New Imaging Techniques in the Evaluation of Patients With Ectopic Cushing Syndrome

Between 10 percent and 20 percent of patients with hypercortisolism (Cushing syndrome) have
ectopic production of adrenocorticotropin hormone (ACTH) that causes cortisol excess. In
approximately 50 percent of these patients, the source of ACTH cannot be found despite very
detailed and extensive examination including imaging studies such as computed tomography
scanning, magnetic resonance imaging, and octreotide scan using the conventional low dose of
indium-111 pentetreotide ([(111)In-DTPA-D-Phe]-pentetreotide). The sensitivity and
specificity of these imaging studies depends on anatomic alterations and/or the dose and
adequate uptake of radiopharmaceutical. In contrast, positron emission tomography (PET) has
the ability to detect pathologic tissue based on physiologic and biochemical processes within
the abnormal tissue. This protocol tests whether [18F]-L-3,4-dihydroxyphenylalanine
(18F-DOPA) or use of a higher dose of [111In-DTPA-D-Phe]-pentetreotide can be used to
localize successfully the source of ectopic ACTH production. In addition the study examines
whether administration of the glucocorticoid antagonist mifepristone can improved the
sensitivity of the standard dose [111 In-DTPA-D-Phe] pentetreotide. Patients participating in
this arm of the study will have a second standard dose scan rather than a higher dose scan.
Others will receive a higher dose octreoscan instead.

- INCLUSION CRITERIA:

All eligible patients are invited to participate in this protocol. Patients are adults with
possible ectopic Cushing syndrome. Since both men and women are affected with ectopic
Cushing syndrome, both sexes are studied. All ethnic and racial groups are at risk and will
be included. 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.

Children (age less than18) 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.

Patients taking medications that alter CYP3A4 activity will not be eligible for the
mifepristone study, since this P450 system metabolizes mifepristone. Such participants
would receive a clinical H-OCT instead, if the L-OCT were negative. Patients with
hypokalemia (K < 3.5 mEq/L), despite medical therapy with replacement or mineralocorticoid
antagonists will also be excluded from the mifepristone studies.

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 or leg edema, and
blood pressure over 190/100), abnormal coagulation (PT and PTT elevated by 30 percent
above the normal values), hematopoietic (hematocrit less than 30 percent, hemoglobin
below 10 g/dl, white count below 3000 K/UL, and platelets below 100,000 K/mm(3)),
hepatic (liver enzymes elevated by 3-fold above normal values) or renal function
(plasma creatinine level over 2.0).

- impaired mental capacity or markedly abnormal psychiatric evaluation 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, of greater than
450 ml.

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

- strong evidence for Cushing disease. This includes those with positive IPSS or a
lesion on pituitary MRI.