Treatment

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ACTH-secreting pituitary tumors Cushings disease
Treatment
Radiotherapy
Medical therapy
?
Surgery
Disease persistence Disease recurrence
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RADIOSURGERY FOR CUSHINGS DISEAE

• CONVENTIONAL IRRADIATION
• LONG TIME TILL EFFECTIVE
• POSSIBLE RISK FOR CVA
• POSSIBLE RISK FOR BRAIN TUM
• GAMMA KNIFE
• GAMMA-RAY PHOTONS
• LINAC
• X-RAY PHOTONS

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LINAC FOR CUSHINGS DISEASE IN ISRAEL

• Beyond physical or theoretical considerations,
  the quality of any treatment has to be judged by
  its clinical results (Spigelmann, IMAJ 2005)
• Similar outcome AV malformations, Acoustic
  Neurinomas, Meningiomas, Brain Metastasis no
  mention of pituitary tumors!
• "???? ????? ???? ????? 6 ????? ?? ???? ??????.
  ???? ??? ??? ?? ???? ??? ????? ?????? " (???????,
  ????? ???? ????, 2005)

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Radiation therapy for Cushings disease a review
(Piruitary, 2002)

• Conventional Radiation
• 10 studies, 255 patients, 64 remissions.
• Gamma Knife
• 8 studies,185 patients, 78 remissions.
• LINAC
• 1 study, 1 patient, ? Remissions.

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Stereotactic radiosurgery for Cushings disease
(Neurosurg Focus, 2004)

• Gamma Knife
• 6 studies, Cure rate 35 90.
• LINAC
• No studies mentioned.

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Stereotactic radiosurgery for pituitary adenomas
a review of the literature (J Neuro-oncology,
2004)

• Gamma Knife
• 18 studies, 227 patients, 55 remissions.
• LINAC
• 2 studies, 6 patients, 33 remissions.

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Efficacy of LINAC vs Gamma knife

• LINAC (Vanderbilt)
• 35 patients
• 17 (49) remissions
• 4 (11) recurrences
• 13 (37) success
• 14 (40) pit insuff.

• Gamma Knife (UVa)
• 45 patients
• 33 (73) remissions
• 4 (9) recurrences
• 29 (64) success
• 14 (31) pit insuff.

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PATIENTS SENT FOR GAMMA KNIFE AT UVa
FOLLOW UP (mo) TIME (mo) REM. TSS NAME
4 24 3 O.A.
9 20 4 S.G.
Response to caberg. 1 ? 2 C.S.
Borderline high UFC 6 ? 1 N.N.
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Compounds employed in Cushings disease

• Acting at peripheral receptor level
• Glucocorticoid antagonist mifepristone
  (RU486)
• Acting at adrenal gland level
• Cytotoxic effect mitotane
• Steroidogenesis inhibitorsmetyrapone,ketoconazol
  e
• Acting at hypothalamic-pituitary level
• Somatostatin analogs octreotide, SOM230
• Dopamin agonists bromocriptine, cabergoline
• PPAR-? binding agents rosiglitazone (avandia)

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METYRAPONE FOR CUSHINGS DISEASE

• Years 1978 1988
• 11 patients, 6F, 5M, ages 15 47.
• Dose 1.25 3.0 gr.
• Duration 8 48 months.
• Basal UFC 543 108 µg/24h.
• Final UFC 85 6.5 µg/24h.

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KETOCONAZOLE FOR CUSHINGS DISEASE

• Years - 1986 1995.
• 11 patients, F11, M 0.
• Dose 600 800 mg.
• Duration 6 85 months.
• Basal UFC 448 76 µg/24h.
• Final UFC 75 6.5 µg/24h.

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ROSIGLITAZONE IN CUSHINGS DISEASE

• RATIONAL
• Rosiglitazone (avandia) is a compound with
  peroxisome proliferator-activated receptor-?
  (PPAR-?) binding affinity.
• It was found to suppress ACTH secretion in mice
  and in pituitary tumor cells.

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SOM230 (pasireotide)

• SOM230 is a novel, multi-ligand, somatostatin
  analog with activity at sst1, 2, 3 and sst5
  receptors
• Compared with octreotide, SOM230 has 30- and
  40-fold higher binding affinity at sst1 and sst5
  receptors, respectively, and comparable affinity
  for sst2 receptors
• SOM230 potentially offers therapeutic benefits in
  classical somatostatin analog indications, such
  as acromegaly and neuroendocrine tumours
• SOM230 potentially offers therapeutic benefits in
  conditions where receptor subtypes other than
  sst2 are important, such as Cushings Disease,
  where 75 are sst5 positive.

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SOM230 IN CUSHINGS DISEASE Boscaro 2005

• Open label, multicenter study.
• Nine Cushings disease patients.
• Fixed dose of SOM230 600 mcg sc bid for 15 days.
• Adverse effects diarrhea, abdominal pain and
  nausea (mild).
• Six patients finished study (unrelated reasons).
• RESULTS
• All patients had reduction of UFC.
• One patients had normalization of UFC 2546
  nmol/24h to 115 nmol/24h.
• Five patients had 17-61 reduction in UFC.

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ACTH-secreting pituitary tumors Background

• Dopaminergic drugs were found to be sporadically
  effective in inhibiting ACTH and cortisol
  secretion in Cushings disease
• Dopamine receptors have never been demonstrated
  on corticotroph pituitary tumours

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ACTH-secreting pituitary tumors Lamberts
Hypothesis
Two different types of ACTH-secreting tumors
may be identified those originating from the
anterior lobe and those originating from the pars
intermedia of the pituitary gland
The ACTH-secreting tumors originating from the
pars intermedia may be sensitive to dopamine
agonists

• The dopamine agonist responsive ACTH-secreting
  tumors may be recognized by
• relative insensitivity to dexamethasone
• hyperprolactinemia
• ACTH suppression after acute administration of
  bromocriptine

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ACTH-secreting pituitary tumors Cabergoline
Experience A case of Nelson Syndrome
1-year treatment with Cabergoline
Pivonello et al., J Clin Endocrinol, 1999
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Aims

• To evaluate dopamine receptor expression on
  corticotroph tumours derived from a series of
  patients with Cushings disease
• To evaluate the effect of 3-month cabergoline
  treatment on ACTH and cortisol secretion in a
  series of patients with Cushings disease

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GROUP 2
In vivo Response to cabergoline treatment and
Immunohistochemical results
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Conclusions

• Dopamine D2 receptors are heterogeneously
  expressed in 75 of ACTH-secreting pituitary
  tumours
• Short-term cabergoline treatment is able to
  induce normalization of ACTH and cortisol levels
  in 50 of cases with Cushings disease
• ACTH and cortisol suppression after cabergoline
  treatment significantly correlated with the
  presence of D2 dopamine receptors on the
  corticotroph tumours
• The presence of the D2 short seems to be
  associated to the best responsiveness of ACTH and
  cortisol to cabergoline treatment.

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GAMMA KNIFE DOSTINEX IN THREE PATIENTS
D
GK
UFC (?g/24h)
TIME (MONTHS)
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CABERGOLINE TREATMENT

• WEEKLY DOSE NEEDED 2 3 MG.
• DOSTINEX (CABERGOLINE) 0.5MG - 8 PILLS IN
  BOTTLE 285 SHEKEL
• 71 SHEKEL PER MG - 855 MONTHLY.
• CABASER (CABERGOLINE) 2.0MG 20 PILLS IN
  BOTTLE 600 SHEKEL
• 15 SHEKEL PER MG 262 MONTHLY.

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ACTH-secreting pituitary tumors Cushings disease
Treatment
Radiotherapy
Medical therapy
?
Surgery
Disease persistence Disease recurrence