European Nuclear Medicine Guide
[111In]In-Pentetreotide, also known as Octreoscan™
[99mTc]Tc-hydrazinonicotinyl-Tyr(3)-octreotide, [99mTc]-HYNIC-TOC, also known as Tektrotyd®
The majority of human neuroendocrine tumours (NET), including gastro-entero-pancreatic (GEP) neoplasms, carcinoids, paragangliomas, pheochromocytomas, medullary thyroid carcinomas, small cell lung cancer, and pituitary tumours share distinct tissue characteristics, notably the expression of somatostatin receptors (SSTR). Oncological tissue with variable SSTR density may also be found in other neoplasms, such as meningiomas, neuroblastomas, astrocytomas, lymphomas, Merkel cell tumours, and breast cancer. Increased SSTR expression may also occur in activated immune-reactive cells, such as macrophages and lymphocytes, as well as in vascular endothelial cells (96,97).
The in vivo kinetic of native somatostatin being too fast, its analogues have been proposed for human medical application because of their more favourable in vivo behaviour. Octreotide, the first somatostatin analogue to be individuated, characterized, and clinically used, binds to the five somatostatin receptors (SSTR 1–5). This molecule shows higher affinity for SSTR2 and SSTR5, with lower affinity for SSTR3, and is essentially negligible for SSTR1 and SSTR4 (98).
It has to be pointed out that the in vivo distribution of radiolabelled peptides is influenced not only by the in vitro affinity for SSTR, but also by their radiochemistry, changing the biodistribution on the basis of the different radiolabel, and by the in vivo production of new radiochemical forms, which lead to a non-specific distribution of radioactivity.
Although the definition of theranostics includes the concept of traceability of the therapeutic distribution through the previous diagnostic test, this difference must be carefully considered. In fact, even for small differences that are not clinically significant, the distribution of the companion diagnostic radiotracer may not be completely superimposable to the therapeutic one (99,100).
The importance of this concept can also be understood by checking the pharmacokinetic differences of the different radiotracers used for SPECT and PET as a function of the radionuclide, the chelator, and the labelling dose (101).
At present, two gamma-emitting somatostatin analogues (octreotide) are commercially available: [111In]In-DTPA octreotide (Octreoscan™) and [99mTc-hydrazinonicotinyl-Tyr(3)-octreotide, [99mTc]-HYNIC-TOC ( Tektrotyd®).
On the basis of receptor affinity, in vivo uptake may be observed in NET and other tumours expressing SSTR2 and/or SSTR5, but also in SSTR-negative neoplasms, such as NSCLC, surrounded by active immune-reactive cells, and in benign conditions, including Graves' exophthalmos, sarcoidosis, rheumatoid arthritis, and cardiovascular diseases (102–107).
Conversely, using these radiopharmaceuticals, low or absent uptake is seen in NET with low SSTR2 (or SSTR5) expression, as is the case with most insulinomas and in undifferentiated NET, the presence of SSTR being strongly associated with tumour differentiation (96,97). Thus, the disappearance of uptake in a previously concentrating lesion during follow-up may indicate either a tumour response or, more rarely, de-differentiation. When malignant lesions are suspected, further evaluation with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography ([18F]FDG PET/CT) is recommended, as it exhibits high uptake in undifferentiated neoplasms but not in well-differentiated lesions. Fortunately, NET are more commonly well-differentiated tumors with a favourable prognosis in the majority of cases (97,108).
The main indication for both of these radiopharmaceuticals is as an adjunct in the management of GEP and other NET tumours expressing? SSTR, finding a clinical role in staging, restaging, in functionally confirming a previous diagnosis, and in the selection of patients for peptide receptor radionuclide therapy (PRRT).
Although gamma-emitting radiopharmaceuticals have a lower diagnostic accuracy in NET than the corresponding [68Ga]Ga-SSR-PET, favourable results also being achievable using [18F]-fluoro-DOPA (108), their utilization may be suggested when the corresponding PET radiotracers are not available in specific NET subtypes.
Their use is also indicated in recruiting and defining tumour response in patients with disseminated NET undergoing therapy with radiolabelled somatostatin analogues. Similarly, SPECT SSTR radiotracers may be proposed for experimental or limited use in recruiting patients to undergo therapy with cold somatostatin analogues (or a medical anti-inflammatory therapy), as in GH-secreting pituitary micro-adenoma and in active Graves’ exophthalmos [103,109].
Further experimental or limited use may be found in radio-guided surgery (RGS), either in operable NET with high SSTR expression, such as GEP-NET and pulmonary carcinoids, or in neoplasms concentrating the radiopharmaceutical in vivo, such as NSCLC (110–112).
At present, Tektrotyd® is the first choice when a gamma-emitting somatostatin analogue is required. The use of Octreoscan™ has almost completely disappeared, with indications mainly limited to theranostics and RGS.
• The main contraindication is pregnancy.
• Breastfeeding should be discontinued for 48 hrs after 111In injection and for 24 h following 99mTc injection. Breast milk may be collected and stored beforehand, in order to be provided to the infant during the interruption period (113).
• In patients with severe renal insufficiency, the administration of 111In should be avoided due to the risk of increased radiation exposure.
• In all cases, and in particular for paediatric patients, SSTR-PET is preferred when available due to the shorter half-life of 68Ga compared to SPECT tracers as well as for its better diagnostic accuracy.
In terms of diagnostic accuracy, the superiority of [68Ga]Ga-SSR PET over [111In]In-Pentetreotide is now unequivocally established (114). Therefore, the large majority of papers on the clinical accuracy of [111In]In-Pentetreotide and its clinical role date back many years. Different sensitivity, specificity, NPV and PPV have been reported in different NETs, with higher values in GEP-NETs and carcinoids. A prognostic value and a relationship to the proliferation index may also be obtained when either 2-[18F]FDG PET/CT or SSTR scans are acquired. In fact, while the former is connected with malignancy, i.e. with an increased growing rate and/or de-differentiation, SSTR-SPECT or PET are positive mainly in cases of differentiated tumours (97, 114-123).
To highlight the clinical value of [¹¹¹In]In-Pentetreotide, it is worth noting that a clinical trial by R. Lebtahi et al. showed a 25% change in therapy options in patients with GEP-NET, with respect to a standard diagnostic strategy (124). In managing these patients, better diagnostic results are obtained with SPECT, and even more using SPECT/CT, compared to a traditional planar approach, based on a dual scan performed at 4 and 24 hours.
It is worth underlining that nowadays Octreoscan™ has been largely superseded by SSTR-PET in most clinical settings. Its current use is mainly limited to centres without PET facilities, for PRRT dosimetry, or for radioguided surgery (RGS). In this setting, a possible role can be found in recruitment, dosimetric calculation, and evaluation of tumour response in patients undergoing PRRT (125-127). A further indication remains in RGS of neoplasm, with or without in vitro SSTR expression, when a high in vivo uptake and a favorable tumour/background ratio is demonstrated (110–112). In this context, the application of the [¹¹¹In]In radiotracer is a valuable choice, considering that the longer half-life is an advantage in terms of RGS performance.
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) (103,128).
The clinical indications for Tektrotyd® largely mirror those of Octreoscan™, particularly with regard to the diagnosis, staging, and longitudinal monitoring of GEP-NET and other neuroendocrine tumors, as well as during the patient’s clinical follow-up (129).
In comparison to Octreoscan™, Tektrotyd ® offers several advantages (130). The superior physical properties of [99mTc]Tc over [¹¹¹In]In allow for better imaging with gamma cameras, SPECT and SPECT/CT systems. Its shorter half-life (~6 hours versus 2.8 days) enables a one-day imaging protocol while still permitting kinetic studies at up to 24 hours. Moreover, Tektrotyd® exhibits reduced physiological uptake in the liver and bowel, leading to improved lesion contrast, lower radiation exposure, and the possibility of administering higher doses for a better image quality, in balance with the ALARA principle of ensuring that radiation exposure remains as low as reasonably achievable.
These benefits, along with lower costs and greater availability, position Tektrotyd® as a more favourable alternative for both tumour and non-tumour indications. Additionally, Tektrotyd® has been applied in patients with tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, a rare paraneoplastic syndrome most often caused by small phosphaturic mesenchymal tumours. Recent studies have emphasized the critical role of SSTR-based scintigraphy in the early diagnosis of TIO due to overexpressed SSTR, particularly the SSTR2 subtype (131-133).
An interesting experimental or limited utilization has been leveraged in cardiovascular imaging (134,135). Because activated macrophages in vulnerable atherosclerotic plaques (VAPs) also overexpress SSTR2, radiotracers with high affinity for this receptor may be used to assess coronary artery disease and the risk of acute events. It has already been shown that [99mTc]Tc-octreotide uptake correlates more closely with the presence of coronary plaques than traditional myocardial perfusion imaging such as coronary angiography (135). These studies suggest that SSTR scintigraphy may be a promising, non-invasive modality for the early detection of VAPs and thereby may help in preventing future cardiac events. Due to the well-established relationship between systemic inflammation and the severity of myocardial infarction, another aspect of a possible cardiovascular implication may be found in the identification of risk of post-myocardial infarction in patients who might benefit from anti-inflammatory therapy to prevent adverse remodelling (135).
The administration of the radiopharmaceutical is performed via a single intravenous injection. The suggested activity to administer is:
• [111In]In-Pentetreotide: 110–220 MBq
• [99mTc]Tc-hydrazinonicotinyl-Tyr(3)-octreotide [99mTc]Tc-HYNIC-TOC: 370 to 740 MBq
Advancements in imaging technology allow consideration of lower administered activities while maintaining diagnostic efficacy. It is worth underlining that SPECT/CT with modern detectors can reduce activity by ~30–40%.
For the paediatric population: Although no specific dosage guidelines have been established, the administered activity should be reduced in accordance with European Association of Nuclear Medicine (EANM) paediatric dosage recommendations (EANM Dosage Calculator).
The common administered activity may range between 110–220 MBq. The effective dose for [111In]In-Pentetreotide is 54 µSv/MBq. The organ with the highest absorbed dose is the spleen: 570 µGy/MBq. The standard effective dose per procedure is 12 mSv (107).
The effective dose for [99mTc-hydrazinonicotinyl-Tyr(3)-octreotide, [99mTc]Tc-HYNIC-TOC, is 5 µSv/MBq. The organ with the highest absorbed dose is the kidney: 20 µGy/MBq. The effective dose per procedure is 1.8-3.7 mSv (136).
The radiation exposure related to a CT scan carried out as part of a SPECT/CT study depends on the intended use of the CT study (diagnostic or not), and may differ from patient to patient depending on the scanner and procedure used (137).
To reduce irradiation of the patient, ensure good hydration prior to administration and an increased daily fluid intake accompanied by frequent voiding during the first day after injection.
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-to-background ratio, which is generally higher in pathological lesions, enhancing their detectability. In routine clinical practice, evaluating focal areas of intense radiotracer uptake corresponding to suspected lesions identified on morphological imaging plays a crucial role in diagnostic accuracy. This approach not only facilitates the confirmation of known lesions but also enables the identification of additional foci of intense activity that may represent previously undetected metastatic deposits—such as those in lymph nodes, liver, bones, and other organs—or even reveal an occult primary tumour. Consequently, the availability of SPECT/CT improves staging, treatment planning, and overall patient management.
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 at hepatic level and, because of the presence of physiological intestinal activity, in individuating sub-diaphragmatic abdominal and pelvic lesions, specifically under 1–2 cm. Since the intestinal activity is mobile and variable compared to the pathological activity, a better visual analysis may be obtained by comparing early images with late ones. 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 widely validated 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 SPECT SSTR radiotracers 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, in the tracheal and pulmonary hilar regions. An intense uptake, as reported above, may also be 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 could 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 (138).
Hydration and Urinary Clearance: Adequate hydration is strongly recommended before radiopharmaceutical administration to enhance renal clearance. Patients should also be advised to urinate frequently in the hours following the injection to facilitate radionuclide elimination and minimize radiation dose.
Renal Impairment: In patients with renal insufficiency, the administered activity must be carefully adjusted due to the risk of increased radiation exposure. In cases of severe renal impairment, [111In]In-labelled compounds should be avoided, as renal dysfunction compromises the primary excretory route, leading to prolonged systemic retention and higher absorbed radiation doses. In case of renal insufficiency, the effective dose for [111In]In is 0.19 mSv/MBq, which can result in excessive radiation exposure. Therefore, renal function must be thoroughly evaluated before radiotracer administration.
Haemodialysis Patients: In patients undergoing haemodialysis, interpretable scintigraphic images can be acquired post-dialysis, as part of the circulating radiopharmaceutical is eliminated during the procedure. Pre-dialysis imaging is not recommended due to the high background activity, which impairs diagnostic accuracy. Post-dialysis imaging has demonstrated an increased physiological uptake of the radiotracer in the liver, spleen, and intestines, as well as a persistently elevated circulating activity.
Hepatic Impairment: No dose modification is required in patients with hepatic dysfunction.
Somatostatin Analogue Therapy: In patients receiving SSTR analogues, such as octreotide, a temporary suspension of therapy is suggested by some authors, although there is no consensus on this prescription.
[111In]In-Pentetreotide
Whole-body scans (and/or regional studies on the basis of indications suggested by previous examinations), are performed at 4 and 24 hours after the i.v. injection, and it is possible to acquire images up to 48 hours and later in the event of dubious results. Images acquired at 4 hours are useful for comparison, allowing a preliminary assessment of radiotracer distribution.
For a comprehensive evaluation of abdominal activity, it is generally always recommended to acquire images at 24 hours. A SPECT/CT is also strongly recommended whenever possible at the level of the sub-diaphragmatic area, or whereever there is suspicious uptake to be defined more correctly. If the activity observed at 24 hours cannot be interpreted with certainty as tumour uptake, but appears to be confounded by the intestinal activity, scintigraphy should be repeated at up to 48 hours. This procedure allows for a better differentiation between tumour activity and non-specific radioactivity due to the intestinal contents.
It is therefore essential to acquire at least two sets of images, including at least one SPECT (SPECT/CT) acquisition, to ensure a more accurate and precise evaluation.
This approach ensures clearer imaging and reduces the risk of confusion between tumour uptake and physiological intestinal activity, enhancing the reliability of the diagnostic test.
Physiological uptake occurs in spleen, liver, kidneys, and bladder. Additionally, thyroid, pituitary, and intestines are visible in the majority of patients. These organs typically show physiological radiotracer uptake, which must be differentiated from pathological uptake during the diagnostic process, or with CT when a SPECT/CT is available.
[99mTc]Tc-HYNIC-TOC:
Early images are optional and can be acquired starting 15 minutes after radiotracer injection, with a first scan generally obtained at 1–2 hours. A second set of images is generally obtained at 4 hours, with further scans at up to 24 hours and later in the event of dubious results, particularly in the abdominal region. It is recommended that the examination be performed using the whole-body technique, combined with SPECT or SPECT/CT for selected areas of the body. This approach allows for a more accurate interpretation, especially when differentiating between physiological and pathological uptake.
Further information may be found in the SNMMI practice guideline for somatostatin receptor scintigraphy 2.0 of the Society of Nuclear Medicine (139).