Outcomes of a 3-Year Prospective Surveillance in Individuals at High Risk of Pancreatic Cancer.

INTRODUCTION: Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before. METHODS: HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195). RESULTS: During the study period (June 2015-September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported. DISCUSSION: PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time.

Gastrointestinal side effects of somatostatin analogs in neuroendocrine tumors: a focused review.

Neuroendocrine tumors (NETs) are a group of well-differentiated heterogeneous neoplasms characterized by slow progression and distinct clinical and biological behavior. In the majority of patients with NET, first-line treatment is represented by somatostatin analogs (SSAs) that, despite being drugs with high tolerability (even at high doses) and providing to carcinoid symptoms control and anti-proliferative effects, may present some side effects, with potential impact on quality of life and nutritional status. The most frequent side effects are represented by gastrointestinal events in particular alterations in bowel habits (diarrhea and constipation), abdominal pain, exocrine pancreatic insufficiency, and cholelithiasis. Considering the relative rarity of NETs, literature about frequency and standard clinical management of adverse events SSA-related is still lacking and heterogeneous. The aim of this review is to arm gastroenterologists and other physicians treating NET patients with essential knowledge on the side effects of SSAs. By identifying and managing these adverse events early, healthcare professionals can offer optimal care, avert foreseeable complications, and ensure the best outcomes for patients. Without such early recognition, there is a risk of diminishing the patient's quality of life and their ability to sustain treatment over time.

Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study.

BACKGROUND: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71). INTERPRETATION: This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. FUNDING: Swiss Cancer Research foundation.

Assessing the safety and activity of cabozantinib combined with lanreotide in gastroenteropancreatic and thoracic neuroendocrine tumors: rationale and protocol of the phase II LOLA trial.

BACKGROUND: Well-differentiated (WD) neuroendocrine tumors (NETs) are a group of rare neoplasms with limited therapeutic options. Cabozantinib is an inhibitor of multiple tyrosine kinases with a pivotal role in NET pathogenesis, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). LOLA is the first prospective phase II trial aiming to assess the safety and activity of cabozantinib combined with lanreotide in WD NETs of gastroenteropancreatic (GEP), thoracic and of unknown origin. METHODS: This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥ 10%; positive 68 Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids (typical or atypical lung and thymus NETs, gastro-intestinal NETs or NETs of unknown origin). In stage I, the primary objective is to find the optimal dose of cabozantinib in combination with lanreotide and to evaluate the safety of the combination (percentage of patients experiencing grade 3-5 toxicities according to NCI-CTCAE version 5.0). Starting dose of cabozantinib is 60 mg/day continuously, plus lanreotide 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST version 1.1. The uninteresting antitumor activity is fixed in ORR ≤ 5%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of c-MET, AXL and VEGFR2 IHC expression, to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop-out rate of 5%, the maximum number of enrolled patients will be 69. DISCUSSION: Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of cabozantinib plus lanreotide in a group of NET patients with relatively aggressive disease and limited therapeutic options. TRIAL REGISTRATION: LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019-004506-10).

Management of Functional Pancreatic Neuroendocrine Neoplasms.

OPINION STATEMENT: Functional pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous diseases in terms of both clinical and pathological aspects. These tumors secrete hormones or peptides, which may cause a wide variety of symptoms related to a clinical syndrome. The management of functional pNENs is still challenging for clinicians due to the need to control both tumor growth and specific symptoms. Surgery remains the cornerstone in the management of local disease because it can definitively cure the patient. However, when the disease is not resectable, a broad spectrum of therapeutic options, including locoregional therapy, somatostatin analogs (SSAs), targeted therapies, peptide-receptor radionuclide therapy (PRRT), and chemotherapy, are available. The present review summarizes the main key issues regarding the clinical management of these tumors, providing a specific highlight on their therapeutic approach.

Survival after active surveillance versus upfront surgery for incidental small pancreatic neuroendocrine tumours.

BACKGROUND: The safety of observing small non-functioning pancreatic neuroendocrine tumours (NF-Pan-NETs) remains under debate. METHODS: This was a multicentre retrospective study of patients with small incidental NF-Pan-NETs. Survival of patients who underwent upfront surgery versus active surveillance was compared. The risk of death was matched with that in the healthy population. The excess hazard rate and probability of a normal lifespan (NLP) were calculated. Propensity score matching (PSM) with a 1 : 1 ratio was used to minimize the risk of selection bias. RESULTS: Some 222 patients (43.7 per cent) underwent upfront surgery and 285 (56.3 per cent) were observed. The excess hazard rate for the entire cohort was quantifiable as 0.04 (95 per cent c.i. 0 to 0.08) deaths per 1000 persons per year, and the NLP was 99.7 per cent. Patients in the active surveillance group were older (median age 65 versus 58 years; P < 0.001), and more often had co-morbidity (45.3 versus 24.8 per cent; P = 0.001), and smaller tumours (median 12 versus 13 mm; P < 0.001), less frequently located in the pancreatic body-tail (59.5 versus 69.6 per cent; P = 0.008, 59.3 versus 73.9 per cent; P = 0.001). Median follow-up was longer for patients who underwent upfront surgery (5.6 versus 2.7 years; P < 0.001). After PSM, 118 patients per group were included. The excess hazard rates were 0.2 and 0.9 deaths per 1000 persons per year (P = 0.020) for patients in the active surveillance and upfront surgery groups respectively. Corresponding NLPs were 99.9 and 99.5 per cent respectively (P = 0.011). CONCLUSION: Active surveillance of small incidental NF-Pan-NETs is a reasonable alternative to resection.

CT-based radiomics for prediction of therapeutic response to Everolimus in metastatic neuroendocrine tumors.

AIM: To test radiomic approach in patients with metastatic neuroendocrine tumors (NETs) treated with Everolimus, with the aim to predict progression-free survival (PFS) and death. MATERIALS AND METHODS: Twenty-five patients with metastatic neuroendocrine tumors, 15/25 pancreatic (60%), 9/25 ileal (36%), 1/25 lung (4%), were retrospectively enrolled between August 2013 and December 2020. All patients underwent contrast-enhanced CT before starting Everolimus, histological diagnosis, tumor grading, PFS, overall survival (OS), death, and clinical data collected. Population was divided into two groups: responders (PFS ≤ 11 months) and non-responders (PFS > 11 months). 3D segmentation was performed on whole liver of naïve CT scans in arterial and venous phases, using a dedicated software (3DSlicer v4.10.2). A total of 107 radiomic features were extracted and compared between two groups (T test or Mann-Whitney), radiomics performance assessed with receiver operating characteristic curve, Kaplan-Meyer curves used for survival analysis, univariate and multivariate logistic regression performed to predict death, and interobserver variability assessed. All significant radiomic comparisons were validated by using a synthetic external cohort. P < 0.05 is considered significant. RESULTS: 15/25 patients were classified as responders (median PFS 25 months and OS 29 months) and 10/25 as non-responders (median PFS 4.5 months and OS 23 months). Among radiomic parameters, Correlation and Imc1 showed significant differences between two groups (P < 0.05) with the best performance (internal cohort AUC 0.86-0.84, P < 0.0001; external cohort AUC 0.84-0.90; P < 0.0001). Correlation < 0.21 resulted correlated with death at Kaplan-Meyer analysis (P = 0.02). Univariate analysis showed three radiomic features independently correlated with death, and in multivariate analysis radiomic model showed good performance with AUC 0.87, sensitivity 100%, and specificity 66.7%. Three features achieved 0.77 ≤ ICC < 0.83 and one ICC = 0.92. CONCLUSIONS: In patients affected by metastatic NETs eligible for Everolimus treatment, radiomics could be used as imaging biomarker able to predict PFS and death.

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice.

Skeletal colonization is often regarded as a rare event in patients with neuroendocrine tumors (NETs) although both national registries and retrospective series report an incidence of bone metastases as high as 20% in subjects with advanced disease. While the biological mechanisms leading to bone metastatic colonization in NETs have been poorly investigated so far, key steps of osteotropic mechanisms, including the epithelial-to-mesenchymal transition, preparation of the premetastatic niche, migration of circulating tumor cells towards the bone marrow as well as the resulting alterations of the skeletal metabolism, are likely to operate also during the development of NET bone metastases. The skeleton involvement by NETs has a detrimental impact on both quality of life and patients' prognosis, leading to pain in the majority of symptomatic subjects. While it is currently unclear whether or not the earlier recognition of bone involvement by PET/CT imaging techniques employing 68Ga-DOTA-conjugated peptides might improve outcomes through the exploitation of timely treatments, the management of bone-colonizing NETs is today based only on clinical experience from other osteotropic tumors. Here, we summarize the fundamental molecular mechanisms driving bone colonization and revisit both established and novel treatments for patients with bone metastatic NETs.

MYC Upregulation Confers Resistance to Everolimus and Establishes Vulnerability to Cyclin-Dependent Kinase Inhibitors in Pancreatic Neuroendocrine Neoplasm Cells.

INTRODUCTION: Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-dependent pathways in pancreatic neuroendocrine neoplasms (PanNENs) underlies the introduction of the mTORC1 inhibitor everolimus as treatment of advanced progressive PanNENs. Although everolimus significantly increases progression-free survival, most patients acquire secondary resistance to the drug. This study aimed at identifying mechanisms involved in acquisition of resistance to everolimus. METHODS: BON-1 and everolimus-resistant (ER) BON-1 cells were used as in vitro system of sensitivity and acquired resistance. Transcriptome changes occurring in BON-1 and ER-BON-1 were investigated by RNA sequencing and validated by quantitative PCR analysis. RNA extracted from patients' biopsies was used to validate MYC upregulation. Drug screening and functional assays were performed using ER-BON-1 cells. Cell cycle progression was evaluated by FACS analysis. RESULTS: Our results show that MYC overexpression is a key event in the development of secondary resistance to everolimus in PanNEN cell lines and in metastatic lesions from neuroendocrine neoplasm patients. MYC knockdown restored ER-BON-1 sensitivity to everolimus. Pharmacological inhibition of MYC mediated by the cyclin-dependent kinase inhibitor dinaciclib strongly reduced viability of ER-BON-1. Dinaciclib synergized with everolimus and inhibited ER-BON-1 cell cycle progression. DISCUSSION: Our findings suggest that MYC upregulation drives the development of secondary resistance to everolimus in PanNENs and that its inhibition is an exploitable vulnerability. Indeed, our results indicate that combined treatments with cyclin-dependent kinase and mTOR inhibitors may counteract secondary resistance to everolimus in PanNENs and may pave the ground for new therapeutic regimens for these tumors.

Morphological Factors Related to Nodal Metastases in Neuroendocrine Tumors of the Appendix: A Multicentric Retrospective Study.

OBJECTIVE: The aim of this study was to evaluate clinical and morphological features related to nodal involvement in appendiceal neuroendocrine tumors (NETs), to identify patients who should be referred for oncological radicalization with hemicolectomy. BACKGROUND: Appendiceal NETs are usually diagnosed accidentally after appendectomy; the indications for right hemicolectomy are currently based on several parameters (ie, tumor size, grading, proliferative index, localization, mesoappendiceal invasion, lymphovascular infiltration). Available guidelines are based on scarce evidence inferred by small, retrospective, single-institution studies, resulting in discordant recommendations. METHODS: A retrospective analysis of a prospectively collected database was performed. Patients who underwent surgical resection of appendiceal NETs at 11 tertiary Italian centers, from January 1990 to December 2015, were included. Clinical and morphological data were analyzed to identify factors related to nodal involvement. RESULTS: Four-hundred fifty-seven patients were evaluated, and 435 were finally included and analyzed. Of them, 21 had nodal involvement. Grading G2 [odds ratio (OR) 6.04], lymphovascular infiltration (OR 10.17), size (OR 18.50), and mesoappendiceal invasion (OR 3.63) were related to nodal disease. Receiver operating characteristic curve identified >15.5 mm as the best size cutoff value (area under the curve 0.747). On multivariate analysis, grading G2 (OR 6.98), lymphovascular infiltration (OR 8.63), and size >15.5 mm (OR 35.28) were independently related to nodal involvement. CONCLUSIONS: Tumor size >15.5 mm, grading G2, and presence of lymphovascular infiltration are factors independently related to nodal metastases in appendiceal NETs. Presence of ≥1 of these features should be considered an indication for oncological radicalization. Although these results represent the largest study currently available, prospective validation is needed.

Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A Multicenter Study.

BACKGROUND: Somatostatin analogs (SSAs) are the mainstay of neuroendocrine tumor (NET) treatment. Biliary stone disease is reported as a common side effect of SSAs, with a frequency ranging from 10% to 63%. Studies on SSA-treated patients for acromegaly report an increased incidence of biliary stone disease compared with the general population, whereas data on patients with NETs are few. Guidelines are based on weak evidence, thus resulting in conflicting recommendations. The aim of the study is to evaluate biliary stone disease incidence, complications, and risk factors in a large population of SSA-treated patients with NETs. MATERIALS AND METHODS: A retrospective analysis of a prospectively collected database was performed. Patients with a diagnosis of NET in seven dedicated centers from 1995 to 2017 were included at the time of SSA start. RESULTS: A total of 754 SSA-treated patients were evaluated. Patients with history of cholecystectomy or with known biliary stone disease were excluded; 478 patients were included. Among them, 118 patients (24.7%) received prophylactic ursodeoxycholic acid (UDCA). During the study period, 129 patients (27.0%) developed biliary stone disease; of them, 36 (27.9%) developed biliary complications. On multivariate analysis, primary gastrointestinal (GI)-NET (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were independent risk factors for biliary stone disease. CONCLUSION: We report a high incidence of biliary stone disease particularly in GI-NET or GI surgery. UDCA prophylaxis does not seem to have a protective role. Our data suggest that all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy; no conclusion could be drawn on the indication of prophylactic cholecystectomy in patients with primary pancreatic or thoracic NET for whom abdominal surgery is not planned. IMPLICATIONS FOR PRACTICE: The results of this study confirm an increased rate of gallstones development and related complications in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointestinal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA-related biliary stone disease.

Surgery with Radical Intent: Is There an Indication for G3 Neuroendocrine Neoplasms?

BACKGROUND: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. PATIENTS AND METHODS: Multicenter analysis of a series of stage I-III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. RESULTS: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23 months (5-187 months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14 months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. CONCLUSIONS: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Occurrence of exocrine pancreatic insufficiency in patients with advanced neuroendocrine tumors treated with somatostatin analogs.

BACKGROUND: Although exocrine pancreatic insufficiency (EPI) has been described in patients with neuroendocrine neoplasia (NEN) treated with somatostatin analogs (SSAs), its role in the therapeutic management of these patients is not well established. AIM: To determine the frequency of EPI in patients with NEN long-term treated with SSAs. METHODS: This is a prospective single-center study evaluating 35 patients treated with SSAs for >12 months due to unresectable/advanced nonpancreatic well-differentiated NEN. Clinical evaluation, biochemical parameters, and fecal elastases 1 (FE-1) were assessed to diagnose EPI. RESULTS: A total of 7 patients (20%) had EPI, given the presence of abdominal symptoms and a median FE-1 value of 180 mcg/g stool (150-198). No patient had severe EPI, defined as FE-1 < 100 mcg/g stool. Elevated glycated Hb levels were a significant predictor for developing EPI (OR 4.81, p = 0.01). No significant difference in terms of duration of SSA treatment was observed between patients with or without EPI diagnosed (84 months and 72 months, respectively; p = 0.950). CONCLUSIONS: Mild-moderate EPI is a relatively common condition in patients receiving long-term treatment with SSAs. Specific clinical and biochemical evaluations, including FE-1, should be planned in these patients to diagnose this relevant condition early, which may deteriorate quality of life and cause malnutrition.

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues.

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Prognostic impact of tumour burden in stage IV neuroendocrine neoplasia: A comparison between pancreatic and gastrointestinal localizations.

BACKGROUND: Although prognosis of NENs is affected by several features including tumour burden, the specific role of this factor in pancreatic NENs (PanNENs) and gastrointestinal NENs (GI NENs) is not well established. AIM: To compare the prognostic role of tumour burden in PanNENs and GI NENs. PATIENTS AND METHODS: This study was a retrospective analysis of stage IV PanNENs and GI NENs. Tumours were classified based on liver tumour volume (<25% or >25%). Overall survival as assessed by Kaplan-Meier curves, and Cox proportional hazards method was used to perform risk factor analysis. RESULTS: The analysis included 300 patients, including 166 panNENs (55.3%) and 134 GI NENs (44.7%). A total of 158 patients (52.7%) had G2 tumours, 107 had G1 tumours (35.7%), and 35 had G3 tumours (11.6%). Tumour liver involvement >25% was observed in 187 patients (62.3%): 106 PanNENs (56.7%), and 81 GI NENs (43.3%) (p = 0.551). Bone metastases were present in 45 patients (15%): 22 PanNENs (13.2%) and 23 GI NENs (17.1%) (p = 0.416). Characteristics of the PanNENs, including: grading (G2 vs G1, HR = 3.7; G3 vs G1, HR = 16.40), liver involvement > 25% (HR = 3.09), and bone metastases (HR = 2.27) were independent predictors for poor survival, whereas the only significant risk factor in GI NENs was grading (G2 vs G1, HR = 4.36; G3 vs G1, HR = 8.60). CONCLUSIONS: PanNENs and GI NENs have different risk profiles. Liver tumour volume and the presence of bone metastases significantly affect survival in patients with PanNENs but has no impact on the clinical outcomes of GI NENs.

Clinical Usefulness of 18F-Fluorodeoxyglucose Positron Emission Tomography in the Diagnostic Algorithm of Advanced Entero-Pancreatic Neuroendocrine Neoplasms.

BACKGROUND: The role of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the diagnostic algorithm of entero-pancreatic neuroendocrine neoplasms (EP NENs) is unclear because most available data derive from heterogeneous populations in terms of tumor biology and disease status at time of examination. The aim of this study was to determine the ability of 18F-FDG PET to identify patients with more aggressive disease among those with advanced EP NENs. Subjects, Materials, and Methods . Patients with advanced EP NENs and known disease status (progressive disease [PD] or stable disease [SD]) according to imaging procedures, who received 18F-FDG PET and computed tomography scans during a time frame of 1 month, were included. RESULTS: A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive 18F-FDG PET, whereas 18F-FDG PET was negative in the remaining 31 patients (33.3%). Overall, 18F-FDG PET sensitivity and specificity to detect PD were 90.6% and 86.2%, respectively, resulting in a diagnostic accuracy of 89.2%. A positive 18F-FDG PET was significantly associated with PD at the time of study entry (p < .0001 at multivariate analysis). Although a higher proportion of 18F-FDG PET-positive examinations were observed in patients with higher tumor grade (p = .01), 53.8% of patients with grade 1 neuroendocrine tumors (NETs) had positive 18F-FDG PET, and 37.5% of patients with grade 2 NETs had negative 18F-FDG PET. Overall survival was significantly shorter in 18F-FDG PET-positive patients (median: 60 months) in comparison with 18F-FDG PET-negative patients (median not reached; p = .008). CONCLUSION: 18F-FDG PET has a high diagnostic accuracy to identify progression of disease with unfavorable clinical outcome in patients with advanced EP NENs. Knowledge of disease status and G grading are key factors for physicians to better select patients for whom 18F-FDG PET is clinically useful. IMPLICATIONS FOR PRACTICE: The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom 18F-fluorodeoxyglucose positron emission tomography is useful to predict poor clinical outcome.

Heterogeneity of Duodenal Neuroendocrine Tumors: An Italian Multi-center Experience.

BACKGROUND: The optimal management of duodenal neuroendocrine neoplasms (dNENs) is unclear, and endoscopic resection is increasingly performed instead of surgery. METHODS: This is a retrospective analysis of patients with histologically confirmed diagnosis of dNENs, managed at five Italian tertiary referral Centers in Italy. RESULTS: From 2000 to 2017, 108 patients (69 males, 39 females, median age 59.5 years) were included in this study. Seventy-one patients had G1, 21 G2, 4 G3 dNENs (12 Ki-67 not available). Fifty-four patients showed metastases at diagnosis, and 20 patients developed metachronous metastases. Thirty patients had a functioning dNEN (14 metastatic). Fifty-seven patients had the dNEN surgically resected, 16 endoscopically, 23 metastatic, received medical therapy + surgery or endoscopy. Seven patients underwent liver-directed therapies, and one patient had PRRT. Median OS was 187 months. During a median follow-up of 76 months, 20 patients died (19 of disease-related causes). At Cox's multivariate proportional hazard regression, grading and age were the only variables independently related to OS. Median PFS was 170 months. Grading and staging at the initial diagnosis were independently related to PFS. No differences in terms of OS and PFS were observed between patients treated surgically or endoscopically. CONCLUSIONS: dNENs prognosis may be highly variable. These tumors can be metastatic in up to 50% of cases at the time of first diagnosis and can develop metastases thereafter. Functioning neoplasms express high metastatic potential. Nuclear imaging should be performed to exclude distant metastases in all dNENs. Endoscopy and surgery play a primary role in the management of the disease. Further prospective studies are needed.

Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study.

INTRODUCTION: Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. AIM: To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. PATIENTS AND METHODS: Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th-75th IQR). RESULTS: Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received ≥ 3 vs ≤ 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1-2 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. CONCLUSIONS: The present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases.

Prognosis of sporadic resected small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors - a multi-institutional study.

BACKGROUND: Malignant potential of small (≤20 mm) nonfunctional pancreatic neuroendocrine tumors (sNF-PNET) is difficult to predict and management remain controversial. The aim of this study was to assess the prognosis of sporadic nonmetastatic sNF-PNETs. METHODS: Patients were identified from databases of 16 centers. Outcomes and risk factors for recurrence were identified by uni- and multivariate analyses. RESULTS: sNF-PNET was resected in 210 patients, and 66% (n = 138) were asymptomatic. Median age was 60 years, median tumor size was 15 mm, parenchyma-sparing surgery was performed in 42%. Postoperative mortality was 0.5% (n = 1), severe morbidity rate was 14.3% (n = 30), and 14 of 132 patients (10.6%) with harvested lymph nodes had metastatic lymph nodes. Tumor size, presence of biliary or pancreatic duct dilatation, and WHO grade 2-3 were independently associated with recurrence. Patients with tumors sized ≤10 mm were disease free at last follow-up. The 1-, 3- and 5-year disease-free survival rates for patients with tumors sized 11-20 mm on preoperative imaging were 95.1%, 91.0%, and 87.3%, respectively. CONCLUSIONS: In sNF-PNETs, the presence of biliary or pancreatic duct dilatation or WHO grade 2-3 advocate for surgical treatment. In the remaining patients, a wait-and-see policy might be considered.

Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome.

BACKGROUND: Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. PATIENTS AND METHODS: A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. RESULTS: Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. CONCLUSION: In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs. The Oncologist 2017;22:409-415Implications for Practice: Clinical outcome of patients with advanced gastro-entero-pancreatic neuroendocrine neoplasms is affected by several risk factors, including the proliferative index Ki67, extension of liver metastases, and the presence of distant extra-abdominal lesions. A risk score that combines these variables may help physicians dealing with these diseases to plan the optimal therapeutic approach and follow-up program.