Comparative analysis of international guidelines on the management of advanced non-functioning well-differentiated pancreatic neuroendocrine tumors.

This review presents a comprehensive comparative analysis of international guidelines for managing advanced, non-functioning, well-differentiated pancreatic neuroendocrine tumors (panNETs). PanNETs, which represent a significant proportion of pancreatic neuroendocrine neoplasms, exhibit diverse clinical behaviors and prognoses based on differentiation, grading, and other molecular markers. The varying therapeutic strategies proposed by different guidelines reflect their distinct emphases and regional considerations, such as the ESMO guideline's focus on advanced disease management and the ENETS guidance paper's multidisciplinary approach. This review examines the most recent guidelines from ESMO, NCCN, ASCO, ENETS, and NANETS, analyzing the recommendations for first-line therapies and subsequent treatment pathways in different clinical scenarios. Significant variations are observed in the recommendations, particularly concerning the choice and sequence of systemic therapies, the role of tumor grading and the Ki-67 index in therapeutic decisions, and the integration of regional regulatory and clinical practices. The analysis highlights the need for a tailored approach to managing advanced NF panNETs, advocating for flexibility in applying guidelines to account for individual patient circumstances and the evolving evidence base. This work underscores the complexities of managing this patient population and the critical role of a multidisciplinary team in optimizing treatment outcomes.

Convolutional Neural Network Model for Intestinal Metaplasia Recognition in Gastric Corpus Using Endoscopic Image Patches.

Gastric cancer (GC) is a significant healthcare concern, and the identification of high-risk patients is crucial. Indeed, gastric precancerous conditions present significant diagnostic challenges, particularly early intestinal metaplasia (IM) detection. This study developed a deep learning system to assist in IM detection using image patches from gastric corpus examined using virtual chromoendoscopy in a Western country. Utilizing a retrospective dataset of endoscopic images from Sant'Andrea University Hospital of Rome, collected between January 2020 and December 2023, the system extracted 200 × 200 pixel patches, classifying them with a voting scheme. The specificity and sensitivity on the patch test set were 76% and 72%, respectively. The optimization of a learnable voting scheme on a validation set achieved a specificity of 70% and sensitivity of 100% for entire images. Despite data limitations and the absence of pre-trained models, the system shows promising results for preliminary screening in gastric precancerous condition diagnostics, providing an explainable and robust Artificial Intelligence approach.

Clinical Outcome of Patients with Gastric, Duodenal, or Rectal Neuroendocrine Tumors after Incomplete Endoscopic Resection.

Objectives: Our aim was to investigate the clinical outcome of patients with well-differentiated gastric, duodenal, and rectal neuroendocrine tumors after treatment with incomplete endoscopic resection due to the finding of microscopic positive resection margins (R1). Methods: This is a retrospective analysis of consecutive patients with type 1 gastric, non-ampullary non-functioning duodenal, or rectal neuroendocrine neoplasms with positive R1 margins after endoscopic resection. The rate of tumor recurrence and progression-free survival were considered to be the study's main endpoints. Statistical analysis was performed using MedCalc® v.17 software and a p-value of <0.05 was considered significant. A Cox proportional-hazard regression was performed to identify risk factors for disease recurrence/progression. Results: After evaluating 110 patients, a total of 58 patients were included in the final analysis (15 gastric NENs, 12 duodenal NENs, and 31 rectal NENs). After evidence of endoscopic R1 resection had been gathered, 26 patients (44.8%) underwent an endoscopic/surgical extension of the previous resection. Tumor progression (all local recurrences) occurred in five out of fifty-eight patients (8.6%) with a median PFS of 36 months. There were no tumor-related deaths. G2 grading and the gastric primary tumor site were the only features significantly associated with the risk of recurrence of the disease (HR: 11.97 [95% CI: 1.22-116.99], HR: 12.54 [95% CI: 1.28-122.24], respectively). Conclusions: Tumor progression rarely occurs in patients with microscopic positive margin excision (R1) after endoscopic resection and does not seem to affect patients' clinical outcomes.

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.

Gastric neuroendocrine neoplasms.

Gastric neuroendocrine neoplasms (gNENs) display peculiar site-specific features among all NENs. Their incidence and prevalence have been rising in the past few decades. gNENs comprise gastric neuroendocrine carcinomas (gNECs) and gastric neuroendocrine tumours (gNETs), the latter further classified into three types. Type I anatype II gNETs are gastrin-dependent and develop in chronic atrophic gastritis and as part of Zollinger-Ellison syndrome within a multiple endocrine neoplasia type 1 syndrome (MEN1), respectively. Type III or sporadic gNETs develop in the absence of hypergastrinaemia and in the context of a near-normal or inflamed gastric mucosa. gNECs can also develop in the context of variable atrophic, relatively normal or inflamed gastric mucosa. Each gNEN type has different clinical characteristics and requires a different multidisciplinary approach in expert dedicated centres. Type I gNETs are managed mainly by endoscopy or surgery, whereas the treatment of type II gNETs largely depends on the management of the concomitant MEN1. Type III gNETs may require both locoregional approaches and systemic treatments; NECs are often metastatic and therefore require systemic treatment. Specific data regarding the systemic treatment of gNENs are lacking and are derived from the treatment of intestinal NETs and NECs. An enhanced understanding of molecular and clinical pathophysiology is needed to improve the management and outcomes of patients' gNETs.

Sequencing Treatments in Patients with Advanced Well-Differentiated Pancreatic Neuroendocrine Tumor (pNET): Results from a Large Multicenter Italian Cohort.

Background: The optimal treatment sequencing for advanced, well-differentiated pancreatic neuroendocrine tumors (pNETs) is unknown. We performed a multicenter, retrospective study to evaluate the best treatment sequence in terms of progression-free survival to first-line (PFS1) and to second-line (PFS2), and overall survival among patients with advanced, well-differentiated pNETs. Methods: This multicenter study retrospectively analyzed the prospectively collected data of patients with sporadic well-differentiated pNETs who received at least two consecutive therapeutic lines, with evidence of radiological disease progression before change of treatment lines. Results: Among 201 patients, 40 (19.9%) had a grade 1 and 149 (74.1%) a grade 2 pNET. Primary tumor resection was performed in 98 patients (48.8%). First-line therapy was performed in 128 patients with somatostatin analogs (SSA), 35 received SSA + radioligand therapy (RLT), 21 temozolomide-based chemotherapy, and 17 SSA + targeted therapy. PFS was significantly longer in patients with grade 1 pNETs compared to those with grade 2, in patients who received primary tumor surgery, and in patients treated with RLT compared to other treatments. At multivariate analysis, the use of upfront RLT was independently associated with improved PFS compared to SSA. Second-line therapy was performed in 94 patients with SSA + targeted therapy, 35 received chemotherapy, 45 SSA + RLT, and 27 nonconventional-dose SSA or SSA switch. PFS was significantly longer in patients treated with RLT compared to other treatments. At multivariate analysis, the type of second-line therapy was independently associated with the risk for progression. OS was significantly longer in patients who received primary tumor surgery, with Ki67 < 10%, without extrahepatic disease, and in patients who received SSA-RLT sequence compared to other sequences. Conclusions: In this large, multicenter study, RLT was associated with better PFS compared to other treatments, and the SSA-RLT sequence was associated with the best survival outcomes in patients with pNETs with Ki67 < 10%. Primary tumor surgery was also associated with improved survival.

Diagnostic and Therapeutic Management of Primary Orbital Neuroendocrine Tumors (NETs): Systematic Literature Review and Clinical Case Presentation.

BACKGROUND: The ocular involvement of neuroendocrine neoplasms (NENs) is uncommon and mainly represented by metastases from gastrointestinal and lung neuroendocrine tumors. Primary orbital NENs are even less common and their diagnostic and therapeutic management is a challenge. METHODS: A systematic review of the literature was conducted from 1966 to September 2023 on PubMed to identify articles on orbital NENs and to summarize their clinical-pathological features, diagnosis and therapeutic management. Furthermore, we presented a case of a locally advanced retro-orbital primary neuroendocrine tumor that was referred to the certified Center of Excellence of Sant'Andrea Hospital, La Sapienza University of Rome, Italy. RESULTS: The final analysis included 63 records on orbital NENs and 11 records focused on primary orbital NENs. The localization was mostly unilateral and in the right orbit; proptosis or exophthalmos represented the initial symptoms. The diagnostic work-up and therapeutic management was discussed and a diagnostic algorithm for the suspicion of primary orbital NENs was proposed. CONCLUSIONS: A multidisciplinary approach is required for the management of primary orbital NENs, emphasizing the importance of early referral to dedicated centers for prompt differential diagnosis, tailored treatment, and an improved quality of life and survival.

Type 3 gastric neuroendocrine neoplasms: the rising promise of conservative endoscopic management.

Gastric neuroendocrine neoplasms (g-NENs) are rare tumors arising from the gastric enterochromaffin-like cells. Recent data suggests an increased detection rate, attributed to more frequent esophagogastroduodenoscopies. While type 3 g-NENs were historically deemed aggressive, emerging research indicates potential for conservative management, especially endoscopic resection, in well-differentiated, small tumors. European guidelines now advocate for endoscopic intervention in selected cases, but North American guidelines remain more conservative. Key factors influencing outcomes are tumor size, grading, and depth of gastric wall infiltration. Endoscopic resection has shown promise for tumors confined to submucosal layers without lymphovascular invasion. Given the complexities, a multidisciplinary team approach is essential for management decisions. Current insights are largely based on retrospective studies, underscoring the need for prospective research to optimize endoscopic approaches.

Endoscopic management of gastric, duodenal and rectal NETs: Position paper from the Italian Association for Neuroendocrine Tumors (Itanet), Italian Society of Gastroenterology (SIGE), Italian Society of Digestive Endoscopy (SIED).

The present paper reflects the position of the Italian Association for Neuroendocrine Tumors (Itanet), the Italian Society of Gastroenterology (SIGE), and the Italian Society of Digestive Endoscopy (SIED) regarding the management of patients affected by gastric, duodenal, and rectal neuroendocrine neoplasms (NENs) amenable to endoscopic treatment. The key questions discussed in this paper are summarized in Table 1. Data were extracted from the MEDLINE database through searches; expert opinions and recommendations are provided in accordance with the available scientific evidence and the authors' expertise. Recommendations are presented alongside a level of evidence and grade of recommendation based on the GRADE system. This paper specifically focuses on subgroups of NENs considered suitable for endoscopic management according to current international guidelines: i. well-differentiated gastric neuroendocrine tumors (gNET) type 1 < 2 cm and selected cases of type 3; ii. well-differentiated duodenal, non-functioning, non-ampullary NET with size < 2 cm; and well-differentiated rectal NET with size < 2 cm.

Epidemiology of gastroenteropancreatic neuroendocrine neoplasms: a review and protocol presentation for bridging tumor registry data with the Italian association for neuroendocrine tumors (Itanet) national database.

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083).

Thyroid transcription factor-1 expression in lung neuroendocrine tumours: a gender-related biomarker?

PURPOSE: Thyroid transcription factor-1 (TTF-1) assessed by immunohistochemistry (IHC) is a specific biomarker for lung adenocarcinoma, and is commonly used to confirm the pulmonary origin of neuroendocrine tumours (NET). The majority of the available data suggest that TTF-1 is favourable prognostic biomarker for lung adenocarcinomas, whereas its role is more conflicting for lung NET. The main aim of this multicenter retrospective study was to investigate the potentially relevant associations between TTF-1 biomarker and clinical and pathological features of the study population, as well as determine TTF-1 prognostic effect on the clinical outcome of the patients. METHODS: A multicentre retrospective study was conducted on 155 surgically-removed lung NET, with available IHC TTF-1 assessment. RESULTS: Median age was 59.5 years (range 13-86), 97 patients (62.6%) were females, 31 cases (20%) were atypical carcinoids, 4 (2.6%) had TNM stage IV. Mitotic count ≥2 per 10 high-power field was found in 35 (22.6%) subjects, whereas necrosis was detected in 20 patients (12.9%). TTF-1 was positive in 78 cases (50.3%). The median overall survival was 46.9 months (range 0.6-323) and the median progression-free survival was 39.1 months (range 0.6-323). Statistically significant associations were found between (1) TTF-1 positivity and female sex (p = 0.007); and among (2) TTF-1 positivity and the absence of necrosis (p = 0.018). CONCLUSIONS: This study highlights that TTF-1 positivity differs according to sex in lung NET, with a more common TTF-1 positive staining in female. Moreover, TTF-1 positivity correlated with the absence of necrosis. These data suggest that TTF-1 could potentially represent a gender-related biomarker for lung NET.

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.

Optimising Radioligand Therapy for Patients with Gastro-Entero-Pancreatic Neuroendocrine Tumours: Expert Opinion from an Italian Multidisciplinary Group.

Radioligand therapy (RLT) with lutetium (177Lu) oxodotreotide is an approved therapy in combination with somatostatin analogues (SSAs) for patients with advanced, well-differentiated G1-G2, gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs) that progress on SSAs. We conducted a series of round table meetings throughout Italy to identify issues related to RLT delivery to patients with GEP-NETs. Four key issues were identified: (1) the proper definition of tumour progression prior to RLT initiation; (2) the impact of RLT in patients with bone metastases and/or high hepatic tumour burden; (3) the optimal follow-up protocol after RLT; and (4) organisational issues related to RLT use and managerial implications. This article reviews the literature relating to the aforementioned issues and makes recommendations based on available evidence and Italian NET experts' opinions. In particular, the group recommends the development of a diagnostic-therapeutic care pathway (DTCP) for patients undergoing RLT which provides systematic guidance but can still be individualised for each patient's clinical and psychosocial needs. A DTCP may clarify the diagnostic, therapeutic and post-treatment monitoring process, and improve communication and the coordination of care between hub and spoke centres. The DTCP may also contribute to changes in the care process related to the 2013/59/EURATOM Directive and to the definition of costs when planning for future or updated reimbursement of RLT in Italy.

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).

When Should We Adopt EUS-Guided Radiofrequency Ablation in Pancreatic Neuroendocrine Tumors?

Pancreatic neuroendocrine neoplasms (PanNENs) are rare and heterogeneous diseases that account for less than 2% of all cases of pancreatic cancer and only 30% of digestive neuroendocrine neoplasia, even if their incidence and prevalence continue to rise globally [...].

Study protocol for a multicenter randomized controlled trial to compare radiofrequency ablation with surgical resection for treatment of pancreatic insulinoma.

BACKGROUND: Insulinoma is the most common functional pancreatic neuroendocrine tumor and treatment is required to address symptoms associated with insulin hypersecretion. Surgical resection is effective but burdened by high rate of adverse events (AEs). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) demonstrated encouraging results in terms of safety and efficacy for the management of these tumors. However, studies comparing surgery and EUS-RFA are lacking. AIMS: The primary aim is to compare EUS-RFA with surgery in term of safety (overall rate of AEs). Secondary endpoints include: (a) severe AEs rate; (b) clinical effectiveness; (c) patient's quality of life; (d) length of hospital stay; (e) rate of local/distance recurrence; (f) need of reintervention; (g) rate of endocrine and exocrine pancreatic insufficiency; (h) factors associated with EUS-RFA related AEs and clinical effectiveness. METHODS: ERASIN-RCT is an international randomized superiority ongoing trial in four countries. Sixty patients will be randomized in two arms (EUS-RFA vs surgery) and outcomes compared. Two EUS-RFA sessions will be allowed to achieve symptoms resolution. Randomization and data collection will be performed online. DISCUSSION: This study will ascertain if EUS-RFA can become the first-line therapy for management of small, sporadic, pancreatic insulinoma and be included in a step-up approach in case of clinical failure.

The meaning of R1 resection after endoscopic removal of gastric, duodenal and rectal neuroendocrine tumors.

INTRODUCTION: Well-differentiated gastric, duodenal, and rectal neuroendocrine neoplasms (NETs) are rare diseases usually managed by endoscopic treatment. Although several endoscopic techniques are available, the number of patients with incomplete (R1) resection is significant. AREAS COVERED: This review focuses on the meaning of incomplete R1 findings after endoscopic resection in type I gastric NETs; nonfunctioning, non-ampullary duodenal NETs; and small rectal NETs. Data were identified by MEDLINE database search without publication date limitation. EXPERT OPINION: An incomplete R1 finding may have no significant impact on a patient's clinical outcome, particularly in small G1 type I gastric NETs, which have an indolent course. A 'stepwise approach,' which uses more advanced endoscopic techniques, or minimally invasive surgery may be justified to achieve complete margin-free resection. This approach must balance the tumor features and the procedure-related risk of complications, particularly in the duodenum, where the role of deep endoscopic resections is limited due to the thin duodenal wall. Gastric and rectal NETs that are incompletely removed after initial resection are more easily amenable to deep endoscopic techniques. However, this might not be necessary for patients with comorbidities, elderly, or both due to the uncertainty of how R1 finding impacts a patient's clinical outcome.

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for gastroduodenal neuroendocrine tumours (NETs) G1-G3.

The aim of the present guidance paper was to update the previous ENETS guidelines on well-differentiated gastric and duodenal neuroendocrine tumours (NETs), providing practical guidance for specialists in the diagnosis and management of gastroduodenal NETs. Type II gastric NETs, neuroendocrine carcinomas (NECs), and functioning duodenal NETs are not covered, since they will be discussed in other ENETS guidance papers.

Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors: Alternatives to RECIST.

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06-3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. CLINICAL TRIAL REGISTRATION: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as "E-NETNET-L-E-CT" July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.