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

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00001849
• Collaborator: (none)
• Enrollment: 95
• Location: 1
• Arm: 1
• Actual Duration (Months): 239.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cushing Syndrome; Endocrine Disease	Drug: Pentetreotide; Drug: 18F-DOPA; Device: CT scan; Device: MRI; Drug: 18-FDG	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 95 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Comparison of results in patients receiving similar imaging scansComparison of results in patients receiving similar imaging scans
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: New Imaging Modalities in the Evaluation of Patients With Ectopic Cushing's Syndrome
• Actual Study Start Date: May 20, 1999
• Actual Primary Completion Date: Apr 26, 2019
• Actual Study Completion Date: Apr 26, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Patients with Cushing Syndrome Patients receive various types of radiologic or nuclear medicine scans to identify tumor

Drug: 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.; Other Names: [111In-diethylenetriaminepentaacetic acid-D-Phe]-pentetreotide ; Drug: 18F-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.; Other Names: 6-fluoro-L-DOPA 56494 ; Device: CT scan; CT scan of chest, abdomen, neck and /or pelvis; Other Names: computed tomography scan ; Device: MRI; MRI scan of head/pituitary, chest, abdomen, neck and /or pelvis; Other Names: magnetic resonance imaging scan ; Drug: 18-FDG; FDG PET scan of body; Other Names: 18-fluorine fluorodeoxyglucose PET scan

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Lynnette K Nieman, M.D., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 6, 2017

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Findling JW, Tyrrell JB. Occult ectopic secretion of corticotropin. Arch Intern Med. 1986 May;146(5):929-33.
• Jex RK, van Heerden JA, Carpenter PC, Grant CS. Ectopic ACTH syndrome. Diagnostic and therapeutic aspects. Am J Surg. 1985 Feb;149(2):276-82.
• Trainer PJ, Grossman A. The diagnosis and differential diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf). 1991 Apr;34(4):317-30. Review.

• Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• ClinicalTrials.gov Identifier: NCT00001849
• Other Study ID Numbers: 990055; 99-CH-0055
• First Posted: Nov 4, 1999
• Last Update Posted: Apr 14, 2021
• Last Verified: Jan 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): PET; fluorine -18(18F)-DOPA; Pentetreotide; ACTH; Octreotide; Cushing's Syndrome; Ectopic Cushing Syndrome
• Additional relevant MeSH terms: Cardiac Complexes, Premature; Cushing Syndrome; Endocrine System Diseases; Syndrome; Edetic Acid; Pentetic Acid

Study Results

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 Detail	27 patients had biochemical testing consistent with Cushing's disease and were excluded from additional participation.

Arm/Group Title	Patients With Presumed Ectopic ACTH Secretion
Arm/Group Description	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: Fluorodeoxyglucose (FDG) is a radiolabeled glucose used as a radiotracer in positron emission tomography (PET); FDG-PET was deleted as a required research study in 2004; thereafter used as clinically indicated. Fluorine-18 dihydroxyphenylalanine (F-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
Period Title: Overall Study
STARTED	68
COMPLETED	54
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Patients With Presumed Ectopic ACTH Secretion
Arm/Group Description	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
Overall Participants	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.1 (13.2)
Sex: Female, Male (Count of Participants)
Female	34 50%
Male	34 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 4.4%
Not Hispanic or Latino	65 95.6%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 4.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	9 13.2%
White	53 77.9%
More than one race	0 0%
Unknown or Not Reported	3 4.4%
Region of Enrollment (participants) [Number]
United States	68 100%
Participants with presumed ectopic corticotropin (ACTH) syndrome (Count of Participants)
Count of Participants [Participants]	68 100%

Outcome Measures

1. Primary Outcome

Title	Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Patients
Description	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

Outcome Measure Data

Analysis Population Description

Tumors identified by specific imaging modality in each patient

Arm/Group Title	CT Scan Results	Magnetic Resonance Imaging (MRI) Results	Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Results	[18F]-L-3,4-dihydroxyphenylalanine (18F-DOPA) PET Results	Standard Dose Pentetreotide Results	High Dose (18 mCi) Pentetreotide Results
Arm/Group Description	Patients receive various types of radiologic or nuclear medicine scans to identify tumor CT Scans of chest, abdomen, neck and/or pelvis are used.	Patients receive various types of radiologic or nuclear medicine scans to identify tumor MRI scans of chest, abdomen, neck, head, and/or pelvis obtained at 1.5 Tesla are shown.	Patients receive various types of radiologic or nuclear medicine scans to identify tumor FDG-PET: FDG is a radiolabeled glucose used as a radiotracer in; FDG-PET deleted as required research study in 2004; thereafter used as clinically indicated.	Patients receive various types of radiologic or nuclear medicine scans to identify tumor 18F-DOPA: F-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.	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 standard dose (6mCi) was negative and scheduling was available. High doses limited to 3 over the course of the study.	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.
Measure Participants	54	48	9	23	51	21
Measure lesions on imaging	69	55	13	24	57	22
Number (95% Confidence Interval) [percentage of patients]	96.3	77.1	66.7	100	45.1	42.9

2. Primary Outcome

Title	Sensitivity of Imaging Modalities for the Detection of ACTH-secreting Non-pituitary Tumor in Specific Lesions
Description	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

Outcome Measure Data

Analysis Population Description

Tumors identified by specific imaging modality by lesions

Arm/Group Title	CT Scan Results	MRI Results	FDG-PET Results	F-DOPA PET Results	Standard Dose Pentetreotide Results	High Dose (18 mCi) Octreotide Results
Arm/Group Description	Patients receive various types of radiologic or nuclear medicine scans to identify tumor CT Scans of chest, abdomen, neck and/or pelvis are used.	Patients receive various types of radiologic or nuclear medicine scans to identify tumor MRI scans of chest, abdomen, neck, head, and/or pelvis obtained at 1.5 Tesla are shown.	Patients receive various types of radiologic or nuclear medicine scans to identify tumor 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.	Patients receive various types of radiologic or nuclear medicine scans to identify tumor 18F-DOPA: F-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.	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 standard dose (6mCi) was negative and scheduling was available. High doses limited to 3 over the course of the study.	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.
Measure Participants	54	48	9	23	51	21
Measure lesions on imaging	69	55	13	24	57	22
Number (95% Confidence Interval) [percentage of lesions]	75.4	67.3	46.2	95.8	40.4	40.9

Adverse Events

Time Frame	Adverse events (AEs) were monitored during each inpatient admission, generally 7 - 14 days.
Adverse Event Reporting Description	AEs within 24 hrs of F-DOPA (ten half-lives rounded up), would be reported to the sponsor. Minor deviations in standard care, such as decisions not to schedule all possible imaging (eg deleting pelvic scans in a patient with a lung mass) will not be reported. Expected AEs (those in the protocol/F-DOPA investigator's brochure, and thromboembolism, hypertension, infection, metabolic derangements, which are common in Cushing's syndrome) would be reported only if they become unanticipated problems.
Arm/Group Title	Patients With Cushing Syndrome
Arm/Group Description	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. 18F-DOPA: F-DOPA is a radiolabeled amino acid used as a radiotracer in positron emission tomography. Limited to 3 doses over the course of the study. CT scan: CT scan of chest, abdomen, neck and /or pelvis MRI: MRI scan of head/pituitary, chest, abdomen, neck and /or pelvis 18-FDG: FDG PET scan of body
All Cause Mortality
	Patients With Cushing Syndrome
	Affected / at Risk (%)	# Events
Total	4/68 (5.9%)
Serious Adverse Events
	Patients With Cushing Syndrome
	Affected / at Risk (%)	# Events
Total	0/65 (0%)
Other (Not Including Serious) Adverse Events
	Patients With Cushing Syndrome
	Affected / at Risk (%)	# Events
Total	0/65 (0%)

Limitations/Caveats

Small number of subjects with this rare disorder; radiation safety risk limited number of some scans; difficulty in scheduling all scans due to lack of availability of slots or radionuclide.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.