Spontaneous hyperadrenocorticism (HAC) is one of the

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1 J Vet Intern Med 2005;9:80 85 A Comparison of the Survival Times of Dogs Treated with Mitotane or 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 48 dogs treated for pituitary-dependent hyperadrenocorticism were studied using clinical records from 3 UK veterinary centers between 998 and Of these animals, 23 (83.%) were treated with trilostane, while 25 (6.9%) 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 8,97) and for mitotane it was 708 days (range 33,399). There were no significant differences between the survival times for animals treated with trilostane and those treated with mitotane. In the multivariable model ( 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 the most common endocrine diseases of the dog. It results from the overproduction of steroid hormones from the adrenal cortex. The most common cause is a functional pituitary neoplasm, which secretes excessive adrenocorticotropic hormone (ACTH) resulting in overstimulation of the adrenal glands. Pituitary-dependent hyperadrenocorticism (PDH) accounts for approximately 80 85% of cases.,2 The majority of the remaining dogs have functional adrenocortical neoplasms leading to adrenal-dependent hyperadrenocorticism (ADH). The excess adrenocortical hormones can result in a number of nonspecific clinical signs, which are reviewed elsewhere. The majority of the clinical signs, while not immediately life threatening, have a considerable impact on the animal s quality of life. Therefore, this condition is usually 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 options have been described. 3 In North America and, until recently, in Europe, HAC is usually treated with mitotane (o,p DDD), an adrenocorticolytic drug. Recent studies from Europe have found trilostane, a competitive 3 -hydroxysteroid dehydrogenase inhibitor, to be an effective alternative in the treatment of canine PDH. 4,5 In addition, there have been reports of the treatment of HAC using ketoconazole, selegiline hydrochloride, and aminoglutethimide. 6 8 From the Department of Veterinary Clinical Studies, University of Glasgow, Bearsden Road, Bearsden, Glasgow G6 QH Scotland (Barker, Campbell, Tebb, Reid, Ramsey); Small Animal Clinic (Internal Medicine), Justus-Liebig Universität Giessen, Giessen, Germany (Neiger); Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK (Herrtage). This study was previously presented in abstract form at the 47th British Small Animal Veterinary Association Annual Congress, April 4, 2004, Birmingham, UK. Reprint requests: Ian K. Ramsey, Veterinary Clinical Sciences, University of Glasgow Veterinary School, Bearsden Road, Bearsden G6 QH, UK; I.Ramsey@vet.gla.ac.uk. Received September 20, 2004; Revised March 6, 2005; Accepted June 2, Copyright 2005 by the American College of Veterinary Internal Medicine /05/ /$3.00/0 Mitotane binds covalently to adrenal proteins before being converted to a reactive metabolite, resulting in the destruction of adrenal tissue. Destruction of the adrenal cortices can be partial or complete, depending on dose and frequency of administration. Complete destruction results in hypoadrenocorticism requiring long-term steroid replacement therapy. 9 Partial destruction involves induction and maintenance periods. 0 Trilostane is an orally active steroid analogue that acts as a competitive inhibitor of 3 -hydroxysteroid dehydrogenase, interrupting the synthesis of several steroids, cortisol. To date, there have been no studies published that directly compare the use of mitotane to trilostane in the treatment 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 trilostane 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, 998, to July 7, 2003, were reviewed. The centers involved were the Queens Veterinary School Hospital of the University of Cambridge (center ), the Small Animal Hospital 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 st 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 treated medically for PDH with either mitotane or trilostane and that had sufficient case records available were included. Animals that had not been treated, had been managed surgically, or had been given more than drug for the treatment of HAC were excluded. Data obtained from the records included breed, sex, weight at diagnosis, 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, lowand high-dose dexamethasone suppression tests (LDDSTs, HDDSTs), endogenous ACTH plasma concentration assays, and abdominal ultra-

2 Canine Hyperadrenocorticism 8 sonographies were also recorded where these were performed. Animals were grouped into breed categories as defined by the Kennel Club of the United Kingdom (996): 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 990 (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 Russell Terriers 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 elsewhere. HAC was confirmed by the demonstration of an exaggerated increase in circulating cortisol concentration ( 600 nmol/l, 2.6 g/ dl) hour postintravenous administration of tetracosactide. a A small number of cases were included that had unequivocal clinical signs, biochemical markers, and a -hour post-acth cortisol concentration 575 nmol/l (20.7 g/dl). In animals with clinical signs and biochemical 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,.44 g/dl) of cortisol concentration 8 hours after intravenous administration of a low-dose of dexamethasone, b or by an exaggerated increase ( 8.5 nmol/l, 2.83 ng/ml) in circulating 7- hydroxyprogesterone (7-OHP) hour postintravenous administration of tetracosactide. 2,3 The test that confirmed the diagnosis was recorded for each case for later analysis. PDH was diagnosed by a combination of LDDST, HDDST, endogenous ACTH concentration, and abdominal imaging as previously described elsewhere. 2,4,4,5 Treatment Regimen The same treatment protocol was used for each drug in each center. Mitotane therapy involved an induction period followed by a maintenance dose. In the induction period, mitotane c was administered at a dose of 50 mg/kg, up to a limit of,000 mg/dog, until polyphagia or polydipsia resolved and the post-acth cortisol concentration was less than 20 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 20 mmol/l (4.32 g/dl) at the end of induction and during the maintenance phase, and good clinical response to treatment, ie, reduction/elimination of polyphagia and polydipsia, 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 trilostane d were based on body weight and given PO q24h: 5 20 kg, 60 mg: 2 40 kg, 20 mg: 40 kg, mg. 4 The aim of the therapy was to achieve a 4-hour postmedication post- ACTH cortisol concentration of mmol/l ( g/dl) with good clinical control of the HAC. The initial dose and dose frequency were adjusted accordingly. Dogs that had a postmedication post-acth cortisol concentration of mmol/l ( 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 appropriate. Categorical data were compared using a chi-square test. Twotailed 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 survival of 90 days (or about 5% of the previously reported median survival time for dogs treated with mitotane). 0 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), concurrent radiotherapy (n 3), insufficient data (n 8), and equivocal adrenal function results (n 5). There was a marked difference in the treatment regimens preferred by the different centers. Center treated 20 patients (57.%) with mitotane and 5 patients (42.9%) with trilostane. Center 2 treated 5 patients (9.4%) with mitotane and 48 patients (90.6%) with trilostane. Center 3 treated 60 patients (00%) with trilostane and none with mitotane. Center treated HAC in 24 patients (68.6%) where it had been confirmed using ACTH stimulation test, 5 patients (4.3%) using LDDST, and 6 patients (7.%) with 7- OHP assays. Center 2 confirmed HAC in 44 patients (83.0%) using ACTH stimulation test, 7 patients (3.2%) with LDDST, and 2 patients (3.8%) with 7-OHP assays. Center 3 confirmed HAC in 50 patients (83.3%) using ACTH stimulation test and 0 patients (6.6%) using LDDST. There were no statistical differences between the dogs seen by each veterinary center when age at diagnosis (P.7), weight at diagnosis (P.29), and reproductive status (P.25) were compared. There were no statistical differences 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 compared. 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 0 years (mean 9.6 years; SD 2.3; range years). The median weight was 4.45 kg (mean 9.0 kg; SD 2.4; range kg). Seventy-five dogs were male (45 entire, 30 castrated), and 73 dogs were female (20 entire, 53 spayed). Forty-four breeds were represented (the breed group distribution and most frequently seen breeds are listed in Table ). When breed was recorded (90.5%), there was a higher prevalence of animals in the toy (26.%) and terrier (2.6%) groups when compared with national registration statistics for 990 for the toy (20.3%) and terrier (6%) groups. In contrast, gun dogs were relatively underrepresented, with a prevalence of 20.%, compared with 28.2% of registrations. Yorkshire Terriers and their crosses were the most frequently encountered breed type (20/48; 3.5%). However, in 990, Yorkshire Terriers were also the most frequently reg-

3 82 Barker et al Table. Breed group distribution for all centers. The numbers of the most common breeds within each group are shown. Breed Group Gun dog, Hound, Pastoral, Terrier, Toy, Utility, Working, Number 27 Labrador 9 Irish Setter 7 English Springer Spaniel 5 8 Dachshund 4 Collie 7 29 Jack Russell Terrier 7 Staffordshire Bull Terrier 5 Cairn Terrier 4 35 Yorkshire Terrier 20 Cavalier King Charles Spaniel 6 Bichon Frisé 5 0 Poodle 3 Miniature Schnauzer 3 4 Boxer 9 Rottweiler 3 Mixed breed 4 istered breed in the UK, accounting for 9.5% of all dogs registered that year. 6 Mitotane was administered to 25 animals (6.9% of those treated). At date of censorship, 7 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 33,399). Trilostane was administered to 23 animals (83.% 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 8,97). There was no significant difference between the survival times for animals treated with trilostane and those treated with mitotane when compared using log rank (P.62) and Wilcoxon (P.8) methods (Fig ). 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 0.8 [confidence limits 0.73, 0.90] P.00) and weight (hazard ratio 0.78 [confidence limits 0.77, 0.80] P.05) were significantly negatively associated with survival in the final model. The -year survival fraction for animals on mitotane was 62% and the 2-year survival fraction was 48%. The -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% level of 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 (.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 4 (7.0%) died of causes that were felt could have been due to the PDH or its treatment. These Fig. 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.

4 Canine Hyperadrenocorticism 83 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 3 Respiratory disease ( dyspnea, tracheal collapse) 7 Heart disease ( congestive heart failure, atrial fibrillation) 6 Renal failure 5 Gastric dilation and volvulus 3 Neoplasia (not central nervous system) 3 Orthopedic disease ( pressure point ulcers, osteo) 2 Pyometritis Diabetes mellitus Pancreatitis Cervical degenerative radiculomyelopathy Anesthetic complication Vague cause recorded that might be attributable to PDH or its treatment Total 4 Progressive deterioration Old age Collapse Specific cause recorded that is likely attributable to PDH or its treatment Total 9 Neurological signs Suspected hypoadrenocorticism Pulmonary thromboembolism included signs of collapse, progressive deterioration, poor quality of life, and what was described as old age. A further 3 (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.%) 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 reproductive 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 reproductive 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 within 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 populations of dogs with PDH. One study reported a mean age of 0.2 years and median weight of 0.3 kg (mean kg; range kg), 0 while another reported a median age of 9 years and a median weight of 2 kg (range 2 5 kg). 9 The same studies also found no sex predisposition. A high incidence of poodles, Dachshunds, and Yorkshire Terriers has been previously reported. 9,0 In our study, when the breed group distribution was compared with national registration statistics for 990 for the toy, terrier, and gun dog groups, it suggested an overrepresentation of toy and terrier breeds, with an underrepresentation of gun dogs. 6 In particular, the Yorkshire Terrier was frequently encountered. In 990, poodles and Dachshunds only comprised 2.7 and.9%, respectively, of the dogs registered that year in the UK, while Yorkshire Terriers were most popular (9.5%). 7 The differences between study populations are therefore likely to be explained by national variation in breed popularity. No comparison was made with the hospital populations, as these records might be influenced 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 trilostane-treated animals. As a greater proportion of animals in the mitotane group (68%) were dead at censorship compared with trilostane (53%), the median survival time for mitotane-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 mitotane-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 mitotane 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.7 years (mean 2.2; range 0 days to 8.2 years) with a 2-year survival of 47%. 0 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 st-line treatment for PDH. Due to changes in the prescription regulations in the UK

5 84 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 st-line medical treatment for PDH. Mitotane can only be dispensed following treatment failure with trilostane. A prospective study was therefore not possible. In addition, it would not be possible to do a blinded trial, as the treatment protocols are so different. It was also not possible to compare survival times of treated 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 adrenocorticolysis, while others have used nonselective adrenocorticolysis for the treatment of PDH. One study of nonselective adrenocorticolysis with mitotane, where a state of hypoadrenocorticism was induced, reported a 2-year survival fraction of 69%. 9 However, they also reported a loss of.6% animals (5/29) during the induction period, while death from overdosage for selective adrenocorticolysis was reported to occur in less than 2% of cases. 8 Another study reported a median survival time of 30 months for animals with HAC treated with mitotane. 9 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 majority of animals in that study had PDH, animals with ADH were not excluded. 9 Surgical treatment for PDH, in the form of hypophysectomy, has been reported in the literature. 3 A 2-year survival fraction of 82% for dogs that had undergone hypophysectomy 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 institution. 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 treatment but rather failure of other organs (heart, liver, kidneys, etc), unrelated neoplasia, or geriatric diseases (eg, gradual deterioration, incontinence). 0 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 8). 9 However, the group for which signs could possibly 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, % 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 7% 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 euthanasia and at postmortem was very variable. Multivariable analysis in this study also found that weight at survival was significantly negatively correlated with survival, although to a lesser extent than age at diagnosis. 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 assess owner compliance. Previous studies have assessed response to medical therapy. 4,0 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, 0 while in over 70% of dogs with PDH treated with trilostane, their polydipsia/polyuria or polyphagia resolved within the st month of treatment, and many of the remaining dogs had a reduction in the severity of clinical signs with dosage adjustment. 4 This suggests a comparable efficacy between mitotane and trilostane. 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. a b c d e Footnotes Synacthen, Alliance Pharmaceuticals, Chippenham, UK Dexadresson, Intervet UK Ltd, Milton Keynes, UK Lysodren, Bristol-Myers, Canada Vetoryl, Arnolds Veterinary Products, Shrewsbury, UK Minitab; Minitab Inc, State College, PA Acknowledgments The authors would like to thank their veterinary and nursing colleagues at the Universities of Cambridge, Glasgow, 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. Guptill L, Scott-Moncrieff JC, Widmer WR. Diagnosis of canine hyperadrenocorticism. Vet Clin North Am Small Anim Pract 997;27: Gould SM, Baines EA, Mannion PA, et al. Use of endogenous

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