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There are currently no standard first-line treatment options for patients with higher grade 2–3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7–13·8) in the control group and 22·8 months (19·4–not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182–0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. Advanced Accelerator Applications, a Novartis Company.

The objective of this work was to establish the quantitative relationship between Lanreotide Autogel® (LAN) on serum chromogranin A (CgA) and progression-free survival (PFS) in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumors (GEP-NETs) through an integrated pharmacokinetic/pharmacodynamic (PK/PD) model. In CLARINET, a phase III, randomized, double-blind, placebo-controlled study, 204 patients received deep subcutaneous injections of LAN 120 mg (n = 101) or placebo (n = 103) every 4 weeks for 96 weeks. Data for 810 LAN and 1298 CgA serum samples (n = 632 placebo and n = 666 LAN) were used to develop a parametric time-to-event model to relate CgA levels and PFS (76 patients experienced disease progression: n = 49 placebo and n = 27 LAN). LAN serum profiles were described by a one-compartment disposition model. Absorption was characterized by two parallel pathways following first- and zero-order kinetics. As PFS data were considered informative dropouts, CgA and PFS responses were modeled jointly. The LAN-induced decrease in CgA levels was described by an inhibitory EMAX model. Patient age and target lesions at baseline were associated with an increment in baseline CgA. Weibull model distribution showed that decreases in CgA from baseline reduced the hazard of disease progression significantly (P < 0.001). Covariates of tumor location in the pancreas and tumor hepatic tumor load were associated with worse prognosis (P < 0.001). We established a semimechanistic PK/PD model to better understand the effect of LAN on a surrogate endpoint (serum CgA) and ultimately the clinical endpoint (PFS) in treatment-naive patients with nonfunctioning GEP-NETs.

Several studies have suggested that chemotherapy prolonged survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA); however, there is still no standard chemotherapy regimen. Here, we evaluated the efficacy and safety of a 5-fluorouracil (5-FU)/L-leucovorin (l-LV)/oxaliplatin (mFOLFOX6) protocol as a first-line therapy for patients with SBA. This was a multicenter, single-arm, open-label phase II study. Eligibility criteria included histologically confirmed adenocarcinoma, age 20–80 years, and an Eastern Cooperative Oncology Group performance status (PS) of 0–2. The primary endpoint was 1-year progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), overall survival (OS), overall PFS, and safety. Between April 2010 and November 2012, 24 patients were enrolled from 12 institutions. The median age of the patients was 63 years (range 31–79) and there was a male/female ratio of 18/6. The number of PS 0/1 patients was 17/7 and locally advanced/metastatic disease was seen in 2/22 patients, respectively. The primary tumor site was the duodenum in 14 patients (58%) and jejunum in 10 patients (42%). The median follow-up time was 14.7 months (3.7–40.3). The 1-year PFS was 23.3%. The ORR was 9/20 (45%). The median PFS and OS times were 5.9 months (95% confidence interval [CI] 3.0–10.2) and 17.3 months (95% CI 11.7–19.0), respectively. Major grade 3/4 toxicities were neutropenia (38%), anemia/peripheral neuropathy (25%), and stenosis (17%). There were no treatment-related deaths. Although the primary endpoint was not met, mFOLFOX6 showed effective and good tolerance as a first-line treatment for SBA.

First author Martyn Caplin (Royal Free Hospital, London, UK) said, \"The CLARINET study demonstrated not only significant anti-tumour effect of lanreotide autogel in both intestinal and pancreatic NET cohorts but also demonstrated impressive results in patients with grade 2 NETs and in patients who had more than 25% of their liver replaced by tumour metastases.\"

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1–2% of gastrointestinal tumours. We investigated the clinical characteristics, outcomes, and prognostic factors of primary SBA. Methods: We retrospectively analysed the characteristics and clinical courses of 205 SBA patients from 11 institutions in Japan between June 2002 and August 2013. Results: The primary tumour was in the duodenum and jejunum/ileum in 149 (72.7%) and 56 (27.3%) patients, respectively. Sixty-four patients (43.0%) with duodenal adenocarcinoma were asymptomatic and most cases were detected by oesophagogastroduodenoscopy (EGD), which was not specifically performed for the detection or surveillance of duodenal tumours. In contrast, 47 patients (83.9%) with jejunoileal carcinoma were symptomatic. The 3-year survival rate for stage 0/I, II, III, and IV cancers was 93.4%, 73.1%, 50.9%, and 15.1%, respectively. Multivariate analysis revealed performance status 3–4, high carcinoembryonic antigen, high lactate dehydrogenase (LDH), low albumin, symptomatic at diagnosis, and stage III/IV disease were independent factors for overall survival (OS). Ten patients (18.5%) with stage IV disease were treated with a combination of resection of primary tumour, local treatment of metastasis, and chemotherapy; this group had a median OS of 36.9 months. Conclusions: Although most SBA patients were diagnosed with symptomatic, advanced stage disease, some patients with duodenal carcinoma were detected in early stage by EGD. High LDH and symptomatic at diagnosis were identified as novel independent prognostic factors for OS. The prognosis of advanced SBA was poor, but combined modality therapy with local treatment of metastasis might prolong patient survival.

Background The diagnosis of neuroendocrine neoplasms (NENs) is often delayed. This first UK population-based epidemiological study of NENs compares outcomes with non-NENs to identify any inequalities. Methods Age-standardised incidence rate (ASR), 1-year overall survival, hazard ratios and standardised mortality rates (SMRs) were calculated for all malignant NENs diagnosed 2013–2015 from UK national Public Health records. Comparison with non-NENs assessed 1-year overall survival (1YS) and association between diagnosis at stage IV and morphology. Results A total of 15,222 NENs were identified, with an ASR (2013–2015 combined) of 8.6 per 100,000 (95% CI 8.5–8.7); 4.6 per 100 000 (95% CI, 4.5–4.7) for gastro-entero-pancreatic (GEP) NENs. The 1YS was 75% (95% CI, 73.9–75.4) varying significantly by sex. Site and morphology were prognostic. NENs (predominantly small cell carcinomas) in the oesophagus, bladder, prostate, and female reproductive organs had a poorer outcome and were three times more likely to be diagnosed at stage IV than non-NENs. Conclusion Advanced stage at diagnosis with significantly poorer outcomes of some NENs compared with non-NENs at the same anatomical site, highlight the need for improved access to specialist services and targeted service improvement.

The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m 2 /d iv on days 1–3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H 0 50%, H 1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile. Immune checkpoint inhibitors have been incorporated as the standard of care for some high-grade neuroendocrine neoplasms (NEN), but their efficacy in digestive NEN is still unclear. Here the authors report the results of a phase II trial of nivolumab (anti-PD1) in combination with platinum-doublet chemotherapy (carboplatin-etoposide) as first-line treatment in patients with unresectable or metastatic advanced grade 3 NENs of gastro-enteropancreatic or unknown origin.

Background Small intestinal neuroendocrine tumors (SI-NETs) are uncommon, with an annual incidence of about 1 per 100,000 individuals. The primary tumor (PT) is generally small, but nevertheless the majority of patients have mesenteric lymph node metastases and liver metastases at diagnosis. Our aim was to identify prognostic factors for survival and to evaluate outcome after surgery in SI-NET patients. Material and Methods We included 603 consecutive patients (325 men; age at diagnosis 63 ± 11 years [mean ± SD]) with histopathologically verified SI-NET, who were diagnosed between 1985 and 2010. Hospital charts were reviewed and were scrutinized for carcinoid heart disease (CHD), flush and/or diarrhea, proliferation by Ki-67 index, mesenteric lymph node metastases (m.lgllm), distant abdominal lymph node metastases (da.lgllm), liver tumor load (LTL), extra-abdominal metastases (EAM), locoregional resective surgery, as well as debulking of LTL, and adverse events after surgery. Results Median overall survival (OS) was 8.4 years; 5-year OS was 67%, and 5-year relative survival was 74%. Independent prognostic factors by univariate and multivariate analysis were age at diagnosis, CHD, m.lgllm, da.lgllm, LTL, EAM, peritoneal carcinomatosis (PC), and proliferation. Locoregional resective surgery was associated with increased survival on crude and multivariate analysis. The 30-day mortality in our institution after initial locoregional resective surgery was 0.5% (1/205). Conclusions For the first time, m.lgllm and da.lgllm, LTL, PC, and EAM are demonstrated to be independent prognostic factors by multivariate analysis. Locoregional removal of the PT/m.lgllm. was a positive prognostic factor by crude and adjusted analysis and may influence survival.

To investigate incidence, treatment patterns and outcomes of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) in the United States. The 2019 National Cancer Database was searched for adult GEP-NEN patients. Main outcomes included overall and site-specific incidence, treatment patterns, and overall survival (OS). Overall survival was evaluated using averaged Cox regression. 86,324 GEP-NEN patients were included (6.33% of all GEP malignancies). From 2004 to 2016, annual GEP-NEN cases increased ( n  = 4,010 to n  = 9,379), largely driven by low-stage, low-grade disease. Most patients received surgery, either alone (72.9%) or in combination with systemic therapy (4.9%). Longest overall survival (OS) was evident in patients with low stage and low grade GEP-NEN of the small intestine and rectum ( p  < 0.001). Patients undergoing surgical resection demonstrated longest OS. The addition of systemic therapy was most effective in high stage G3 NEN. Having higher income ( ≥ $63,333) and private insurance or Medicare, but not Medicaid, was associated with improved survival. GEP-NEN incidence increases, likely due to improved detection and diagnosis. Treatment patterns have evolved to follow the latest international guidelines and site-specific improvement in survival is noted. In addition to disease specific factors, insurance access and socioeconomic factors emerged as potential targets for improving outcomes.

Although the incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have been thought to have increased during the past decades, updated epidemiologic and survival data are lacking. To conduct an epidemiologic and survival analysis of the largest cohort of patients with GEP-NETs using the latest data and to establish a novel nomogram to predict the survival probability of individual patients with GEP-NETs. In this cohort study, 43 751 patients with GEP-NETs diagnosed from January 1, 1975, to December 31, 2015, were identified from the Surveillance, Epidemiology, and End Results Program. Associated data were used for epidemiologic and survival analysis, as well as the establishment and validation of a nomogram to predict the survival probability of individual patients with GEP-NETs. The study cutoff date was December 31, 2018. Statistical analysis was performed from February 1 to April 30, 2020. Incidence, factors associated with overall survival, and a nomogram model for patients with GEP-NETs. A total of 43 751 patients received a diagnosis of GEP-NETs from 1975 to 2015 (22 398 women [51.2%], 31 976 White patients [73.1%], 7097 Black patients [16.2%], 3207 Asian and Pacific Islander patients [7.3%], 270 American Indian and Alaska Native patients [0.6%], and 4546 patients of unknown race [10.4%]; mean [SD] age at diagnosis, 58 [15] years). The age-adjusted incidence rate of GEP-NETs increased 6.4-fold from 1975 to 2015 (annual percentage change [APC], 4.98; 95% CI, 4.75-5.20; P < .001). Furthermore, among site groups, the incidence of GEP-NETs in the rectum increased most significantly (APC, 6.43; 95% CI, 5.65-7.23; P < .001). As for stage and grade, the incidence increased the most in localized GEP-NETs (APC, 6.53; 95% CI, 6.08-6.97; P < .001) and G1 GEP-NETs (APC, 18.93; 95% CI, 17.44-20.43; P < .001). During the study period, the mean age at diagnosis for localized disease increased by 9.0 years (95% CI, 3.3-14.7 years; P = .002), which remained unchanged for regional and distant cases. On multivariable analyses, age, sex, marital status, and tumor size, grade, stage, and site were significantly associated with overall survival for patients with GEP-NETs (eg, patients with distant vs localized disease: hazard ratio, 10.32; 95% CI, 8.56-12.43; G4 vs G1 GEP-NET: hazard ratio, 6.37; 95% CI, 5.39-7.53). Furthermore, a nomogram comprising age, size, grade, stage, and site was established to predict the 3-year and 5-year survival probability, with the concordance indexes of 0.893 (95% CI, 0.883-0.903) for the internal validations and 0.880 (95% CI, 0.866-0.894) for the external validations. The receiver operating characteristic curve demonstrated that the nomogram exhibited better discrimination power than TNM classification (area under the curve for 3-year overall survival, 0.908 vs 0.795; for 5-year overall survival, 0.893 vs 0.791). In this study, the incidence and prevalence of GEP-NETs have continued to increase over 40 years, especially among patients with rectal GEP-NETs. In addition, this study suggests that a nomogram with 5 prognostic parameters may accurately quantify the risk of death among patients with GEP-NETs, indicating that it has satisfactory clinical practicality.