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8/4/2019 A Comparison of the Survival Times of Dogs Treated With Mitotane or Trilostane for Pituitary-Dependent Hyperadre

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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-


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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-


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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


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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


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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.

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