Somatostatin Receptor Imaging in Oncology

Richard C. Hom, M.D., Ph.D.

Annick Van den Abbeele, M.D.

November 1, 1994

Case Presentation:

A 69 year old man presented with a history of a persistent cough progressing to dyspnea and unresponsive to antibiotic therapy. A chest X-ray was performed and a 5 cm left hilar lung mass was found. Bronchoscopic biopsy of the lesion revealed a small cell lung carcinoma. Bone scintigraphy (27k bytes) demonstrated increased tracer accumulation in the left anterolateral second rib. Correlation radiographs of the abnormality were nondiagnostic. The patient was treated with ICE-T (Ifosfamide, Carboplatin, Etoposide, and Taxol) for 4 cycles. The patient was further evaluated with a CT scan and an octreoscan.

Findings:

The CT scan (36k bytes) of the patient's chest obtained following therapy demonstrated a marked reduction in the left hilar and subcarinal mass which is almost gone. Because the patient's management depended on whether or not the lesion seen on the bone scan was malignant, an octreoscan (41k bytes) was performed. No abnormal tracer accumulation was seen in the region of the bone scan abnormality seen on bone scintigraphy. There were, however, two foci of increased uptake in the left hilum. The patient was then started on a course of radiotherapy to the left hilum.

Imaging Technique:

The bone scan was performed using a Siemens Bodyscan equipped with a low energy all purpose collimator following the injection of 24.2 mCi of 99mTc-labeled MDP. Static (600K to 1.5M counts/image) and whole body images (2M counts) were obtained using a matrix size of 128 x 128. Indium-111-Octreoscan planar and SPECT images were obtained at 4, 24, and 48 hours following the injection of 6.3mCi of Octreoscan and were acquired using a Siemens MS-2 MultiSpect dual head camera equipped with medium energy collimators for 64 views (2 x 32), 180o, 50 sec/image with a matrix size of 64 x 64. A Butterworth filter was used in the reconstruction of the raw data using a cut-off of 0.6 and an order of 7.

Discussion:

Somatostatin

Somatostatin is a 14-amino-acid peptide hormone found on many cells of neuroendocrine origin. It acts as a neurotransmitter in the central nervous system. Hormonally, when it binds to cells, it inhibits the release of growth hormone, insulin, glucagon, and gastrin. Somatostatin receptors have been demonstrated on the surface of human tumor cells which includes the cells with amine precursor uptake and decarboxylation (APUD) properties such as pituitary tumors, endocrine pancreatic tumors, carcinoids, paragangliomas, small cell lung cancers, medullary thyroid carcinomas and pheochromocytomas. Other non-APUD cells may also bear somatostatin receptors, such as activated lymphocytes, astrocytomas, and some breast carcinoma. Studies have shown that somatostatin analogs may inhibit growth of many of these tumors in vivo in animal studies.

Somatostatin Analogs

Analogs of somatostatin were developed because human somatostatin has a very short half-life in circulation (2-3 minutes) and is easily broken down by endogenous peptidases (Rens-Domiano and Reisine, 1992). The analogs preserved two important molecular features of somatostatin: its cyclic form and the 4 amino acids involved in the binding to the receptor. One somatostatin analog that has been studied in vitro and in vivo extensively is octreotide (SandostatinTM). It has been used as hormonal treatment in patients with carcinoid syndrome.

I-123 Labelled Octreotide Derivative

In vivo studies with the radioiodinated derivative of octreotide have demonstrated the visualization of somatostatin receptor-positive tumors within minutes after the administration of the tracer. The substitution of D-amino acids and alcohol derivatization decreased the degree of enzymatic degradation resulting in a prolonged half-life (approximately 120 minutes). The presence of somatostatin receptors on tumors was found to be predictive of the ability of octreotide to suppress hormonal secretion (Lamberts et al, 1993). It has been used to detect and localize carcinoid, islet cell tumors (Kvols et al, 1993) and small-cell lung cancer (Leitha et al, 1993; Krenning et al, 1993). This compound has not, however, been used extensively because:

the expense of I-123 and its unavailability in certain regions of the world
the time consuming preparation requiring more expertise than most facilities have
the short physical half life of I-123 rendering delayed images difficult to obtain with adequate counts
the extensive biliary tract excretion of the tracer into the bowel making evaluation of intra-abdominal tumors difficult.

In-111 Labelled Octreotide Derivative

To avoid these problems, [In-111-DTPA-D-Phe1]-octreotide was prepared (Bakker, 1991). It was found to have a high affinity for somatostatin receptors and similar biological properties as octreotide. The compound, also called OctreoScan, is easily labeled with In-111. Since this radiotracer is mainly eliminated via the kidneys, intra-abdominal evaluation of somatostatin-receptor positive tumors could be performed.

The normal distribution of the tracer are:

the kidneys and bladder (the route of excretion)
the liver (diffuse low uptake)
the spleen (marked uptake)
the pituitary gland (modest)
thyroid gland (modest)
occasionally the large bowel at 24 hours.

Comparision of I-123 and In-111 labeled Octreotide Derivatives

One small series involving 6 patients (small-cell lung cancer, gastrinoma, insulinoma, carcinoid and pheochromocytoma) had a head to head comparison of I-123-Tyr3-octreotide and [In-111-DTPA-D-Phe1] octreotide scans and demonstrated a more rapid clearance of the former (Krenning, et al, 1992). However, the iodine-labeled compound had a higher background because of degradation products and a higher intestinal background because of biliary excretion. There appeared to be an overall higher sensitivity of the indium-labeled compound in this small series. Insufficient data were provided to compute sensitivity, specificity or accuracy.

Tumor Imaging

Krenning et al (1993) at Rotterdam have published the results of scintigraphy using [In-111-DTPA-D-Phe1]- and [I-123-Tyr3]-octreotide in over 1000 patients with various neuroendocrine tumors and non-neuroendocrine tumors such as brain tumors, breast cancer, non-small cell lung cancers, lymphomas and adenocarcinomas of unknown origin. This was a multicenter study. Some of the data obtained are provided in the table below. The scintigraphy and in vitro studies were not done on the same patients and the number of patients in each group comes from various centers.

In vivo vs. in vitro studies with [In-111-DTPA-D-Phe1]-Octreotide

                              Scintigraphy        In vitro
Medullary thyroid carcinoma   20/28   71%        10/26   38%
Pheochromocytoma              12/14   86%        38/52   73%
Carcinoid                     69/72   96%        54/62   88%
Small cell lung cancer        34/34  100%         4/7    57%
Non-small cell lung cancer    36/36  100%         0/17    0%
Meningiomas                   14/14  100%        54/55   98%
Breast cancer                 37/50   74%        33/72   46%
Non-Hodgkin's Lymphoma        59/74   80%         0/17    0%
Hodgkin's disease             23/24   96%         2/2   100%

Note that tumors that did not express somatostatin receptors such as non-small cell lung carcinoma, were nonetheless imaged. One possible explanation of this finding is that the uptake of tracer is not by the receptor-negative tumor but by the surrounding tissues such as somatostatin receptor-positive white blood cells or neuroendocrine cells nearby the primary tumors. As a matter of fact, in the case of non-small cell lung cancer, only the primary tumor can be visualized, not its metastases. One problem in the interpretation of this multicenter study is the fact that the in vitro studies were not performed on the patients who were imaged. In addition, various methods of obtaining tissues (biopsies, fine-needle aspirations, etc.) may contribute to the differences between scintigraphic and in vitro results. The results of the multicenter study also yielded information about the localizations not known before in 28% of cases, demonstrated uptake in lesions known to exit but not verified as neuroendocrine tumors in 28% of the cases and detected evidence of tumor in patients with clinical and hormonal evidence of tumor but no localization by conventional methods in 37% of the cases. It also demonstrated an overall impact on patient management in 32% of the cases. This included starting octreotide therapy (17%), changing the dose (7%), or performing or canceling surgery (9%).

In a prospective study (Lamberts, 1991), 39/52 (75%) somatostatin receptor positive primary breast carcinoma could be visualized by [In-111-DTPA-D-Phe1]-octreotide imaging. Up to 46% of large breast tumor samples were somatostatin-receptor positive as determined in vitro. No prospective controlled trials have been performed to determine the prognostic implications of a receptor positive breast tumor. Retrospective studies, however, have shown that 82% of patients with receptor positive tumors have a 5-year disease-free survival versus. 46% for patients with receptor negative breast tumors (Foekens et al, 1989).

Leitha et al have studied 20 patients with histologically proven small cell lung cancer with 50 radiologically staged tumor sites using [I-123-Tyr3]-octreotide. The primary tumor site was visualized 84% of the time. Lymph node metastases were seen in 73%. Krenning, on the other hand, using [In-111-DTPA-D-Phe1]-octreotide found the primary tumors and their metastases in 100% of 34 patients with small cell lung cancer. Only the primary tumors were seen in 36 patients with non-small cell carcinoma.

Factors which affect Visualization

Factors which could affect the visualization of somatostatin receptor positive tumors include the secretion of somatostatin by auto-, para- or endocrine production of somatostatin (such as by pheochromocytoma and medullary thyroid carcinoma), treatment by somatostatin analogue, lower affinity of somatostatin analogs by somatostatin receptor subtypes, and variability of receptor expressions by primary tumor and its metastases. Krenning et al has noted a number of caveats which must be considered in the accurate analysis of [In-111-DTPA-D-Phe1]-octreotide studies:

in a patient with an upper respiratory infection, nasal and lung hila uptake can be seen, possibly due to the binding of the tracer to activated lymphocytes
external irradiation can cause local pulmonary accumulation
Bleomycin can also cause pulmonary uptake
the tracer may accumulate at sites of recent surgery and in arthritic sites

While [In-111-DTPA-D-Phe1]-octreotide has been used in the diagnosis and staging of tumors, non-malignant diseases can demonstrate uptake of the tracer:

sarcoidosis (23/23 cases)
Wegener's granulomatosis (4/4)
tuberculosis (6/6)

Summary:

Somatostatin-receptor imaging can be a useful technique for the diagnosis of many tumors of neuroendocrine and non-neuroendocrine origins. A positive finding may be predictive of the ability of octreotide to suppress the neuroendocrine tumors. Other benefits include: absence of human antibody response allowing for repeated administration, whole body imaging, more informed patient management decisions, optimal therapy selection based on tumor biochemistry and monitoring of therapy.

References:

Foekens, JA, H Portengen, WLJ van Putten, AMAC Trapman, JC Reubi, J Alexieva-Figuch, JGM Klijn. Prognostic value of receptors for insulin growth factor 1, somatostatin and epidermal growth factor in human breast cancer. Cancer 1989; 49:7002-7009.

Lamberts, SWJ, WH Bakker, JC Reubi, EP Krenning. Somatostatin receptor imaging in the localization of endocrine tumors. New Engl. J. Med. 1990; 323:1246-1249.

Lamberts, SWJ, EP Krenning and J-C Reubi. The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrine Rev. 1991; 12:450-482.

Rens-Domiano S and T Reisine. Biochemical and functional properties of Somatostatin receptors. J. Neurochem. 1992; 58:1987-1996.

Krenning, EP, WH Bakker, PPM Kooij, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]-octreotide in man: metabolism, dosimetry and comparison with [123I-Tyr-3]-octreotide. J. Nucl. Med. 1992; 33:652-658.

Westlin, J-E, ET Janson, H Ahlstrom, S Nilsson, U Ohrvall and K Oberg. Scintigraphy using a 111Indium-labeled somatostatin analogue for tumor localization of neuroendocrine tumors. Antibody, Immunoconj. and Radiopharm. 1992; 5:367-384.

Krenning, EP, DJ Kwekkeboom, WH Bakker et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1] and [123I-Tyr3]-octreotide: The Rotterdam experience with more than 1000 patients. Eur. J. Nucl. Med., 1993; 20:716-731.

Leitha, T, S Meghdadi, M Studnicka, et al. The role of iodine-123-tyr-3-octreotide scintigraphy in the staging of small -cell lung cancer. J. Nucl Med. 1993; 34:1397-1402.

Lamberts, SWJ, J-C Reubi and EP Krenning. Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors. Acta Oncologica 1993; 32:167-170.

Arnberg, H, J-E Westlin, S Husin and S Nilsson. Distribution and elimination of the somatostatin analogue (111In-DTPA-D-Phe1)-Octreotide (Octreoscan111). Acta Oncologica 1993 32:177-182.

Kvols, LK, ML Brown, MR O'Connor, JC Hung, RJ Hayostek, JC Reubi and SWH Lamberts. Evaluation of a radiolabeled somatostatin analog (I-123 Octreotide) in the detection and localization of carcinoid and islet cell tumors. Radiology 1993 187:129-133.

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J. Anthony Parker, MD PhD, Tony_Parker@bih.harvard.edu