Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial.

BACKGROUND: There is no standard second-line treatment after platinum-etoposide chemotherapy for gastroenteropancreatic neuroendocrine carcinoma. We aimed to evaluate the efficacy of FOLFIRI plus bevacizumab, and FOLFIRI alone, in this setting. METHODS: We did a randomised, non-comparative, open-label, phase 2 trial (PRODIGE 41-BEVANEC) at 26 hospitals in France. We included patients aged 18 years or older with locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinoma or neuroendocrine carcinoma of unknown primary origin, documented progressive disease during or after first-line platinum-etoposide chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1; block size of three), without stratification, to receive FOLFIRI (irinotecan 180 mg/m2, calcium folinate 400 mg/m2 or levofolinate 200 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) plus bevacizumab 5 mg/kg or FOLFIRI alone, intravenously, every 2 weeks until disease progression or unacceptable toxicity. Neither patients nor investigators were masked to group assignment. The primary outcome was overall survival at 6 months after randomisation, evaluated in the modified intention-to-treat population (all enrolled and randomly assigned patients who received at least one cycle of FOLFIRI). This study is now complete and is registered with ClinicalTrials.gov, NCT02820857. FINDINGS: Between Sept 5, 2017, and Feb 8, 2022, 150 patients were assessed for eligibility and 133 were enrolled and randomly assigned: 65 to the FOLFIRI plus bevacizumab group and 68 to the FOLFIRI group. 126 patients (59 in the FOLFIRI plus bevacizumab group and 67 in the FOLFIRI group) received at least one cycle of FOLFIRI and were included in the modified intention-to-treat population, 83 (66%) of whom were male and 43 (34%) were female, and the median age of the patients was 67 years (IQR 58-73). The primary tumour location was colorectal in 38 (30%) of 126 patients, pancreatic in 34 (27%), gastro-oesophageal in 22 (17%), and unknown in 23 (18%). After a median follow-up of 25·7 months (95% CI 22·0-38·2), 6-month overall survival was 53% (80% CI 43-61) in the FOLFIRI plus bevacizumab group and 60% (51-68) in the FOLFIRI group. Grade 3-4 adverse events that occurred in at least 5% of patients were neutropenia (eight [14%] patients), diarrhoea (six [10%]), and asthenia (five [8%]) in the FOLFIRI plus bevacizumab group, and neutropenia (seven [10%]) in the FOLFIRI group. One treatment-related death (ischaemic stroke) occurred in the FOLFIRI plus bevacizumab group. INTERPRETATION: The addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma. FUNDING: French Ministry of Health and Roche SAS.

Molecular deciphering of primary liver neuroendocrine neoplasms confirms their distinct existence with foregut-like profile.

Isolated hepatic localizations of neuroendocrine tumors (NETs) are generally considered as metastatic NETs of unknown primary but could correspond to primary hepatic NETs (PHNETs), a poorly explored entity. We aimed to describe the clinicopathological and molecular features of PHNETs and compare them with other primary NETs. We assembled a retrospective cohort of patients managed for hepatic localization of NET without extra-hepatic primary tumor after exhaustive clinical, imaging, and immunohistochemical characterization. We performed whole-exome sequencing with mutational and copy number analysis. Transcriptomic profiles were compared with pancreatic (n = 31), small-bowel (n = 22), and lung (n = 15) NETs using principal component analysis, unsupervised clustering, and gene set enrichment analysis. Among 27 screened patients, 16 had PHNET (solitary tumor in 63%, median size 11 cm, G2 NETs in 81%) following clinical and pathological review. DNA analyses showed 'foregut-like' genomic profiles with frequent alterations in pathways of Fanconi DNA repair (75%), histone modifiers (58%), adherens junctions (58%), and cell cycle control (50%). The most frequently involved genes were KMT2A (58%), ATM (42%), CDH1, CDKN2C, FANCF, and MEN1 (33% each). Transcriptomic analyses showed that PHNETs clustered closer to foregut (pancreatic, lung) NETs than to midgut (small-bowel) NETs, while remaining a distinct entity with a specific profile. Assessment of potentially predictive biomarkers suggested efficacy of treatments usually active in foregut NETs. In conclusion, PHNETs display a foregut-like molecular profile distinct from other types of NETs, with recurrent molecular alterations. Upon exhaustive work-up to exclude an unrecognized primary tumor, PHNETs should not be considered metastatic NETs from an unknown primary. © 2022 The Pathological Society of Great Britain and Ireland.

Laparoscopic-assisted liver transplantation: A realistic perspective.

Laparoscopic approach was rarely described in recipients for liver transplantation (LT). We report the feasibility and safety of laparoscopic-assisted LT (LA-LT) in patients with unresectable liver metastases of neuroendocrine tumors. Total hepatectomy was performed laparoscopically with graft implantation through an upper midline incision. Liver grafts were retrieved from deceased donors. From July 2019 to July 2021, six patients (4 women, 2 men) underwent LA-LT. Median age and BMI were 46 (29-54) and 24 (19-35) kg/m2 , respectively. Implanted grafts were reduced (n = 3), full (n = 2), and a right split liver (n = 1). Median surgical time was 405 min (390-450) and median blood loss was 425 ml (250-600). Median cold and warm ischemia times were 438 min (360-575) and 35 min (30-40), respectively. Median anhepatic phase was 51 min (40-67) and midline incision was 14 cm (13-20) long. On postoperative day 5, median prothrombin index and serum bilirubin levels were 95% (70-117) and 11 (10-37) µmol/L, respectively. No Clavien-Dindo > III complications were encountered. Median hospital stay was 12 days (10-14). After a median follow-up of 8 (8-32) months, all patients were alive without tumor recurrence or adverse event. This preliminary series suggests that in selected patients, LA-LT is a safe and effective option.

Immunophenotypic and molecular characterization of pancreatic neuroendocrine tumors producing serotonin.

Serotonin producing pancreatic neuroendocrine tumors (SP-PanNET) account for 0.58-1.4% of all pancreatic neuroendocrine tumors (PanNET). They may present with atypical symptoms, such as acute pancreatitis and are often radiologically characterized by main pancreatic duct dilatation. SP-PanNET are well differentiated neuroendocrine tumors (NET) distinct from classical PanNET by atypical serotonin secretion and abundant dense stroma deposition, like serotonin producing ileal NET leading in some cases to difficulties to reliably distinguish SP-PanNET from ileal NET metastases. The biology and molecular profile of SP-PanNET remain poorly characterized and the cell of origin within the pancreas is unclear. To address these questions, we analyzed a large cohort of SP-PanNET by immunohistochemistry (n = 29; ATRX, DAXX, MENIN, Islet1, PAX6, PDX1, ARX, CDX2), whole genome copy number array (Oncoscan™) and a large NGS panel (NovoPM™) (n = 10), FISH (n = 13) and RNA sequencing (n = 24) together with 21 ileal NET and 29 nonfunctioning PanNET (NF-PanNET). These analyses revealed a unique genomic profile with frequent isolated loss of chromosome 1 (14 cases-61%) and few pathogenic mutations (KMT2C in 2 cases, ARID1A in 1 case). Unsupervised RNAseq-based clustering showed that SP-PanNET were closer to NF-PanNET than ileal NET with an exclusive beta cell-like signature. SP-PanNET showed TGF-ß pathway activation signatures associated with extracellular matrix remodeling and similar signature were reproduced in vitro when pancreatic stellate cells were exposed to serotonin. SP-PanNET immunohistochemical profile resemble that of ileal NET except for PDX1 and PAX6 expression to a lesser extend suggesting that these two markers may be useful to diagnose SP-PanNET. Taken together, this suggests that SP-PanNET are a very specific PanNET entity with a peculiar biology leading to the characteristic fibrotic aspect.

Oxaliplatin and 5-Fluorouracil in Advanced Well-Differentiated Digestive Neuroendocrine Tumors: A Multicenter National Retrospective Study from the French Group of Endocrine Tumors.

INTRODUCTION: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs); however, the available data are limited. Our aim was to assess the efficacy of FOLFOX (association of 5-fluorouracil with oxaliplatin) in a large series of patients with advanced digestive NETs. METHODS: All patients with advanced digestive well-differentiated NETs treated with at least 3 cycles of FOLFOX between January 2004 and December 2018 in 12 centers from the French Group of Endocrine Tumors were included. Tumor response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, progression free survival (PFS), and overall survival, as well as prognostic factors, were analyzed retrospectively. RESULTS: One hundred fifty-five patients were included. Primary tumor locations were pancreas (n = 89), small intestine (n = 40), unknown with no evidence for lung primary (n = 13), stomach (n = 7), and rectum (n = 6). Median Ki-67 was 10%, and 65% of the tumors were grade 2. The partial response rate was 30% for pancreatic NETs, 12.5% for small intestine NETs, 38.5% for unknown primary NETs, 14% for gastric NETs, and 17% for rectal NETs. Significant prognostic factors for poor PFS after FOLFOX were progressive disease at the beginning of treatment (hazard ratio [HR] = 1.83, p = 0.007), hepatic involvement superior to 50% (HR = 2.67, p = 0.0001), and rectal primary tumor location (HR = 2.6, p = 0.0036). Among pancreatic NETs, insulinomas had a better median PFS (22 months) than other pancreatic NETs (9 months, p = 0.026) and showed a high rate (8/9) of serum glucose normalization. CONCLUSIONS: FOLFOX shows a promising antitumor activity in advanced digestive NETs. Rapid symptomatic response is observed in metastatic insulinomas.

The long-term outcomes of laparoscopic versus open pancreatoduodenectomy for ampullary carcinoma showed similar survival: a case-matched comparative study.

BACKGROUND: Few studies have compared the oncological benefit of laparoscopic (LPD) and open pancreatoduodenectomy (OPD) for ampullary carcinoma. The aim of this study was to compare the oncological results of these two approaches. METHODS: Between 2011 and 2020, 103 patients who underwent PD for ampullary carcinoma, including 31 LPD and 72 OPD, were retrospectively analyzed. Patients were matched on a 1:2 basis for age, sex, body mass index, American Society of Anaesthesiologists score, and preoperative biliary drainage. Short- and long-term outcomes of LPD and OPD were compared. RESULTS: The 31 LPD were matched (1:2) to 62 OPD. LPD was associated with a shorter operative time (298 vs. 341 min, p = 0.02) than OPD and similar blood loss (361 vs. 341 mL, p = 0.747), but with more intra- and post-operative transfusions (29 vs. 8%, p = 0.008). There was no significant difference in postoperative mortality (6 vs. 2%), grades B/C postoperative pancreatic fistula (22 vs. 21%), delayed gastric emptying (23 vs. 35%), bleeding (22 vs. 11%), Clavien ≥ III morbidity (22 vs. 19%), or the length of hospital stay (26 vs. 21 days) between LPD and OPD, respectively, but there were more reinterventions (22 vs. 5%, p = 0.009). Pathological characteristics were similar for tumor size (21 vs. 22 mm), well differentiated tumors (41 vs. 38%), the number of harvested (23 vs. 26) or invaded lymph nodes (48 vs. 52%), R0 resection (84 vs. 90%), and other subtypes (T1/2, T3/4, phenotype). With a comparable mean follow-up (41 vs. 37 months, p = 0.59), there was no difference in 1-, 3-, and 5-year overall (p = 0.725) or recurrence-free survival (p = 0.155) which were (93, 74, 67% vs. 97, 79, 76%) and (85, 58, 58% vs. 90, 73, 73%), respectively. CONCLUSION: This study showed a similar long-term oncological results between LPD and OPD for ampullary carcinoma. However, the higher morbidity observed with LPD compared to OPD, restricting its use to experienced centers.

Efficacy and tolerance of gemcitabine and nab-paclitaxel in elderly patients with advanced pancreatic ductal adenocarcinoma.

BACKGROUND: The efficacy and safety of gemcitabine and nab-paclitaxel (GnP) among elderly patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. We aimed to evaluate the safety and efficacy of GnP in this setting. PATIENTS AND METHODS: We retrospectively included all consecutive patients aged ≥65 years with histologically proven PDAC who received at least one cycle of GnP (January 2014 to May 2018) in four academic centers. The primary endpoints were toxicity and overall survival (OS). Secondary endpoints were progression-free survival (PFS) and objective response rate. We compared patients aged ≥ or <75 years. RESULTS: The study included 127 patients; among them 42 (33.1%) were aged ≥ 75 years. Fifty-seven and seventy patients received GnP as the first-line and the second-line treatment or beyond, respectively. Sixty-seven patients had at least one grade 3/4 adverse event, the most frequent being neutropenia and peripheral neuropathy. No deaths were related to toxicity. OS (median, 8.0 months; 95% confidence interval (CI), 5.8-10.2) and PFS (median, 5.5 months; 95% CI, 4.8-6.2) were similar for patients aged <75 or ≥75 years in the whole cohort and among patients receiving GnP as the first-line treatment. Cephalic PDAC, liver metastases, hypoalbuminemia, and GnP received beyond the first-line were associated with a significantly shorter OS on the multivariate analysis. CONCLUSION: GnP is well tolerated and effective in elderly patients with advanced PDAC, even patients aged ≥75 years. The data from daily clinical practice are consistent with the results reported with first-line treatment and highlight the relevance of GnP administration in elderly patients.

Contribution of Immune-Mediated Paraneoplastic Syndromes to Neurological Manifestations of Neuroendocrine Tumours: A Retrospective Study.

INTRODUCTION: Neurological symptoms associated with neuroendocrine tumours (NETs) may be related to metastatic disease or paraneoplastic syndromes (PNSs); these last are often associated with autoantibodies targeting various onconeural antigens. To better characterize neurological PNSs related to NETs, we report the largest case-series study to date. METHODS: We retrospectively reviewed the charts of all patients diagnosed with NETs of the gastrointestinal tract who presented with neurological symptoms at either of 2 tertiary academic hospitals (Henri Mondor and Beaujon, France) between 1994 and 2016. All patients underwent extensive neurological tests including clinical, laboratory, and radiological investigations. The clinical response to immunomodulating agents was recorded. RESULTS: In the 13 identified patients, the most common presentations were peripheral neuropathy (46.2%) and encephalopathy (26.6%). Of the 6 (53.3%) patients whose serum anti-neuronal antibodies were assayed, 5 had high titres. Short-term oral corticosteroid and immunosuppressant drug therapy was given to 4 of these patients, of whom 3 had a clinical response and 1 no response. Repeated high-dose intravenous immunoglobulin therapy induced a complete clinical response in 1 patient. Encephalopathy resolved fully after hepatectomy or intrahepatic chemoembolization for liver metastases in another 2 patients. DISCUSSION: The neurological symptoms associated with NETs may be due in part to autoimmune PNS. Based on experience at our 2 centres, we estimate that autoimmune PNS occurs in about 1% of patients with NETs. Early symptom recognition allows the initiation of effective treatments including corticosteroids, immunosuppressive drugs, and/or intravenous immunoglobulins.

Prognostic impact of bone metastases detected by 18F-DOPA PET in patients with metastatic midgut neuroendocrine tumors.

OBJECTIVES: Bone metastases (BM) may influence negatively the prognosis of midgut neuroendocrine tumors (NET). The diagnostic sensitivity of 18F-DOPA PET for midgut NET and associated metastases is high. This study aimed to assess the prognostic impact of BM detected by 18F-DOPA PET in metastatic midgut NET. METHODS: All patients with a metastatic midgut NET, who underwent a 18F-DOPA PET between June 2011 and June 2018, were included. BM were defined following imaging criteria and were classified as poly-BM or oligo-BM, according to their number (< 5 or ≥ 5, respectively). The variables associated with the presence of BM were evaluated by logistic regression. The factors associated with overall survival were explored by Cox regression models. RESULTS: Among 155 patients included, 46 had BM (29.7%). A carcinoid syndrome (OR 2.96, p = 0.009) and ≥ 3 extra-skeletal metastatic organs (OR 4.99, p = 0.002) were independently associated with the presence of BM. BM were mainly osteoblastic (78%), rarely symptomatic (8.9%), and had a short-term therapeutic impact for 3 patients (6.5%). The presence of BM (HR 2.67, p = 0.034), older age (HR 1.07, p = 0.016), and higher Ki67 (HR 1.09, p = 0.025) were independent prognostic factors. Unlike poly-BM (HR 1.92, p = 0.007), oligo-BM was not a poor prognosis factor (HR 0.77, p = 0.699) compared to the group without BM. CONCLUSION: 18F-DOPA PET frequently detects BM in patients with metastatic midgut NET. BM have a negative prognostic impact, especially poly-BM. Conversely, oligo-BM do not influence the prognosis and may not impact therapeutic decisions. KEY POINTS: • 18F-DOPA PET detected bone metastases in 46 (29.7%) of 155 patients with metastatic midgut neuroendocrine tumors. • Bone metastases have a negative prognostic impact in metastatic midgut neuroendocrine tumors. • Bone oligo-metastases (< 5) do not influence the prognosis and may not impact therapeutic decisions.

Serotonin immunoreactive pancreatic neuroendocrine neoplasm associated with main pancreatic duct dilation: a recognizable entity with excellent long-term outcome.

OBJECTIVES: Dilatation of the main pancreatic duct (MPD) is rare in pancreatic neuroendocrine neoplasm (panNEN) and may be due to different mechanisms. We compared the imaging and pathological characteristics as well as the outcome after resection of positive (S+) and negative (S-) serotonin immunoreactive panNENs causing MPD dilatation. METHODS: This retrospective study included patients with panNEN, with MPD dilatation (≥ 4 mm) on preoperative CT/MRI and resected between 2005 and 2019. Clinical, radiological, and pathological features were compared between S+ and S- panNENs. Imaging features associated with S+ panNEN were identified using logistic regression analysis. The diagnostic performance of imaging for the differentiation of S+ and S- panNENs was assessed by ROC curve analysis. Recurrence-free survival (RFS) was compared between the two groups. RESULTS: The final population of 60 panNENs included 20/60 (33%) S+ panNENs. S+ panNENs were smaller (median 12.5 mm vs. 33 mm; p < 0.01), more frequently hyperattenuating/intense on portal venous phase at CT/MRI (95% vs. 25%, p < 0.01), and presented with more fibrotic stroma on pathology (60.7 ± 16% vs. 40.7 ± 12.8%; p < 0.01) than S- panNENs. Tumor size was the only imaging factor associated with S+ panNEN on multivariate analysis. A tumor size ≤ 20 mm had 95% sensitivity and 90% specificity for the diagnosis of S+ panNEN. Among 52 patients without synchronous liver metastases, recurrence occurred in 1/20 (5%) with S+ panNEN and 18/32 (56%) with S- panNEN (p < 0.01). Median RFS was not reached in S+ panNENs and was 31.3 months in S- panNENs (p < 0.01). CONCLUSIONS: In panNENs with MPD dilatation, serotonin positivity is associated with smaller size, extensive fibrotic stroma, and better long-term outcomes. KEY POINTS: • S+ panNENs showed a higher percentage of fibrotic stroma, higher microvessel density, and lower proliferation index (Ki-67) compared to S- panNENs. • Radiologically, S+ panNENs causing dilatation of the MPD were characterized by a small size (< = 20 mm) and a persistent enhancement on portal phase on both CT and MRI. • Patients with S+ panNENs presented with longer RFS when compared to those with S- panNENs.

O-positive blood type is associated with prolonged recurrence-free survival following curative resection of pancreatic neuroendocrine tumors.

BACKGROUND: The ABO blood group may influence the development and progression of cancer. In particular, the prognosis of patients with blood type O is better for pancreatic adenocarcinoma, although this has not been extensively explored in pancreatic neuroendocrine tumors (PanNET). OBJECTIVE: To assess the influence of the ABO and Rhesus blood types on the risk of recurrence in patients who underwent curative intent PanNET surgical resection. METHODS: All consecutive patients operated on for well-differentiated panNET in an expert center from 2003 to 2018 were retrospectively included. Blood group, Rhesus system, demographic and clinical data were collected. The primary endpoint was recurrence free survival (RFS). Factors associated with RFS were explored using Cox proportional hazard models. RESULTS: Overall, 300 patients (male 43%) were included, median age 54 years old (IQR 45-64). The ABO blood group distribution was similar to that of the French population. There was no association between blood group and tumor features. The median postoperative follow-up was 43.9 months (17.0-77.8). The 5- and 10-year RFS rates were 85 ± 4% and 71 ± 13% in O RhD + patients, versus 72 ± 4% and 63 ± 6% otherwise, respectively (p = 0.035). The O RhD + blood group was associated with a decreased risk of recurrence (HR 0.34, 95% CI [0.15-0.75]), p = 0.007 in multivariable analysis adjusted for age, ki67, functioning syndrome, resection margins, tumor size, lymph node status, oncogenetic syndrome. CONCLUSIONS: After curative-intent surgical resection for PanNET, patients with a non-O RhD + blood group may have an increased risk of recurrence and could benefit from closer follow-up.

Temozolomide Alone or Combined with Capecitabine for the Treatment of Advanced Pancreatic Neuroendocrine Tumor.

BACKGROUND: The combination of capecitabine (CAP) with temozolomide (TEM) chemotherapy in advanced pancreatic neuroendocrine tumors (PanNET) relies on limited evidence. We compared TEM-CAP to TEM alone in patients with advanced PanNET. METHODS: Consecutive patients with advanced PanNET treated with TEM or TEM-CAP between 2004 and 2017 in three expert centers were included. Progression-free survival (PFS), tolerance, tumor response, and overall survival were compared between the two groups. Propensity-based analyses were performed to reduce confounding bias due to the nonrandomized setting. RESULTS: TEM and TEM-CAP were administered to 38 patients and 100 patients, respectively, with a median age of 58 years. The patients in the TEM group more often had hormonal syndromes (p = 0.03), a longer median delay to diagnosis (p = 0.001), and a higher number of pretreatment lines (p < 0.001). The performance status was 0 in 58% versus 65% of the patients, and tumor's median Ki-67 index was 8% versus 11%, respectively. Tolerance was similar, except that there were more cases of asthenia in the TEM group (p = 0.017) and more cases of hand-foot syndrome in the TEM-CAP group (p = 0.025). The objective response rate was 34% versus 51% (p = 0.088). The raw median PFS was similar with TEM and with TEM-CAP (21.4 vs. 19.8 months, p = 0.84). Although CAP tended to decrease the risk of progression in Cox multivariate analysis (HR 0.65, p = 0.12), it had no effect after adjustment for the propensity score (HR 1.06, p = 0.80). CONCLUSIONS: TEM-CAP might not prolong PFS but might achieve a higher response rate than TEM alone. Hence, TEM-CAP might be preferred when tumor shrinkage is the main therapeutic objective. Otherwise, TEM might be adequate for patients with an impaired performance status or in case of extrahepatic metastases.

The Postoperative Occurrence or Worsening of Diabetes Mellitus May Increase the Risk of Recurrence in Resected Pancreatic Neuroendocrine Tumors.

INTRODUCTION: The goal of this retrospective study was to investigate the potential link between diabetes mellitus (DM) and the recurrence of pancreatic neuroendocrine tumors (PanNET) following curative intent surgery. METHODS: We included patients who underwent surgical resection of nonmetastatic well-differentiated PanNET. Exacerbation of DM was defined as the postoperative occurrence of DM or worsening of preexisting DM. We explored the variables associated with PanNET recurrence-free survival (RFS). RFS was compared in a subset of patients with and without DM operated on by anatomical resection, after matching for the main prognostic factors. The impact of antidiabetic therapy on RFS was assessed. RESULTS: A total of 268 patients (median age 54.7, 40% men) were included. Most PanNET were sporadic (85%), G1 (61%), pT1/pT2 (79%), and pN0 (76%). Postoperative DM exacerbation occurred in 38 patients (14%), including 27 with new-onset DM. On multivariable analysis, DM exacerbation was independently associated with an increased risk of PanNET recurrence (HR 2.35, 95% CI [1.24-4.47], p = 0.009) after adjustment for age, multiplicity of tumors, grade, pT, and pN stages. Similar results were found when 27 patients with and 48 patients without DM exacerbation, matched for grade, pT stage and pN stage, were compared (HR 3.03, 95% CI [1.05-8.77], p = 0.032). The postoperative use of metformin tended to decrease the risk of recurrence (HR 0.59, 95% CI 0.24-1.47, p = 0.26). CONCLUSION: Patients with postoperative DM exacerbation may have an increased risk of PanNET recurrence. Closer follow-up might be beneficial in these patients. The protective role of metformin should be further explored.

Chemotherapy in Resected Neuroendocrine Carcinomas of the Digestive Tract: A National Study from the French Group of Endocrine Tumours.

BACKGROUND: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy. OBJECTIVES: We aimed to evaluate the effect of neoadjuvant +/- adjuvant and adjuvant therapy in this indication. METHODS: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity. RESULTS: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/- adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death. CONCLUSIONS: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results.

Correction to: Prediction of pancreatic neuroendocrine tumour grade with MR imaging features: added value of diffusion-weighted imaging.

The original version of this article, published on 19 August 2016, unfortunately contained a mistake.

How Does Chemoradiotherapy Following Induction FOLFIRINOX Improve the Results in Resected Borderline or Locally Advanced Pancreatic Adenocarcinoma? An AGEO-FRENCH Multicentric Cohort.

BACKGROUND: Patients with borderline (BR) or locally advanced (LA) pancreatic adenocarcinoma (PAC) are often treated with induction FOLFIRINOX (FLX). However, the role of additional preoperative chemoradiotherapy (CRT) is controversial. The aim of this study is to evaluate its impact in patients who underwent resection after induction FLX. PATIENTS AND METHODS: Retrospective analysis of prospective consecutive surgical BR or LA PAC patients after induction FLX in 23 French centers between November 2010 and December 2015, treated with or without preoperative additional CRT (FLX vs FLX + CRT groups). RESULTS: Two hundred three patients were included (106 BR, 97 LA PAC). Median number of FLX cycles was 6 (range 1-30); 50% (n = 102) of patients received additional CRT. Median duration between diagnosis and surgery was 5.4 and 8.7 months (P = 0.001) in the FLX and FLX + CRT group, respectively. The 90-day mortality, major complications, and pancreatic fistula rates were 4.4%, 17.7%, and 5.4%, respectively. After 45.1 months follow-up, overall survival (OS) and disease-free survival were 45.4 months and 16.2 months, respectively. Patients with additional CRT had higher R0 resection rate (89.2% vs 76.3%; P = 0.017), ypN0 rate (76.2% vs 48.5%; P < 0.001), and higher rate of pathologic major response (33.3% vs 12.9%; P = 0.001). In the FLX + CRT group, patients had lower rate of locoregional relapse (28.3% vs 50.7%; P = 0.004). Patients with additional CRT had longer OS than those receiving FLX alone (57.8 vs 35.5 months; P = 0.007). CONCLUSIONS: Pathological results and survival data argue for interest in additional CRT. Prospective studies on an intention-to-treat basis are needed to confirm these results.

Comparison of Temozolomide-Capecitabine to 5-Fluorouracile-Dacarbazine in 247 Patients with Advanced Digestive Neuroendocrine Tumors Using Propensity Score Analyses.

INTRODUCTION: Although chemotherapy combining 5-fluorouracil (5FU)-dacarbazine (DTIC) or temozolomide (TEM)-capecitabine (CAP) is extensively used in patients with neuroendocrine tumors (NET), they were never compared. We compared their tolerance and efficacy in advanced NET. METHODS: We evaluated the records of consecutive patients with pancreatic or small-intestine advanced NET who received 5FU-DTIC or TEM-CAP between July 2004 and December 2017 in 5 French centers. Tolerance, tumor response and progression-free survival (PFS) were compared. Factors associated with PFS were analyzed using Cox multivariate regression model. To reduce the confounding bias of the nonrandomized design, PFS was compared using propensity score analyses. RESULTS: Ninety-four (5FU-DTIC) patients and 153 (TEM-CAP) patients were included. Pancreatic NET represented 82.3% of cases and 17.1, 61.8 and 10.9% of patients had G1, G2 or G3 NET respectively. Progression at baseline was reported in 92.7% of patients with available data. Grades 3-4 adverse events occurred in 24.7 and 8.5% of TEM-CAP and 5FU-DTIC patients respectively (p = 0.002). The overall response rate was 38.3 and 39.2% respectively (p = 0.596). Median PFS on raw analysis was similar to 5FU-DTIC and TEM-CAP (13.9 vs. 18.3 months, respectively p = 0.86). TEM-CAP was associated with an increased risk of progression on the raw multivariate analysis (hazard ratio [HR] 1.90, 95% CI [1.32-2.73], p = 0.001) and when adjusted on propensity score (HR 1.65, 95% CI [1.18-2.31], p = 0.004). CONCLUSION: PFS may be longer with 5FU-DTIC than TEM-CAP in patients with advanced NET. Although patients often prefer oral chemotherapy, 5FU-DTIC is a relevant alternative. A randomized comparison is needed to confirm these results.

18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation.

BACKGROUND: 18F-FDG-PET scan positivity correlates with poor prognosis in neuroendocrine neoplasms (NEN). Glucose transporter 1 (GLUT1) and carbonic anhydrase 9 (CA9) are markers of aggressiveness in tumors. Together with von Hippel-Lindau protein (pVHL), they are involved in tumor cell metabolism via the hypoxia-inducible factor signaling pathway. The aim of this study was to compare, in a series of well-differentiated neuroendocrine tumors (NET), the 18F-FDG uptake and expression of the proliferation markers Ki-67, GLUT1, CA9, and pVHL. PATIENTS AND METHODS: This retrospective study included 27 patients with well-differentiated NET. 18F-FDG-PET images were evaluated by the maximum standardized uptake value (SUVmax). GLUT1, CA9, and pVHL were analyzed by immunohistochemistry. RESULTS: The NET were of pancreatic (n = 19), midgut (n = 4), duodenal (n = 1), esophageal (n = 1), rectal (n = 1), and pulmonary (n = 1) origin. Eight, 11, and 8 tumors were grade 1, 2, and 3, respectively. The mean/median Ki-67 index was 15/10% (1-60). The mean/median SUVmax was 6.2/5.2 (1.4-18.7). SUVmax correlated with greater tumor size (p = 0.03), higher expression of Ki-67 (p = 0.04), and lower expression of pVHL (p = 0.008). In the group of 16 NET with a low proliferative index (Ki-67 index <10%), 5/6 (83%) of the tumors with a high SUVmax had decreased pVHL expression (p = 0.0013). CONCLUSION: This study confirms that 18F-FDG-PET uptake correlates with both tumor size and proliferation in well-differentiated NET, and it highlights a subset of low-grade but 18F-FDG-PET-positive NET related to sporadic inactivation of the VHL pathway.

Chemotherapy for Well-Differentiated Pancreatic Neuroendocrine Tumours with a Ki-67 Index ≥10%: Is There a More Effective Antitumour Regimen? A Retrospective Multicentre Study of the French Group of Endocrine Tumours (GTE).

BACKGROUND: The best chemotherapy regimen for well- differentiated pancreatic neuroendocrine tumours (pNETs) with a Ki-67 index ≥10% is still debated. We evaluated the antitumour efficacy of various first-line chemotherapy regimens (streptozocin based, platinum based, or dacarbazine/temozolomide based) in this situation. METHODS: In this retrospective multicentre study of the French Group of Endocrine Tumours (GTE), we recruited consecutive patients with advanced well-differentiated pNETs and a Ki-67 index ≥10% receiving chemotherapy between 2000 and 2012. The primary endpoint was progression-free survival (PFS) according to RECIST. RESULTS: Seventy-four patients (42 men, median age 55.5 years) were enrolled from 10 centres. Fifty-one patients (69%) had grade 2 NET and 61 (82%) were stage IV. Median overall survival was 36.3 months. Forty-four patients (59%) received streptozocin-based, 18 (24%) platinum-based, and 12 (16%) dacarbazine/temozolomide-based chemotherapy regimens. These 3 groups were similar regarding age, functioning tumours, grade, the number of metastatic sites, and surgery for primary tumours, but not regarding surgery for metastases and time since diagnosis. Grade 3 NET (HR 2.15, 95% CI: 1.18-3.92, p = 0.012) and age above 55 years (HR 1.84, 95% CI: 1.06-3.18, p = 0.030) were associated with shorter median PFS in the multivariate analyses. Compared to streptozocin-based chemotherapy, no difference was found in terms of PFS for the platinum-based or for the dacarbazine/temozolomide-based chemotherapy regimen: median PFS was 7.2, 7.5, and 7.2 months, respectively (p = 0.51). CONCLUSIONS: Patients with intermediate or highly proliferative well-differentiated pNETs may benefit from 1 of the 3 chemotherapy regimens. Increased age and grade 3 were associated with shorter median PFS. Randomised studies searching for response predictors and the best efficacy-tolerance ratio are required to personalise the strategy.

Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms.

BACKGROUND/AIMS: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3. METHODS: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRß, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1. RESULTS: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89-0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET. CONCLUSION: Sunitinib showed evidence of activity in patients with GEPNEN-G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3.