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PurposeFDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT). The aim of this prospective phase II study was to evaluate the efficacy and toxicity of PRRT with 177Lu-DOTATATE associated with metronomic capecitabine as a radiosensitizer agent in patients with advanced progressive FDG-positive gastro-entero-pancreatic (GEP) NETs.Patients and methodsPatients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 < 55%) were treated with a cumulative activity of 27.5 GBq of 177Lu-DOTATATE divided in five cycles of 5.5 GBq each every 8 weeks. Capecitabine (1000–1500 mg daily) was administered orally in the inter-cycle period between 177Lu-DOTATATE treatments. Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test. Only DPD-proficient individuals were enrolled. The primary objectives were disease control rate (DCR) and safety. Secondary aims included progression-free (PFS) and overall survival (OS). Treatment response was assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.ResultsFrom August 2015 to December 2016, 37 subjects were consecutively enrolled. A total of 25 (68%) were affected by pancreatic neuroendocrine tumors (P-NETs), and 12 (32%) had gastrointestinal neuroendocrine tumors (GI-NETs). By grading (WHO 2010 classification), 12 patients (32%) had G1 (Ki67 ≤ 2%), 22 (59%) had G2 (3% < Ki67 ≤ 20%), and 3 patients (9%) had G3 (Ki67 > 20%) NETs. Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2% of patients. Other G3-G4 adverse events were diarrhea in 5.4% of cases and asthenia in 5.4%. No renal toxicity was observed for the duration of follow-up. In 37 patients, 33 were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%) and stable disease (SD) in 18 patients (55%), with a DCR of 85%. The median follow-up was 38 months (range 4.6–51.1 months). The median PFS was 31.4 months (17.6–45.4), and mOS was not reached.ConclusionsThis study demonstrated that the combination of PRRT with 177Lu-DOTATATE and metronomic capecitabine is active and well tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs. These data constitute the basis for a randomized study of PPRT alone vs. PRRT plus metronomic capecitabine.

PurposeRadioligand therapy (RLT) with 177Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate cancer (mCRPC). The present study was designed to define the safety and initial response to a minimal effective injected activity/cycle of 177Lu-PSMA-617 in mCRPC patients. New protective agents for salivary glands and kidney were co-administered and dosimetry was carried out.Patients and methodsA prospective single-arm, open label phase II study on mCRPC was activated at our institute in April 2017. Patients with histologically confirmed advanced mCRPC previously treated with standard life-prolonging agents were enrolled. Folic polyglutamate tablets were orally administered as parotid gland protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake before the injection of 3.7–5.5 GBq of 177Lu-PSMA-617 repeated four times at interval of 8 weeks. The adsorbed dose calculation was performed with MIRD formalism (OLINDA/EXM software). The Bryant and Day design was used to estimate the sample size taking account of both activity and toxicity.ResultsForty-three eligible patients were evaluated for toxicity and initial response. Dosimetry was carried out in 13 patients. Two (4.8%) patients had G3 and 8 (19.5%) had G2 hematological toxicity. Only 3 (6.9%) patients had mild G1 salivary gland toxicity and 8 (19.5%) had G1 renal toxicity. A decrease of ≥ 30% in prostate-specific antigen (PSA) was achieved after the first cycle in 17 (40.5%) patients, of whom 13 had a PSA decline of >50% after the second cycle. The median adsorbed doses were 0.65 mGy/MBq (range 0.33–2.63) for parotid glands, 0.42 mGy/MBq (0.14–0.81) for kidneys, 0.036 mGy/MBq (0.023–0.067) for red marrow, and 0.038 mGy/MBq (0.018–0.135) for the whole body.ConclusionIn advanced, heavily pre-treated mCRPC patients, 3.7 GBq/cycle of 177Lu-PSMA-617 was safe and produced early biochemical and imaging responses at PSMA whole-body scan post injection. Dosimetry of salivary glands suggests that the co-administration of polyglutamate tablets may reduce salivary gland uptake.Clinical trial registrationEU Clinical Trials Register No.: 2016-002732-32; NCT03454750. Collection and assembly of data: April 2017 and February 2019.

Background/Objectives: This report examines the future of academic studies involving investigational therapeutic radiopharmaceuticals within the framework of Regulation (EU) No. 536/2014. It discusses the impact of Good Manufacturing Practice (GMP) requirements (EudraLex-Volume 4-Good Manufacturing Practice guidelines) on the development of radiopharmaceuticals, based on local experience and analysis. Methods: The report was drafted by analysing multiple factors, including the European regulatory context regarding EMA guidance for investigational medicinal products (IMPs) and GMP requirements for radiopharmaceuticals, as well as position papers from various scientific associations. An analysis of all the relevant changes was conducted by a multidisciplinary team comprising radiopharmacists, nuclear medicine physicians, research experts and technology transfer specialists. They conducted a literature review to examine the clinical implications of the regulatory change and assess the impact of Regulation 536/2014 on academic clinical trials. Results: IRST has around 20 years’ experience in radiopharmaceutical clinical research. From 2008 to 2025, it conducted 16 clinical trials with radiopharmaceuticals under the Directive, and it is currently promoting five studies under the Regulation. During this time, more than 1000 patients were enrolled. The transition was based on staff training in quality documentation, the constitution of a contract research organisation (CRO) to ensure data quality and transfer, careful budget planning, the evaluation of innovative business models and the role of a Contract Development and Manufacturing Organization (CDMO). These integrated approaches enabled IRST to transform regulatory constraints into an opportunity to enhance its organisational model, improve data reliability, and strengthen its position as a centre of excellence for radiopharmaceutical research and production. Conclusions: The implementation of EU Regulation 536/2014 has significantly impacted academic research centres, especially those specialising in radiopharmaceuticals. Adhering to Good Manufacturing Practice (GMP) for therapeutic radiopharmaceuticals requires a considerable investment in infrastructure and personnel. However, the regulation also presents opportunities for research centres to enhance their capabilities. Meeting GMP standards can help institutions improve the quality and reliability of their clinical trials, potentially making them more competitive in the international research arena.

Background: Peptide receptor radionuclide therapy (PRRT) could be a therapeutic option for patients with advanced, recurrent or progressing meningiomas overexpressing somatostatin receptors. The aim of this study is to perform an updated meta-analysis to establish the disease control rate of PRRT in these patients. Methods: A comprehensive literature search of studies on PRRT in patients with advanced, recurrent or progressing meningioma was carried out. Four different databases (PubMed/MEDLINE, EMBASE, Cochrane library, Google Scholar) were screened until April 2025. Only original articles about PRRT in advanced, progressive or refractory meningiomas were selected. Case reports were excluded. Three review authors independently performed the literature search, the article selection and the data extraction. Main findings of eligible studies were summarized and a proportion meta-analysis on the disease control rate was carried out using a random-effects model. Results: In total, 18 studies (269 patients) published from 2006 to 2025 were included in the analysis. In most of the included studies, PRRT was performed using [177Lu]Lu-DOTATATE. The pooled disease control rate was 67.7% (95% confidence interval values: 59.6–75.7%). PRRT was well-tolerated in most patients with advanced, recurrent or progressive meningioma. Moderate statistical heterogeneity was found in the meta-analysis (I-square: 53%). Conclusions: PRRT is an effective and well-tolerated treatment in patients with advanced, progressive or recurrent meningiomas, showing a significant disease control rate (in about two-thirds of patients). Even if well-designed clinical trials are needed to corroborate these findings, evidence-based data seem to support the clinical use of PRRT for this indication.

Background In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [ 177 Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Methods We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of 177 Lu-PSMA-617. Results Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD ( p  = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83–16.36, p  = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23–79.27, p  = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR -gained had a significant shorter OS compared to AR -normal patients (7.4 vs 19.1 months, p  = 0.020). No treatment interruptions due to adverse effects were reported. Discussion Plasma AR status helped to indicate mCRPC with early resistance to 177 Lu-PSMA-617. Trial registration NCT03454750.

PurposeIn March 2014, we reported the activity and safety of 177Lu-DOTA-octreotate peptide receptor radionuclide therapy (Lu-PRRT) at two different dosages (18.5 GBq and 27.5 GBq in 5 cycles) in patients with progressive metastatic gastrointestinal neuroendocrine tumors (GI-NETs). Disease control rate (DCR) and toxicity were addressed. Herein, we report the late toxicity, progression-free survival (PFS), and overall survival (OS) in the same cohort after a 10-year follow-up.MethodsWe conducted an open-label, disease-oriented prospective phase II trial. From March 2008 to June 2011, 43 patients received 3.7 GBq or 5.5 GBq of Lu-PRRT every 6 to 8 weeks, each cycle repeated 5 times. All patients showed 68Gallium-DOTA-peptide PET/Octreoscan® positivity (score 3–4 Rotterdam scale) in known lesions. Tumor burden was estimated radiologically. Time-to-event data (PFS and OS) were described using Kaplan-Meier curves and compared with the log-rank test.ResultsForty-three patients (28 males and 15 females) were evaluable and were monitored for a median period of 118 months (range 12.6–139.6). Median PFS in patients receiving 18.5 GBq was 59.8 months (95% confidence interval [95% CI] 14.3–79.6), identical to that of patients treated with 27.5 GBq (59.8 months, 95% CI 23.4–82.0). Median OS was 71.0 months (95% CI 46.1–107.3) in the group who received 18.5 GBq and 97.6 months (95% CI 64.3-not reached) in the group treated with 27.5 GBq (P = 0.22). Patients with progression limited to lymph nodes showed significantly longer median PFS and OS than those with hepatic lesions (P = 0.02 for PFS and P = 0.04 for OS). Age over 65 years at the time of PRRT was also significant for OS. Of note, no late hematological or renal toxicity was observed in either group.ConclusionsThe long-term follow-up of the IRST phase II study shows that Lu-PRRT is a safe and effective therapy for patients with advanced GI-NET, the most important prognostic factor being tumor burden, hepatic lesions, and age. We believe that Lu-PRRT should be offered to patients with early-stage disease.

Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6–15%, I2 = 67%, p < 0.1) and 42% (95% CI: 28–56%, I2 = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6–5.4; I2 = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8–21.1; I2 = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens.

Peptide receptor radionuclide therapy (PRRT), developed over the last two decades, is carried out using radiopharmaceuticals such as 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotate (177Lu-Dotatate). These radiocompounds are obtained by labeling a synthetic somatostatin analog with a β-emitting radioisotope. The compounds differ from each other in terms of their energetic features (due to the radionuclide) and peptide receptor affinity (due to the analog) but share the common characteristic of binding specific membrane somatostatin receptors that are (generally) overexpressed in neuroendocrine neoplasms (NENs) and their metastases. NENs are tumors arising from diffuse neuroendocrine system cells that are classified according to grading based on Ki67 percentage values (Grades 1 and 2 are classed as neuroendocrine tumors [NETs]) and to the anatomical site of occurrence (in this paper, we only deal with gastroenteropancreatic [GEP]-NETs, which account for 60%-70% of all NENs). They are also characterized by specific symptoms such as diarrhea and flushing (30% of cases). Despite substantial experience gained in the area of PRRT and its demonstrable effects in terms of efficacy, safety, and improvement in quality of life, these compounds are still not registered (registration of 177Lu-Dotatate for the treatment of midgut NETs is expected soon). Thus, PRRT can only be used in experimental protocols. We provide an overview of the work of leading groups with wide-ranging experience and continuity in data publication in the area of GEP-NET PRRT and report our own personal experience of using different dosage schedules based on the presence of kidney and bone marrow risk factors. Our results on the retreatment of patients previously administered 90Y-DOTA-Tyr3-octreotide with a low dosage of 177Lu-Dotatate are also included. A comment on potential future developments of PRRT in GEP-NETs is provided.

There is a critical need for innovative therapies beyond the current standard of care for meningiomas and gliomas. Radioligand therapy (RLT), with its theranostic approach, holds significant promise in this regard. Although several reviews on this topic have been published, none yet have combined the utilization of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology with the Critical Appraisal Skills Programme (CASP) analysis, along with a dedicated subsection specifically addressing ongoing and completed clinical trials. This review aims to fill this gap in the literature by providing a comprehensive assessment of the current evidence on RLT in these tumors. Published studies were searched through PubMed, Scopus, and Web of Science up to 30 April 2025. Only original articles and clinical studies were included. Following a structured selection process, data extraction was performed. Study quality was critically appraised using CASP analyses. For clinical trials, an additional search was conducted on ClinicalTrials.gov beginning on 12 May 2025. A total of 30 studies were included in the review: 22 on meningiomas (290 patients) and 8 on gliomas (259 patients). For each study, first author, journal, year of publication, somatostatin receptor imaging, study design, radiopharmaceutical used, main topics, response criteria, toxicity assessment, post-therapy scintigraphy, number of patients, WHO grade, demographics, findings and median follow-up were considered. Among clinical trials, 22 were analyzed, including study site, year of first submission, proposed radiopharmaceutical, study type, primary endpoints and status. Efficacy and toxicity data were the primary focus, and the findings were generally encouraging. Studies on RLT in meningiomas was more robust, while in gliomas remained largely experimental. Nevertheless, the authors' critical appraisal was generally positive. Clinical trials confirmed the more \"traditional\" nature of research in meningiomas compared to gliomas. Despite the heterogeneity of the studies, RLT emerges as a promising therapeutic strategy in neuro-oncology. Its theranostic paradigm offers a distinctive advantage, enabling patient selection, treatment personalization, and response monitoring. The development of potentially novel radiopharmaceuticals and the conduct of well-designed multicenter trials with standardized response criteria are needed to further increase the impact and clinical translation of RLT in neuro-oncology.

Objectives: The aim of this study was to investigate the treatment patterns and outcomes in two propensity score-matched cohorts of patients with neuroendocrine tumours (NETs) treated with first-line somatostatin analogue (SSA). Methods: Metastatic NET patients treated with first-line SSA (2009–2022) were retrospectively examined. First-line lanreotide vs. octreotide cohorts were matched 1:1 by propensity scores for demographics, tumour characteristics, and diagnosis year. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier analysis and the Cox proportional hazards model. Results: Among 441 patients, 310 were matched (155 in both the octreotide and lanreotide groups). First-line SSA was monotherapy (63.5%) or combination with other medications (36.5%). A total of 77% of second-line patients (188/244) maintained their initial SSA medication in combination with other therapies. Radioligand therapy with lanreotide (N = 72; 29.5%) or octreotide (N = 70; 28.7%) was the most common second-line treatment. First-line lanreotide and octreotide cohorts had similar median PFS (15.5; 95% CI: 13.6–19.1 vs. 14.0; 95% CI: 12.0–15.8 months), despite octreotide having a 36% higher likelihood of moving to the second line than lanreotide (95% CI: 1.05–1.76, p = 0.018). Multiple metastases (HR = 1.45; p = 0.004, 95% CI: 1.13–1.87) and Ki-67 > 20% (HR = 2.34; p < 0.001, 95% CI: 1.43–3.83) were significantly associated with the worst PFS. First-line lanreotide patients had a median OS of 10.4 years (95% CI: 7.5-NA) and octreotide 9.2 years (95% CI: 7.3-NA) (p = 0.537). Bone metastases increased death risk by 91% (p = 0.014; 95% CI: 1.14–3.20). Conclusions: SSA monotherapy is the main first-line treatment and most subsequent treatments include SSA with additional medications. Cohorts had similar PFS/OS, but octreotide demonstrated a 36% significantly higher likelihood of moving to the second-line treatment.