Nuclear Medicine
CLINICAL DECISION SUPPORT
Octreotide is a somatostatin analogue which binds with varying affinity to the five somatostatin receptors (SSTR), a higher affinity for SSTR2 and SSTR5 and a lower affinity for the other three. Octreoscan™ is the radiolabelled analogue of [111In]In-DTPA octreotide. Receptors with a high affinity for [111In]In-Pentetreotide have been found in a wide variety of human neuroendocrine tumours (NET), such as gastro-entero-pancreatic (GEP) neoplasm, carcinoids, paragangliomas, , pheochromocytomas, medullary thyroid carcinomas, small cell lung cancer, and pituitary tumours. An uptake mediated by SSTR expression has also been observed in meningioma, neuroblastoma, astrocytoma, lymphoma, Merkel cell tumours, and breast cancer.
An increased expression of SSTR may be present on activated immune-reactive cells, such as macrophages and lymphocytes, and on vascular endothelial cells. In this sense, an in vivo uptake may be observed not only in NET and other expressing SSTR tumours, but also in SSTR negative neoplasm surrounded by immune-reactive cells, as NSCLC, and in active benign diseases, such as Graves’ exophthalmos, sarcoidosis, and rheumatoid arthritis. Conversely, low or absent uptake is observed in NET with a low expression of SSTR2, as is the case in the majority of insulinoma and in undifferentiated NET where SSTR expression is strongly associated with tumour differentiation. Therefore, the disappearance in follow up of an uptake in the level of a concentrating lesion may be either expression of a tumour response, or, more rarely, of a de-differentiation. When the appearance of malignant lesions is suspicious, patients should be further evaluated with FDG which has an intense uptake in undifferentiated neoplasm but not in differentiated lesions. Fortunately, NET are more frequently tumours with a favourable prognosis and are well differentiated lesions in the large majority of tumour locations.
The main indication of [111In]In-Pentetreotide is as adjunct in the management of GEP and other NET tumours bearing SSTR, finding a clinical role in staging, restaging, and in functionally confirming a previous diagnosis.
Although it has a lower sensitivity in primary tumours than do 68Ga-SSR-PET or [18F]-fluoro-DOPA,, its utilization may be further suggested as adjunct in first diagnosis of NET, when diagnosis has not been reached by a traditional strategy and/or the corresponding PET radiotracers are not available.
Its use is also indicated in recruiting and defining tumour response in patients with disseminated NET undergoing therapy with radiolabelled somatostatin analogues. Similarly, [111In]In-Pentetreotide may be proposed in recruiting patients to be submitted to a therapy with cold somatostatin analogues (or a medical anti-inflammatory therapy), as in GH secreting pituitary micro-adenoma or in Graves’ exophthalmos.
[111In]In-Pentetreotide may be also used in radio-guided surgery, either in operable SSTR highly expressing NET, as GEP NET, pulmonary carcinoids, other surgically removable tumours, or in vivo concentrating the radiopharmaceutical as for NSCLC and many brain tumours.
Currently [111In]In-Pentetreotide is the only ubiquitously available NET radiotracer which is licensed across the EU.
In all the cases above, either for the shorter half-life of 68Ga compared to 111In and for its better diagnostic accuracy, SSR-PET is preferred when available.
The large majority of papers on clinical accuracy of 111In-Pentetreotide, mainly concerning its sensitivity and specificity in GEP and other SSTR expressing NET, date back many years. The clinical trial by R. Lebtahi et al showed a 25% change in therapy options and 24% in surgical treatment in patients with GEP-NET [264]. In the management of these patients, better diagnostic results are obtained with SPECT and SPECT/CT compared to a traditional planar approach. However, in terms of diagnostic accuracy, the superiority of Ga-68 DOTA-PET over 111In-Pentetreotide is now unequivocally established.
A further role for [111In]In-Pentetreotide might be found in recruitment, dosimetric calculation, and evaluation of tumour response in patients undergoing Peptide Receptor Radiotherapy. An increased utilization could be suggested in RGS of neoplasm, with or without in vitro SSTR expression, when increased in vivo uptake of the radiotracer is shown with a favourable tumour/background ratio. Further studies could support the demonstration of clinical usefulness in helping to define therapeutic strategies in patients with pituitary adenomas or with inflammatory lesions which show a high uptake determined by an increased concentration of activated reactive cells (lymphocytes or macrophages).
The suggested activity to administer is:
The effective dose for [111In]In-Pentetreotide is 54 µSv/MBq [3]. The organ with the highest absorbed dose is the spleen: 570 µGy/MBq.
The effective dose for [111In]In-Pentetreotide is: 12 mSv per procedure.
The radiation exposure related to a CT scan carried out as part of an SPECT/CT study depends on the intended use of the CT study and may differ from patient to patient. To reduce irradiation of the patient, good hydration before the administration and an increasing daily fluid intake accompanied by frequent voiding during the first day after injection should be adopted.
Caveat:
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
Visual assessment is influenced by the Lesion/Background ratio. Although visual analysis is fairly simple at the level of pulmonary carcinoids in the absence of normal activity at the level of lungs, obtaining results is more difficult, because of the presence of physiological intestinal activity in individuating sub-diaphragmatic abdominal and pelvic lesions, specifically lesions under 1-2 cm. Since the intestinal activity is mobile and variable compared to the pathological one, a better visual analysis may be obtained by comparing images obtained at 4 and 24 h after injection. A significant improvement, mainly in individuating primary lesions and liver metastases, may be obtained using SPECT, and even more so SPECT/CT, which should be regarded as the method of choice.
There are no reliable quantitative or semi-quantitative methods allowing further improvement in clinical analysis. False negative results are the greatest problem. Major pitfalls, significantly reduced when SPECT/CT is available, are more frequently observed at the level of sub-diaphragmatic lesions. Physiological uptake may be observed at the level of the gallbladder and in the uncinated process of the pancreas.
Concentration of [111In]In-Pentetreotide by immune-reactive cells is possible, such as activated lymphocytes or macrophages, and false positive results may be observed at the level of inflamed lesions. This might be observed in the nasopharynx and, to a lesser extent, at the level of tracheal and pulmonary hilar areas. An intense uptake, as reported above, may be also observed in patients affected with diseases such as sarcoidosis, rheumatoid arthritis, and Graves’ exophthalmos when examined in their active phase. In the opinion of some authors, the sensitivity may be negatively influenced by the administration of somatostatin analogue therapy, so such therapy must be discontinued. However, this opinion is not shared by all the authors. Diffuse pulmonary or pleural accumulation can be observed after radiation therapy to the thoracic area or following bleomycin therapy. The tracer may also accumulate in areas of recent surgery and at colostomy sites.
Hydration prior to administration and increasing the daily fluid intake and the voiding during the first day after injection is suggested. The examination is contraindicated in patients with renal failure, and it must be carefully evaluated in patients with diabetes who take high insulin doses. Although there is no rigorous clinical evidence, it is suggested by many investigators to discontinue somatostatin analogue therapy, when this suspension is clinically feasible. Although widely adopted, after consent of the treating physician and mainly in centres without a SPECT/CT, there is no general consensus regarding the administration of laxatives (in patients not suffering from diarrhoea) to minimize the potential of artefacts in the intestine.
Detailed recommendations are available in the EANM Oncology Guidelines.