Cushing Syndrome, Endocrine Disease
Conditions
Keywords
PET, fluorine -18(18F)-DOPA, Pentetreotide, ACTH, Octreotide, Cushing's Syndrome, Ectopic Cushing Syndrome
Brief summary
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 corticotropin (ACTH) in the pituitary gland. 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 computed tomography (CT) scans, magnetic resonance imaging (MRI), 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 abnormal tissue. This study will test whether fluorine-18-fluorodeoxyglucose (FDG), fluorine-18-dihydroxyphenylalanine (F-DOPA) or use of a higher dose of 111-indium pentetreotide can be used to successfully localize the source of ectopic ACTH production.
Detailed description
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 (octreoscan) using the conventional low dose of indium-111 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 fluorine-18 dihydroxyphenylalanine (F-DOPA) or use of a higher dose of indium-111 pentetreotide (Octreoscan) 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 Octreoscan. Eligible patients participating in this arm of the study will have a second standard dose scan. Others will receive a higher dose octreoscan instead.
Interventions
DRUGPentetreotide
Binds primarily to the somatostatin receptors subtypes (sst) 2 and 5. A high dose (18mCi) was used if the conventional dose (6mCi) was negative and scheduling was available. High doses limited to 3 over the course of the study.
DRUG18F-DOPA
18F-DOPA is a radiolabeled amino acid used as a radiotracer in positron emission tomography (PET). Limited to 3 doses over the course of the study.
DEVICECT scan
CT scan of chest, abdomen, neck and /or pelvis
DEVICEMRI
MRI scan of head/pituitary, chest, abdomen, neck and /or pelvis
DRUG18-FDG
FDG PET scan of body
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
Comparison of results in patients receiving similar imaging scans
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* 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 the National Institutes of Health (NIH) Clinical Center 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 high dose (18 mCi) octreoscan (H-OCT) instead, if the standard 6 mCi octreoscan (L-OCT) was negative. Patients with hypokalemia (K \< 3.5 milliequivalent (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 (partial thromboplastin time or prothrombin time elevated by 30 percent above the normal values), hematopoietic (hematocrit less than 30 percent, hemoglobin below 10 g/dl, white count below 3000 K/microliter (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 111-indium pentetreotide or other somatostatin analogues. * strong evidence for Cushing disease. This includes those with positive inferior petrosal sinus sampling or a lesion on pituitary MRI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients | six months or less | The percentage of patients in whom imaging correctly identified an ACTH-secreting non-pituitary tumor within six months of resection or in which imaging identified a recurrence at a site of previous resection. |
| Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions | six months or less | The percentage of lesions for which imaging correctly identified an ACTH-secreting non-pituitary tumor within six months of resection or for which imaging identified a recurrence at a site of previous resection. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited based on physician referral to the NIH Clinical Center from 4/1999 to 12/2015. The first participant enrolled on 5/20/99 and the last participant enrolled on 11/19/15. Of 95 enrolled participants, 68 met inclusion criteria and underwent imaging studies.
Pre-assignment details
27 patients had biochemical testing consistent with Cushing's disease and were excluded from additional participation.
Participants by arm
| Arm | Count |
|---|---|
| Patients With Presumed Ectopic ACTH Secretion Patients receive various types of radiologic or nuclear medicine scans to identify tumor
Pentetreotide: Binds primarily to the somatostatin receptors subtypes (sst) 2 and 5. A high dose (18mCi) was used if the conventional dose (6mCi) was negative and scheduling was available. High doses limited to 3 over the course of the study.
FDG-PET: FDG is a radiolabeled glucose used as a radiotracer in positron emission tomography; FDG-PET deleted as required research study in 2004; thereafter used as clinically indicated.
Fluorine-18 (18F)-DOPA: 18F-DOPA is a radiolabeled amino acid used as a radiotracer in positron emission tomography. F-DOPA scans are limited to 3 over the course of the study.
CT Scans, MRI scans | 68 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 4 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | tumor remained occult | 6 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Patients With Presumed Ectopic ACTH Secretion |
|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 13.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Participants with presumed ectopic corticotropin (ACTH) syndrome | 68 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 53 Participants |
| Region of Enrollment United States | 68 participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 68 |
| other Total, other adverse events | 0 / 65 |
| serious Total, serious adverse events | 0 / 65 |
Outcome results
Primary
Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients
The percentage of patients in whom imaging correctly identified an ACTH-secreting non-pituitary tumor within six months of resection or in which imaging identified a recurrence at a site of previous resection.
Time frame: six months or less
Population: Tumors identified by specific imaging modality in each patient
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CT Scan Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients | 96.3 percentage of patients |
| Magnetic Resonance Imaging (MRI) Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients | 77.1 percentage of patients |
| Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients | 66.7 percentage of patients |
| [18F]-L-3,4-dihydroxyphenylalanine (18F-DOPA) PET Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients | 100 percentage of patients |
| Standard Dose Pentetreotide Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients | 45.1 percentage of patients |
| High Dose (18 mCi) Pentetreotide Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients | 42.9 percentage of patients |
Primary
Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions
The percentage of lesions for which imaging correctly identified an ACTH-secreting non-pituitary tumor within six months of resection or for which imaging identified a recurrence at a site of previous resection.
Time frame: six months or less
Population: Tumors identified by specific imaging modality by lesions
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CT Scan Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions | 75.4 percentage of lesions |
| Magnetic Resonance Imaging (MRI) Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions | 67.3 percentage of lesions |
| Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions | 46.2 percentage of lesions |
| [18F]-L-3,4-dihydroxyphenylalanine (18F-DOPA) PET Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions | 95.8 percentage of lesions |
| Standard Dose Pentetreotide Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions | 40.4 percentage of lesions |
| High Dose (18 mCi) Pentetreotide Results | Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions | 40.9 percentage of lesions |