Peptide radionuclide radiation therapy with Lutathera in multirecurrent nonanaplastic meningiomas: antitumoral activity study by growth rate analysis.

PURPOSE: Several retrospective studies and meta-analyses of Peptide Radionuclide Radiation Therapy in meningiomas suggest six-month progression-free survival improvement for WHO grade 1 and 2 meningiomas. In the present study, we aimed to evaluate the impact of such treatment on three-dimensional volume growth rate (3DVGR) in nonanaplastic meningiomas. METHODS: The authors performed a retrospective study including eight patients treated with Lutathera®. Millimetric 3D T1-weighted with gadolinium enhancement magnetic resonance imaging sequences were requested for volume measurement. Then, tumor growth rate was classified following a previously described 3DVGR classification (Graillon et al.). RESULTS: Patients harbored seven WHO grade 2 meningiomas and one aggressive WHO grade 1. All patients, except one, underwent four treatment cycles. 3DVGR significantly decreased at 3, 6, and 12 months after treatment initiation analyzing each lesion separately. Mean and median 3DVGR from all patients were respectively at 29.5% and 44.5%/6 months before treatment initiation, then at 16.5% and 25%/6 months at three months post-treatment initiation, 9.5% and 4.5%/6 months after 6 months, as well as 9.5% and 10.5%/6 months after 12 months. At 3, 6, and 12 months after treatment initiation, 4/8, 6/7, and 5/6 patients were class 2 (stabilization or severe 3DVGR slowdown), respectively. No patient was class 1 at 6 and 12 months, suggesting a lack of drug response. CONCLUSION: In nonanaplastic meningiomas, Lutathera®'s antitumoral activity appeared delayed and more likely observed at six months, while no major response was observed under treatment. Moreover, its antitumoral activity persisted for 12-18 months following treatment initiation.

Efficacy of [177Lu]Lu-DOTATATE in metastatic neuroendocrine neoplasms of different locations: data from the SEPTRALU study.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282). RESULTS: The sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7-not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8-28.1) in pancreatic, and 17.6 months (14.4-33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity. CONCLUSION: This study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

Neuroblastoma xenograft models demonstrate the therapeutic potential of 177Lu-octreotate.

BACKGROUND: Neuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40-50%, indicating the need for novel and improved treatment options. 177Lu-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of 177Lu-octreotate for treatment of NB. METHODS: BALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5-7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1-5, and Ki67 were carried out for tumor xenografts from the three cell lines. RESULTS: High 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq 177Lu-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32. CONCLUSION: T/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of 177Lu-octreotate as a therapeutic alternative for metastatic NB.

Advances in Molecular Classification and Therapeutic Opportunities in Meningiomas.

PURPOSE OF REVIEW: Our understanding of the genetic and epigenetic alterations in meningioma and the underlying tumor biology of meningioma has significantly changed over the past decade and resulted in revision of prognostically relevant meningioma subclasses within and beyond the WHO classification of CNS tumors. RECENT FINDINGS: The 2016 WHO classification of CNS tumors recognizes WHO grade I, II, and III based on histopathological features. Recent work has identified genetic alterations with prognostic implications, including mutations of the TERT promoter, loss of function of the DMD gene, and inactivation of the tumor suppressor BAP-1. Studies of DNA methylation patterns in meningiomas have resulted in a novel and prognostically relevant meningioma subclassification schema. There have been major advances in our understanding of prognostically relevant genetic and epigenetic changes in meningioma which will hopefully allow for improvement in clinical trial design and the development of more effective therapies for meningioma.

Comparison of 177Lu-octreotate and 177Lu-octreotide for treatment in human neuroblastoma-bearing mice.

Background: Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of 177Lu-octreotate and 177Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes. Methods: The biodistribution of 177Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of 177Lu-octreotate or 177Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR. Results: The activity concentration was generally lower in most tissues for 177Lu-octreotide compared to 177Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for 177Lu-octreotide and 2.9 and 0.45 Gy/MBq for 177Lu-octreotate, respectively. 177Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes TNSFS8, TNSFS10, and TRADD were regulated after administration with 177Lu-octreotate. Treatment with 177Lu-octreotide yielded regulation of the pro-apoptotic genes CASP5 and TRADD, and of the anti-apoptotic gene IL10 as well as the apoptosis-related gene TNF. Conclusion: 177Lu-octreotide gave somewhat better anti-tumor effects than 177Lu-octreotate. The similar effect observed in the treated groups with 177Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals.

Radioligand therapy (RLT) used to treat cardiac metastasis of pancreatic neuroendocrine tumor.

Radioligand Therapy (RLT) in the form of [177Lu] Lu-DOTA-TATE (Lutathera®) is a promising treatment for pancreatic neuroendocrine tumors (pNETs) with cardiac metastasis. We present a patient treated with [177Lu] Lu-DOTA-TATE that showed shrinkage of metastasis after four treatments at 7.4 GBq every 8 weeks.

Management of metastatic pheochromocytomas and paragangliomas: when and what.

Recently, the treatment landscape for metastatic pheochromocytomas and paragangliomas (MPPGL) has seen both progress and setbacks. We provide an up-to-date review of the multimodality management of MPPGL and discuss novel opportunities and current challenges in the treatment landscape. Given the unique clinical presentation of MPPGL, we discuss the management of hormone-related clinical sequelae and traditional modalities of therapy. Advances in the understanding of the molecular biology of these diverse tumors have enabled novel strategies such as augmenting DNA damage by targeted delivery of radionuclides such as 131I and 177Lu, abrogating tumor angiogenesis, hypoxia resistance, and DNA damage repair. Despite progress, we address the significant challenges still faced by patients and researchers engaged in efforts to improve outcomes in these rare cancers.

Approach to the patient: Concept and application of targeted radiotherapy in the paraganglioma patient.

Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and 177Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes.

Dealing with dry waste disposal issues associated with 177mLu impurities: a long-term challenge for nuclear medicine departments.

PURPOSE: A strategy for management of radioactive waste associated with 177Lu-dotatate (Lutathera®) treatments was established in our institution, based on predicted storage times of 3-5 years extrapolated from the results of a 2-year measurement study. The aim of this work was to validate this strategy by identifying contaminants and confirming disposal based on the clearance level twice-the-background was within expected time frames. METHODS: We conducted a prospective series of measurements of radioactive waste associated with the first 65 treatments administered. Sequential measurements of the first 45 vials used were performed on a dose calibrator to identify contaminants. Exposure rates in contact were monitored with a dose ratemeter on a 6-monthly basis for all waste stored: 46 empty vials, 19 vials partially used and 61 biohazard containers. RESULTS: Initial median activity of the first vials used was 118 MBq [4-4188 MBq]. For each vial, the decay curve of activity obtained was adjusted to a bi-exponential model. The major component, representing 99.7% of the activity, has a median half-life of 6.6 days [5.7-7.2 days] corresponding to 177Lu. The second, representing only 0.3% of the activity and having a median half-life of 152 days [104-205 days] corresponding to 177mLu, determines necessary storage times. Partially used vials can be disposed of after 5 years, other waste after 3 years. Compliance with the regulatory clearance level is achieved within expected time frames. CONCLUSION: Although only present as traces, 177mLu associated with the direct production route results in major radioactive waste disposal issues for hospitals. Availability of radiopharmaceuticals without impurities appears to be crucial for an expanding use of targeted radionuclide therapy.

Neuroendocrine metastasis to the thyroid from unknown primary and extrathyroidal disease response to peptide receptor radionuclide therapy.

Neuroendocrine tumor (NET) metastasis to the thyroid is rare, and its presentation as the first manifestation of primary malignancy elsewhere is even more uncommon. We present a case of a 41-year-old female who underwent biopsy of enlarging thyroid nodules with findings suspicious for medullary thyroid cancer (MTC). Subsequent thyroidectomy demonstrated NET of unknown primary in the left lower lobe. Immediate workup with 68Ga-DOTATATE-PET/CT revealed abnormal somatostatin receptor (SR) expressing lesions in the liver, right cervical nodes, thoracic paravertebral soft tissue, precoccygeal soft tissue, and right acetabulum concerning for sites of neuroendocrine malignancy. Due to disease progression while on octreotide injections, a decision was made at the multidisciplinary NET board for the patient to receive peptide receptor radionuclide therapy (PRRT) which includes 4 cycles of 77Lu-DOTATATE (Lutathera). The patient had no side effects nor toxicities during the 8 months of PRRT and achieved a partial treatment response in the early post-treatment scan at 6 weeks. This case illustrates the importance of distinguishing NET metastasis to the thyroid from MTC to ensure appropriate workup and treatment as well as predict the response of neuroendocrine malignancies to PRRT based on the visualized overexpression of SR in the SR-PET scans, despite the organ of origin.

Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE.

Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still "Lutathera orphans", and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.

Risk of Radiation Exposure to Clinical Staff from Paracenteses of Large-Volume Chylous Ascites After 177Lu-DOTATATE Infusion.

177Lu-DOTATATE has gained wide clinical acceptance for the treatment of advanced gastroenteropancreatic neuroendocrine tumors; however, little is known regarding its accumulation in ascites. As such, clinical staff performing paracenteses shortly after a treatment dose may be concerned about their potential radiation exposure or the risk of contamination. Methods: In this report, therapeutic paracenteses were performed on a patient with metastatic intestinal carcinoid complicated by recurrent chylous ascites at various time intervals after a standard 7.4 GBq dose of 177Lu-DOTATATE. Samples of the fluid were analyzed in a scintillation counter to estimate the concentration of radioactivity. Results: The concentration of activity in the ascitic fluid obtained 3 d after an infusion was exceptionally low (175.3 ± 25.9 Bq/mL). Conclusion: Our findings suggest that paracenteses conducted as soon as 3 d after a standard dose of 177Lu-DOTATATE pose little to no risk in terms of radiation safety to staff performing the procedure.

Hyperfractionated Treatment with 177Lu-Octreotate Increases Tumor Response in Human Small-Intestine Neuroendocrine GOT1 Tumor Model.

Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using 177Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with 177Lu-octreotate. BALB/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30-120 MBq of 177Lu-octreotate: 1 × 30, 2 × 15, 1 × 60, 2 × 30, 1 × 120, 2 × 60, or 3 × 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 × 15 = 30 and 1 × 30 MBq 177Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 × 30 = 60 and 1 × 60 MBq 177Lu-octreotate, respectively. After 120 MBq 177Lu-octreotate, given as 1-3 fractions, the mean tumor volume was reduced by 91-97%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20-25% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of 177Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth.

177Lu-DOTA-0-Tyr3-octreotate infusion modeling for real-time detection and characterization of extravasation during PRRT.

PURPOSE: Given the recent and rapid development of peptide receptor radionuclide therapy (PRRT), increasing emphasis should be placed on the early identification and quantification of therapeutic radiopharmaceutical (thRPM) extravasation during intravenous administration. Herein, we provide an analytical model of 177Lu-DOTA0-Tyr3-octreotate (Lutathera®) infusion for real-time detection and characterization of thRPM extravasation. METHODS: For 33 Lutathera®-based PRRT procedures using the gravity infusion method, equivalent dose rates (EDRs) were monitored at the patient's arm. Models of flow dynamics for nonextravasated and extravasated infusions were elaborated and compared to experimental data through an equivalent dose rate calibration. Nonextravasated infusion was modeled by assuming constant volume dilution of 177Lu activity concentration in the vial and Poiseuille-like laminar flow through the tubing and patient vein. Extravasated infusions were modeled according to their onset times by considering elliptically shaped extravasation region with different aspect ratios. RESULTS: Over the 33 procedures, the peak of the median EDR was reached 14 min after the start of the infusion with a value of 450 µSv h-1. On the basis of experimental measurements, 1 mSv h-1 was considered the empirical threshold for Lutathera® extravasation requiring cessation of the infusion and start again with a new route of injection. According to our model, the concentration of extravascular activity was directly related to the time of extravasation onset and its duration, a finding inherent in the gravity infusion method. This result should be considered when planning therapeutic strategy in the case of RPM extravasation because the local absorbed dose for ß-emitters is closely linked to activity concentration. For selected EDR values, charts of extravasated activity, volume, and activity concentration were computed for extravasation characterization. CONCLUSION: We proposed an analytical model of Lutathera® infusion and extravasation (gravity method) based on EDR monitoring. This approach could be useful for the early detection of thRPM extravasation and for the real-time assessment of activity concentration and volume accumulation in the extravascular medium.

Imaging Advancements in Nuclear Medicine: Pancreatic Neuroendocrine Tumor Localization and Treatment.

BACKGROUND: This case report details a 57-year-old African American man with pancreatic neuroendocrine tumors (NETs). The patient underwent positron emission tomography (PET) imaging using gallium Ga 68 dotatate, which localized the tumors. Selected tumors were treated with 4 doses of 200 mCi of lutetium Lu 177 dotatate during a period of 8 months. At the conclusion of treatment, the patient demonstrated improvement, progressing from bedbound and confused to ambulatory and coherent. In addition, the patient stated he felt no adverse effects. DISCUSSION: Pancreatic NETs are rare tumors affecting 0.001% of the population. These tumors are associated with various symptoms and are classified as functional or nonfunctional. Imaging modalities, such as computed tomography (CT), magnetic resonance (MR) imaging, and gallium Ga 68-labeled PET, are essential in detecting and evaluating pancreatic NETs. For patients with localized NETs, the primary treatment is surgery; however, the radiopharmaceuticals yttrium Y 90 microspheres and lutetium Lu 177 dotatate are used as therapy to treat nonresectable tumors. CONCLUSION: Lutetium Lu 177 dotatate is used in NET cases that are deemed inoperable and for patients who are not responding to treatment. This case study demonstrates the effectiveness of combining imaging with Ga 68-labeled PET and treatment with lutetium Lu 177 dotatate. This treatment is not a cure but has been shown to improve a patient's quality of life.

A Case of 177Lu-DOTATATE Therapy Without the Use of Antiemetics.

Recommended 177Lu-DOTATATE treatment regimens involve prophylaxis with antiemetics to counteract the emetogenic properties of the nephroprotective amino acid solution infusion. We describe a 58-y-old woman treated with 177Lu-DOTATATE for metastatic small-bowel carcinoid, who was allergic to many classes of antiemetics. Therefore, she was treated with 177Lu-DOTATATE without antiemetic prophylaxis. She tolerated the compounded amino acid infusion of lysine and arginine, followed by 177Lu-DOTATATE, without significant nausea or any vomiting. We hypothesize that aggressive antiemetic prophylaxis may not be necessary if a 177Lu-DOTATATE patient receives compounded lysine/arginine amino acid solutions. The omission would decrease overall health-care costs and limit possible medication side effects.

Efficacy of Lutetium-Peptide Receptor Radionuclide Therapy in Inducing Prolonged Tumour Regression in Small-Bowel Neuroendocrine Tumours: A Case of Favourable Response to Retreatment after Initial Objective Response.

INTRODUCTION: The efficacy of 177Lu-Dotatate was shown in the NETTER-1 trial, an international, open-label, multicentre phase III clinical trial that evaluated the safety and efficacy of 177Lu-Dotatate in patients with well-differentiated, advanced midgut neuroendocrine tumours (NETs) with evidence of disease progression. Recently, retreatment with peptide receptor radionuclide therapy (PRRT) has been proposed as a valid therapeutic option in patients without other effective options who had responded to initial PRRT; however, data on this therapeutic option are still inadequate. CASE REPORT: In this report, we present the case of a patient who achieved a delayed complete radiological response after initial 177Lu-Dotatate treatment and who had a complete tumour response with PRRT retreatment 5 years later. CONCLUSIONS: This case report shows that, although rare, a complete, prolonged tumour response may occur in patients with advanced small-bowel NETs receiving PRRT. Retreatment with PRRT may be a valid option in cases of subsequent disease recurrence.

Case Report: Primary Hypothyroidism Associated With Lutetium 177-DOTATATE Therapy for Metastatic Paraganglioma.

Background: Lutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited. Case Description: A 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27-4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9-1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0-34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65-193 ng/dl)] and FT4 [3.9 ng/dl (1.2-2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi 177Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved. Summary: We report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Conclusions: Thyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.

Overview and Current Status of Peptide Receptor Radionuclide Therapy.

Peptide receptor radionuclide therapy (PRRT) is an effective form of treatment of patients with metastatic neuroendocrine tumors, delivering modest objective tumor response rates but notable survival and symptomatic benefits. The first PRRT approved by the US Food and Drug Administration was lutetium 177-DOTATATE and is for use in adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. The treatment paradigm typically leads to significant improvement in symptomology coupled with an extended period of progression-free survival. Side effects are limited, with a small fraction of individuals experiencing clinically significant long-term renal or hematologic toxicity.

In Vivo Instability of 177Lu-DOTATATE During Peptide Receptor Radionuclide Therapy.

Peptide receptor radiotherapy using 177Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors, with 177Lu-DOTATATE having acquired marketing authorization in Europe and the United States. The investigation of the pharmacokinetics of these radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. Such an investigation requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of the in vivo stability of 177Lu-DOTATATE in humans affected by neuroendocrine tumors. Methods: Blood samples of 6 patients undergoing 177Lu-DOTATATE were taken at 0.5, 4, 24, and 96 h after injection. Analysis of metabolic stability was performed using high-performance liquid chromatography. Results: A fast metabolism of the radiopharmaceutical was observed, with the fraction of intact 177Lu-DOTATATE in plasma decreasing rapidly to 23% ± 5% (mean ± SD) at 24 h and 1.7% ±0. 9% at 96 h after injection. Conclusion: The in vivo stability of 177Lu-DOTATATE is much lower than previously assumed, with the major part of radioactivity in plasma consisting of 177Lu-labeled metabolites already at 24 h after injection.