Peptide Receptor-targeted Radionuclide Therapy Research Articles

Démarche d’optimisation des modalités de gestion des déchets lors des traitements au 177Lu-oxodotréotide (Lutathera®)

This paper provides an experience report on the handling and disposal procedures of waste contaminated with Lutetium-177 (177Lu, Lu-177) that have been established in the context of peptide receptor-targeted radionuclide therapy with 177Lu dotatate (Lutathera®). Treatments are administered in a dedicated infusion room within the nuclear medicine department where dry waste is separated and collected into appropriate containers. The expected duration of storage in decay was extrapolated from the results of a 2-year iterative measurement study for each type of waste. Effluents from hot sinks are collected in decay tanks whose radioactive concentration measured when closed as full is used to calculate the duration of storage required before discharge. Lu-177 activity eliminated by renal excretion for the 6hours after injection of the radiopharmaceutical was evaluated from the analysis of urine samples. First micturitions are directed to three septic tanks whose efficacy was estimated comparing Lu-177 activity at the inlet and at the outlet of the system. Results of six-monthly controls performed by continuous measurement of radioactive concentration in wastewater were used to evaluate the fraction of the total activity administered annually that is finally discharged into the main sewage system and to define guide values. The impact of hospital radioactive discharge to sewers for the workers exposed at different steps of wastewater treatment was assessed using the numerical model called CIDRRE developed by the Institute of Radiation protection and Nuclear Safety (IRSN).

Performance Evaluation and Quantitative Accuracy of Multipinhole NanoSPECT/CT Scanner for Theranostic Lu-177 Imaging

SPECT plays important role in peptide receptor targeted radionuclide therapy using theranostic radionuclides such as Lu-177 for the treatment of various cancers. However, SPECT studies must be quantitatively accurate because the reliable assessment of tumor uptake and tumor-to-normal tissue ratios can only be performed using quantitatively accurate images. Hence, it is important to evaluate performance parameters and quantitative accuracy of preclinical SPECT systems for therapeutic radioisotopes before conducting pre- and post-therapy SPECT imaging or dosimetry studies. In this study, we evaluated system performance and quantitative accuracy of NanoSPECT/CT scanner for Lu-177 imaging using point source and uniform phantom studies. We measured recovery coefficient, uniformity, spatial resolution, system sensitivity and calibration factor for mouse whole body standard aperture. We also performed the experiments using Tc-99m to compare the results with that of Lu-177. We found that the recovery coefficient of more than 70% for Lu-177 at the optimum noise level when nine iterations were used. The spatial resolutions of Lu-177 with and without adding uniform background was comparable to that of Tc-99m in axial, radial and tangential directions. System sensitivity measured for Lu-177 was almost three times less than that of Tc-99m.

Radionuclide imaging and therapy in patients with neuroendocrine tumors

Neuroendocrine tumors (NETs) are heterogeneous group of the tumors that arise from the enterochromaffin cells of the diffuse neuroendocrine system and occurr in 0.5% of all neoplasms. Recently there has been a significant increase in the incidence of neuroendocrine tumors, which is undoubtedly associated with the improvement of diagnostic methods. However, despite significant success in studying the biological and molecular mechanisms of its behavior, a single algorithm for the diagnosis and treatment of neuroendocrine tumors remains unclear today. Treatment of neuroendocrine tumors largely depends on their functional status and the stage of the disease. While the treatment of localized NETs is surgical resection, varieties of therapeutic options are available for patients with advanced NETs. These include medical control of excess hormone levels and associated symptoms, cytoreductive surgery for patients with advanced disease, systemic chemotherapy, somatostatin analogues, and peptide receptor-targeted radionuclide therapy. However, the right choice of the therapeutic approach in current clinical practice in heterogeneous group of patients with neuroendocrine tumors requires further discussion.

Systemic Therapeutic Options for Carcinoid

"Carcinoids" are mostly slow-growing neuroendocrine neoplasms (NENs) with low proliferative activity. A wide range of therapeutic options with variable efficacy exist, including locoregional ablative strategies. Thereafter, some patients may not require medical therapy for years depending on the rate of progression or recurrence. However, the majority of patients require systemic treatment and therein lies the dilemma, since no antiproliferative agent is currently approved for carcinoids. Somatostatin analogs (SSAs), and to a lesser extent interferon-alpha, are standard therapy for carcinoids associated with the carcinoid syndrome. These drugs have some antiproliferative efficacy. SSAs rarely lead to tumor remission but may modestly prolong time to tumor progression. Chemotherapy is of limited value in carcinoids with low proliferation indices but may be useful in higher grade tumors. Peptide receptor-targeted radionuclide therapy may be of benefit and is mostly used after medical therapies fail. However, it is considered an investigational modality. More recently, targeted drugs such as mammalian target of rapamycin (mTOR) inhibitors and anti-angiogenics have been investigated. Objective remissions are rare. Their value remains to be rigorously elucidated. Increased efficacy requires a better understanding of the underlying tumor biology and identification of molecular pathological criteria to allow appropriate preselection of candidates for targeted therapies.

Additional Lesions Detected in Therapeutic Scans with 177Lu-DOTATATE Reflect Higher Affinity of 177Lu-DOTATATE for Somatostatin Receptors

Objective: Peptide receptor-targeted radionuclide therapy (PRRT) of somatostatin receptor (SR)-expressing neuroendocrine tumors (NETs) has become an established therapeutic option in patients with advanced NETs. The aim of this study was to compare the lesion detection rate of ^99mTc-EDDA/HYNIC-TOC, a newly developed tracer for NET imaging, with ¹⁷⁷Lu-DOTATATE used for PRRT. Methods: 8 patients (4 women, 4 men, age range 46–76 years) with histologically proven NETs, who showed high SR loads by ^99mTc-EDDA/HYNIC-TOC scintigraphy, were treated with ¹⁷⁷Lu-DOTATATE. After treatment, all patients were subjected to whole-body scintigraphy with additional low-dose single-photon emission computed tomography (SPECT-CT) of the chest and abdomen. Results: All patients demonstrated ¹⁷⁷Lu-DOTATATE accumulation in all lesions previously detected by ^99mTc- EDDA/HYNIC-TOC scintigraphy. Three patients showed additional lesions in the liver and lungs. Conclusions: SPECT-CT after ¹⁷⁷Lu-DOTATATE therapy may be helpful in detecting additional lesions not seen using ^99mTc-EDDA/HYNIC-TOC. This could reflect the broader affinity of ¹⁷⁷Lu-DOTATATE for SRs compared with ^99mTc-EDDA/HYNIC-TOC.

Somatostatin analogs for the treatment of neuroendocrine tumors

Somatostatin is an important regulator of endocrine and exocrine secretion, affecting the release of many hormones. The effects of somatostatin are mediated through its interaction with one of five somatostatin receptors. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express multiple somatostatin receptors, making them excellent potential therapeutic targets. Many trials have shown that treatment with somatostatin analogs is associated with disease stabilization and prolonged survival. More recently, somatostatin analogs have been shown to have antiproliferative effects, thus broadening the scope of their uses. In this review, we update the current data on the treatment of GEP-NETs with somatostatin analogs, with particular emphasis on the results of the PROMID study. In addition, we discuss the current state of knowledge of novel therapies against GEP-NETs, including the use of somatostatin analogs with broader receptor binding profiles, chimeric somatostatin-dopamine molecules, combinations of somatostatin analogs with other active chemotherapy agents, and peptide receptor-targeted radionuclide therapy.

Radiolabeled regulatory peptides for imaging and therapy

The purpose of the present review is to describe new, innovative strategies of diagnosing and treating specific human cancers using a cadre of radiolabeled regulatory peptides. Peptide receptor-targeted radionuclide therapy is a method of site-directed radiotherapy that specifically targets human cancers expressing a cognate receptor-subtype in very high numbers. Ideally, the procedure targets only the primary or metastatic disease and is minimally invasive, with little radiation damage to normal, collateral tissues. For treatment strategies of this type to be effective, it is critical to evaluate the toxicity of the treatment protocol, the radiation dosimetry of the therapeutic regimen, and the biological profile of the radiopharmaceutical, including biodistribution and pharmacokinetics of the drug. Site-directed molecular imaging procedures via gamma-scintigraphy can address many of the critical issues associated with peptide receptor-targeted radionuclide therapy and it is, therefore, necessary to describe the effective balance between the clinical benefits and risks of this treatment strategy. Continued development in the design or chemical structure of radiolabeled, biologically active peptides could do much to improve the targeting ability of these drugs, thereby creating new and innovative strategies for diagnosis or treatment of human cancers.

Selection of radiolabeled gastrin analogs for peptide receptor-targeted radionuclide therapy.

The gastrin/cholecystokinin-2 (CCK-2) receptor has been identified as a possible target for peptide receptor radionuclide imaging and therapy. Several radiolabeled peptides binding to this receptor have been explored in animal models and clinical trials but either low tumor uptake or high renal retention has been found. The aim of this study was to identify a peptide with improved tumor-to-kidney pharmacodynamics when compared with current candidates. A small peptide-chelator library of 34 compounds based on the C-terminal sequences of CCK-8 or minigastrin was constructed. The peptides were radiolabeled with (111)In with high labeling efficiency (>90%), as determined by high-performance liquid chromatographic analysis. The labeled peptides were screened by assessing tumor and kidney uptake in pancreatic xenograft nude mouse models, including AR42J. An extensive biodistribution analysis was performed on the lead candidate from the library. Minigastrin analogs containing a pentaglutamate sequence showed the highest tumor uptake but very high renal retention. CCK analogs showed the lowest tumor and renal uptake. Deletion of the pentaglutamate sequence in the gastrin analogs lowered the tumor uptake by a factor of 3 but decreased the kidney uptake by a factor of 20. Insertion of histidine residues in the sequence reduced kidney uptake by a further factor of almost 2-fold. In AR42J tumor-bearing mice, the peptide with the sequence DOTA-HHEAYGWMDF-NH(2) (DOTA is tetraazacyclododecane tetraacetic acid) showed the highest tumor-to-kidney ratio of all peptides studied, with saturable uptake in target organs and low uptake by nontarget tissues other than the kidney. This peptide is a worthwhile candidate for clinical studies to determine whether it is suitable for use in peptide receptor-targeted radionuclide therapy.

Reduction of skeletal accumulation of radioactivity by co-injection of DTPA in [ 90Y-DOTA 0,Tyr 3]octreotide solutions containing free 90Y 3+

Peptide receptor-targeted radionuclide therapy is nowadays being performed with radiolabeled DOTA-conjugated peptides, such as [ 90Y-DOTA 0,Tyr 3]octreotide (also known as OctreoTher® or 90Y-DOTATOC). The incorporation of 90Y 3+ is typically ≥99%, however, since a total patient dose can be as high as 26 GBq or 700 mCi the amount of free 90Y 3+ (=non-DOTA-incorporated) can be substantial. Free 90Y 3+ accumulates in bone with undesired radiation of bone marrow as a consequence. 90Y-DTPA is excreted rapidly via the kidneys. Incorporation of free 90Y 3+ into 90Y-DTPA might prevent this fraction from being accumulated into bone, therefore we have investigated: the biodistribution in rats of 90YCl 3, [ 90Y-DOTA 0,Tyr 3]octreotide, and 90Y-DTPA; possibilities to complex 10% of free 90Y 3+ in a [ 90Y-DOTA 0,Tyr 3]octreotide containing solution into 90Y-DTPA prior to intravenous injection; and effects of 10% free 90Y 3+ in [ 90Y-DOTA 0,Tyr 3]octreotide solution, in the presence and in the absence of excess DTPA, on the biodistribution of in rats. The following results are presented: 90YCl 3 showed high skeletal uptake (i.e., 1% ID (injected dose) per gram femur, with main localization in the epiphyseal plates) and a 24 h total body retention of 74% ID; 90Y-DTPA had rapid renal clearance, and 24 h total body retention of <5% ID; added free 90Y 3+ in [ 90Y-DOTA 0,Tyr 3]octreotide solution could rapidly be incorporated into 90Y-DTPA at room temperature; and accumulation of 90Y 3+ in femur, blood, and liver was related to the amount of free 90Y 3+, whereas these accumulations could be prevented by the addition of DTPA. In conclusion, the addition of excess DTPA to [ 90Y-DOTA 0,Tyr 3]octreotide with incomplete 90Y-incorporation is recommended.