Evaluation of 68Ga-DOTATATE PET/CT, Octreotide and F-DOPA PET Imaging in Patients With Ectopic Cushing Syndrome

Between 10% and 15% of patients with endogenous hypercortisolism (Cushing syndrome) have
ectopic (non-pituitary) production of adrenocorticotropin hormone (ACTH) that causes cortisol
excess. In approximately 50% of these patients, the tumoral source of ACTH cannot be found
initially despite very detailed and extensive imaging, including studies such as computed
tomography, magnetic resonance imaging, and octreotide scan (Octreoscan) using the standard
dose of indium-111 pentetreotide ([(111)In-DTPA-D-Phe]-pentetreotide). The sensitivity and
specificity of structurally based imaging studies depends on anatomic alterations and the
size of the tumor. In contrast, positron emission tomography (PET) and somatostatin ligand
(like octreotide) imaging detect pathologic tissue based on physiologic and biochemical
processes within the abnormal tissue. This protocol tests the ability of
[18F]-L-3,4-dihydroxyphenylalanine (18F-DOPA) PET, Octreoscan and another somatostatin
imaging analogue, 68Ga-DOTATATE-PET, to localize the source of ectopic ACTH production. The
study also examines whether administration of the glucocorticoid antagonist mifepristone can
improve the sensitivity of the 68Ga-DOTATATE PET/CT.

- INCLUSION CRITERIA:

- Adults with possible ectopic Cushing syndrome

- Age 18-90

- Patients must be willing to return to NIH for follow-up studies.

EXCLUSION CRITERIA:

- Pregnant or lactating women. A pregnancy test is performed in women of childbearing
potential (up to age 55) unless they have a history of hysterectomy and/or bilateral
oophorectomy.

- Children (age less than 18) are excluded. Because ectopic ACTH secretion is rare in
this age group, the likelihood of benefit is less and does not balance the risk of
radiation.

- Very elderly patients (> 90 years)

- For the mifepristone studies only: Patients taking medications that alter CYP3A4
activity will not be eligible for the mifepristone study, since this P450 system
metabolizes mifepristone. Patients with hypokalemia (K < 3.5 mEq/L), despite medical
therapy with replacement or mineralocorticoid antagonists will also be excluded from
the mifepristone studies. Such patients may participate in other components of the
protocol. Medications affecting CYP3A4 may be adjusted to allow participation in the
mifepristone component, with a one week washout period.

- The presence of severe active infection.

- clinically significantly impaired cardiovascular (e.g. history of abnormally low
ejection fraction, the presence of moderate pulmonary fluid overload, and/or blood
pressure over 190/100), abnormal coagulation in the absence of medically-indicated
treatment (PT and PTT elevated by 30% above the normal values), hematopoietic
(hematocrit less than 30%, hemoglobin below 10 g/dl, white count below 3000 K/UL, and
platelets below 100,000 K/mm(3)), hepatic (liver enzymes elevated by 4-fold above
normal values), or renal function (plasma creatinine level over 2.1).

- Based on the clinical judgment of the attending physician, other medical problems may
prompt exclusion.

- impaired mental capacity or markedly abnormal psychiatric condition that precludes
informed consent.

- body weight over 136 kg, which is the limit for the tables used in the scanning areas.

- combined blood withdrawal during the six weeks preceding the study greater 450 ml.

- known allergy to [(111)In-DTPA-D-Phe]-pentetreotide or other somatostatin analogues.

- strong evidence for Cushing s disease. This includes those with a central to
peripheral ACTH gradient during IPSS or a lesion on pituitary MRI. We anticipate that
these exclusion criteria will increase the ratio of patients with ectopic ACTH
syndrome to those with Cushing s disease from the usual 1: 8 to 1: 2, thus we would
accrue 3 patients to identify one with ectopic ACTH secretion.