Cushing Syndrome is an endocrine disorder causing an over production of the hormone cortisol.
Cortisol is produced in the adrenal gland as a response to the production of ACTH in the
Between 10% and 20% of patients with hypercortisolism (Cushing Syndrome) have ectopic
production of the hormone ACTH. Meaning, the hormone is not being released from the normal
site, the pituitary gland. In many cases the ectopic ACTH is being produced by a tumor of the
lung, thymus, or pancreas. However, in approximately 50% of these patients the source of the
ACTH cannot be found even with the use of extensive imaging studies such as CT scans, MRIs,
and nuclear scans (111-indium pentetreotide). The ability of these tests to locate the source
of the hormone production is dependent on the changes of anatomy and / or the dose and
adequate uptake of the radioactive agent. The inability to detect the source of ectopic ACTH
production often results in unnecessary pituitary surgery or irradiation.
Unlike the previously described tests, positron emission tomography (PET scan) has the
ability to detect pathologic tissue based on physiologic and biochemical processes within the
This study will test whether [18-F]-fluorodeoxyglucose (FDG) or use of a higher dose of
[111In-DTPA-D-Phe]-pentetreotide can be used to successfully localize the source of ectopic
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.
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
- 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
- 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.