PROCEDURE GUIDELINES Procedure Guideline for Somatostatin Receptor Scintigraphy with 111In-Pentetreotide

Helena R. Balon, Stanley J. Goldsmith, Barry A. Siegel, Edward B. Silberstein, Eric P. Krenning, Otto Lang, and Kevin J. Donohoe

William Beaumont Hospital, Royal Oak, Michigan; New York Hospital–Cornell Medical, New York, NY; Mallinckrodt Institute of Radiology, St. Louis, Missouri; University of Cincinnati Medical Center, Cincinnati, Ohio; Beth Israel Deaconess Medical Center, Boston, Massachusetts; University Hospital Dijkzigt, Rotterdam, The Netherlands; and Third Medical School, Charles University, Prague, Czech Republic

● Paraganglioma. Key Words: guideline; octreotide; somatostatin receptor ● Pituitary adenomas. J Nucl Med 2001; 42:1134–1138 ● Small cell lung carcinoma.

Other tumors and disease processes may also be detected by 111In-pentetreotide scintigraphy and knowledge of the PART I: PURPOSE patient’s history is thus important. These disorders may The purpose of this guideline is to assist nuclear medicine include, but are not limited to, the following: practitioners in recommending, performing, interpreting, and reporting the results of somatostatin receptor scintigra- ● Astrocytomas. phy with 111In-pentetreotide. ● Benign and malignant bone tumors. ● Breast carcinoma. PART II: BACKGROUND INFORMATION AND ● Differentiated thyroid carcinoma (papillary, follicular, DEFINITIONS and Hu¨rthle cell). 111In-pentetreotide is a [111In-DTPA-D-Phe-] conjugate of ● Lymphoma (Hodgkin’s and non-Hodgkin’s). octreotide, a somatostatin analog that binds to somatostatin ● Meningioma. receptors (predominantly somatostatin receptor subtypes ● Non–small cell lung carcinoma. sst2 and sst5). This octapeptide concentrates in neuroendo- ● Prostate carcinoma. crine and some nonneuroendrocrine tumors containing so- ● Renal cell carcinoma. matostatin receptors. Tumors that may be detected by so- ● Sarcomas. matostatin receptor scintigraphy with 111In-pentetreotide ● Autoimmune diseases (e.g., rheumatoid arthritis, include, but are not limited to, the following: Graves’ disease, and Graves’ ophthalmopathy). ● Bacterial pneumonia. ● Adrenal medullary tumors (pheochromocytoma, neu- ● Cerebrovascular accident. roblastoma, and ganglioneuroma). ● Fibrous dysplasia. ● Gastroenteropancreatic tumors (e.g., gastrinoma, insu- ● Granulomas (e.g., tuberculosis and sarcoid). linoma, glucagonoma, vasoactive intestinal polypep- ● Radiation pneumonitis. tide secreting tumor [VIPoma], and nonfunctioning gastroenteropancreatic tumors). In addition to these tumors, healthy organs, such as the ● Carcinoid tumors. pituitary, thyroid, spleen, liver, and renal parenchyma, also ● Medullary thyroid carcinoma. show avidity for this tracer. The gallbladder, bowel, renal ● Melanoma. collecting systems, ureters, and urinary bladder are seen as ● Merkel cell tumor of the skin. a result of clearance of 111In-pentetreotide.

For correspondence or reprints contact: Louis Morgan, Associate Director, PART III: COMMON INDICATIONS Health Care Policy, Society of Nuclear Medicine, 1850 Samuel Morse Dr., Reston, VA 20190-5316 or by e-mail at [email protected]. Note: All SNM-approved procedure guidelines are available on the Soci- A. Detection and localization of a variety of suspected ety’s home page. We encourage you to download these documents through neuroendocrine and some non-neuroendocrine tumors the Internet at www.snm.org. If you would like to order a compendium of all procedure guidelines, contact the SNM Service Center at (703) 326-1186 or and their metastases (see Interpretation Criteria, Sec- by e-mail at [email protected]. tion IV.H).

1134 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 42 • No. 7 • July 2001 B. Staging patients with neuroendocrine tumors. TABLE 1 C. Determination of somatostatin receptor status (pa- Radiation Dosimetry for Adults tients with somatostatin receptor–positive tumors may Organ Effective be more likely to respond to octreotide therapy). receiving the dose D. Follow-up of patients with known disease to evaluate Administered largest dose equivalent potential recurrence. activity MBq mGy/MBq mSv/MBq E. Selection of patients with metastatic tumors for pep- Radiopharmaceutical (mCi) (rad/mCi) (rem/mCi) tide receptor radionuclide therapy and prediction of 111In-pentetreotide spleen the effect of peptide receptor radionuclide therapy, 222 0.665 0.117 where available. (6) (2.46) (0.433)

PART IV: PROCEDURE Data adapted from (11).

A. Patient Preparation 1. When appropriate, consideration should be given in the blood pool at 10 min, 1% at 20 h after injec- to discontinuing octreotide therapy for 24 h before tion). Excretion is almost entirely through the kidneys 111In-pentetreotide administration, as the patient is (50% of the injected dose is recovered in the urine by monitored for signs of withdrawal. See also Sec- 6 h, 85% within 24 h). Hepatobiliary excretion is only tion IV.K.2.a. about 2% of the administered dose. It is not known 2. To reduce the radiation exposure, patients should whether 111In-pentetreotide is removed by dialysis. be well hydrated before and for at least 1 d after E. Image Acquisition injection. 1. Patients should void before imaging. 3. The use of laxatives should be considered, espe- 2. Images are acquired at 4 and 24 h or 24 and 48 h cially when the abdomen is the area of interest. A after injection. The 48 h images may be needed mild oral laxative (e.g., bisacodyl or lactulose) when there is significant bowel activity at 24 h, may be administered in the evening before injec- which may potentially obscure lesions. Four-hour tion and in the evening after injection. The need images may be obtained to enable evaluation be- for bowel preparation should be assessed on an fore appearance of activity in the gut, but since individual basis and laxatives should not be used tumor-to-background ratio is lower at 4 h than at in patients with active diarrhea. 24 and 48 h, some lesions may be missed at 4 h. B. Information Pertinent to Performing the Procedure 3. Planar images are acquired using a large-field-of- A relevant history of the type of suspected or view gamma camera fitted with a medium-energy known primary tumor, its hormonal activity, the re- collimator. Symmetrical 20% energy windows are sults of other imaging studies (CT or MRI), labora- centered over both photopeaks of 111In (173 and tory results (tumor markers), history of recent sur- 247 keV) and the data from both windows are gery, chemotherapy, radiation therapy, and octreotide added. Planar localized images of the head, chest, therapy should be obtained. History of cholecystec- abdomen, pelvis, and, if needed, the extremities tomy should also be noted. can be acquired for 10–15 min/image, using a C. Precautions 512 ϫ 512 word matrix or 256 ϫ 256 word matrix. 1. In patients suspected of having insulinoma, an Occasionally, images may be required in areas intravenous infusion of glucose should be avail- with low tracer activity. If this is the case, images able because of the potential for inducing severe should be acquired in a suitable byte mode acqui- hypoglycemia. sition matrix. For whole-body images using a dual- 2. 111In-pentetreotide should not be injected into in- head camera, it is suggested that anterior and pos- travenous lines for, or together with solutions for terior images be acquired into a 1024 ϫ 512 word total parenteral nutrition. matrix or 1024 ϫ 256 word matrix for a minimum D. Radiopharmaceutical (see Table 1) of 30 min (head to upper femurs) and longer for 111In-pentetreotide is a [111In-DTPA-D-Phe-] conju- the entire body (e.g., a speed of 3 cm/min has been gate of octreotide, a long-acting somatostatin analog suggested) in a single pass. Since cervical lymph (OctreoScan). The recommended administered activ- node metastases may be missed on the whole-body ity is 222 MBq (6 mCi) in adults and 5 MBq/kg (0.14 images, additional planar localized images of the mCi/kg) in children. The amount of pentetreotide head and neck, including lateral views, are sug- injected is 10–20 ␮g; that dose is not expected to have gested. a clinically significant pharmacologic effect (see Sec- SPECT imaging of the appropriate regions, as tion IV.C.1). 111In-pentetreotide is cleared rapidly indicated based on the clinical history, should be from the blood (one third of the injected dose remains performed preferably with a multi-detector gamma

PROCEDURE GUIDELINE FOR SOMATOSTATIN RECEPTOR SCINTIGRAPHY WITH 111IN-PENTETREOTIDE • Balon et al. 1135 camera. Early and delayed SPECT may be helpful cept for insulinoma, where it may be as low as in distinguishing bowel activity from pathological 50%–60%, because of the presence of different lesions. If only one SPECT acquisition is obtained, somatostatin receptor subtypes on this tumor. acquisition at 24 h is preferred because of higher 6. Pheochromocytomas, neuroblastomas, and para- target-to-background ratio. gangliomas: The advantage of somatostatin recep- Although imaging systems may vary, an exam- tor scintigraphy with 111In-pentetreotide is the ple of potentially useful acquisition parameters for ability to detect primary lesions and metastases in a multi-detector system are the following: 3° an- unexpected (extra-adrenal) sites not investigated gular sampling, 128 ϫ 128 matrix, 360° rotation, by CT or MRI. Tumors in the adrenal glands may 20–30 s/stop. be difficult to detect because of high renal activity; For more information see the Society of Nuclear imaging with 131I- or 123I-metaiodobenzylguani- Medicine Procedure Guideline for General Imaging. dine may be preferable for tumor localization in F. Interventions the adrenal area. The sensitivity of 111In-pentet- None reotide for these tumors is over 85%. G. Processing 7. Medullary thyroid carcinoma: The sensitivity of See the Society of Nuclear Medicine Procedure 111In-pentetreotide scintigraphy may be lower than Guideline for General Imaging. for other tumors (65%–70%). Comparison with In general, SPECT raw data are prefiltered using an 99mTc sulfur colloid scintigraphy for liver metas- appropriate low-pass filter, with the order and fre- tases or with 123I scintigraphy for intrathyroidal quency set according to local preferences and soft- tumors may increase the rate of lesion detection, ware manufacturer recommendations. The data are especially when the uptake of 111In-pentetreotide then reconstructed using a ramp filter and attenuation in these organs is homogeneous. correction. Newer systems may include iterative re- 8. Carcinoid: The overall sensitivity of 111In-pente- construction algorithms, which may eliminate some treotide scintigraphy is approximately 86%–95%. of the artifacts seen with filtered backprojection in For extrahepatic lesions, sensitivity for lesions areas adjacent to intense tracer activity. over 1 cm in diameter may exceed 90%; however, H. Interpretation Criteria hepatic lesions may be isointense. SPECT imag- 1. When possible, images should be evaluated in ing of the liver is recommended even if the planar conjunction or fused with relevant anatomic im- images appear normal. ages (e.g., CT or MRI). 9. Intracranial tumors: Meningiomas are rich in so- 2. The optimal time interval to localize tumors is at matostatin receptors and are therefore highly de- 24 h after injection or later. At 4 h the background 111 activity may be high. Nevertheless, early images tectable. In-pentetreotide scintigraphy may be may be important for comparison and evaluation used for postoperative follow-up of this tumor. of abdominal activity imaged at 24 h. Grade I and II astrocytomas are also somatostatin 3. Images are best viewed at the computer display receptor–positive, grade III astrocytomas may with individualized physician-directed optimiza- or may not be, whereas grade IV (glioblastoma tion of intensity and contrast. Three-dimensional multiforme) is typically somatostatin receptor– 111 rendering of the SPECT data and its review in negative. Localization of In-pentetreotide in an cinematic display is encouraged. astrocytoma also requires that the blood–brain 4. Knowledge of normal tissue accumulation of barrier be impaired. 111In-pentetreotide is important for study interpre- 10. Lung carcinoma: The sensitivity for primary sites tation. This radiotracer is seen in the pituitary, of disease is reported to be 80%–100% for small thyroid, liver, spleen, kidneys, bladder, and occa- cell lung cancer, and it may be lower for non– sionally the gallbladder. Intestinal activity is usu- small cell lung cancer. ally not present at 4 h, but may be present at 24 h; I. Reporting images at 48 h may be necessary to clarify ab- In addition to the general information to be pro- dominal activity. vided in each Nuclear Medicine report as recom- 5. Islet cell tumors: Peptide hormone-producing mended in the Society of Nuclear Medicine Guideline endocrine tumors of the pancreas and gastroin- on General Imaging (Section VI.D), it is suggested testinal tract and their metastases, including that the report contain the following information: gastrinomas, insulinomas, vasoactive intestinal 1. Indication: Results of laboratory tests (e.g., neu- polypeptide-secreting tumors, and glucagono- roendocrine tumor markers if applicable), or re- mas, as well as nonfunctioning islet cell tumors, sults of other imaging studies as well as other may be imaged with 111In-pentetreotide. The relevant history (known tumor and its type, recent sensitivity for these lesions is 75%–100% ex- radiation therapy, and chemotherapy).

1136 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 42 • No. 7 • July 2001 2. Relevant medications: For example, octreotide eration, especially with insulinomas and med- therapy and, when stopped, chemotherapy and/or ullary thyroid carcinomas. laxatives, if given. c. Liver metastases of neuroendocrine tumors 3. Procedure description: Timing of imaging relative may appear isointense because of a similar de- to radiopharmaceutical administration; areas im- gree of tracer accumulation by the normal liver. aged; whether SPECT was performed and, if so, its Correlation with anatomic imaging or subtrac- timing and body areas included. tion scintigraphy with sulfur colloid may be 4. Study limitations: The referring physician may be considered. reminded that some tumors may lack somatostatin receptors or the appropriate receptor subtypes and, PART V: ISSUES REQUIRING FURTHER therefore, may not be detected. The differential CLARIFICATION diagnosis should consider the many potential causes for a false-positive study, as listed in Sec- 1. Because 111In-pentetreotide elimination in patients tion IV.K.1. with impaired renal function has not been studied, J. Quality Control possible dosage adjustment in these patients needs to 1. Before the administration of 111In-pentetreotide, be clarified. the labeling yield of the radiopharmaceutical 2. The role of 111In-pentetreotide scintigraphy in breast should be tested according to the manufacturer’s carcinoma, renal cell carcinoma, Hodgkin’s and non- instructions. The product should not be used if Hodgkin’s lymphoma, and other tumors (see Section radiochemical purity is less than 90%. II), as well as in the evaluation and management of 2. The radiopharmaceutical should be used within 6 h some granulomatous and autoimmune processes (e.g., of preparation. activity of sarcoidosis, response of Graves’ ophthal- 3. 111In-pentetreotide should be inspected visually mopathy to steroids, etc.) is yet to be determined. before administration. Preparations containing 3. This procedure guideline only covers imaging with particulate matter or color should not be adminis- 111In-pentetreotide. Imaging with other somatostatin tered. analogs (e.g., 99mTc-depreotide) is not a subject of this K. Sources of Error guideline. 1. Potential causes for a false-positive interpretation: a. Accumulation of 111In-pentetreotide in the nasal PART VI: CONCISE BIBLIOGRAPHY and pulmonary hilar areas can be seen with respiratory infections. 1. Gibril F, Reynolds JC, Chen CC, et al. Specificity of b. Diffuse pulmonary or pleural accumulation of somatostatin receptor scintigraphy: a prospective study and 111In-pentetreotide can be observed after radia- effects of false-positive localizations on management in tion therapy to the lung or bleomycin therapy. patients with gastrinomas. J Nucl Med. 1999;40:539–553. c. The tracer may accumulate at recent surgical 2. Gibril F, Reynolds JC, Doppman JL, et al. Somatostatin and colostomy sites. receptor scintigraphy: its sensitivity compared with that of d. Accumulation of the tracer in normal structures other imaging methods in detecting primary and metastatic gastrinomas. Ann Intern Med. 1996;125:26–34. (pituitary, thyroid, liver, spleen, kidneys, 3. Hochstenbag MM, Heidendal GAK, Wouters EFM, at al. bowel, gallbladder, ureters, bladder, or stimu- In-111 octreotide imaging in staging of small cell lung lated adrenal glands) and in multiple disorders cancer. Clin Nucl Med. 1997;22:811–816. (some listed in Section II) must be kept in 4. Jamar F, Fiasse R, Leners N, et al. Somatostatin receptor mind. Caution must be used to avoid interpret- imaging with indium-111-pentetreotide in gastroenteropan- ing physiologic gallbladder activity as hepatic creatic neuroendocrine tumors: safety, efficacy and impact metastasis. on patient management. J Nucl Med. 1995;36:542–549. 2. Potential causes for a false-negative interpretation: 5. Klutmann S, Bohuslavizki KH, Brenner W, et al. Soma- a. Presence of unlabeled somatostatin, either as a tostatin receptor scintigraphy in postsurgical follow-up ex- result of octreotide therapy or because produc- aminations of meningioma. J Nucl Med. 1998;39:1913– tion of somatostatin by the tumor itself may 1917. lower tumor detectability; however, there are 6. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Soma- tostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- also literature reports of improved tumor-to- and [123I-Tyr3]-octreotide: the Rotterdam experience with background ratio after pretreatment with non- more than 1000 patients. Eur J Nucl Med. 1993;20:716– radioactive octreotide. 731. b. Different somatostatin receptor subtypes have 7. Krenning EP, Kwekkeboom DJ, Pauwels S, et al. Soma- different affinities for the radioligand; variable tostatin receptor scintigraphy. Nucl Med Annual. 1995:1– tumor differentiation/receptor expression also 50. influences tumor detectability. This is a consid- 8. Kwekkeboom DJ, Krenning EP, Kho GS, et al. Somatosta-

PROCEDURE GUIDELINE FOR SOMATOSTATIN RECEPTOR SCINTIGRAPHY WITH 111IN-PENTETREOTIDE • Balon et al. 1137 tin receptor imaging in patients with sarcoidosis. Eur J Nucl trum of patients seen in a specialized practice setting may be Med. 1998;25:1284–1292. quite different than the spectrum of patients seen in a more 9. Kwekkeboom DJ, Krenning EP. Radiolabeled somatostatin general practice setting. The appropriateness of a procedure analog scintigraphy in oncology and immune diseases: an will depend in part on the prevalence of disease in the overview. Eur Radiol. 1997;7:1103–1109. patient population. In addition, the resources available to 10. Lebtahi R, Cadiot G, Sarda L, et al. Clinical impact of care for patients may vary greatly from one medical facility somatostatin receptor scintigraphy in the management of patients with neuroendocrine gastroenteropancreatic tu- to another. For these reasons, guidelines cannot be rigidly mors. J Nucl Med. 1997;38:853–858. applied. 11. OctreoScan package insert. Mallinckrodt Medical Inc. Advances in medicine occur at a rapid rate. The date of a March 1995. guideline should always be considered in determining its 12. Olsen JO, Pozderac RV, Hinkle G, et al. Somatostatin current applicability. receptor imaging of neuroendrocrine tumors with indium- 111-pentetreotide (OctreoScan). Semin Nucl Med. 1995;25: PART VIII: LAST HOUSE OF DELEGATES APPROVAL 251–261. DATE 13. Reisinger I, Bohuslavitzki KH, Brenner W, et al. Soma- February 11, 2001 tostatin receptor scintigraphy in small-cell lung cancer: results of a multicenter study. J Nucl Med. 1998;39:224– 227. PART IX: NEXT ANTICIPATED APPROVAL DATE 14. Schmidt M, Scheidhauer K, Luyken C, et al. Somatostatin 2004–2005 receptor imaging in intracranial tumors. Eur J Nucl Med. 1998;25:675–686. ACKNOWLEDGMENTS The authors thank Louis N. Morgan, PhD, CNMT, FS- PART VII: DISCLAIMER NMTS, Associate Director, Health Care Policy, Society of The Society of Nuclear Medicine has written and ap- Nuclear Medicine, and Sandra Griffith, CNMT, former As- proved guidelines to promote the cost-effective use of high- sociate Director, Health Care Policy, Society of Nuclear quality nuclear medicine procedures. These generic recom- Medicine, for project coordination, data collection, and ed- mendations cannot be applied to all patients in all practice iting. The authors thank J. Anthony Parker, MD, PhD, settings. The guidelines should not be deemed inclusive of Henry Royal, MD, and Donald Podolff, MD, who contrib- all proper procedures or exclusive of other procedures rea- uted their time and expertise to the development of this sonably directed to obtaining the same results. The spec- information.

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