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Introduction: VIPoma is an extremely rare functioning pancreatic neuroendocrine tumor. Therefore, data regarding treatment and outcome are very limited. Aim (s): This multicenter study aimed to analyze clinical characteristics, real-world management, and outcomes of patients with VIPoma. Methods: Patients with VIPoma treated in a 20-year period at 14 referral centers for neuroendocrine tumors (NET) were collected in the ENETS Database. Clinical characteristics, therapeutic interventions, and outcomes were analyzed retrospectively. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Of 70 patients, 59 (54% male) with a median age of 55 years were included. Forty-six (78%) patients were diagnosed due to the classical watery diarrhea-hypokalemia-achlorhydria (WDHA) syndrome, and 40 (68%) presented with distant metastases at diagnosis. Fifty-two (88%) had serum VIP levels >2 times the upper normal limit and the median Ki-67 index was 5% (range 1%-40%). Surgery of the primary VIPoma was performed in 32 (54%), with curative intent in 22 (37%). In patients with stage I-III disease (n = 19), long-term cure was achieved in only 26% (5/19), with a median DFS of 81 (95%-CI: 1-215) months and 10-year OS of 78% (95%-CI: 61%-100%). In stage IV patients (n = 53, 40 at diagnosis, 13 disease progression), the sequence and type of 354 treatment lines varied, while SSA (n = 77, 22%), loco-regional liver-directed therapy (n = 72, 20%), and chemotherapy (n = 69, 19%) were most often applied. Median OS for patients with stage IV at diagnosis was 142 (95%-CI: 87-not available (NA)) months with 10-year survival of 50% (95%-CI: 35%-73%). Conclusion: Patients with VIPoma treated at NET centers have relatively favorable survival, even with distant metastases at diagnosis, although long-term cure rates remain low.

The role of primary tumour resection (PTR) in metastatic small intestinal (SiNETs) and pancreatic neuroendocrine tumours (PanNETs) remains debated. While retrospective studies suggest improved survival and possible reduction of local complications, the evidence is limited by heterogeneity, selection bias, and an absence of prospective validation. Under the auspices of the European Neuroendocrine Tumor Society (ENETS) Advisory Board, this position paper summarises current knowledge and expert consensus on the rationale, potential benefits, patient selection, timing, integration with systemic therapies, and future perspectives for PTR. PTR may be considered in selected patients with liver-limited or liver-dominant disease, indolent tumour biology, and good performance status, especially to prevent obstruction, bleeding, or ischaemia, to reduce symptomatic tumour burden, or to facilitate systemic and liver-directed therapies. However, the risks of major surgery, including intestinal and pancreatic resections, with long-term impact on digestion and nutrition, must be carefully considered. Decisions should be made in dedicated multidisciplinary tumour boards. Future directions include incorporation of molecular biomarkers, functional imaging, tumour growth rate, radiomics, and real-world data to refine patient selection. Quality of life and patient-reported outcomes remain underexplored and should be co-primary endpoints in prospective studies. PTR should not currently be regarded as standard of care for all cases but may have a role in carefully selected patients within integrated and individualised management strategies.

Ki-67 index and mitotic count form the basis of grading of small intestinal neuroendocrine tumours (siNET). We hypothesized that the mitosis-specific marker phosphohistone H3 (PHH3) might better correlate with cancer-specific survival (CSS) and with response to treatment. We evaluated the association between Ki-67 index, PHH3-estimated mitotic count, and survival outcomes in a retrospective cohort of 73 consecutive patients with metastatic siNET. Additionally, we estimated the optimal cut-off for PHH3 and cross-validated the outcome. Both markers adequately distinguished CCS when comparing lower and higher proliferation groups (Ki-67: 128 vs. 95 m; PHH3: 149 vs. 88 m). They were strongly associated with CSS as continuous (HR 1.18 [1.08–1.28] and 1.16 [1.09–1.25]), and dichotomous variables (HR 2.96 [1.31–6.67] and 3.11 [1.50–6.46]). The Cox model based on PHH3 displayed slightly better optimism-corrected Harrell's c-index (0.71 vs. 0.68) and Akaike information criterion (219 vs. 223). Additionally, PHH3 showed significant association with PFS after treatment with somatostatin analogues (HR 1.12 [1.03–1.21]), and borderline significant association with PFS after treatment with peptide receptor radionuclide therapy (HR 1.11 [1.00–1.24]). A cut-off of >2 mitoses per 10 high-power fields estimated by PHH3 seemed to have better discrimination power compared to the standard WHO cut-off (<2). Mitotic count based on PHH3 is associated with CSS and with PFS after treatment with first-line SSA and possibly with PRRT for metastatic siNET. It may be an alternative to Ki-67 for estimation of proliferation and grading. A cut-off of >2 mitoses per 10 HPF might better distinguish G1 and G2 tumours.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual. ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines.

Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more.

Purpose

To develop a clinical practice guideline and recommendations for symptom management of patients with well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors.

Methods

ASCO convened an Expert Panel to develop a clinical practice guideline by reviewing the literature for relevant guidelines, systematic reviews, randomized controlled trials (RCTs), and observational studies to develop recommendations for clinical practice.

Results

The literature review identified eight guidelines, 19 systematic reviews, and three RCTs that informed the development of guideline recommendations.

Recommendations

Recommendations are included for carcinoid syndrome, carcinoid heart disease and carcinoid crisis, and functional pancreatic neuroendocrine tumor syndromes. Recommendations are provided for surgical management, liver-directed therapy, and systemic therapy options, as well as palliative care. Limited guidance is provided for sequencing of interventions.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Background: Digestive high-grade neuroendocrine neoplasms (HG-NEN) are rare and classified as neuroendocrine carcinomas (NEC) or neuroendocrine tumours G3 (NET G3), and differ in clinical and molecular characteristics, response to treatment and prognosis.

Methods: Prospective multicenter study registering clinical data on patients with digestive HG-NEN. Treatment outcome in patients with advanced disease was compared after centralized pathological re-evaluation.

Results: 427 NEC and 117 NET G3 received palliative chemotherapy. Immediate progression rate was 41% and 24%, progression-free survival (PFS) 3.4 m and 7.4 m, overall survival (OS) 7.4 m and 21.8 m for NEC and NET G3, respectively. Significant factors for OS in NEC were performance status (PS), Ki-67 > 55%, alkaline phosphatase (ALP), age, sex and for PFS colorectal primary and PS. NEC Ki-67 < 55% had similar OS comparing treatment. Significant factors for OS in NET G3 were platinum-based treatment, PS, age and ALP, and for PFS platinum-based treatment.

Conclusions: Survival was shorter than expected in this unique population-based cohort of advanced digestive HG-NEN, likely due to inclusion of elderly and patients with poor PS. Several novel prognostic factors were identified for NEC and NET G3. An initial sub-effective platinum-based treatment for NET G3 could not be compensated by later-line treatment.

Several inflammation scores have shown association with survival outcomes for patients with neuroendocrine tumours (NET) treated with peptide receptor radionuclide therapy (PRRT). However, whether these scores add value to established prognostic factors remains unknown. In this retrospective, cohort study of 557 NET patients undergoing PRRT in a tertiary referral centre from 2005 to 2015, we examined inflammatory markers and scores previously associated with cancer outcomes, using Cox proportional hazard models and Akaike's information criterion. Lower albumin (hazard ratio [95% confidence interval], .91 [.87-.95] per unit), as well as higher C-reactive protein (CRP; 1.02 [1.01-1.02]), Glasgow Prognostic Score (GPS; 1 vs. 0: 1.67 [1.14-2.44], 2 vs. 0 3.60 [2.24-5.79]), CRP/albumin ratio (1.84 [1.43-2.37]) and platelet count (Plt) x CRP, but not white blood cell, neutrophil and thrombocyte counts or derived neutrophil to lymphocyte ratio (dNLR), were associated with shorter median overall survival (OS) in an adjusted analysis. The addition of parameters based on albumin and CRP, but not dNLR, to a base model including age, chromogranin A, the cell proliferation marker Ki-67, performance status, tumour site and previous treatments improved the predictive accuracy of the base model. In an exploratory analysis of patients with available erythrocyte sedimentation rate (ESR) and CRP, ESR emerged as the most powerful predictor. When added to a prognostic model for OS in NET patients treated with PRRT, most inflammation scores further improved the model. Albumin was the single marker adding most value to the set of established prognostic markers, whereas dNLR did not seem to improve the model's prognostic ability.

We aimed to assess the symptoms and impact on overall survival (OS) from bone metastases (BM) diagnosed on Gallium-68-labelled DOTA tyrosine octreotide positron emission tomography with computed tomography (⁶⁸Ga-DOTATOC-PET/CT) in patients with well-differentiated small intestinal neuroendocrine tumours (Si-NETs). Patients with well-differentiated Si-NETs, who underwent ⁶⁸Ga-DOTATOC-PET/CT between 2010 and 2023 at two tertiary referral centres in Sweden, were included. Their number of BM, ≤5 BM versus >5 BM, symptoms and need for analgesics were recorded. To further assess the impact of BM on OS, we used a control group of age- and sex-matched Si-NET patients with liver metastases (Stage IV disease) but without BM. The prevalence of BM in Si-NET patients was 23% (175/753); among these, complete clinical data were available in 138 patients. Synchronous BM were found in 33% (46/138). Sixty-one patients (44%) showed >5 BM at the time of BM detection. Fractures were diagnosed in 4% (n = 6) and 14% (n = 20) needed analgesics for BM-associated pain. In univariable analysis, patients with >5 BM experienced shorter OS from the time of BM detection compared to those with ≤5 BM (18 months vs. 75 months, p < .001). Among patients with Stage IV disease with and without BM, OS was shorter in patients with BM compared to patients with no BM (72 months vs. 288 months, p = .002). In multivariable analysis of patients with BM, higher Ki-67% (hazard ratio [HR] = 1.06, p = .007), older age (HR = 1.07, p < .01), presence of >5 BM (HR = 1.93, p = .021) and synchronous BM (HR = 2.14, p = .016) were identified as independent prognostic factors for shorter OS. In the matched cohort of patients with Stage IV disease with and without BM, presence of BM (HR = 1.94, p = .009), age at diagnosis of Stage IV (HR = 1.08, p < .001) and locoregional surgical resection (HR = 0.47, p = .015) were independent prognostic factors for survival. BM are detected in approximately 25% of Si-NET patients subjected to ⁶⁸Ga-DOTATOC-PET/CT. Pain occurs in approximately 14% and fractures in 4%. The presence of BM among Stage IV patients, the extent of bone disease (>5 BM) and synchronous BM are independent prognostic factors for shorter OS.