.
Cheltenham, UK: British Small Animal Veterinary Association; 1998:
5573
12. Ristic JME, Ramsey IK, Heath FM, et al. The use of 17-hy-
droxyprogesterone in the diagnosis of canine hyperadrenocorticism. J
Vet Int Med 2002;16:433439.
13. Chapman RS, Mooney CT, Ede J, et al. Evaluation of the basal
and post-adrenocorticotrophic hormone serum concentrations of 17-
hydroxyprogesterone for the diagnosis of hyperadrenocorticism in
dogs. Vet Rec 2003;153:771775.14. Hoerauf A, Reusch C. Visualisation of the suprarenal glands by
means of ultrasound examination in healthy dogs, in dogs with non-
endocrine diseases, as well as in dogs with hyperadrenocorticism.
Kleintierpraxis 1995;40:351360.
15. Feldman EC, Nelson RW, Feldman MS. Use of low- and high-
dose dexamethasone tests for distinguishing pituitary dependent from
adrenal tumor hyperadrenocorticism in dogs. J Am Vet Med Assoc
1996;209:772775.
16. The Kennel Club. First twenty breeds in registration order for
the years 1989 and 1990. Kennel Gazette April 1991:70.
17. The Kennel Club. Comparative tables of registrations for the
years 19871996 inclusive. Kennel Club Breed Record Supplements,
1996; CXVII(1315);8990.
18. Feldman EC. Hyperadrenocorticism. In: Ettinger SJ, Feldman
EC, eds. Textbook of Veterinary Internal Medicine, 5th ed. Philadel-phia, PA: WB Saunders; 2000:14601488.
19. Dunn KJ, Herrtage ME, Dunn JK. Use of ACTH stimulation
tests to monitor the treatment of canine hyperadrenocorticism. Vet Rec
1995;137:161165.
20. Michell AR. Longevity of British breeds of dog and its rela-
tionship with sex, size, cardiovascular variables and disease. Vet Rec
1999;145:625629.