Search Results (58)

Background/Objectives: Lutathera^® ([¹⁷⁷Lu]Lu-DOTA-TATE) is the first radiolabelled somatostatin (SST) analog approved for the treatment of patients with well-differentiated (G1 and G2) unresectable or metastatic gastro-entero-pancreatic neuro-endocrine-neoplasms (GEP-NENs). The bone marrow and kidneys are critical organs for RLT with [¹⁷⁷Lu]Lu-DOTA-TATE. Our purpose was to evaluate hematological and renal toxicity in 29 patients (18 males, 11 females) treated with Lutathera^®. Methods: According to standard protocols, four cycles of (¹⁷⁷Lu)Lu-DOTA-TATE were administered every eight/nine weeks. Patients received pre-medication with anti-emetic and anti-acid drugs and a slow amino acid infusion for renal protection. Blood count and serum creatinine data were collected at three time points: before the first cycle, after the second cycle, and at the end of treatment. Results: We found that almost all hematological parameters significantly decreased between the baseline and/or interim and post-therapy evaluation, although without a clinical impact. The presence of total tumor load or bone metastases had no influence on these findings, while male patients showed less hematological toxicity than females. Conversely, creatinine levels did not vary during treatment. Conclusions: Our study confirms that [¹⁷⁷Lu]Lu-DOTATATE RLT is safe and well tolerated despite some minor (grade 1) hematological toxicity. Full article

Background: Atherosclerosis and its sequels, such as coronary artery disease and cerebrovascular stroke, still represent global health burdens. The pathogenesis of atherosclerosis consists of growing calcified plaques in the arterial wall and is accompanied by inflammatory processes, which are not entirely understood. This study aims to evaluate the effect of peptide receptor radionuclide therapy (PRRT) using ⁹⁰Y- and ¹⁷⁷Lu-DOTATATE on atherosclerotic plaque inflammation. Methods: Atherosclerotic plaques in 57 cancer patients receiving PRRT using ⁹⁰Y- and ¹⁷⁷Lu-DOTATATE were longitudinally monitored by ⁶⁸Ga-DOTATATE PET/CT. The target-to-background ratio (TBR) and overall vessel uptake (OVU) were measured in eight distinct arterial regions (ascending aorta, aortic arch, descending aorta, abdominal aorta, both iliac arteries, and both carotid arteries) to monitor calcified plaques. Results: PET/CT analysis shows a positive correlation between calcified plaque scores and the ⁶⁸Ga-DOTATATE overall vessel uptake (OVU) in cancer patients. After PRRT, an initially high OVU was observed to decrease in the therapy group compared to the control group. An excellent correlation could be shown for each target-to-background ratio (TBR) to the OVU, especially the ascending aorta. Conclusions: The ascending aorta could present a future reference for estimating generalized atherosclerotic inflammatory processes. PRRT might represent a therapeutic approach to modulating atherosclerotic plaques. Full article

Background: Neuroendocrine neoplasms (NENs) are neoplastic tumors developing in every part of the body, mainly in the gastrointestinal tract and pancreas. Their treatment involves the surgical removal of the tumor and its metastasis, long-acting somatostatin analogs, chemotherapy, targeted therapy, and radioligand therapy (RLT). Materials and Methods: A total of 127 patients with progressive neuroendocrine neoplasms underwent RLT—4 courses, administered every 10 weeks—with the use of 7.4 GBq [¹⁷⁷Lu]Lu-DOTA-TATE or tandem therapy with 1.85 GBq [¹⁷⁷Lu]Lu-DOTA-TATE and 1.85 GBq [⁹⁰Y]Y-DOTA-TATE. Assessment of short- and long-term complications, as well as the calculation of progression-free survival (PFS) and overall survival (OS) were performed. Results: RLT caused a statistically but not clinically significant decrease in blood morphology parameters during both short- and long-term observations. Glomerular filtration rate (GFR) significantly decreased only in a long-term observation after RLT; however, it was clinically acceptable. Computed predictions of progression-free survival (PFS) and overall survival (OS) indicated that five years post-RLT, there is a 74% chance of patients surviving, with only a 58.5% likelihood of disease progression. Conclusions: Computed predictions of PFS and OS confirmed treatment efficiency and good patient survival. RLT should be considered a safe and reliable line of treatment for patients with progressive NENs as it causes only a low number of low-grade adverse events. Full article

The aim of the present study was to evaluate the safety and efficacy of radionuclide therapy with [¹⁷⁷Lu]Lu-DOTA-TATE according to our single center experience at the University of Naples Federico II. For the present analysis, we considered 21 patients with progressive, advanced, well-differentiated G1 and G2 in patients with gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs) treated with [¹⁷⁷Lu]Lu-DOTA-TATE according to the decisions of a multidisciplinary team. All patients underwent four cycles of 7–8 GBq of [¹⁷⁷Lu]Lu-DOTA-TATE every 8 weeks. A whole-body scan (WBS) was performed 4, 48, and 168 h after each treatment. The dosimetry towards the organ at risk and target lesions was calculated. For each patient, renal and bone marrow parameters were evaluated before, during, and 3 months after the end of the treatment. Follow-up data were obtained and RECIST criteria were considered as the endpoint. Among 21 patients enrolled (mean age 65 ± 9 years); 17 (81%) were men and the small intestine was the most frequent location of disease (n = 12). A mild albeit significant variation (p < 0.05) in both platelets and white blood cell counts among all time points was observed, despite it disappearing 3 months after the end of the therapy. According to the RECIST criteria, 11 (55%) patients had a partial response to therapy and 8 (40%) had stable disease. Only one (5%) patient had disease progression 4 months after treatment. Our data confirm that [¹⁷⁷Lu]Lu-DOTA is safe and effective in controlling the burden disease of G1/G2 GEP-NETs patients. Full article

Rationale: Evaluating the long-term safety and efficacy of peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumors (mNETs) who have undergone prior bland hepatic transarterial embolization (TAE). Methods: Retrospective review of mNET patients who received PRRT with ¹⁷⁷Lu-DOTATATE between 4/2018 and 02/2022 with and without prior TAE. The most recent clinical, imaging, and laboratory findings, including hepatic Common Terminology Criteria for Adverse Events v5.0, were compared to pre-PRRT. Results: 171 patients (95 M, 76 F, median age = 66) with mNET of different primary sites (9 foregut, 100 midgut, 9 hindgut, 44 pancreas, 9 unknown) received at least 1 cycle of PRRT with at least 6 months of follow-up, 110 of whom were embolization-naïve and 61 who had prior TAE. The median follow up was 22 months (range: 6–43). Patients with prior TAE had higher liver tumor burden on average than patients without prior TAE; however, the difference was not statistically significant (p = 0.06). There was no significant difference in the rates of G3 or G4 hepatotoxicity (p = 0.548 and p = 0.999, respectively) in patients who underwent prior TAE and those who were TAE-naïve. The hepatic progression-free survival was 22.9 months in TAE-naïve patients and 25.7, 20.2, and 12.8 months in patients with 1, 2, and 3 prior TAE treatments, respectively. Conclusion: Peptide receptor radionuclide therapy following transarterial bland embolization for mNET is safe and effective. Full article

Peptide receptor radionuclide therapy (PRRT) using ¹⁷⁷Lu-DOTA-TATE has recently been evaluated for the treatment of meningioma patients. However, current knowledge of the underlying radiation biology is limited, in part due to the lack of appropriate in vitro models. Here, we demonstrate proof-of-concept of a meningioma patient-derived 3D culture model to assess the short-term response to radiation therapies such as PRRT and external beam radiotherapy (EBRT). We established short-term cultures (1 week) for 16 meningiomas with high efficiency and yield. In general, meningioma spheroids retained characteristics of the parental tumor during the initial days of culturing. For a subset of tumors, clear changes towards a more aggressive phenotype were visible over time, indicating that the culture method induced dedifferentiation of meningioma cells. To assess PRRT efficacy, we demonstrated specific uptake of ¹⁷⁷Lu-DOTA-TATE via somatostatin receptor subtype 2 (SSTR2), which was highly overexpressed in the majority of tumor samples. PRRT induced DNA damage which was detectable for an extended timeframe as compared to EBRT. Interestingly, levels of DNA damage in spheroids after PRRT correlated with SSTR2-expression levels of parental tumors. Our patient-derived meningioma culture model can be used to assess the short-term response to PRRT and EBRT in radiobiological studies. Further improvement of this model should pave the way towards the development of a relevant culture model for assessment of the long-term response to radiation and, potentially, individual patient responses to PRRT and EBRT. Full article

Introduction: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. Method: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-Dotatate or ⁹⁰Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8–14-week intervals. Results: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15–76) years. The median follow-up time was 31 (IQR 17–37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). Conclusions: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to ¹³¹I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group. Full article

The use of metabolically stabilized, radiolabeled somatostatin (SST) analogs ([⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-TATE/TOC/NOC) is well established in nuclear medicine. Despite the pivotal role of these radioligands in the diagnosis and therapy of neuroendocrine tumors (NETs), their inability to interact with all five somatostatin receptors (SST_1–5R) limits their clinical potential. [¹¹¹In]In-AT2S is a radiolabeled DOTA-conjugate derived from the parent peptide SST-14 that exhibits high binding affinity to all SSTR subtypes, but its poor metabolic stability represents a serious disadvantage for clinical use. In order to address this issue, we have replaced strategic trans-amide bonds of [¹¹¹In]In-AT2S with metabolically stable 1,4-disubstituted 1,2,3-triazole bioisosteres. From the five cyclic triazolo-peptidomimetics investigated, only [¹¹¹In]In-XG1 combined a preserved nanomolar affinity for the SST_1,2,3,5R subtypes in vitro and an improved stability in vivo (up to 17% of intact peptide 5 min postinjection (pi) versus 6% for [¹¹¹In]In-AT2S). The involvement of neprilysin (NEP) in the metabolism of [¹¹¹In]In-XG1 was confirmed by coadministration of Entresto^®, a registered antihypertensive drug, in vivo releasing the selective and potent NEP-inhibitor sacubitrilat. A pilot SPECT/CT imaging study conducted in mice bearing hSST₂R-positive xenografts failed to visualize the xenografts due to the pronounced kidney uptake (>200% injected activity (IA)/g at 4 h pi), likely the result of the formation of cationic metabolites. To corroborate the imaging data, the tumors and the kidneys were excised and analyzed with a γ-counter. Even if receptor-specific tumor uptake for [¹¹¹In]In-XG1 could be confirmed (1.61% IA/g), further optimization is required to improve its pharmacokinetic properties for radiotracer development. Full article

Background: Treatment of metastatic neuroendocrine tumors (NET) with ¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) results in favorable response only in a subset of patients. We investigated the prognostic value of quantitative pre-treatment semi-automatic ⁶⁸Ga-DOTATATE PET/CT analysis in NET patients treated with PRRT. Methods: The medical records of 94 NET patients who received at least one cycle of PRRT at a single institution were retrospectively reviewed. On each pre-treatment ⁶⁸Ga-DOTATATE PET/CT, the total tumor volume (TTV), maximum tumor standardized uptake value for the patient (SUVmax), and average uptake in the lesion with the lowest radiotracer uptake (SUVmin) were determined with a semi-automatic tumor delineation method. Progression-free survival (PFS) and overall survival (OS) among the patients were compared based on optimal cutoff values for the imaging parameters. Results: On Kaplan–Meier analysis and univariate Cox regression, significantly shorter PFS was observed in patients with lower SUVmax, lower SUVmin, and higher TTV. On multivariate Cox regression, lower SUVmin and higher TTV remained predictive of shorter PFS. Only higher TTV was found to be predictive of shorter OS on Kaplan–Meier and Cox regression analyses. In a post hoc Kaplan–Meier analysis, patients with at least one high-risk feature (low SUVmin or high TTV) showed shorter PFS and OS, which may be the most convenient parameter to measure in clinical practice. Conclusions: The tumor volume and lowest lesion uptake on ⁶⁸Ga-DOTATATE PET/CT can predict disease progression following PRRT in NET patients, with the former also predictive of overall survival. NET patients at risk for poor outcomes following PRRT can be identified with semi-automated quantitative analysis of ⁶⁸Ga-DOTATATE PET/CT. Full article

Neuroendocrine neoplasms (NENs) are a group of neoplasms arising from neuroendocrine cells. The worldwide incidence and prevalence of the NENs are estimated to be 6/100,000 and 35/100,000, respectively. Those numbers are increasing every decade, requiring higher and higher diagnosis and treatment costs. Radioligand therapy (RLT) using beta-emitting radioisotopes is an efficient and relatively safe method of treatment, typically used as a second-line treatment. RLT tolerability is higher than other available pharmacotherapies (chemotherapy or tyrosine kinase inhibitors). Recent studies show an increase in overall survival among patients treated with RLT. The present study aimed to learn the epidemiology of NENs in Poland and assess the effectiveness of RLT in a high-reference center. A prospective analysis of 167 patients treated with RLT in one of Poland’s highest-reference NEN centers was performed. The analysis covered 66 months of observation (1 December 2017–30 May 2023), during which 479 RLT single administrations of radioisotope were given. The standard procedure was to give four courses of [¹⁷⁷Lu]Lu-DOTA-TATE alone, or tandem therapy—[¹⁷⁷Lu]Lu-DOTA-TATE and [⁹⁰Y]Y-DOTA-TATE. Grading analysis showed that most patients had non-functioning G2 NEN with a mean Ki-67 of 6.05% (SD ± 6.41). The most common primary tumor location was the pancreas. Over two-thirds of patients did undergo surgery due to primary tumors or distant metastases. The majority of patients were using lanreotide as a chronically injected somatostatin analog. Median progression-free survival (PFS) on somatostatin analogs was 21.0 (IQR = 29.0) months. Directly after the last course of RLT, disease stabilization was noted in 69.46% of patients, partial regression was noted in 20.36% of patients, complete regression was noted in 0.60% of patients, and progression was noted in 9.58% of patients. In long-term follow-up, the median observation time among patients who underwent four treatment cycles (n = 108) was 29.8 (IQR = 23.9) months. Stabilization of the disease was observed in 55.56% of the patients and progression was observed in 26.85% of the patients, while 17.59% of patients died. Median PFS was 29.3 (IQR 23.9), and the median OS was 34.0 months (IQR 16.0). The mean age of NEN diagnosis is the sixth decade of life. It takes almost three years from NEN diagnosis to the start of RLT. In long-term observation, RLT leads to disease stabilization in over half of the patients with progressive disease. No differences in PFS or OS depend on the radioisotope used for RLT. In Poland, organized coordination of NEN treatment in high-reference centers ensures the continuity of patient care. Full article

Lung carcinoids are neuroendocrine tumors, categorized as typical or atypical carcinoids based on their histological appearance. While most of these tumors are slow-growing neoplasms, they still possess malignant potential. Many patients are diagnosed incidentally on chest X-rays or CT scans. Presenting symptoms include cough, hemoptysis, wheezing, dyspnea, and recurrent pneumonia. Endocrine symptoms, such as carcinoid syndrome or ectopic Cushing’s syndrome, are rare. Surgery is the primary treatment and should be considered in all patients with localized disease, even when thoracic lymph node metastases are present. Patients with distant metastases may be treated with somatostatin analogues, chemotherapy, preferably temozolomide-based, mTOR inhibitors, or peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE. Most patients have an excellent prognosis. Poor prognostic factors include atypical histology and lymph node metastases at diagnosis. Long-term follow-up is mandatory since metastases may occur late. Full article

Radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-DOTA-TATE is a standard of care for adult patients with somatostatin-receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Taking advantage of this precision nuclear medicine approach requires diligent monitoring and surveillance, from the use of diagnostic SSTR-targeted radioligand imaging for the selection of patients through treatment and assessments of response. Published evidence-based guidelines assist the multidisciplinary healthcare team by providing acceptable approaches to care; however, the sheer heterogeneity of GEP-NETs can make these frameworks difficult to apply in individual clinical circumstances. There are also contradictions in the literature regarding the utility of novel approaches in monitoring and surveilling patients with GEP-NETs receiving RLT. This article discusses the emerging evidence on imaging, clinical biochemistry, and tumor assessment criteria in the management of patients receiving RLT for GEP-NETs; additionally, it documents our own best practices. This allows us to offer practical guidance on how to effectively implement monitoring and surveillance measures to aid patient-tailored clinical decision-making. Full article

Background: Neuroendocrine neoplasms (NENs) are a rare group of tumors with a different clinical course, prognosis and location. Radioligand therapy (RLT) can be used as a first or second line of treatment. It is registered in gastroenteropancreatic NENs (GEP-NENs) as grades G1 and G2. Tumors with an unknown point of origin, diagnosed outside the gastrointestinal tract and pancreas (non-GEP) or at the G3 grade, remain in the “grey area” of treatment. Materials and Methods: Analysis of 51 patients with NENs who underwent RLT in a single highest reference center from 2018 to 2023 was performed. Treatment was administrated to the patients with neoplasms of unknown origin, non-GEP-NENs, and ones with G3 grade. In total, 35 patients received 177-Lutetium (7.4 GBq), while 16 received 177-Lutetium and 90-Yttrium with equal activities (1.85 + 1.85 GBq). Results: The progression-free survival (PFS) before RLT qualification was 34.39 ± 35.88 months for the whole study group. In subgroups of patients with an unknown tumor location (n = 25), the median PFS was 19 months (IQR = 23), with “other” locations (n = 21) at 31 months (IQR = 28), and with NEN G3 (n = 7) at 18 months (IQR = 40). After RLT, disease stabilization or regression was observed in 42 (87.5% of) patients. RLT did not cause statistical changes in creatinine or GFR values. Hematological parameters (RBC, WBC, PLT, HGB) as well as chromogranin A concentration decreased significantly. There were no statistical differences between both subgroups regarding the type of radioisotope (177-Lutetium vs. 177-Lutetium and 90-Yttrium). After RLT in long-term observation, the median observation time (OT) was 14 months (IQR = 18 months). In patients with progression (n = 8), the median PFS was 20 months (IQR = 16 months), while in patients with confirmed death (n = 9), the median overall survival (OS) was 8 months (IQR = 14 months). Conclusions: Our study showed that 87.5% of NEN patients with unknown origin, non-GEP-NENs, and those with GEP-NEN G3 grade had benefited from the radioligand therapy. There were no significantly negative impacts on renal parameters. The decrease of bone marrow parameters was acceptable in relation to beneficial disease course. The decrease of chromogranin concentration was confirmed as a predictive factor for disease stabilization or regression. Full article

¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although ¹⁷⁷Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. α₁-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M’s renal protective effect in a mouse ¹⁷⁷Lu-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-¹⁷⁷Lu-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with ¹⁷⁷Lu-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with ¹⁷⁷Lu-DOTATATE. Full article

Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE improves the outcome of patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Nevertheless, stable disease has been the main response pattern observed, with some rare complete responses. Lu-177 exerts about two-thirds of its biological effects via the indirect effects of ionizing radiation that generate reactive oxygen species, eventually leading to oxidative damage and cell death. This provides a rationale for targeting the antioxidant defence system in combination with ¹⁷⁷Lu-DOTATATE. In the present study, the radiosensitizing potential and the safety of depleting glutathione (GSH) levels using buthionine sulfoximine (BSO) during ¹⁷⁷Lu-DOTATATE therapy were assessed in vitro and in vivo using a xenograft mouse model. In vitro, the combination resulted in a synergistic effect in cell lines exhibiting a BSO-mediated GSH decrease. In vivo, BSO neither influenced ¹⁷⁷Lu-DOTATATE biodistribution nor induced liver, kidney or bone marrow toxicity. In terms of efficacy, the combination resulted in reduced tumour growth and metabolic activity. Our results showed that disturbing the cell redox balance using a GSH synthesis inhibitor increased ¹⁷⁷Lu-DOTATATE efficacy without additional toxicity. Targeting the antioxidant defence system opens new safe treatment combination opportunities with ¹⁷⁷Lu-DOTATATE. Full article