Peptide Receptor Radionuclide Therapy Research Articles

Meeting Notes of the Taiwan Neuroendocrine Tumor Society & Taiwan Society of Nuclear Medicine Joint Conference - Peptide Receptor Radionuclide Therapy Targeting for Gastroenteropancreatic Neuroendocrine Tumors: Basic Principles and State-of-the-art Clinical Practice

Abstract Objective: The current study aimed to investigate the basic principles and clinical applications, including the selection of proper candidates, follow-up strategies, and radiation protection issues relating to peptide receptor radionuclide therapy (PRRT). Data Sources and Study Selection: We searched various scientific databases using specific keywords. Results: Due to the overexpression of somatostatin receptors in neuroendocrine tumors (NETs), PRRT is currently considered an important therapeutic modality for the management of NETs. Conclusion: PRRT incorporates the systemic administration of a tumor-targeting radiolabeled peptide to patients with tumors, allowing for more precise delivery of radiation doses to tumor sites while sparing normal tissues.

Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

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. 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. 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). 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.

SPECT/CT Image-Derived Absorbed Dose to Red Marrow Correlates with Hematologic Toxicity in Patients Treated with [177Lu]Lu-DOTATATE.

Hematologic toxicity, although often transient, is the most common limiting adverse effect during somatostatin peptide receptor radionuclide therapy. This study investigated the association between Monte Carlo-derived absorbed dose to the red marrow (RM) and hematologic toxicity in patients being treated for their neuroendocrine tumors. Methods: Twenty patients each receiving 4 treatment cycles of [177Lu]Lu-DOTATATE were included. Multiple-time-point 177Lu SPECT/CT imaging-based RM dosimetry was performed using an artificial intelligence-driven workflow to segment vertebral spongiosa within the field of view (FOV). This workflow was coupled with an in-house macroscale/microscale Monte Carlo code that incorporates a spongiosa microstructure model. Absorbed dose estimates to RM in lumbar and thoracic vertebrae within the FOV, considered as representations of the whole-body RM absorbed dose, were correlated with hematologic toxicity markers at about 8 wk after each cycle and at 3- and 6-mo follow-up after completion of all cycles. Results: The median of absorbed dose to RM in lumbar and thoracic vertebrae within the FOV (D median,vertebrae) ranged from 0.019 to 0.11 Gy/GBq. The median of cumulative absorbed dose across all 4 cycles was 1.3 Gy (range, 0.6-2.5 Gy). Hematologic toxicity was generally mild, with no grade 2 or higher toxicity for platelets, neutrophils, or hemoglobin. However, there was a decline in blood counts over time, with a fractional value relative to baseline at 6 mo of 74%, 97%, 57%, and 97%, for platelets, neutrophils, lymphocytes, and hemoglobin, respectively. Statistically significant correlations were found between a subset of hematologic toxicity markers and RM absorbed doses, both during treatment and at 3- and 6-mo follow-up. This included a correlation between the platelet count relative to baseline at 6-mo follow up: D median,vertebrae (r = -0.64, P = 0.015), D median,lumbar (r = -0.72, P = 0.0038), D median,thoracic (r = -0.58, P = 0.029), and D average,vertebrae (r = -0.66, P = 0.010), where D median,lumbar and D median,thoracic are median absorbed dose to the RM in the lumbar and thoracic vertebrae, respectively, within the FOV and D average,vertebrae is the mass-weighted average absorbed dose of all vertebrae. Conclusion: This study found a significant correlation between image-derived absorbed dose to the RM and hematologic toxicity, including a relative reduction of platelets at 6-mo follow up. These findings indicate that absorbed dose to the RM can potentially be used to understand and manage hematologic toxicity in peptide receptor radionuclide therapy.

Treatment and Long-Term Safety Outcomes of Peptide Receptor Radionuclide Therapy for Metastatic Neuroendocrine Tumours: An Asian Experience

Purpose: Peptide receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NETs). It has been shown to be effective and well tolerated in patients with metastatic NETs in several centres in the USA, Europe, and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. Methods: One hundred and seven (107) patients with metastatic NETs who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST 1.1 and qualitative analysis were examined. The overall and progression-free survival curves were also evaluated. Results: The median progression-free survival was 49 months. Response assessment after completion of treatment showed that 33 (37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression-free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. Conclusion: Our results show that PRRT is safe and effective in the treatment of metastatic NET in the Asian population. There was a significant difference in the progression-free survival curves between low-grade and high-grade NET and in the progression-free and overall survival comparing the number of cycles received.

Abstract 7614: Mutations in MEN1/DAXX/ATRX are associated with improved progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy

Abstract Background: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTATATE is an effective treatment for metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs). However, it remains unknown why some patients (pts) respond more favorably than others. Pre-clinical data suggests that mutations in the MEN1, DAXX, and/or ATRX genes influence DNA repair capabilities and increase radiation effect in cancer cells. We therefore thought to evaluate the association between response to PRRT and the presence of MEN1, DAXX, and/or ATRX mutations in patients with GEP-NETs. Methods: We retrospectively analyzed CLIA certified tissue-based Next Generation Sequencing (NGS) assay results and clinicopathological data from 28 pts with GEP-NETs treated with PRRT at our center from 2017 to 2023. Genetic findings were correlated with progression-free survival (PFS) using Kaplan-Meier estimators and Cox proportional hazards regression modeling. Objective response was assessed per RECIST v1.1 by investigator review. Results: Pts with mutations in MEN1, DAXX, or ATRX (n = 13, 46.42%) had a longer PFS [mPFS, 26.47 months (95% CI, 17.97 - NA) vs. 12.13 months (95% CI, 9.17 - NA); HR, 0.19; 95% CI, 0.06 - 0.68; p = 0.01] than wildtype (n = 15, 53.58%) pts, when adjusted for surgery prior to PRRT and tumor grade. Pts with mutations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended towards better PFS compared to patients without concurrent mutations [only MEN1mt or DAXXmt/ATRXmt, but not both; mPFS, 31.53 months (95% CI, 28.43 - NA) vs. 17.97 months (95% CI, 11.17 - NA); HR, 0.25; 95% CI, 0.05 - 1.29; p = 0.09]. Among evaluable pts, objective response rate was higher in pts with a mt in MEN1, DAXX, or ATRX compared to wild-type pts (41.67% vs. 15.38%; p = 0.09). In the pancreatic NET (PNET) subset, mutations in either MEN1, DAXX, or ATRX were found in 11/16 pts (68.75%) and were also associated with a better PFS compared to wild type patients [mPFS, 28.43 months (95% CI, 11.50 - NA) vs. 9.83 months (95% CI, 7.83 - NA); HR, 0.21; 95% CI, 0.05 - 0.95; p = 0.04). Conclusions: Mutations in MEN1/DAXX/ATRX correlate with improved PFS in patients with GEP-NETs receiving PRRT. Concurrent mutations in MEN1 and DAXX/ATRX may have additive effects on response to PRRT. If validated in larger studies, these findings may represent a novel biomarker to predict PRRT response. Limitations: Limited sample size precludes generalization of results and might overestimate effect sizes. Citation Format: Rushabh Gujarathi, Sara Abou Azar, Joseph Tobias, Xavier Keutgen, Chih-Yi Liao. Mutations in MEN1/DAXX/ATRX are associated with improved progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7614.

Abstract 5165: Development and validation of an assay for the characterization of SSTR2 expression on CTCs from liquid biopsies

Abstract Background: Expression of Somatostatin Receptor subtype 2 (SSTR2) is observed in multiple cancers, including breast and colorectal cancer. Its role as a prognostic or predictive marker is cancer-type dependent. Recently, there has been renewed interest in assessing this biomarker since it plays a critical role as a target for radiotherapeutics (peptide receptor radionuclide therapy - PRRT) in patients with neuroendocrine tumors (NETs). Blood-based liquid biopsies are a non-invasive tool with proven effectiveness in characterizing cancer biomarker expression in patients. In this study, we describe the development and validation of a novel assay to analyze circulating tumor cells (CTCs) for expression of SSTR2 using the RareCyte platform. Experimental Procedures: Using AccuCyte®, an unbiased density-based method for collecting nucleated cells from whole blood, we transferred nucleated cells to slides and stained for SSTR2, CD45, and CK/EpCAM to identify CTCs (CK+/EpCAM+, CD45-), and evaluate SSTR2 expression. Slides were imaged with CyteFinder®, an automated multiparameter immunofluorescent (IF) microscopy system that applies machine learning algorithms for rare cell identification. Both clinical and spike-in samples were used for assay validation. Single-cell SSTR2 mean fluorescence intensities (MFI) were analyzed to determine protein expression levels. Colorectal cancer with neuroendocrine features and Merkel cell cancer (neuroendocrine tumor of the skin) patient samples were evaluated for CTC enumeration and SSTR2 expression. Results: The assay’s performance metrics for SSTR2 expression were 90+% accuracy, 85% sensitivity, 100% specificity with repeatability and intermediate precision CVs of 14.4% and 16.4%, respectively. A small cohort of colorectal cancer (1) and Merkel cell cancer (2) patient blood samples were tested using the assay. All 3 patients had high CTC levels (300+ per 7.5 mL). The percentage of SSTR2-positive CTCs ranged from 20-60%, reflective of tumor heterogeneity. Conclusions: SSTR2 is an important target now in the advent of theranostics - PRRT. Prognostic and therapeutic implications of SSTR2 expression is an area of active clinical research. SSTR2 targeted therapeutics like 177Lu-dotatate illustrate the possible utility of SSTR2 as a predictive biomarker of treatment response. To date, most of the work has been focused on assessing SSTR2 on tissue. Herein, we show how a CTC platform can be adapted to assess a clinically relevant cell surface protein biomarker. This is now included as an important correlative in a clinical trial for Merkel Cell Cancer patients called iPRRT that is actively accruing (NCT05583708). Citation Format: Erin G. Bayer, Rachel N. Ponting, Ciara M. Kelly, Areeb Lutfi, Maaz K. Afghan, Arturo B. Ramirez, Pashtoon M. Kasi. Development and validation of an assay for the characterization of SSTR2 expression on CTCs from liquid biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5165.

Responses to Medical Treatment in 192 Patients with Pancreatic Neuroendocrine Neoplasms Referred to the Copenhagen Neuroendocrine Tumour Centre in 2000-2020.

Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). Median OS was 36 (95% CI: 26-46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9-9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1-7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide.

177 Lu-DOTATATE Salvage Therapy in Rapidly Progressing Neuroendocrine Tumor With Poor Performance Status.

Peptide receptor radionuclide therapy (PRRT) has shown to be effective and safe in metastatic gastroenteropancreatic and nongastroenteropancreatic neuroendocrine tumors. However, the selection criteria for PRRT are restricted to patients with good performance status (Eastern Cooperative Oncology Group score ≤2 or Karnofsky performance score ≥60). This denies many patients with adequate somatostatin receptor expression and biochemical profiles from the beneficial effects of PRRT on the quality of life, daily function, and overall survival. The 2 cases highlight the favorable response of PRRT in patients with metastatic neuroendocrine tumor having a very poor performance status initially.

Lung NETs and GEPNETs: One Cancer with Different Origins or Two Distinct Cancers?

Lung neuroendocrine tumors (LNETs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are two distinct types of neuroendocrine tumors (NETs) that have traditionally been treated as a single entity despite originating from different sources. Although they share certain phenotypic characteristics and the expression of neuroendocrine markers, they exhibit differences in their microenvironment, molecular mutations, and responses to various therapeutic regimens. Recent research has explored the genetic alterations in these tumors, revealing dissimilarities in the frequently mutated genes, the role of EGFR in carcinogenesis, the presence of transcription factors, and the immunogenicity of the tumor and its microenvironment. Spread Through Air Spaces (STAS), a phenomenon unique to lung carcinomas, appears to play a crucial role in LNET prognosis. These distinctions are also evident in the cascade response of lung and GI tract neuroendocrine tumors to somatostatin analogs, Peptide Receptor Radionuclide Therapy (PRRT), chemotherapy, and immunotherapy. Identifying similarities and differences between the two groups may improve our understanding of the underlying mechanisms and facilitate the development of more effective treatment strategies.

A Case Series of Choroidal and Orbital Neuroendocrine Tumors: Metastasis: Two Patients Treated With Peptide Radionuclide Therapy.

Neuroendocrine tumors (NETs) are rare cancers with heterogeneous histologies, response to treatments, and prognoses. Majority of these cancers originate in the gastrointestinal tract and metastasize to the liver. We report the cases of 5 patients with low-grade NET disease with rare metastases to the choroids. Two of the patients were treated with peptide receptor radionuclide therapy (lutetium 177 [ 177 Lu]). This is the first report confirming peptide radionuclide therapy safety in patients with low-grade NET with ocular metastases.

Efficacy of [67Cu]Cu-EB-TATE Theranostic Against Somatostatin Receptor Subtype-2-Positive Neuroendocrine Tumors.

β--emitting 177Lu-octreotate is an approved somatostatin receptor subtype 2 (SSTR2)-directed peptide receptor radionuclide therapy for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). However,177Lu-octreotate has fast pharmacokinetics, requiring up to 4 treatment doses. Moreover, 177Lu is less than ideal for theranostics because of the low branching ratio of its γ-emissions, which limits its SPECT imaging capability. Compared with 177Lu, 67Cu has better decay properties for use as a theranostic. Here, we report the preclinical evaluation of a long-lived somatostatin analog, [67Cu]Cu-DOTA-Evans blue-TATE (EB-TATE), against SSTR2-positive NETs. Methods: The invitro cytotoxicity of [67Cu]Cu-EB-TATE was investigated on 2-dimensional cells and 3-dimensional spheroids. In vivo pharmacokinetics and dosimetry were studied in healthy BALB/c mice, whereas ex vivo biodistribution, micro-SPECT/CT imaging, and therapy studies were done on athymic nude mice bearing QGP1.SSTR2 and BON1.SSTR2 xenografts. Therapeutic efficacy was compared with [177Lu]Lu-EB-TATE. Results: Projected human effective doses of [67Cu]Cu-EB-TATE for male (0.066 mSv/MBq) and female (0.085 mSv/MBq) patients are tolerable. In vivo micro-SPECT/CT imaging of SSTR2-positive xenografts with [67Cu]Cu-EB-TATE showed tumor-specific uptake and prolonged accumulation. Biodistribution showed tumor accumulation, with concurrent clearance from major organs over a period of 72 h. [67Cu]Cu-EB-TATE was more effective (60%) at eliminating tumors that were smaller than 50 mm3 within the first 15 d of therapy than was [177Lu]Lu-EB-TATE (20%) after treatment with 2 doses of 15 MBq administered 10 d apart. Mean survival of [67Cu]Cu-EB-TATE-treated groups was 90 d and more than 90 d, whereas that of [177Lu]Lu-EB-TATE was more than 90 d and 89 d against vehicle control groups (26 d and 53 d), for QGP1.SSTR2 and BON1.SSTR2 xenografts, respectively. Conclusion: [67Cu]Cu-EB-TATE exhibited high SSTR2-positive NET uptake and retention, with favorable dosimetry and SPECT/CT imaging capabilities. The antitumor efficacy of [67Cu]Cu-EB-TATE is comparable to that of [177Lu]Lu-EB-TATE, with [67Cu]Cu-EB-TATE being slightly more effective than [177Lu]Lu-EB-TATE for complete remission of small tumors. [67Cu]Cu-EB-TATE therefore warrants clinical development.

Hypoalbuminemia, but not derived neutrophil to lymphocyte ratio (dNLR), predicts overall survival in neuroendocrine tumours undergoing peptide receptor radionuclide therapy: A retrospective, cohort study of 557 patients.

Several inflammation scores have shown association with survival outcomes for patients with neuroendocrine tumours (NET) treated with peptide receptor radionuclide therapy (PRRT). However, whether these scores add value to established prognostic factors remains unknown. In this retrospective, cohort study of 557 NET patients undergoing PRRT in a tertiary referral centre from 2005 to 2015, we examined inflammatory markers and scores previously associated with cancer outcomes, using Cox proportional hazard models and Akaike's information criterion. Lower albumin (hazard ratio [95% confidence interval], .91 [.87-.95] per unit), as well as higher C-reactive protein (CRP; 1.02 [1.01-1.02]), Glasgow Prognostic Score (GPS; 1 vs. 0: 1.67 [1.14-2.44], 2 vs. 0 3.60 [2.24-5.79]), CRP/albumin ratio (1.84 [1.43-2.37]) and platelet count (Plt) × CRP, but not white blood cell, neutrophil and thrombocyte counts or derived neutrophil to lymphocyte ratio (dNLR), were associated with shorter median overall survival (OS) in an adjusted analysis. The addition of parameters based on albumin and CRP, but not dNLR, to a base model including age, chromogranin A, the cell proliferation marker Ki-67, performance status, tumour site and previous treatments improved the predictive accuracy of the base model. In an exploratory analysis of patients with available erythrocyte sedimentation rate (ESR) and CRP, ESR emerged as the most powerful predictor. When added to a prognostic model for OS in NET patients treated with PRRT, most inflammation scores further improved the model. Albumin was the single marker adding most value to the set of established prognostic markers, whereas dNLR did not seem to improve the model's prognostic ability.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) - Current literature review of diagnostics and therapy. What has changed in the management?

<b>Introduction:</b> Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are malignancies originating from cells of the diffuse endocrine system. They are rare and localize in the upper and lower parts of the gastrointestinal tract and in the pancreas. Despite such a varied location, GEP-NENs are considered a common group of neoplasms due to the fact of their similar morphology and ability to secrete peptide hormones and biologically active amines. They are associated with clinical manifestations specific to the substances produced by a particular neoplasm. The classification of GEP-NENs is constantly systematized and updated based on their differentiation and grading. The development of available diagnostic and treatment methods for these tumors has made significant progress over the past 10 years and is still ongoing.<b>Aim:</b> In the following paper, we review the diagnostics and treatment of GEP-NENs, taking into account the latest molecular, immunological, or gene-based methods. Imaging methods using markers for receptors allow for high diagnostic sensitivity<b>Methods:</b> Medical databases were searched for the latest information. The authors also sought confirmation of the content of a particular publication in another publications, so as to present the most reliable information possible.<b>Results:</b> Research results revealed that the diagnostics and treatment of GEP-NENs have significantly advanced in recent years. Surgical interventions, especially minimally invasive techniques, have shown efficacy in treating GEP-NENs, with specific therapies such as somatostatin analogs, chemotherapy, and peptide receptor radionuclide therapy demonstrating promising outcomes. The evolution of diagnostic methods, including imaging techniques and biomarker testing, has contributed to improved patient care and prognosis.<b>Conclusions:</b> The increasing incidence of GEP-NENs is attributed to enhanced diagnostic capabilities rather than a rise in population prevalence. The study emphasizes the importance of ongoing research to identify specific markers for early detection and targeted therapies to further enhance the effectiveness of treating these rare and heterogeneous malignancies. The findings suggest a positive trajectory in the management of GEP-NENs, with future prospects focused on personalized and targeted treatment approaches.

Peritoneal metastases in patients with neuroendocrine neoplasms: a challenging site of metastases with clinical and prognostic implications.

Peritoneal metastases (PM) of neuroendocrine neoplasm (NEN) origin are identified with increasing frequency and exert a significant effect on quality of life and clinical status of the patients. The aim of this study was to identify the characteristics and the prognostic significance of PM in patients with NENs. A retrospective analysis of the data of patients from two tertiary referral centers was performed. We defined a control group of age- and gender-matched NEN patients with comparable stage IV disease but no PM. We analysed 70 patients (41 females) with PM. Small intestine was the most common primary NEN site (87.1%). PM prevalence was 10.3%. Forty-four patients presented with synchronous PM, whereas 26 developed metachronous PM. The majority of patients had other concomitant metastases (50 hepatic, 6 lung and 12 bone metastases). Twelve patients developed intestinal obstruction. After PM diagnosis, 76% of patients received treatment with somatostatin analogues while six patients (8.6%) were treated with peptide receptor radionuclide therapy (PRRT). The median progression-free survival (PFS) in the PRRT-treated group was 15months (95% CI 2-28). Median overall survival (OS) in the PM group was 142months [95% CI 71-213] while it was not reached in the control group. Peritoneal metastases show low prevalence among NEN patients and are most likely to develop in patients with small intestinal NENs and advanced metastatic disease. The presence of PM does seem to be associated with a negative prognostic impact on OS of NEN patients and their identification and prompt treatment is of major importance.

Extravasation After [ 177 Lu]Lu-HA-DOTATATE Therapy.

Extravasation of the radiopharmaceutical during peptide receptor radionuclide therapy infusion is an unwanted infrequently reported event. We present the case of a 74-year old woman with a neuroendocrine tumor who was referred for peptide receptor radionuclide therapy. During intravenous infusion of 7.4 GBq [ 177 Lu]Lu-HA-DOTATATE in the upper right arm, extravasation of the radiopharmaceutical occurred through a displaced intravenous catheter. Planar scintigraphy showed pooling of radioactivity in the right upper arm. After 24 hours, the swelling in the arm was decreased; however, erythema was increased. One week later, symptoms had disappeared, and the patient did not experience any complications during follow-up of 11 months.

Towards Effective Targeted Alpha Therapy for Neuroendocrine Tumours: A Review.

This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from β-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to β-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols.

Peptide Therapeutics: Unveiling the Potential against Cancer-A Journey through 1989.

The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody-drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects.

PRRT with Lu-177 DOTATATE in Treatment-Refractory Progressive Meningioma: Initial Experience from a Tertiary-Care Neuro-Oncology Center.

Refractory and/or recurrent meningiomas have poor outcomes, and the treatment options are limited. Peptide receptor radionuclide therapy (PRRT) has been used in this setting with promising results. We have documented our experience of using intravenous (IV) and intra-arterial (IA) approaches of Lu-177 DOTATATE PRRT. Eight patients with relapsed/refractory high-grade meningioma received PRRT with Lu-177 DOTATATE by IV and an IA route. At least 2 cycles were administered. Time to progression was calculated from the first PRRT session to progression. The response was assessed on MRI using RANO criteria, and visual analysis of uptake was done on Ga-68 DOTANOC PET/CT. Post-therapy dosimetry calculations for estimating the absorbed dose were performed. Median time to progression was 8.9 months. One patient showed disease progression, whereas seven patients showed stable disease at 4 weeks following 2 cycles of PRRT. Dosimetric analysis showed higher dose and retention time by IA approach. No significant peri-procedural or PRRT associated toxicity was seen. PRRT is a safe and effective therapeutic option for relapsed/refractory meningioma. The IA approach yields better dose delivery and should be routinely practised.

The Impact of Posttreatment Imaging in Peptide Receptor Radionuclide Therapy.

Posttreatment imaging of γ-emissions after peptide receptor radionuclide therapy (PRRT) can be used to perform quantitative dosimetry as well as assessment response using qualitative measures. We aimed to assess the impact of qualitative posttreatment imaging on the management of patients undergoing PRRT. Methods: In this retrospective study, we evaluated 100 patients with advanced well-differentiated neuroendocrine tumors undergoing PRRT, who had posttreatment SPECT/CT imaging at 24 h. First, we evaluated the qualitative assessment of response at each cycle. Then using a chart review, we determined the impact on management from the posttreatment imaging. The changes in management were categorized as major or minor, and the cycles at which these changes occurred were noted. Additionally, tumor grade was also evaluated. Results: Of the 100 sequential patients reviewed, most (80% after cycle 2, 79% after cycle 3, and 73% after cycle 4) showed qualitatively stable disease during PRRT. Management changes were observed in 27% (n = 27) of patients; 78% of those (n = 21) were major, and 30% (n = 9) were minor. Most treatment changes occurred after cycle 2 (33% major, 67% minor) and cycle 3 (62% major, 33% minor). Higher tumor grade correlated with increased rate of changes in management (P = 0.006). Conclusion: In this retrospective study, qualitative analysis of posttreatment SPECT/CT imaging informed changes in management in 27% of patients. Patients with higher-grade tumors had a higher rate of change in management, and most of the management changes occurred after cycles 2 and 3. Incorporating posttreatment imaging into standard PRRT workflows could potentially enhance patient management.

Intra-arterial PRRT with Lu-177 DOTATATE in Liver-dominant Metastatic Neuroendocrine Tumors: Early Assessment of Efficacy and Toxicity.

We proposed to administer Lu-177-DOTATATE in intra-arterial (IA) mode for higher first-pass localization to somatostatin receptors, higher residence time in liver metastases, and more radiation to tumor. This study aimed at assessing early hematological, renal and hepatotoxicity; and objective response to IA peptide receptor radionuclide therapy (PRRT). Fourteen patients (4 females and 10 males) were prospectively assessed. 5/14 patients underwent 2 cycles, whereas 3/14 underwent 3 cycles, and 6/14 received 1 cycle of IA PRRT. 200 mCi of Lu-177-DOTATATE was administered in 15-20 min by IA route under angiographic guidance. Patients were asked to follow-up at 4 and 8 weeks with hematological, liver, and renal functional parameters, and Ga-68 DOTATATE positron emission tomography/computed tomography (PET/CT) after 8 weeks. Response was assessed using RECIST 1.1 and EORTC PET criteria. Safety: 2/14 patients had high total and direct bilirubin, which reverted to normal after IA PRRT. Three patients had low albumin, which improved after 1 cycle. Nine patients showed no worsening of liver function. Two patients showed Grade 1 hematotoxicity which reverted to normal. Five patients showed high creatinine, but preserved glomerular filtration rate and EC clearance. On follow-up at 8 weeks, serum creatinine reverted to normal. Efficacy: In five patients who underwent 2 cycles of IA PRRT, 3 showed partial response (PR) on RECIST 1.1 and partial metabolic response (PMR) on EORTC criteria, whereas 2 showed stable disease (SD). In patients who underwent 3 cycles, 1 showed SD, whereas other patient showed PMR on DOTANOC PET/CT, with PR in size. Among the remaining seven patients, 5 showed PMR, whereas the other 2 showed SD. Thus 9/14 patients showed PR, whereas 5 showed SD on metabolic and size criteria. IA PRRT is a safe and efficacious approach for the treatment of liver dominant metastatic neuroendocrine tumors.