Page 589 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 26 Tumors of the Endocrine System 567

mm in diameter, medical therapy and repeat imaging in 12–18 which may limit its current use in many patients. Selegiline
months should be recommended. For masses greater than 8 mm (l-deprenyl, Anipryl) acts by inhibiting degradation of dopamine,
9
thereby potentially inhibiting ACTH secretion from the inter-
in diameter, RT should be recommended. Unfortunately this
VetBooks.ir approach is not available or feasible for many clients, and medi- mediate lobe of the pituitary gland; unfortunately only 20% of
canine PDH cases arise from disease in this area. Additional dis-
cal therapy alone is often the mainstay of treatment. Theoreti-
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cally, measurement of plasma ACTH precursor concentrations advantages are documented poor efficacy, expense, and inability
could help in the selection of patients for brain imaging because to monitor response with ACTH stimulation testing. Cabergo-
it has been shown that pro-opiomelanocortin/pro-ACTH levels line is a dopamine D2 receptor agonist that also acts to reduce
in plasma are correlated with pituitary tumor size in dogs with pituitary ACTH secretion by increasing dopaminergic tone. In
PDH. However these tests are not commercially available. 37,38 the only published study of cabergoline use in dogs with PDH,
Unfortunately, plasma cortisol concentrations at baseline and 4 17 of 40 dogs showed a favorable clinical response. Decreases
or 8 hours after administration of a low dose of dexamethasone in ACTH concentrations, urine cortisol:creatinine ratios, and
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do not appear to correlate with the development of neurologic pituitary tumor size also were reported. Further studies are
signs. Consequently, there is no readily available, inexpensive, needed before this is likely to become a widely adopted treatment
6
simple diagnostic test that can predict pituitary tumor size in for canine PDH. Bromocriptine is a dopamine agonist and also
dogs with PDH. acts to reduce plasma ACTH concentrations. Because of adverse
effects and lack of demonstrated efficacy, it is not recommended
Treatment of Canine Pituitary-Dependent for treatment of canine PDH. Use of the antiserotoninergic
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Hypercortisolism medication cyproheptadine arose from the hypothesis that exces-
sive ACTH secretion could result from excessive serotoninergic
Medical Therapy stimulation of the pituitary gland. This drug has been shown to
50
Although PDH is a disease of the pituitary gland, most dogs with be ineffective in clinical cases. Retinoic acid also has been used
this disorder are treated with medical therapies that address adreno- in the management of canine PDH. This medication may inhibit
cortical hyperplasia and hyperfunction. The most commonly used pituitary tumor development, reduce ACTH production, and
medications are trilostane and mitotane. Mitotane (o,p′-DDD, inhibit cell proliferation. One study showed promise in terms of
Lysodren) is a potent adrenocorticolytic agent that is cytotoxic a decrease in the size of pituitary tumors and subjective improve-
to the adrenal cortex, particularly the zona fasciculata and zona ment in clinical signs. Unfortunately experience with this med-
51
reticularis. Trilostane (Vetoryl) is an orally active synthetic cor- ication is very limited, particularly when contrasted with proven
ticosteroid analog that competitively inhibits 3-β-hydroxysteroid therapies such as trilostane and mitotane. Availability and cost of
39
dehydrogenase. This enzyme is essential for synthesis of cortisol the appropriate formulation of retinoic acid are also significant
and other steroids, such as corticosterone, androstenedione, and concerns.
aldosterone. Both mitotane and trilostane are widely and suc-
cessfully used in the management of PDH, and each has its own Surgery
advantages and disadvantages. 40–43 A detailed discussion of these Hypophysectomy is the treatment of choice for PDH in
treatment modalities for PDH is beyond the scope of this chap- humans and can be successful in dogs. 2,52–55 Once PDH is
ter, and readers are strongly encouraged to consult any of several diagnosed, if surgical management is an option, advanced
excellent reviews of this subject before initiating medical therapy imaging is required. Both CT and MRI have been used to
in any patient. 9,10 evaluate the pituitary gland before surgery. 53,56–58 The relative
As noted previously, the two medications most commonly size of the pituitary gland is assessed by evaluating the pituitary
used to treat PDH in dogs are trilostane and mitotane. But several height:brain area (P:B) ratio; a P:B ratio >0.31 is consistent
other medications also have been used in dogs with PDH, some with pituitary enlargement. 56,59
of which are targeted against the pituitary lesion in these patients. Transsphenoidal hypophysectomy first was reported in a
When canine pituitary corticotroph adenomas were evaluated large cohort of dogs in 1998. In that study the 1- and 2-year
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for expression of receptors that are potential therapeutic targets estimated survival rates were 84% and 80%, respectively.
for human Cushing’s disease, it was found that canine tumors Forty-three dogs went into remission, and recurrence of HAC
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removed after transsphenoidal surgery expressed a predominance was reported in five dogs. The same group since has published
of somatostatin receptor subtype 2 (SST2), in contrast to human the largest cohort of dogs with PDH treated with transsphe-
tumors, which express predominantly subtype 5 (SST5). Canine noidal hypophysectomy to date, reporting the outcomes in
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tumors express much lower levels of SST5 and express the dopa- 306 dogs. In that study 91% of the dogs survived the 4-week
mine receptor D2 at levels that were described as moderate and perioperative period. The median survival time (MST) was 781
44
comparatively less than expressed in tumors from humans. days, and the median disease-free interval (DFI) was 951 days.
Pasireotide is a somatostatin receptor analog that binds to recep- The recurrence rate was 27%, and recurrence of HAC was diag-
tors of the subtypes SST1, SST2, SS, and SST5. In a small study nosed a median of 555 days from surgery. When the pituitary
of 20 dogs with PDH, pasireotide therapy produced improve- gland size was evaluated using the P:B ratio, dogs with larger
ments in plasma ACTH concentrations, urine cortisol:creatinine tumors had a shorter survival time (ST) and an increased risk
ratios, tumor size, and clinical signs in most dogs, although three of recurrence. Postoperative ACTH and cortisol concentra-
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dogs developed diabetes mellitus. In a more recent study, pasir- tions may give some indication of the risk of residual disease.
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eotide therapy was combined with trilostane therapy (eight dogs) However, this should be evaluated in light of the tumor size,
or mitotane therapy (one dog) in nine dogs with PDH resulting baseline ACTH levels, and individual patient hormone pro-
from a macroadenoma. No adverse effects were noted, and tumor files. Postoperative management includes lifelong admin-
60
volume decreased in six of the nine dogs, but it increased in three istration of thyroid hormone and glucocorticoids, and either
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of the nine. Unfortunately pasireotide is extremely expensive, short- or long-term administration of desmospressin. 53,56