Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited.
We conducted a ...randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index on staining for the Ki-67 antigen of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel known in the United States as Depot, Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety.
Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval CI, 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group).
Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).
In 2010, the World Health Organization (WHO) classification of neuroendocrine neoplasms was reviewed and validated the crucial role of the proliferative rate. According to the WHO classification ...2010, gastroenteropancreatic neuroendocrine neoplasms are classified as well‐differentiated neuroendocrine tumors (NETs) of grade 1 or 2 in up to 84%, or poorly differentiated neuroendocrine carcinomas in 6%–8%. Neuroendocrine carcinomas are of grade G. Recently, a proportion of neuroendocrine tumors presenting a number of mitoses or a Ki‐67 index higher than 20% and a well‐differentiated morphology have been identified, calling for a new category, well‐differentiated grade 3 NET (NET G‐3). Studies that have reported the characteristics of neuroendocrine neoplasms have identified more well‐differentiated NET G‐3 than neuroendocrine carcinomas. The main localizations of NET G‐3 are the pancreas, stomach, and colon. Treatment for NET G‐3 is not standardized and is balanced between G‐1/2 neuroendocrine tumor and neuroendocrine carcinoma treatments. In nonmetastatic neuroendocrine tumors, the European and American guidelines recommended a surgical resection for localized neuroendocrine neoplasm, irrespective of the tumor grading. In NET G‐3, chemotherapy is the benchmark if the main treatment goal is reduction of the tumor mass, particularly if it would allow a secondary surgery. In the present work, we review the epidemiology and make recommendations for the management of NET G‐3.
Implications for Practice:
Neuroendocrine tumors presenting a number of mitoses or a Ki‐67 index higher than 20% and a well‐differentiated morphology have been identified and named well‐differentiated grade 3 neuroendocrine tumors (NET G‐3). The main localizations of NET G‐3 are the pancreas, stomach, and colon. The prognosis is worse than that for NET G‐2. In nonmetastatic NET G‐3, surgery appeared to be the first option. The chemotherapy regimen in pancreatic NET G‐3 should be in line with that implemented in NET G‐1/2 when the Ki‐67 index is below 55% and should be in line with that implemented for neuroendocrine carcinoma when Ki‐67 is above 55%.
摘要
世界卫生组织(WHO)在2010年对神经内分泌肿瘤的分级进行了审查, 并确认了增殖率具有至关重要的作用。根据WHO分级2010版, 胃肠胰神经内分泌肿瘤可分为: 1级或2级高分化神经内分泌瘤(NET, 多达84%的患者为这一类型), 或者低分化神经内分泌癌(见于6%∼8%的患者)。神经内分泌癌为3级。近期研究确认了一部分出现大量有丝分裂或Ki‐67指数高于20%, 且具有高分化形态学的神经内分泌瘤, 称为3级NET(NET G3)。有研究报告了神经内分泌肿瘤的特征, 发现NET G3分化要好于神经内分泌癌。NET G3主要见于胰腺、胃和结肠。NET G3目前尚无标准治疗, 其治疗方案与NET G1/2或神经内分泌癌均有所区别。对于非转移性NET, 欧洲和美国的指南都建议无论肿瘤分级如何, 均手术切除局部NET病灶。对于NET G3, 如果治疗的主要目的是减小肿瘤体积, 尤其是意图后续手术的, 则应进行化疗。本文回顾了NET G3的流行病学, 并就其治疗管理给出了建议。The Oncologist 2016;21:1191–1199
对临床实践的提示:目前已鉴别出一种有大量有丝分裂或Ki‐67指数>20%, 且形态学分化良好的神经内分泌瘤, 命名为高分化3级神经内分泌瘤(NET G3)。NET G3主要位于胰腺、胃和结肠。NET G3预后差于NET G2。对于非转移性NET G3, 手术看来是治疗的首选措施。对于胰腺NET G3, Ki‐67<55%时化疗方案应该与NET G1/2一致, Ki‐67>55%时应与神经内分泌癌的化疗方案一致。
Neuroendocrine tumors presenting a number of mitoses or a Ki‐67 index higher than 20% and a well‐differentiated morphology have been identified and named well‐differentiated grade 3 neuroendocrine tumors (NET G‐3). The chemotherapy regimen in pancreatic NET G‐3 should be in line with that implemented in NET G‐1/2 when the Ki‐67 index is below 55% and as for the neuroendocrine carcinoma chemotherapy regimen when Ki‐67 is above 55%.
Abstract Background Although laparoscopic pancreatic resection (LPR) has become a routine, large single center series are still lacking. Our aim was to analyze the results of a large European single ...center series of LPR. Study Design Between January 2008 and September 2015, 300 LPR were performed and studied prospectively including 165 (55%) distal pancreatectomies, 68 (23%) pancreatoduodenectomies (PD), 30 (10%) enucleations, 35 (11%) central pancreatectomies and 2 (1%) total pancreatectomies. Results Mean age was 54 ± 15.4 years old (17-87) and most patients were women (58%). LPR was performed for malignancy (46%), low potential malignant (44%) or benign (10%) diseases. The mean operative duration was 211 ± 102 min (30-540) and 351± 59 (240-540) min for PD, and decreased with the learning curve. Mean blood loss was 229 ±269 ml (0-1500) and 13 patients (4%) were transfused. Conversion was required in 12 patients (4%), and only 5 in the last 250 patients (2% vs 14%, P<0.001). Mortality occurred in 4 (1.3%) patients and only after PD (5.8%). Common complications were pancreatic fistula (n=124, 41%), bleeding (n=35, 12%) and reoperation (n=28, 9%). The postoperative outcome was less favorable in procedures with a reconstruction phase (n=105) than in those without (n=195) with increased mortality (3.8% vs 0%, p=0.04), overall morbidity (76% vs % 52%, p<0.001) and mean hospital stay (26 ±15vs 16±10 days, p<0.001). Conclusions LPR without a reconstruction phase has an excellent outcome. LPR with a reconstruction phase, especially PD, has a less favorable outcome and further randomized studies are required to conclude on the safety and benefits of this approach.
Background Pancreatic fistula (PF) after pancreatoduodenectomy (PD) remains a challenging problem. The only commonly accepted risk factor is the soft consistency of the pancreatic remnant. Methods In ...all, 100 consecutive patients underwent PD. All data, including commonly accepted risk factors for PF and PF defined according to the International Study Group of Pancreatic Fistula, were collected prospectively. On the pancreatic margin, a score of fibrosis and a score of fatty infiltration were assessed by a pathologist blinded to the postoperative course. Results PF occurred in 31% of patients. In univariate analysis, male sex, age greater than 58 years, body mass index (BMI) ≥25 kg/m2 , pre-operative high blood pressure, operation for nonintraductal papillary and mucinous neoplasm (IPMN) disease and for ampullary carcinoma, operative time, blood loss, soft consistency of the pancreatic remnant, absence of pancreatic fibrosis, and presence of fatty infiltration of the pancreas were associated with a greater risk of PF. In a multivariate analysis, only BMI ≥25kg/m2 , absence of pancreatic fibrosis, and presence of fatty pancreas were significant predictors of PF. A score based on the number of risk factors present divided the patient population into 4 subgroups carrying a risk of PF that ranged from 7% (no risk factor) to 78% (3 risk factors) and from 0% to 81%, taking into account only symptomatic PF (grade B and C). Conclusion The presence of an increased BMI, the presence of fatty pancreas, and the absence of pancreatic fibrosis as risk factors of PF allows a more precise and objective prediction of PF than the consistency of pancreatic remnant alone. A predictive score based on these 3 factors could help to tailor preventive measures.
The roles of intravisceral and subcutaneous fat are unknown, and the prevalence of precancerous lesions in obese patients was never evaluated. This study aims to assess the frequency and severity of ...pancreatic intraepithelial neoplasia (PanIN) and to correlate pathologic findings with metabolic abnormalities, type of fat, and fatty pancreatic infiltration.
Normal pancreatic tissue from surgical specimens was analyzed. Fatty infiltration and fibrosis in intra- and extralobular locations and PanIN lesions were assessed. General characteristics were collected: body mass index (BMI), diabetes, and tobacco intake. Liver steatosis and subcutaneous and intravisceral fat were assessed by CT scan (ImageJ software).
Of note, 110 patients were included median age, 53.8 (17-85) years. Arterial hypertension, diabetes, and tobacco intake were found in 19%, 9%, and 23%, respectively. Median BMI was 24 (16-37; BMI < 25: 45%, 25 ≤ 30: 24%, ≥30: 11%). Overall, PanIN lesions were found in 65% (type I, II, and III PanIN in 62%, 38%, and 1%, respectively). Fibrosis and fatty pancreas (intra- and extralobular locations) were found in 1% and 24% and in 30% and 51%, respectively. A correlation was observed between PanIN lesions and fatty pancreas extralobular (0.01) and intralobular (<0.0001), intralobular fibrosis (0.003), high BMI (P = 0.02), and subcutaneous (P = 0.02) and intravisceral fat (P = 0.02). The number of PanIN lesions was correlated with intravisceral fat (r = 0.22, P = 0.04), but not with subcutaneous fat (r = 0.14, P = 0.22). In multivariate analysis, PanIN lesions were associated with intralobular fibrosis OR, 5.61; 95% confidence interval (CI), 1.18-42.99 and intralobular fat (OR, 17.86; 95% CI, 4.935-88.12).
Obesity (especially android obesity) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions.
Background Laparoscopic pancreaticoduodenectomy (LPD) is a difficult procedure that has become increasingly popular. Nevertheless, comparative data on outcomes remain limited. Our aim was to compare ...the outcomes of LPD and open pancreaticoduodenectomy (OPD). Study Design Between April 2011 and April 2014, 46 LPD were performed and compared with 46 OPD, which theoretically can be done by the laparoscopic approach. Patients were also matched for demographic data, associated comorbidities, and underlying disease. Patient demographics and perioperative and postoperative outcomes were studied from our single center prospective database. Results Lower BMI (23 vs 27 kg/m2 , p < 0.001) and a soft pancreas (57% vs 47%, p = 0.38) were observed in patients with LPD, but there were no differences in associated comorbidities or underlying disease. Surgery lasted longer in the LPD group (342 vs 264 minutes, p < 0.001). One death occurred in the LPD group (2.1% vs 0%, p = 0.28) and severe morbidity was higher (28% vs 20%, p = 0.32) in LPD due to grade C pancreatic fistula (PF) (24% vs 6%, p = 0.007), bleeding (24% vs 7%, p = 0.02), and revision surgery (24% vs 11%, p = 0.09). Pathologic examination for malignant diseases did not identify any differences between the LPD and OPD as far as size (2.51 vs 2.82 cm, p = 0.27), number of harvested (20 vs 23, p = 0.62) or invaded (2.4 vs 2, p = 0.22) lymph nodes, or R0 resection (80% vs 80%; p = 1). Hospital stays were similar (25 vs 23 days, p = 0.59). There was no difference in outcomes between approaches in patients at a lower risk of PF. Conclusions This study found that LPD is associated with higher morbidity, mainly due to more severe PF. Laparoscopic pancreaticoduodenectomy should be considered only in the subgroup of patients with a low risk of PF.
The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.
We conducted a multinational, ...randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.
The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval CI, 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.
Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).
Nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs) are often indolent neoplasms without lymph node (LN) metastasis at diagnosis. Therefore, in patients with low risk of LN metastasis, the ...extent of surgery and lymphadenectomy could be limited and follow-up adjusted to the very low risk of relapse.
To construct a predicting model to assess the risk of pN+ prior to surgical resection for NF-PanNETs using preoperative retrievable variables.
Retrospective review using multiple logistic regression analysis to construct predictive model of pN+ based on preoperatively available data.
The combined prospective databases of the Surgical Departments of the University of Verona, Verona, Italy, and Beaujon Hospital, Clichy, France, were queried for clinical and pathological data.
All patients with resected (R0 or R1), pathologically confirmed NF-PanNETs between January 1, 1993 and December 31, 2009.
Risk of lymph node metastases in patients with pancreatic neuroendocrine tumors.
Among 181 patients, nodal metastases were reported in 55 patients (30%) and were associated with decreased 5-year disease-free survival (70% vs 97%, P < .001). Multivariable analysis showed that independent factors associated with nodal metastasis were radiological nodal status (rN) (odds ratio OR, 5.58; P < .001) and tumor grade (NET-G2 vs NET-G1: OR, 4.87; P < .001) (first model). When the tumor grade was excluded, rN (OR, 4.73; P = .001) and radiological tumor size larger than 4 cm (OR, 2.67; P = .03) were independent predictors of nodal metastasis (second model). The area under the receiver operating characteristic curve for the first and second models were 80% and 74%, respectively.
Patients with NF-PanNET-G1 have a very low risk of pN+ in the absence of radiological signs of node involvement. When preoperative grading assessment is not achieved, the radiological size of the lesion is a powerful alternative predictor of pN+. The risk of pathological nodal involvement in patients with NF-PanNETs can be accurately estimated by a clinical predictive model.
Context:
Asymptomatic sporadic nonfunctioning, well-differentiated pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed, and their management is controversial because of their ...overall good but heterogeneous prognosis.
Objective:
The objective of the study was to assess the natural history of asymptomatic sporadic NF-PNETs smaller than 2 cm in size and the risk-benefit balance of nonoperative management.
Experimental Design:
From January 2000 to June 2011, 46 patients with proven asymptomatic sporadic NF-PNETs smaller than 2 cm in size were followed up for at least 18 months with serial imaging in tertiary referral centers.
Results:
Patients were mainly female (65%), with a median age of 60 years. Tumors were mainly located in the pancreatic head (52%), with a median lesion size of 13 mm (range 9–15). After a median follow-up of 34 months (range 24–52) and an average of four (range 3–6) serial imaging sessions, distant or nodal metastases appeared on the imaging in none of the patients. In six patients (13%), a 20% or greater increase in size was observed. Overall median tumor growth was 0.12 mm per year, and neither patients nor tumor characteristics were found to be significant predictors of tumor growth. Overall, eight patients (17%) underwent surgery after a median time from initial evaluation of 41 months (range 27–58); all resected lesions were European Neuroendocrine Tumor Society T stage 1 (n = 7) or 2 (n = 1), grade 1, node negative, with neither vascular nor peripancreatic fat invasion.
Conclusions:
In selected patients, nonoperative management of asymptomatic sporadic NF-PNETs smaller than 2 cm in size is safe. Larger and prospective multicentric studies with long-term follow-up are now needed to validate this wait-and-see policy.
This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org).
All French medical ...societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019.
The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET.
These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
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