Metastatic Gastroenteropancreatic Neuroendocrine Tumors Research Articles

Surgery enhances the effectiveness of peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumors

BackgroundWith the advent of peptide receptor radionuclide therapy, the timing and sequence of surgery in the treatment of metastatic gastroenteropancreatic neuroendocrine tumors merits further study. We hypothesized that surgery before peptide receptor radionuclide therapy might enhance its effectiveness in patients with metastatic gastroenteropancreatic neuroendocrine tumors. MethodsEighty-nine patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors treated with 177Lutetium-dotatate peptide receptor radionuclide therapy between 2018 and 2023 were included. Fifty-six patients underwent surgery (primary tumor resection and/or liver debulking) before peptide receptor radionuclide therapy and 33 patients did not. Primary outcome was progression-free survival according to Response Evaluation Criteria in Solid Tumors. Pretreatment dotatate positron emission tomography/computed tomography was used to calculate tumor volumes. ResultsThe surgery and no-surgery groups were well-matched. Median progression-free survival after peptide receptor radionuclide therapy was 15.6 months (interquartile range, 9.1–22.7 months) in the no-surgery group compared with 26.1 months (interquartile range, 12.7–38.1 months) in the surgery group (P = .04). On subgroup analysis, median progression-free survival was 18.1 months (interquartile range, 11.9–38.4 months) in patients who underwent primary tumor resection only compared with 26.2 months (interquartile range, 14.0–38.1 months) in patients who underwent liver debulking (P = .04). Tumor volume was lowest in patients who underwent liver debulking (median 146.07 mL3) compared with no surgery (median 626.42 mL3) (P = .001). On univariable analysis, a tumor volume <138.8 mL3 was associated with longer progression-free survival (hazard ratio, 2.03; 95% confidence interval, 0.95–4.34, P = .05), with a median progression-free survival of 38.1 months (interquartile range, 16.9–41.3 months) compared with 17.8 months (interquartile range, 10.8–28.7 months). ConclusionSurgery may enhance the effectiveness of 177Lutetium-dotatate in the treatment of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors. This positive effect may be the result of a lower tumor volume in patients after surgery. Our findings fortify the concept of using surgical debulking to improve systemic therapies such as peptide receptor radionuclide therapy.

Claims-based analysis of treatment practices of patients with metastatic gastroenteropancreatic neuroendocrine tumors (mGEP-NET) in the USA.

e16286 Background: GEP-NET is a rare disease with variable tumor biology. An indolent disease course with subtle symptoms renders timely diagnosis difficult; 2/3 of patients (pts) are diagnosed at locally advanced or metastasized stage. In clinical decision-making, disease-specific factors, patient (pt) age and long-term disease control must be balanced against the aggressiveness of therapies. NCCN, NANETS and ENETS guidelines recognize the diversity of mGEP-NET by recommending individualized treatment approaches. We aimed to describe treatment (Tx) utilization patterns in mGEP-NET. Methods: Retrospective cohort study using MarketScan® Commercial and Medicare Databases spanning 07/01/2017-01/31/2023. Eligible were GEP-NET pts with ≥1 inpatient or ≥2 outpatient claims, a subsequent new diagnosis of metastatic disease (index), no secondary malignancy, and follow-up time of ≥12 months (m) after index. Results: Of 16218 GEP-NET pts, 2002 (mean age 60y; 50% female) met inclusion criteria. Mean follow-up time after index was 17m, with 49%, 27% and 15% followed up for ≥12, 24 and 36m, resp. Medical history (12m baseline before index) included mean Charlson Comorbidity Index of 2.62, with hypertension (HTN), type 2 diabetes (T2DM), chronic liver disease (CLD), asthma/COPD, cardiovascular disease (CVD), and chronic kidney disease (CKD) present in 56, 26, 22, 18, 17 and 10% of pts, resp.; 5% had carcinoid syndrome. In total, 949 pts (47.4%) received first-line (1L) systemic Tx: somatostatin analogs (SSA; 61.6%) of either very short or long duration (median 116d vs 775d), chemotherapy (38.8%), targeted therapies (3.4%) and PRRT (0.5%). Relative to NCCN cancer surveillance guidelines, 49.5% received more and 36.8% received fewer than 4 scans in the first year of treatment. Conversely, 1053 (52.6%) did not receive any 1L systemic Tx. With the exception of CLD, pts with vs without 1L Tx had similar proportions of medical conditions during the 12m baseline and during follow-up (HTN 72.4 vs 66.5%; T2DM 34.0 vs 30.3%; asthma/COPD 16.5 vs 19.3%; CVD 27.3 vs 36.9%; CKD 18.9 vs 17.9%; however, CLD 54.0 vs 36.7%). See Table comparing both cohorts on insurance, treatments, and health care utilization during follow-up. Conclusions: This claims analysis reveals treatment differences among mGEP-NET pts that cannot be explained by the parameters assessed herein. Further research should investigate factors influencing diagnosis and treatment decision-making, applying also pt-level health record data; and analyze economic barriers to diagnosis and treatment. [Table: see text]

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.

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.

Surgical cytoreduction vs systemic therapy in patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETS): NCDB analysis

Surgical cytoreduction vs systemic therapy in patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETS): NCDB analysis

Clinical impact of unsuccessful subcutaneous administration of octreotide LAR instead of intramuscular administration in patients with metastatic gastroenteropancreatic neuroendocrine tumors.

Octreotide LAR is a long-acting somatostatin analogue (SSA) used in the management of metastatic gastroenteropancreatic neuroendocrine tumors (GEP NETs). It requires intramuscular (IM) injection. Missed IM injections cause subcutaneous nodules (SCNs) on radiologic images. We reviewed the rates of SCNs in a real-world cohort of GEP NETs receiving octreotide LAR and explored treatment outcomes. Patients commencing octreotide LAR between August 5, 2010 and March 8, 2018 at a single cancer center in Canada were identified from pharmacy records. Patients were included if they had a computed tomography (CT) scan performed at the time of progression and a preceding CT with pelvis included to enable assessment for the presence of nodules. Fisher's exact test was used to examine predictors of SCNs, and Kaplan-Meier curves summarized differences in progression free (PFS) and overall survival (OS) that were compared with log-rank tests. Of 243 patients receiving octreotide LAR, 45 had all required CT images available for central review. SCNs were found in 20/45 (44%) of patients on the last scan showing stable disease before progression and were numerically but not statistically more likely in females (OR: 2.36, 95% CI: 0.66-8.29, p = .23). There was an increased risk of SCNs in patients with a skin-to-muscle distance >38 mm (the length of an octreotide LAR needle) on CT (OR: 5.09, 95% CI: 1.39-16.6, p = .018) and a trend toward increased risk in obese patients (OR: 5.71, 95% CI: 1.26-23.4, p = .061). PFS (HR: 1.01, 95% CI: 0.56-1.78, p = .98) and OS (HR: 0.86, 95% CI: 0.41-1.8, p = .70) was similar between those with/without SCNs. In conclusion, almost half of patients receiving octreotide LAR had SCNs; however, missed administration of SSA did not appear to result in worse survival in this small study. Factors such as sex, younger age skin-to-muscle distance, and obesity may affect SCN development and should be considered when choosing an SSA.

Experience with 177Lu-Dotatate in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumors at a Single Urban Cancer Center

177Lu-Dotatate is an FDA approved peptide receptor radiotherapeutic (PRRT) agent for metastatic well differentiated midgut neuroendocrine tumors (NETs). Questions remain regarding tolerability in diverse subpopulations with higher grade disease, more than one prior line of treatment, and in non-ileal primaries. In this retrospective analysis, we review the outcomes of patients with histologically proven metastatic GEP-NETs who received 177Lu-Dotatate at a single racially diverse urban cancer center. Treated patients had disease that progressed on systemic therapy. Uptake at disease sites was demonstrated in all patients using 68-Gallium-Dotate PET/CT. ECOG performance score (PS) was 0 to 2. 177Lu-Dotatate was administered in 200 mCi doses every 8 weeks for a total of 4 cycles and a maximum of 800 mCi. Patients were followed with serial CT scan and/or abdominal MRI with best objective response assessed per RECIST criteria. Fifty-one patients were treated between December 2017 and September 2021. 42 patients completed a minimum 3-month follow-up imaging. Median age was 66 years, 59% were female, 66% identified as white, 26% as Black, 8% as other or chose not to specify. Most frequent primary site was small intestine (69%). All had metastatic disease involving the liver except for one. Median time from diagnosis to 177Lu-Dotatate was 51 months. Time from first line therapy to first 177Lu-Dotatate was 3.65 years CTCAE grade 3/4 hematologic toxicity was seen in 6 of 51 patients (12%) of patients. Grade 3/4 thrombocytopenia occurred in 3 pts, grade 3/4 leukopenia occurred in 2 pts and grade 3 anemia occurred in 1 patient. One patient developed myelodysplastic syndrome 1 year after first 177Lu-Dotatate. Patients who identified as non-white did not experience significantly higher rate of toxicity. Of the 42 patients who reached 3-month follow-up 29% had a partial response, 45% had a mixed or stable response, and 36% had progressive disease. Only gender demonstrated significant difference; with male gender associated with worse response categories (p = 0.001). Median overall survival (OS) was 2.13 years. Metastatic disease in the liver only (p = 0.013), tumor grade > 1 (p = 0.027), and no history of surgery (p = 0.011) were associated with significantly worse OS. The median progression free survival (PFS) was 1.56 years. Patients of male gender (p = 0.037), with liver only metastases (p = 0.013), and with higher grade tumors (p = 0.024) had worse PFS. There was no difference in PFS by race, primary tumor site (pancreatic vs small bowel), performance status, or prior treatment history. In this retrospective study, investigating a racially and socioeconomically diverse patients, we report similar toxicity to prior studies investigating 177Lu-Dotatate. Despite similar toxicity, median PFS and OS were inferior to reported outcomes in NETTER-1 which we suspect may be partly due to timing of treatment and differences in patient populations.

Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.

To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. Eight randomized controlled trials met the inclusion criteria for the systematic review. Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)-positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Systemic Therapy for Tumor Control in Well-Differentiated Metastatic Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline Q and A.

ASCO recently published new guidance on systemic therapy for tumor control in well-differentiated metastatic gastrointestinal and pancreatic neuroendocrine tumors in the Journal of Clinical Oncology. A companion Q and A article in the JCO-OP addresses some of the questions that clinicians may face as they implement these recommendations into clinical practice, including the role of somatostatin receptors and observation, definition of terms used within the guideline, considerations related to therapy options for G3 NETs, and future direction in research and treatment. ASCO also plans to address recommendations on the topic of symptom control of GEP-NETs in a forthcoming guideline

The NETFIT trial: Smart wearable medical devices to assess the quality of life of patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET).

e13627 Background: Patients diagnosed with an advanced NET are frequently deteriorating their quality of life due to tumor volume, hormone-release related symptoms and treatment toxicity. Changes on lifestyle of patients with solid tumors have shown an improvement in quality of life. However, NET patients are missed in those studies. Methods: We conducted a prospective, multicenter, observational study that included 40 patients with advanced NETs from 10 Spanish hospitals belonging to the Spanish Taskforce Group of Neuroendocrine and Endocrine Tumors (GETNE). The aim of the trial was to assess and monitor changes on different aspects in quality of life by a customized smartphone app linked to an activity wearable tracker. Data were analyzed at baseline and monthly for 16 weeks after physical activity, sleep and nutritional intervention. The primary objective was to evaluate improvement in the quality of life of patients with metastatic G1 and G2 GEP-NETs based on changes registered on the EORTC QOL-C30-GI.NET21 questionnaire during the first 16 weeks since the onset of an active systemic treatment with somatostatin analogs. Secondary endpoints included description of changes in physical exercise and sleep variables from baseline, as well as the evaluation of functional scales in patients with or without carcinoid syndrome. Results: A total of 40 patients were included in the study and all quality of life questionnaires were collected from week 0 to week 16 from 25 patients. In 15 patients there was a lack of compliance filling the questionnaires. All of the 25 patients analyzed experienced an improvement in at least one of the items of the QOL-C30 questionnaires of the primary endpoint after the first 16 weeks. As secondary outcomes it was shown a trend towards an improvement in vital signs, such as decrease in systolic blood pressure (median W0:130.7mmHg to W16:124.3mmHg p=0.3), diastolic (W0:88.7mmHg vs W16:83.3mmHg p=0.4) and heart rate (W0:93.3bpm vs W16:86bpm p=0.25). In addition, an improvement in sleep quality was observed, measured by the amount of deep REM sleep (W0:102.59 vs W16:115.3 median min/day p=0.31) or periods of light non-REM sleep (W0:301,43 vs W16:341,1 median min/day p=0.21). In the EORTC QLQ-C30 questionnaire, an improvement was observed in all functional scales (emotional function mean functional improvement (MFI) 5.3 (p=0.2), cognitive function MFI 4.0 (p=0.27), social function MFI 6.0 (p=0.3)), being deeply significant in role function (MFI 13.3 points; p=0.0156). There was an improvement in the symptomatology scales between W0 and W16, fatigue -3.7 p=0.3, nausea -1.3 p=0.5, pain -2.5 p=0.3, insomnia -9.7 p=0.05, anorexia -2.7 p= 0.3, diarrea -17.3 p=0.01. Conclusions: NETFIT trial showed that lifestyle intervention has a significant impact on the quality of life and symptomatic control of patients with metastatic G1/2 GEP-NETs.

The impact of surgery and survival prediction in patients with gastroenteropancreatic neuroendocrine tumors: a population-based cohort study.

This study aimed at assessing the impact of surgical treatments in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A propensity score-matched analysis based on data in the Surveillance, Epidemiology, and End Results database was used to assess the efficacy of surgical treatment in patients with GEP-NETs. A total of 7515 patients diagnosed with GEP-NETs from 2004 to 2015 were evaluated from the Surveillance, Epidemiology, and End Results database. There were 1483 patients in the surgery group and 6032 patients in the nonsurgery group. Compared with patients in the surgery group, patients in the nonsurgery group were inclined to receive chemotherapy (50.8 vs. 16.7%) and radiation (12.9 vs. 3.7%) as treatment options. Multivariate Cox regression analysis revealed higher rates of overall survival (OS) outcomes for GEP-NETs patients who had been subjected to surgery (hazard ratio=0.483, 95% CI=0.439-0.533, P <0.001). Then, to reduce the impact of bias, a 1:1 propensity score-matched analysis was performed for the two groups of patients. A total of 1760 patients were assessed and each subgroup included 880 patients. In the matched population, the patients exhibited the ability to significantly benefit from surgery (hazard ratio=0.455, 95% CI=0.439-0.533, P <0.001). The OS outcomes for radiation or chemotherapy patients who had been treated with surgery were better than those of patients who had not been treated with surgery ( P <0.001). In addition, it was found that the OS of patients was not significant after rectum and small intestine surgery, whereas there was a significant difference in OS after colon, pancreas, and stomach surgery on the patients. Patients who had been subjected to surgery in the rectum and small intestines exhibited better therapeutic benefits. Patients with GEP-NETs who are treated with surgery have better OS outcomes. Therefore, surgery is recommended for specified selected patients with metastatic GEP-NETs.

Outcome analysis in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with Lu-177-DOTATATE.

Patients with neuroendocrine tumors (NET) of the gastroenteropancreatic tract (GEP-NET) were effectively treated with peptide receptor radionuclide therapy (PRRT) with Lu-177-DOTATATE in the NETTER-1 trial. The aim of this study was to assess the outcome of metastatic GEP-NET patients within a European Neuroendocrine Tumor Society (ENETS) certified center of excellence after this treatment. A total of 41 GEP-NET patients who received PRRT with Lu-177-DOTATATE between 2012 and 2017 at a single center were included in this analysis. Data on pre- and post-PRRT treatments [selective internal radiation therapy (SIRT), somatostatin analogue therapy (SSA), blood parameters, patient symptomatic burden and overall survival] was extracted from patient records. Overall, PRRT was well tolerated and did not increase patient symptomatic burden. Blood parameters were not significantly affected by PRRT (means before and after therapy: hemoglobin: 125.4 vs. 122.3 mg/L, P=0.201; creatinine: 73.8 vs. 77.7 µmol/L, P=0.146), while leukocytes (6.6 vs. 5.6 G/L, P<0.01) and platelets (269.9 vs. 216.7 G/L, P<0.001) were significantly decreased yet without clinical significance in our study. Seven of 9 patients with SIRT treatment prior to PRRT were deceased (mortality odds ratio =4.083). The mortality odds ratio of patients with a pancreatic tumor and SIRT was 1.33 compared to patients with a different tumor origin. 6 of 15 patients (40%) with post-PRRT SSA were deceased (mortality odds ratio =0.429 without SSA after PRRT). Patients with advanced GEP-NET might benefit from PRRT with Lu-177-DOTATATE as it can provide a valuable treatment modality in advanced disease stages. Safety profiles of PRRT were manageable without increasing the symptomatic burden. SIRT before PRRT or lack of SSA after PRRT seem to impair the response and reduce survival.

The predictive impact of dual somatostatin receptor/fluorodeoxyglucose (FDG) positron emission tomography (PET) in metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs): review of literature and a single institution experience.

Treatment with radiolabelled somatostatin analogs, a form of peptide receptor radionuclide therapy (PRRT), has changed the management of patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). There is a subgroup of patients who have suboptimal benefit and rapidly progress on PRRT, indicating that accurate prognostic and predictive markers are urgently needed. Currently, most of the literature concentrate on the prognostic impact of the dual positron emission tomography (PET) scan with very few information regarding the predictive value. We report a case series and review the literature to summarizes the predictive value of combined somatostatin receptor (SSTR) and fluorodeoxyglucose (FDG) PET in metastatic GEP-NETs. We conducted a review of the literature for data published from 2010 to 2021 in MEDLINE, Embase, the National Institutes of Health trial registry, Cochrane CENTRAL, and published proceedings from major gastrointestinal and neuroendocrine cancer meetings. Our main criteria included all published prospective and retrospective data in which the predictive value of dual PET scans using SSTR and FDG was correlated with PRRT response in patients with metastatic GEP-NETs. We summarized clinical outcomes including progression-free survival (PFS), overall survival (OS), and post-therapy complications associated with PRRT according to FDG avidity. We excluded studies that did not include FDG PET scan, GEP patients, studies with no clear predictive value of the FDG PET scan, and studies that did not report a direct correlation between FDG avidity and primary outcome. Additionally, we summarized our institutional experience in eight patients who progressed during or within the first year of PRRT treatment. Our search identified 1306 articles; most of them showed only the prognostic value of Integrated SSTR/FDG PET imaging biomarker in GEP-NETs. Only three studies (n=75 patients) met our inclusion criteria and retrospectively investigated the predictive value of dual SSTR and FDG imaging in subjects being considered for PRRT. The results confirmed that FDG avidity correlates with advanced NET grades. Lesions that are both SSTR and FDG avid had early disease progression. In one study, at multivariate analysis, FDG PET results were independently predictive of lower PFS for PRRT. In our case series, there were eight patients with metastatic well-differentiated GEP-NETs (grades 2 and 3) who progressed within one year of PRRT. Seven of them had positive FDG PET scan at the time of progression. In conclusion, Dual SSTR/FDG PET imaging has a potential predictive impact for PRRT in GEP-NETs. It permits the capturing of the disease complexity and aggressiveness, which correlates with PRRT response. Therefore, prospective future trials should validate the predictive value of dual SSTRs/FDG PET for better PRRT stratification.

225Ac-Labeled Somatostatin Analogs in the Management of Neuroendocrine Tumors: From Radiochemistry to Clinic.

The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroendocrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of 225Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of 225Ac, its physical and radiochemical properties, as well as the place of 225Ac-DOTATOC and 225Ac-DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors.

Prevalence of Sarcopenia and Impact on Survival in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumours.

Sarcopenia in patients with cancer is associated with adverse outcomes such as shorter survival. However, there exists little evidence regarding the prevalence of sarcopenia in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Patients with a histologically confirmed newly diagnosed metastatic GEP-NET between 2006 and 2018, CT scan, and anthropometric data at diagnosis were included in this study. CT scans were analysed for the presence of sarcopenia and correlated with overall survival (OS). In total, 183 patients, 87 male (48%), with a median age of 62 years (IQR 52-68 years), were included. In 44 patients (24%), there was a pancreas NET, and in 136 patients, there was a small bowel NET (74%). Sarcopenia was present in 128 patients (69%) and unrelated to BMI (median 25.1). There were significant survival differences between patients with pancreatic and small bowel NETs at 86 vs. 141 months, respectively (p = 0.04). For patients with pancreatic NETs, the presence of sarcopenia was independently associated with shorter OS (HR 3.79 95% CI 1.1-13.03, p-value 0.035). A high prevalence of sarcopenia at the time of diagnosis of a metastatic GEP-NET was seen and associated with worse OS in patients with pancreatic NETs. Further research should focus on how to reverse sarcopenia and its impact on OS and/or quality of life.

Liver resection for gastroenteropancreatic neuroendocrine tumors with extrahepatic disease

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NET) comprise a heterogenous group of cancers defined by their primary site of origin and malignant potential. The liver is the most common site for metastases, and a significant proportion of these patients also have extrahepatic disease (EHD). We performed a population-based study to characterize the impact of liver resection on survival outcomes for metastatic GEP-NET with concurrent EHD.

Lanreotide Depot to Treat Gastroenteropancreatic Neuroendocrine Tumors in a US Community Oncology Setting: A Prospective, Observational Study.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can result in symptoms such as diarrhea, flushing, abdominal pain, and fatigue and are often associated with a significant disease burden and poor prognosis. This non-interventional, prospective, observational study evaluated the real-world safety and effectiveness of lanreotide depot, a somatostatin analog (SSA) used to treat GEP-NETs, in a community setting. In this prospective, non-interventional study (NCT02730104), adult patients with locally advanced (inoperable), metastatic GEP-NETs treated with lanreotide depot were evaluated by their physician every 6 months from enrollment for 24months. Clinically defined time to disease progression (TTDP) and overall survival (OS) were estimated for the total population and by primary tumor type (gastrointestinal [GI], pancreatic, unknown origin), and an exploratory analysis determined the rate of progression-free survival (PFS) at 12 and 24months. Patient satisfaction was evaluated via the Treatment Satisfaction Questionnaire for Medication (TSQM-9), and safety information was recorded. Of 99 patients, the 24-month PFS rate was 73.7% (95% confidence interval [CI] 63.1-81.7) and 24-month OS rate was 84.2% (95% CI 74.0-90.7). Median TTDP was not reached because few patients experienced disease progression during the study period. The majority of responding patients expressed satisfaction with treatment on each domain of the TSQM-9. Treatment-related adverse events (AEs) occurred in 19.2% of patients, while no serious AEs (SAEs) were related to the study drug. Lanreotide depot is an effective and well-tolerated treatment for GEP-NETs in the real-world community setting. ClinicalTrials.gov identifier, NCT02730104.

Liver Cytoreduction Threshold In Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): Systematic Review of Current Literature

Liver Cytoreduction Threshold In Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): Systematic Review of Current Literature

Survival Outcomes in Metastatic Gastroenteropancreatic Neuroendocrine Tumor Patients receiving Concomitant 225Ac-DOTATATE Targeted Alpha Therapy and Capecitabine: A Real-world Scenario Management Based Long-term Outcome Study.

Rationale: Although the short-term results of targeted alpha therapy (TAT) with 225Ac-DOTATATE in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have proven effective, none have assessed the long-term outcome results. In this study, we aimed to evaluate the long-term outcome of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with somatostatin receptor (SSTR)-expressing advanced-stage metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: Patients with 68Ga-DOTANOC PET/CT scans showing moderate-to-high SSTR expression were recruited. Systemic TAT was performed in 91 adults with GEP-NET [54 males, and 37 females] mean age 54 years (y) (range: 25-75y)] using 225Ac-DOTATATE (100-120 kBq/kg body weight). All patients were given capecitabine therapy as a radiosensitizer (dose 2 g/day) from day 0 to 14 of every 225Ac-DOTATATE treatment cycle. Patients were categorized into three groups based on the status of prior 177Lu-PRRT: prior 177Lu-PRRT-refractory-group; prior 177Lu-PRRT-disease-control group; and 177Lu-PRRT naïve group. Primary endpoints were overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective tumour response, clinical response, and the assessment of treatment-related toxicities. Results: Among the 91 patients, 57 underwent prior 177Lu-DOTATATE therapy [24 disease controlled (PR/SD), 33 progressive diseases (PD)]. A total of 453 225Ac-DOTATATE TAT cycles were administered [median four cycles per patient; range 1-10] in a median follow-up duration of 24 months (range 5-41mo). Median OS was not attained with a 24-month overall survival probability of 70.8%. In multivariate analysis, prognostic factors associated with a poor OS included, the presence bone metastases [HR: 2.501; 95% CI: 1.826 - 5.791; P<0.032], and 225Ac-DOTATATE therapy refractory disease [HR: 8.781; 95% CI: 3.843 - 20.062; P<0.0001]. Median PFS was also not reached with a 24-month progression-free survival probability of 67.5%. The multivariate analysis revealed only 177Lu-PRRT refractory disease significantly associated with a reduced PFS. [HR: 14.338; 95% CI: 1.853 - 97.698; P = 0.011]. Two of 79 patients (2.5%) with assessable disease experienced complete response; 38 (48%) had a partial response, 23 (29%) had SD, and 16 (20.2%) had PD. PD was observed in more patients from the prior 177Lu-PRRT-refractory group (11/33; 34%) as compared to 177Lu-PRRT-naïve patients (4/24; 11%), P-0.056. Patients from the prior 177Lu-PRRT-refractory group had the highest risk of poor PFS [HR:13.91; 95% CI: 4.45 - 42.271; P = 0.0009]. A significant clinical benefit was achieved post 225Ac-DOTATATE therapy with minimal treatment-related toxicities. Conclusion: The long-term results reveal 225Ac-DOTATATE TAT has shown promising results and improves overall survival, even in patients refractory to prior 177Lu-DOTATATE treatment, with transient and acceptable adverse effects.

Advances in the treatment of gastroenteropancreatic neuroendocrine neoplasms with somatostatin analogs

Neuroendocrine neoplasms (NENs) include well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Somatostatin receptors (SSTRs) are highly expressed on NETs cells, and somatostatin analogs (SSAs) could bind to SSTRs with high affinities, regulating cell proliferation and hormone secretion. As many clinical trials have demonstrated the antiproliferative efficacy and safety of SSAs in metastatic gastroenteropancreatic NETs (GEP-NETs), SSAs have been recommended by multiple NEN guidelines as the first-line therapy of GEP-NETs. In recent years, more and more researches have been exploring new therapeutic possibilities of SSA in GEP-NETs, such as high-dose SSA as second-line therapy, SSA in metastatic GEP-NETs with Ki-67 &gt; 10%, SSA as adjuvant therapy for postoperative pancreatic NETs patients, and combinations of SSA with chemotherapy or targeted therapy. In this review, we summarized the latest published or released researches and discussed new application attempts of SSA in GEP-NETs.