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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary Neuroendocrine Tumor (NF-PitNET) Cells.

Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08)%, p < 0.001 vs. basal, n = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, p < 0.001 vs. basal, n = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.

Radionuclide Theranostics in Neuroendocrine Neoplasms: An Update.

PURPOSE OF REVIEW: This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT). RECENT FINDINGS: Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.

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.

Effectiveness and Safety of Retreatment with 177Lu-DOTATATE in Patients with Progressive Neuroendocrine Tumors: A Retrospective Real-World Study in the United States.

Advanced neuroendocrine tumors (NETs) are associated with a poor prognosis. A regimen of 4 cycles of 177Lu-DOTATATE has been shown to improve both progression-free survival (PFS) and overall survival (OS) in patients with advanced NETs. To the best of our knowledge, this is the first study in the United States to evaluate the effectiveness and safety of additional cycles of 177Lu-DOTATATE therapy in patients with progressive NETs. Methods: This was a retrospective chart review of adults with advanced NETs. The patients had undergone initial treatment with up to 4 cycles of 177Lu-DOTATATE and, after disease progression and a period of at least 6 mo since the end of the initial treatment, were retreated with at least 1 additional cycle at a single center (2010-2020). Patient characteristics, treatment patterns, and clinical outcomes were evaluated descriptively. Response was evaluated according to RECIST 1.1; toxicity was defined using criteria from Common Terminology Criteria for Adverse Events, version 5.0. Kaplan-Meier plots were used to evaluate PFS and OS. Results: Of the 31 patients who received 177Lu-DOTATATE retreatment, 61% were male and 94% were White. Overall, patients received a median of 6 cycles (4 initial cycles and 2 retreatment cycles), and the mean administered activity was 41.9 GBq. Two patients also went on to receive additional retreatment (1 and 2 cycles, individually) after a second period of at least 6 mo and progression after retreatment. Best responses of partial response and stable disease were observed in 35% and 65% of patients after the initial treatment and 23% and 45% of patients after retreatment, respectively. The median PFS after the initial treatment was 20.2 mo and after retreatment was 9.6 mo. The median OS after the initial treatment was 42.6 mo and after retreatment was 12.6 mo. Hematologic parameters decreased significantly during both the initial treatment and retreatment but recovered such that there was little difference between the values before the initial treatment and before the retreatment. Clinically significant hematotoxicity occurred in 1 and 3 patients after the initial treatment and retreatment, respectively. No grade 3 or 4 nephrotoxicity was observed. Conclusion: Retreatment with 177Lu-DOTATATE after progression appeared to be well tolerated and offered disease control in patients with progressive NETs after initial 177Lu-DOTATATE treatment.

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

ABSTRACT: 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.

Efficacy and Safety of 225 Ac-DOTATATE in the Treatment of Neuroendocrine Neoplasms With High SSTR Expression.

PURPOSE: We aimed to evaluate the efficacy and safety of 225 Ac-DOTATATE targeted α therapy (TAT) in various neuroendocrine neoplasms (NENs) with high somatostatin receptor (SSTR) expression. PATIENTS AND METHODS: This single-center prospective study included 10 patients with histologically diagnosed NENs that exhibited increased SSTR expression on 68 Ga-DOTATATE PET/CT imaging. All patients received 225 Ac-DOTATATE TAT. The primary end points were molecular imaging-based response and disease control rate (DCR), measured using the slightly modified Positron Emission Tomography Response Criteria in Solid Tumors 1.0. The secondary end points were adverse event profiles and clinical responses. The adverse event profile was determined according to the Common Terminology Criteria for Adverse Events version 5.0. Clinical response was assessed using the EORTC QLQ-C30 v3.0 (European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire version 3.0). RESULTS: A molecular imaging-based partial response was observed in 40% of all patients, SD in 40%, PD in 20%, and DCR in 80%. The DCR was 83.3% (5/6) in patients who were previously treated with 177 Lu-DOTATATE. According to the EORTC QLQ-C30 v3.0 score, most symptoms improved after 225 Ac-DOTATATE treatment, with only diarrhea showing no improvement. Grade III/IV hematological, kidney, and liver toxicities were not observed. The median follow-up time was 14 months (7-22 months), and no deaths were reported. CONCLUSIONS: This initial study suggests that 225 Ac-DOTATATE is a potentially promising option for treating NENs with elevated SSTR expression, with an acceptable toxicity profile and well-tolerated adverse effects.

Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly.

PURPOSE: Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly. METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics. RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma. CONCLUSION: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

Chylous Ascites Associated with Advanced Pancreatic Cancer That Improved with Appropriate Treatment: A Case Report.

Chylous ascites is a rare form of ascites with high triglyceride content arising from the thoracoabdominal lymph nodes in the peritoneal cavity due to various benign or malignant etiologies, including pancreatic cancer. During cancer chemotherapy, the accumulation of ascites can lead to the deterioration of the patient's general condition, making chemotherapy administration difficult, and resulting in a poor prognosis. We encountered a rare case of chylous ascites complicated by advanced pancreatic cancer. The patient presented with a discrepancy between the shrinkage of the pancreatic cancer and the accumulation of ascites. Therefore, we were able to promptly diagnose chylous ascites by performing biochemical tests. The patient was treated with octreotide, reportedly effective in treating chylous ascites, which rapidly improved the chylous ascites and general condition of the patient, allowing the patient to continue chemotherapy for pancreatic cancer. Therefore, physicians should consider the possibility of chylous ascites when clinically unexplained ascites are observed in patients with advanced cancer. The investigation and treatment of chylous ascites should be initiated as soon as possible.

Low-dose targeted radionuclide therapy synergizes with CAR T cells and enhances tumor response.

Ionizing radiation has garnered considerable attention as a combination partner for immunotherapy due to its potential immunostimulatory effects. In contrast to the more commonly used external beam radiation, we explored the feasibility of combining chimeric antigen receptor (CAR) T cell therapy with targeted radionuclide therapy (TRT), which is achieved by delivering ß-emitting 177Lu-DOTATATE to tumor via tumor-infiltrating CAR T cells that express somatostatin receptor 2 (SSTR2). We hypothesized that the delivery of radiation to tumors could synergize with CAR T therapy, resulting in enhanced antitumor immunity and tumor response. To determine the optimal dosage and timing of 177Lu-DOTATATE treatment, we measured CAR T cell infiltration and expansion in tumors longitudinally through positron emission tomography (PET) using a SSTR2-specific positron-emitting radiotracer,18F-NOTA-Octreotide. In animals receiving CAR T cells and a low-dose (2.5 Gy) of TRT following the administration of 177Lu-DOTATATE, we observed a rapid regression of large subcutaneous tumors, which coincided with a dramatic increase in serum proinflammatory cytokines. Tumor burden was also reduced when a higher radiation dose (6 Gy) was delivered to the tumor. However, this higher dose led to cell death in both the tumor and CAR T cells. Our study suggests that there may exist an optimum range of TRT dosage that can enhance T cell activity and sensitize tumor cells to T cell killing, which may result in more durable tumor control compared to a higher radiation dose.

Central hyperthyroidism due to an ectopic TSH-secreting pituitary tumor: a case report and literature review.

Ectopic thyroid-stimulating hormone (TSH)-secreting tumors are extremely rare, with only 15 reported cases in the literature. Herein, we described a 60-year-old female patient with thyrotoxicosis and elevated or unsuppressed levels of TSH. Family history and laboratory and genetic tests did not support a diagnosis of resistance to thyroid hormone (RTH). Given the unsuppressed TSH, TSH-secreting tumor was suspected, and magnetic resonance imaging (MRI) of the pituitary gland was performed. Surprisingly, the MRI scans revealed a nodule in the nasopharynx rather than a pituitary tumor in the sella region. Further evaluation using Gallium-68 DOTATATE positron emission tomography/computed tomography (68Ga-DOTATATE PET/CT) demonstrated increased DOTATATE uptake in the nasopharyngeal nodule. Additionally, an octreotide suppression test (OST) revealed an obvious reduction in TSH levels, further supporting the suspicion of the nasopharyngeal mass as the cause of inappropriate TSH secretion. To prepare for surgery, the patient received preoperative administration of octreotide, resulting in the normalization of TSH and thyroid hormone levels. The patient subsequently underwent successful surgical removal of the nasopharyngeal mass. Following the procedure, the patient experienced complete resolution of hyperthyroidism symptoms, with TSH declined and thyroid hormone levels returned to normal. Histochemistry analysis of the tumor revealed positive staining for TSH, growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), and somatostatin receptor 2 (SSTR2). We discussed differential diagnosis of hyperthyroidism due to inappropriate TSH secretion, with a particular emphasis on the importance of 68Ga-DOTATATE PET/CT in combination with OST for identifying ectopic pituitary tumors.

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.

A PBPK model for PRRT with [177Lu]Lu-DOTA-TATE: Comparison of model implementations in SAAM II and MATLAB/SimBiology.

Physiologically based pharmacokinetic (PBPK) models offer the ability to simulate and predict the biodistribution of radiopharmaceuticals and have the potential to enable individualised treatment planning in molecular radiotherapy. The objective of this study was to develop and implement a whole-body compartmental PBPK model for peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE in SimBiology to allow for more complex analyses. The correctness of the model implementation was ensured by comparing its outputs, such as the time-integrated activity (TIA), with those of a PBPK model implemented in SAAM II software. METHODS: A combined PBPK model for [68Ga]Ga-DOTA-TATE and [177Lu]Lu-DOTA-TATE was developed and implemented in both SAAM II and SimBiology. A retrospective analysis of 12 patients with metastatic neuroendocrine tumours (NETs) was conducted. First, time-activity curves (TACs) and TIAs from the two software were calculated and compared for identical parameter values. Second, pharmacokinetic parameters were fitted to activity concentrations, analysed and compared. RESULTS: The PBPK model implemented in SimBiology produced TIA results comparable to those generated by the model implemented in SAAM II, with a relative deviation of less than 0.5% when using the same input parameters. The relative deviation of the fitted TIAs was less than 5% when model parameter values were fitted to the measured activity concentrations. CONCLUSION: The proposed PBPK model implemented in SimBiology can be used for dosimetry in radioligand therapy and TIA prediction. Its outputs are similar to those generated by the PBPK model implemented in SAAM II, confirming the correctness of the model implementation in SimBiology.

Peptide receptor radionuclide therapy with 177Lu- or 90Y-SSTR peptides in malignant pheochromocytomas (PCCs) and paragangliomas (PGLs): results from a single institutional retrospective analysis.

BACKGROUND: Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare tumors and available systemic therapies are limited. AIM: To explore the role of peptide receptor radionuclide therapy (PRRT) with Yttrium-90 (90Y) and Lutetium-177 (177Lu) peptides in pheochromocytomas (PCCs) and paragangliomas (PGLs). METHODS: We retrospectively analyzed more than 1500 patients with histologically proven neuroendocrine tumors treated with 177Lu- or 90Y-DOTA-TATE or -TOC between 1999 to 2017 at our Institute. Overall, 30 patients with confirmed malignant PCCs and PGLs matched inclusion/exclusion criteria and were considered eligible for this analysis. RESULTS: Thirty (n = 30) patients were treated: 22 with PGLs and 8 with PCCs (12 M and 18 F, median age 47 [IQR: 35-60 years]). Eighteen patients (n = 18) had head and neck PGLs, 3 patients thoracic PGLs and 1 patient abdominal PGL. Sixteen patients (53%) had locally advanced and fourteen (47%) had metastatic disease. Twenty-seven (90%) patients had disease progression at baseline. Four (13%) patients were treated with 90Y, sixteen (53%) with 177Lu and ten (33%) with 90Y + 177Lu respectively. The median total cumulative activity from treatment with 90Y- alone was 9.45 GBq (range 5.11-14.02 GBq), from 177Lu- alone was 21.9 GBq (7.55-32.12 GBq) and from the combination treatment was 4.94 GBq from 90Y- and 6.83 GBq from 177Lu- (ranges 1.04-10.1 and 2.66-20.13 GBq, respectively). Seven out of 30 (23%) patients had partial response and 19 (63%) stable disease. Median follow up was 8.9 years (IQR: 2.9-12). The 5-y and 10-y PFS was 68% (95% CI: 48-82) and 53% (95% CI: 33-69), respectively, whereas 5-y and 10-y OS was 75% (95% CI: 54-87) and 59% (95% CI: 38-75), respectively. Grade 3 or 4 acute hematological toxicity occurred in three patients, two with leucopenia and one with thrombocytopenia, respectively. CONCLUSION: PRRT with 177Lu- or 90Y-DOTA-TATE or -TOC is feasible and well tolerated in advanced PGLs and PCCs.

Octreotide for long-lasting malignant bowel obstruction: two case reports.

BACKGROUND: Efficacy of the combination of octreotide and other drugs for the management of malignant bowel obstruction (MBO) has been well described. However, long-lasting stages with lack of stool emission are a challenging clinical condition of MBO that have never described. CASE DESCRIPTION: We describe two cases in which the addition of octreotide to supportive care measures, even given late after more than 3 weeks of no stool emission, resulted to be still effective in recovering the bowel transit. In the first case, a patient admitted to home palliative care had a nasogastric tube and reported to not have stool emission and passing gas for 25 days. Two days after starting the combination of octreotide and other drugs, the patient evacuated and the nasogastric tube was removed, without reporting nausea or episodes of vomiting. In the second case, a patient admitted to an acute palliative care unit, the patient had no stool emission for more than 3 weeks. A nasogastric tube was placed and comprehensive palliative care treatment was provided. Two days after starting a combination of octreotide and other drugs, the nasogastric tube was removed, without reporting vomiting. In both cases, bowel transit recovered and patients were able to initiate oral nutrition. CONCLUSIONS: The combination of octreotide with other drugs described for standard treatment for the management of MBO, should be attempted even in patients with very long periods of lack of feces emission.

Does Telotristat Have a Role in Preventing Carcinoid Heart Disease?

Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse's condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p < 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.