Gastroenteropancreatic Research Articles

The Increasing Incidence of Neuroendocrine Neoplasms Worldwide: Current Knowledge and Open Issues

Neuroendocrine neoplasms (NENs) include a heterogeneous group of tumors derived from neuroendocrine cells, most commonly arising from the gastro-entero-pancreatic (GEP) and bronchopulmonary tracts [...].

Evaluation of multidisciplinary team decisions in neuroendocrine neoplasms: Impact of expert centres.

To evaluate the impact of multidisciplinary team (MDT) meetings on the management of patients with neuroendocrine neoplasms (NENs). All newly referred gastro-entero-pancreatic (GEP)-NEN patients discussed from 1 April to 1 October 2017 in the MDT of seven European expert centres were prospectively included. The impact on patients' management was defined as a change in diagnosis, grade, stage or treatment. A total of 292 patients were included, mainly small intestinal (siNENs) (32%) and pancreatic NENs (28%), with distant metastases in 51%. Patients had received prior surgery in 43% of cases and prior medical treatment in 32%. A significant change occurred in 61% of NENs: 7% changes in diagnosis, 8% in grade and 16% in stage. The MDT recommended a new treatment for 51% of patients, mainly surgery (9%) or somatostatin analogues (20%). A significant change was most frequently observed in patients with Stage IV disease (hazard ratio [HR] 3.6, 95% confidence interval [CI]: 1.9-6.9 vs. Stage I) and G2 NENs (vs. G1, HR 2.1 95% CI: 1.2-3.8). NEN-dedicated MDT discussion in expert centres yields significant management changes in over 60% of patients and thus represents the gold standard for the management of these patients.

Volumetric parameters from [18 F]FDG PET/CT predicts survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms.

A positive fluorine‐18 labelled 2‐deoxy‐2‐fluoroglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has been associated with more aggressive disease and less differentiated neuroendocrine neoplasms (NEN). Although a high maximum standardized uptake value (SUVmax) predicts poor outcome in NEN, volumetric parameters from [18F]FDG PET have not been evaluated for prognostication in a pure high‐grade gastroenteropancreatic (GEP) NEN cohort. In this retrospective observational study, we evaluated the volumetric PET parameters total metabolic tumour volume (tMTV) and total total lesion glycolysis (tTLG) for independent prognostication of overall survival (OS). High‐grade GEP NEN patients with [18F]FDG PET/CT examination and biopsy within 90 days were included. Total MTV and tTLG were calculated using an adaptive thresholding software. Patients were dichotomised into low and high metabolic groups based on median tMTV and tTLG. OS was compared using Kaplan–Meier estimator and log‐rank test. Uni and multivariable Cox regression was used to estimate effect sizes and adjust for tumour differentiation and SUVmax. Sixty‐six patients (median age 64 years) were included with 14 NET G3 and 52 NEC cases after histological re‐evaluation. Median tMTV was 208 cm3 and median tTLG 1899 g. Median OS in the low versus high tMTV‐group was 21.2 versus 5.7 months (HR 2.53, p = 0.0007) and 22.8 versus 5.7 months (HR 2.42, p = 0.0012) in the tTLG‐group. Adjusted for tumour differentiation and SUVmax, tMTV and tTLG still predicted for poor OS, and both tMTV and tTLG were stronger prognostic parameters than SUVmax. Both regression models showed a strong association between volumetric parameters and OS for both neuroendocrine tumours (NET) G3 and neuroendocrine carcinomas (NEC). OS for the tTLG low metabolic NEC was much higher than for the tTLG high metabolic NET G3 (18.3 vs. 5.7 months). High‐grade GEP NEN patients with high tMTV or tTLG had a worse OS regardless of tumour differentiation (NET G3 or NEC). Volumetric PET parameters were stronger prognostic parameters than SUVmax.

Practical Considerations for Implementation of 177Lu-DOTATATE Neuroendocrine Tumor Treatment Programs.

The 2018 FDA approval of 177Lu-DOTATATE for the treatment of somatostatin receptor-positive (SSTR) neuroendocrine tumors (NETs) represents a paradigm shifting approach to cancer treatments around the globe. Gastroenteropancreatic (GEP) NETs overexpress the somatostatin subtype receptor 2, which is now exploited for receptor-based imaging and therapy, thus generating significant progress in the diagnosis and treatment of this orphan disease. The recent FDA approval of receptor-based PET radiopharmaceuticals and a new peptide receptor radiopharmaceutical therapy (PRRT), 177Lu-DOTATATE, has dramatically impacted NET patient management. The focus of this paper is to review clinical considerations associated with implementing a 177Lu-DOTATATE program. We review receptor-based NET radiopharmaceuticals, 177Lu-DOTATATE patient selection criteria, administration methods, clinical, regulatory, and radiation safety considerations, technical factors, tissue dosimetry, and reimbursement guidelines.

Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: A systematic review and meta-analysis.

e16217 Background: Neuroendocrine carcinoma (NEC) is a poorly differentiated pathological neuroendocrine neoplasm exhibiting aggressive clinical behaviors; the most common extrapulmonary site is the gastroenteropancreatic (GEP) system. Treatment strategies for GEP-NEC are primarily based on those employed for small cell lung cancer, and platinum-doublet chemotherapy, such as platinum plus etoposide (EP) or platinum plus irinotecan (IP), has been widely used as initial systemic therapy for patients with advanced/metastatic disease; however, clinical data for GEP-NEC are chiefly derived from small-scale retrospective studies, and the reported efficacy is heterogenous among studies. Methods: We conducted a systematic database search using PubMed/MEDLINE and EMBASE. Eligible studies included randomized trials, single-arm trials, prospective observational studies, and retrospective studies documenting the clinical efficacy of platinum-doublet chemotherapy (EP and IP) for advanced GEP-NEC. The pooled overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were calculated and weighted using generic inverse variance in a random-effects meta-analysis model. Results: Based on initial screening and eligibility assessment, 19 studies with a combined total of 1,157 patients were identified through a systematic review. Studies included 3 comparative studies between EP and IP with 1 randomized phase II trial and 2 retrospective studies. The pooled ORR in all patients who received the platinum-doublet regimen was 49.1% (95% confidence interval [CI], 41.8–56.5), and subgroup analysis for EP and IP groups showed ORRs of 44.4% (95% CI, 35.9–53.0) and 59.4% (95% CI, 48.0–70.8), respectively. According to the three studies directly comparing EP to IP, the odds ratio of ORR using EP as reference was 1.95 (95% CI, 0.86–4.39, P = 0.11). The pooled median OS in all patients who received the platinum-doublet regimen was 12.9 (95% CI, 10.9–15.3) months, where EP and IP subgroups had median OS of 12.9 (95% CI, 10.8–15.4) and 12.9 (95% CI, 6.0–27.8) months, respectively. The pooled median PFS was 5.4 (95% CI, 4.5–6.4) months in all patients with platinum-regimen, 5.4 (95% CI, 4.5–6.5) months in the EP subgroup, and 4.0 (95% CI, 1.4–11.7) months in IP subgroup, respectively. Conclusions: This study was the first systematic review and meta-analysis assessing patients with GEP-NEC; it has revealed considerable ORR following platinum-doublet chemotherapy. EP and IP regimens can be reasonably employed in patients with advanced GEP-NEC. These results can serve as reference information for clinicians in deciding a suitable chemotherapy regimen. Larger randomized trials and individual patient data meta-analyses are warranted to obtain robust clinical evidence.

REGOMUNE: Phase II study of regorafenib plus avelumab in solid tumors—Results of the gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) cohort.

4125 Background: There is no standard treatment for patients (pts) with advanced extra-pulmonary neuroendocrine tumors (NET) and carcinomas (NEC) after failure of chemotherapy in the metastatic setting. PD-1/PD-L1 expression is frequent in these tumors. Combining anti-PD1/PDL1 agents with anti-angiogenics has been shown to be synergistic in several tumor models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of regorafenib (R) (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in pts with advanced or metastatic grade 2 or 3 (G2/3) gastroenteropancreatic (GEP)-NET or GEP-NEC. The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between May 2019 and Apr. 2021, 46 pts were enrolled in 6 centers. Median age was 63 (range 31 – 80). 10 pts presented with a NEC and 36 pts with a G2/3 NET. Median follow-up was 6.5 months (95% CI: 5.3 - 9.6). Median number of previous treatment lines was: 2 (range 0 – 8). 39 (84.8%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were : Hypertension (13% of pts), fatigue (13%), and diarrhea (11%). One death was related to the treatment. Among the 42 assessable pts, 7 (16.7%) achieved a partial response: 6 pts with a G2/3 NET and 1 patient with a NEC. 22 (52.4%) pts demonstrated stable disease, 22 (52.4%) pts had tumor shrinkage and 10 (23.8%) pts had progressive disease. 3 (7.1%) pts were inevaluable as per RECIST. The median duration of response was 15.5 months (95%CI: 3.7 - not reached (NR)). The median PFS and OS were 5.5 months (95% CI: 3.6 – 9.2) and NR respectively. One year OS rate was 69.4 % (95% CI: 45.1 % – 84.5 %). Conclusions: REGOMUNE is the largest prospective study ever conducted in pts with grade 2/3 GEP-NET or GEP-NEC refractory to cytotoxic chemotherapy. The R+A combination has significant clinical activity in pts with refractory disease. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

P-279 A rare subset of well-differentiated gastro-entero-pancreatic neuroendocrine tumors with positive FDG PET/CT: Is it a sign of an aggressive disease?

Neuroendocrine tumors (NETs) are relatively rare and heterogeneous, mostly asymptomatic and discovered incidentally. PET-CT is one of the gold diagnostic standards and typically detects well-differentiated NETs using 68Gallium-Dotatate (Ga-PET/CT) and more aggressive undifferentiated NETs using 18F-FDG (FDG-PET/CT). However, some well-differentiated NETs are displaying atypical high-grade features and are being detected on FDG-PET/CT. In this study, we aim to study the diagnostic role of FDG-PET/CT in patients with well-differentiated gastro-entero-pancreatic (GEP) NETs, with positive uptake on FDG-PET/CT. A retrospective chart review of all GEP NETs cases diagnosed, from 2014 to 2021, at the American University of Beirut Medical Center was done. Patients who have low (G1) or intermediate (G2) well-differentiated NETs with positive findings on FDG-PET/CT were included based on WHO classification with Ki 67 ≤2 for low grade and >2-≤20 for intermediate grade well-differentiated NETs. Out of 36 patients with G1 or G2 GEP NET diagnosed during that period, 9 (25%) patients met the inclusion criteria for this study. Median age at diagnosis was 60 years, and 6 (66%) were males. 8 (88.9%) patients were both FDG-PET/CT and Ga-PET/CT positive, while 1 (11.1%) was FDG-PET/CT positive with Ga-PET/CT negative. 1 (11.1%) of the patients had grade 1 tumors and 8 (88.9%) had grade 2 disease. All patients had metastatic disease except for 1 patient who had locally advanced disease. The tumor originated from the small bowels in 6 (66%) of patients and from the pancreas in the remaining 3 (33%). As for the initial treatment after diagnosis, 2 patients received octreotide, 2 patients received octreotide, capecitabine and temozolomide, 2 patients received octreotide and underwent surgical resection, 1 patient received octreotide and everolimus, 1 patient received capecitabine and temozolomide and 1 patient with locally advanced disease underwent Whipple surgical procedure. 5 patients had disease progression while on initial treatment plan. In patients positive for both Ga-PET/CT and FDG-PET/CT, median progression free survival (PFS) was 40.1 months (95% CI, 15.4 – 64.9) and mean PFS was 36.2 months (95% CI, 23.1 – 49.2). The PFS in these patients is significantly lower that the PFS reported in the literature for G1/G2 NETs with positive Ga-PET/CT and negative FDG-PET/CT (36.2 vs 71 months, p = 0.0162). Patients with G1/G2 GEP NETs with positive FDG PET/CT have shorter PFS than in the literature. Should we include FDG PET/CT in the GEP NET prognostic score?.

P-173 Understanding the treatment algorithm of patients with advanced G2 gastroenteropancreatic neuroendocrine neoplasms: A single-institution retrospective analysis

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are rare and heterogeneous malignancies and there is no consensus on treatment sequences, especially for intermediate grade subgroup (G2). The aim of our study is to provide additional information on response to subsequent oncological treatments. Clinical records of patients (pts) with a histological diagnosis of G2 well differentiated GEP NENs and distant metastases, evaluated at the University of Palermo – Regional Reference Center for Rare Tumors- between 2006 and 2021 were retrospectively analyzed. Data on patient demographics, pathology, imaging exams, oncological treatments and clinical outcomes were collected. The analysis was focused on patients who had received at least two lines of systemic therapy. Kaplan-Meier analysis was used for overall survival (OS). A total of 32 pts with G2 metastatic GEP NEN were included in the study. Median age was 55 years (range 30-72), with a slight prevalence of male pts (59%). The high number of small-bowel as primary tumor (61%) and the presence of liver metastases in the majority of cases (90%), might justify the relatively high percentage of functional clinical presentation (33%). Median Ki67 level was 8,5% (range 3-20), and synchronous metastatic disease was reported in 68%. The median mOS of overall population was 48 months (range 6-177). Considering that most pts showed high level of somatostatin receptor (SSTR) expression on functional imaging (92%), the 18F-fluorodeoxyglucose (FDG) PET/TC confirmed its prognostic role, with significant worse survival outcomes in high FDG uptake tumors (HR 0.12; 95% CI 0.008-0.77, p=0.003). Somatostatin analogue (SSA) was the most common first-line treatment (68%), with stable disease as best response (BR) in 74% of cases, followed by peptide receptor radionuclide therapy (PRRT) (13%) and temozolomide or oxaliplatin-based chemotherapies (CT) (13%). Patients treated with CT upfront were characterized by higher Ki67 level (>7%) and showed partial response as BR in 50% of cases. PRRT as first-line treatment showed more durable response, expressed by PFS (26 months), compared with SSA and CT (15,5 and 16 months respectively). Second-line treatment was mainly performed with PRRT (48%) and targeted therapies (TT) (36%), including everolimus and sunitinib. Patients who performed PRRT as second line showed an advantage in OS compared to the ones who received TT (HR 0.22; 95% CI 0.01-1.01, p=0.05) and higher mPFS (13,5 vs 8 months). Decision making in advanced G2 GEP NENs is an interesting research field, because the rarity of this condition and the recent increase of the therapeutic armamentarium. A multidisciplinary discussion within a dedicated team remains critical. We need considering several factors, such as primary tumor, Ki67 level, tumor burden, functional disease, combined functional imaging and goals of treatment. Our study confirmed the prognostic role of FDG PET/TC in G2 GEP NENs. Independently from ki67 level, SSA represents the backbone of the first-line treatment. As Second-line treatment, PRRT showed a survival advantage and a more durable response than TT. Temozolomide or oxaliplatin-based chemotherapies might be a choice in Ki67>10% tumors and when cytoreduction is the aim.

Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: a systematic review and meta-analysis

BackgroundPlatinum-doublet chemotherapy has been conventionally used for patients with advanced gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) but evidence of chemotherapy is based on studies with small sample sizes and remains scarce. Thus, we conducted a systematic review and meta-analysis to elucidate the efficacy of platinum-doublet chemotherapy for advanced GEP-NEC.MethodsWe performed a database search in PubMed/MEDLINE and EMBASE. Eligible studies were prospective and retrospective studies documenting the efficacy of platinum plus etoposide (EP) and platinum plus irinotecan (IP) for advanced GEP-NEC. Overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were pooled and weighted using generic inverse variance in a random-effects meta-analysis model.ResultsNineteen studies including 1157 patients were identified. The ORR of the platinum-doublet regimen, EP, and IP was 49.1% (95% confidence interval [CI], 41.8–56.5), 44.4% (95% CI: 35.9–53.0), and 59.4% (95% CI: 48.0–70.8). The pooled median OS of the platinum-doublet regimen, EP, and IP was 12.9 months (95% CI:10.9–15.3), 12.9 months (95% CI: 10.8–15.4), and 12.9 months (95% CI: 6.0–27.8), and the pooled median PFS of the platinum-doublet regimen, EP, and IP was 5.4 months (95% CI: 4.5–6.4), 5.4 months (95% CI 4.5–6.5), and 4.0 months (95% CI: 1.4–11.7), respectively.ConclusionConsiderable response rate and survival time of the platinum-doublet regimen for advanced GEP-NEC were observed. IP and EP regimens can be reasonably applicable and these results provide a reference for oncologists in deciding the suitable regimen for patients with advanced GEP-NEC.

Avelumab in unresectable/metastatic, progressive, grade 2–3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials

BackgroundHigher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. MethodsNET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0–2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. ResultsTwenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37–80), 30% ECOG PS 1–2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10–100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2–24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3–4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). ConclusionSingle-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

BackgroundPreclinical studies have suggested that metformin has anti-tumour effects, likely due to blockage of mammalian target of rapamycin pathway through adenosine monophosphate-activated protein kinase and decreased insulin levels. A retrospective study showed that metformin added to everolimus to treat type 2 diabetes mellitus offered longer progression-free survival (PFS) in patients with pancreatic neuroendocrine tumours (NET).Aim(s)To evaluate the efficacy and safety of metformin monotherapy in patients with advanced/metastatic well-differentiated NET (WD-NET) of gastroenteropancreatic (GEP) or pulmonary origin.Patients and methodsSingle-arm phase II trial of metformin 850 mg PO twice daily until progression or intolerance for patients with progressive metastatic well-differentiated GEP or pulmonary NET. The primary endpoint was disease control rate (DCR) by RECIST 1.1 at 6 months. Secondary endpoints were response rate, PFS, toxicity and variations in glycaemic profiles (glycaemia, glycated haemoglobin and peptide C and insulin) at baseline, at 30 and 90 days.ResultsFrom 2014 to 2019, 28 patients were enrolled: median age was 50 years; 84% had non-functional NET, 86% were of GEP origin and 62% had G2 NET. At the time of last follow-up, 26 patients had progression, with 13 (46%) presenting DCR at 6 months and a median PFS of 6.3 months (95% confidence interval: 3.2–9.3). There was no objective response, but one patient with refractory carcinoid syndrome had complete symptom relief, lasting for more than 5 years. Variations in glycaemic profiles were not associated with DCR at 6 months. Diarrhoea was the most common adverse event, being grade 3 or 4 in 10% of the cases.ConclusionMetformin monotherapy offers modest anti-tumour activity in well-differentiated GEP or lung NET.

The role of HMGA1 protein in gastroenteropancreatic neuroendocrine tumors

ABSTRACT Neuroendocrine tumors (NETs) are neoplasms derived from neuroendocrine cells. One of their main features is to often remain asymptomatic and clinically undetectable. High Mobility Group A (HMGA) proteins belong to a family of non-histone chromatinic proteins able to modulate gene expression through the interaction with DNA and transcription factors. They are overexpressed in most of the human malignancies, playing a critical role in carcinogenesis. However, their expression levels and their role in neuroendocrine carcinogenesis has not been exhaustively evaluated until now. Therefore, in this study, we have addressed the validity of using the expression of HMGA1 as a diagnostic marker and have investigated its role in NET carcinogenesis. The expression of HMGA1 has been evaluated by qRT-PCR and immunohistochemistry, using NET tissue microarrays, in a cohort of gastroenteropancreatic (GEP)-NET samples. The expression levels of HMGA1 have been then correlated with the main clinical features of NET samples. Finally, the contribution of HMGA1 overexpression to NET development has been addressed as far as the modulation of proliferation and migration abilities of NET cells is concerned. Here, we report that HMGA1 is overexpressed in GEP-NET samples, at both mRNA and protein levels, and that the silencing of HMGA1 protein expression interferes with the ability of NET cells to proliferate and migrate through the downregulation of Cyclin E, Cyclin B1 and EZH2. These results propose the HMGA proteins as new diagnostic and prognostic markers.

Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers

BackgroundThe programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies.Patients and methodsThis phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated.ResultsOverall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively.ConclusionsAtezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.

Two birds with one stone: can [68Ga]Ga-DOTANOC PET/CT image quality be improved through BMI-adjusted injected activity without increasing acquisition times?

To assess how patients' dependent parameters may affect [68Ga]Ga-DOTANOC image quality and to propose a theoretical body mass index (BMI)-adjusted injected activity (IA) scheme, to improve imaging of high weight patients. Among patients prospectively enrolled (June-2019 and May-2020) in an Institutional Ethical Committee-approved electronic archive, we included those affected by primary gastro-entero-pancreatic (GEP) or lung neuroendocrine tumour and referred by our Institutional clinicians (excluding even minimal radiopharmaceutical extravasation, movement artefacts, renal insufficiency). All PET/CT images were acquired following EANM guidelines and rated for visual quality (1 = non-diagnostic, 2 = poor, 3 = moderate, 4 = good). Collected data included patient's body mass, height, BMI, age, IA (injected activity), IA/Kg (IAkg), IA/BMI (IABMI), liver SUVmean, liver SUVmax standard deviation, liver-signal-to-noise (LSNR), normalised_LSNR (LSNR_norm) and contrast-to-noise ratio (CNR) for positive scans and were compared to image rating (poor vs moderate/good). Overall, 77 patients were included. Rating concordance was high (agreement = 81.8%, Fleiss k score = 0.806). All patients' dependent parameters resulted significantly different between poor-rated and moderate/good-rated scans (IA: p = 0.006, IAkg: p =< 0.001, body weight: p =< 0.001, BMI: p =< 0.001, IABMI: p =< 0.001). Factors significantly associated with moderate/good rating were BMI (p =< 0.001), body weight (p =< 0.001), IABMI (p =< 0.001), IAkg (p = 0.001), IA (p = 0.003), LSNR_norm (p = 0.01). The BMI-based model presented the best predictive efficiency (81.82%). IABMI performance to differentiate moderate/good from poor rating resulted statistically significant (IA-AUC = 0.78; 95% CI: 0.68-0.89; cut-off value of 4.17 MBq*m2/kg, sensitivity = 81.1%, specificity = 66.7%). If BMI-adjusted IA (=4.17*BMI) would have been applied in this population, the median IA would have slightly inferior (-4.8%), despite a different IA in each patient. BMI resulted the best predictor of image quality. The proposed theoretical BMI-adjusted IA scheme (4.17*BMI) should yield images of better quality (especially in high-BMI patients) maintaining practical scanning times (3 min/bed).

Peptide receptor radionuclide therapy implementation and results in a predominantly gastrointestinal neuroendocrine tumor population: A two-year experience in a nonuniversity setting.

Neuroendocrine tumors (NETs) are rare, but the incidence and prevalence of NETs are increasing in the United States. While surgery is the preferred treatment for NETs, it is not a viable option for metastatic disease. Lutathera (177Lu-DOTATATE) is approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of gastroenteropancreatic (GEP)-NETs in adults. There is limited information on GEP-NET treatment responses to Lutathera.Our institution launched a peptide receptor radionuclide therapy (PRRT) service line using Lutathera with involvement from a multidisciplinary team and complete collaboration between hospital administration and clinical providers. A prospective registry study was also established in order to collect patient demographics and clinical data regarding the treatment of GEP primary NETs with Lutathera.Between August 2018 and July 2020, 35 GEP-NET patients were treated with Lutathera, of which 65.71% received 4 complete cycles and 25.71% received 3 cycles; 5.71% and 2.86% received 2 and 1 cycles of PRRT, respectively. Most adverse events during the course of our study were low grade using the common terminology criteria for adverse events system. Of the patients who completed all 4 cycles: 22% showed partial response to Lutathera, 44% showed stable disease, and 13% showed disease progression based on a qualitative assessment of positron emission tomography/computed tomography imaging.From our experience, Lutathera was well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with GEP-NET treatment as well as financial considerations for hospitals embarking on a PRRT program.

A Multinational Pilot Study on Patients' Perceptions of Advanced Neuroendocrine Neoplasms on the EORTC QLQ-C30 and EORTC QLQ-GINET21 Questionnaires.

Among the available neuroendocrine neoplasm (NEN)-specific HR-QoL scales, only the EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires have been validated in several languages. We aim to assess patients’ perceptions of these questionnaires. A cross-sectional qualitative pilot study was conducted among 65 adults from four countries with well-differentiated advanced gastro-entero-pancreatic (GEP) or unknown primary NENs. Patients completed the EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires and then a survey containing statements concerning the questionnaires. The majority of patients had a small intestine NET (52%). Most tumors were functioning (55%) and grade 2 NET (52%). Almost half of the patients identified limitations in the questionnaires, with nine (14%) patients scoring the questionnaires as poor and 16 (25%) patients as moderate. Overall, 37 (57%) patients were positive towards the questionnaires. Approximately a quarter of patients considered the questionnaires not suitable for all ages, missing some of their complaints, not representative of their overall HR-QoL regarding the treatment of their NET and too superficial. The current validated EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires may show some limitations in the design of questions and the patients’ final satisfaction reporting of the questionnaire. Large-scale, high-quality prospective studies are required in HR-QoL assessment regarding NETs.

Patterns of Use and Clinical Outcomes with Long-Acting Somatostatin Analogues for Neuroendocrine Tumors: A Nationwide French Retrospective Cohort Study in the Real-Life Setting.

IntroductionLong-acting somatostatin analogues such as lanreotide autogel (LAN) and octreotide long-acting release (OCT) are recommended as first-line treatment for patients with neuroendocrine tumors (NETs). However, only few real-world studies have compared the two medications. This retrospective, observational cohort study used a French claims database to compare patterns of use with LAN vs. OCT in patients with NETs.MethodsData on LAN and OCT patterns of use were obtained retrospectively from the National System of Health Data (SNDS), a national French claims database. Patients 18 years of age or older who initiated treatment for NETs between 2009 and 2016, and who received at least six subsequent dispensings of first-line LAN or OCT during the first year of treatment, were included. A subgroup analysis was performed on patients with gastroenteropancreatic (GEP)-NETs.ResultsPatients receiving LAN (n = 2327) vs. OCT (n = 2090) had greater median treatment duration (31.8 months vs. 22.1 months, respectively; p < 0.0001; log-rank test) and were less likely to discontinue treatment; adjusted hazard ratio (HR) 0.74 (95% confidence interval [CI] 0.69–0.80). In year 1, a significantly lower percentage of patients receiving LAN vs. OCT switched treatments (10.4% vs. 22.2%, respectively; p < 0.0001), received an average monthly dose per trimester above recommended dose (3.0% vs. 7.3%, respectively; p < 0.0001), and used rescue medication (3.1% vs. 10.0%, respectively; p < 0.0001). Dispensing of pancreatic enzymes was significantly higher in patients receiving LAN than OCT (16.4% vs. 13.9%, respectively). In the subgroup of patients with GEP-NETs, those receiving LAN (n = 1478) vs. OCT (n = 1278) had greater treatment duration and less treatment discontinuation, switching, dosage above the recommended dose, and rescue medication use, but no significant difference in dispensing of pancreatic enzymes or time to second-line treatment.ConclusionThese real-world data suggest potential clinical and economic advantages of LAN over OCT in the management of patients with NETs in the French population.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02060-1.

A74 SURVEILLANCE IMAGING FOLLOWING COMPLETELY RESECTED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS: A SINGLE CENTER AUDIT OF LOCAL PRACTICE PATTERNS

BackgroundNeuroendocrine tumours (NET) are a heterogenous group of neoplasms that secrete peptides and neuroamines. For patients with potentially malignant gastroenteropancreatic (GEP) NET, surgical resection represents the only curative option. GEP NETs are characterized by long periods of disease-free survival and time-to-recurrence following surgical resection. Clinical guidelines recommend surveillance with cross sectional imaging, either CT or MRI, for at least 10 years.AimsThe purpose of this study was to characterize local practice patterns of imaging surveillance (modality, frequency, and duration of follow-up) and how this compares to guideline recommendations.MethodsWe retrospectively reviewed clinical and imaging records from patients diagnosed with well-differentiated GEP NET at our center from January 2005 to July 2020 inclusive. Eligible cases were identified by a data analyst from the Alberta Cancer Board with each case being manually screened for eligibility. Exclusion criteria included patients with metastatic disease at presentation, G1 appendiceal NET < 1 cm, R0 G1 T1 rectal NET, and insulinoma. Location of primary NET, modality of surveillance imaging, date of test and duration of follow-up collected. The mean number of surveillance scans per person and per person-year follow-up based on the location of the primary NET were calculated.ResultsA total of 387 cases were initially retrieved with 62 eligible cases identified. The mean length of follow-up was 71 months (range 8 to 147). The mean number of surveillance scans was 7 (range 2 to 14) and the mean number of surveillance scans per person year was 1.1. Frequency of surveillance scans per year of follow-up did not differ based on the location of the primary tumor (p=0.966). Imaging modalities included cross sectional imaging (MRI and contrast enhanced CT) and nuclear medicine imaging (octreotide, MIBG, F-18 FDG-PET, and Gallium-68 DOTATATE PET CT). Most commonly, cross-sectional imaging was performed with CT or MRI representing 38% (n=166) and 39% (n=170) of all surveillance respectively. Nuclear medicine imaging was used in 15% (n=61) of surveillance scans and 3% used combined cross-sectional and nuclear medicine. Amongst cases with resection date >10 years (n=8) mean length of follow-up was 119 months (9.9 years).ConclusionsFrequency and modality of imaging at our center is generally in accordance with current clinical guidelines, though the role of nuclear medicine imaging in this setting has not been established. CT and MRI were utilized equally during surveillance. The burden of these modalities in terms of radiation exposure and cost warrants further evaluation. Funding AgenciesNone

Survival According to Primary Tumor Location, Stage, and Treatment Patterns in Locoregional Gastroenteropancreatic High-grade Neuroendocrine Carcinomas.

BackgroundAlthough the gastrointestinal tract (including the pancreas, gastroenteropancreatic (GEP) is the most common site for extrapulmonary neuroendocrine carcinoma (NEC), the current treatment patterns of locoregional GEP NEC and in particular, the role of surgical resection is unclear.MethodsData from the National Cancer Database between 2004 and 2016 were used for this study.ResultsOf 2314 GEP NEC cases (stages I–III), 52.5% were stage III. Colon was the most common site (30%); 30.9% of all cases were small cell morphology. Age, morphology, stage, and primary site were associated with significant differences in treatment patterns. Management of NEC mimicked that of adenocarcinomas arising at the respective sites: colon NEC most likely to be treated with surgery and chemotherapy; anal and esophageal NEC was primarily likely to receive chemotherapy and radiation, and rectal NEC mostly likely to receive trimodality therapy. However, 25%-40% of patients did not undergo surgical resection even at sites typically managed with curative resection, and there was a trend toward lesser resection over time. The prognostic impact of surgical resection was significant across all stages and correlated with variations in survival across primary sites. Even in patients undergoing chemoradiation, surgery was the only prognostic variable that significantly affected survival in stages I–II patients (HR 0.63) and showed a strong trend in stage III (HR 0.77) patients.ConclusionsTreatment patterns in GEP NEC vary considerably according to stage and primary tumor site. Surgery significantly improved survival in stages I–II patients and showed a strong trend in stage III patients regardless of primary tumor location and other perioperative therapies.

Clinicopathological and molecular profile of grade 3 gastroenteropancreatic neuroendocrine neoplasms.

The 2019Word Health Organization (WHO) subclassified grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) into neuroendocrine carcinoma (NEC) or tumours (G3NET) based on morphology and proliferation. Yet, few data exist on molecular profiles for G3NEN. We compared clinicopathological and molecular characteristics of these two groups. We retrospectively reviewed consecutive G3 GEP NEN patients and had their tumour tissues reviewed, reclassified as per the WHO 2019, and analyzed by a next-generation sequencing (NGS) panel. Between 2000 and 2019, 43 patients had pathology revision: 29 (67%) were NEC and 14 (33%) were G3NET, with a 23% change in diagnosis. Median overal survival for G3NET and NEC patients was 55.6 and 11.9months, respectively (hazard ratio=2.78 [95% confidence interval=1.09-7.11], p=.042), which was confirmed by an adjusted analysis (hazard ratio=2.90NEC vs. G3NET; p=.03). NGS was performed in 32 cases: 21NEC and 11 G3NET. Mutations in RB1 and PTEN were exclusively encountered in NEC. Median tumour mutational burden was 5 (0-67) mutations per megabase in NEC and 4.5 (0-9) among G3NET. Microsatellite instability was found in 3 (14.3%) NEC cases. In conclusion, pathology revision is essential to estimate prognosis and therapeutic plan. G3 GEP NEN generally harbour low tumor mutation burden and fewer actionable mutations, but 14% of NEC cases were microsatellite unstable and could benefit from immune checkpoint inhibitors.