Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs

Basically, pancreatic neuroendocrine tumor (PNET) should be treated surgically; however, in unresectable cases, a treatment that aims to improve the prognosis by inhibiting the growth of the tumor and control the clinical symptoms becomes necessary. In the case of functional tumors, the quality of life of patients is decreased by not only the symptoms with tumor invasion and/or metastasis but also by the symptoms of hormone excess. The efficacy of somatostatin analogs against the latter has been previously reported, and their sustained release formulations have been developed. Somatostatin analogs are recommended to treat the endocrine symptoms of functional PNET; however, in case they can cause hypoglycemia in patients with insulinoma. On the other hand, results from the PROMID study demonstrated a tumor‐stabilizing effect when octreotide LAR (long acting repeatable) was used to treat patients with advanced midgut NET; however, there has been no consensus regarding its antitumor effect for PNET. Additionally, a recent result from the CLARINET study suggests that lanreotide autogel has an antitumor effect against nonfunctional NET including PNET. Further clinical study results are awaited.     

Treatment of neuroendocrine tumors with somatostatin analogs

Neuroendocrine tumors constitute a group of hormone producing tumors originating from neuroendocrine cells in different organs. Most tumors have a low proliferation index measured by Ki67 and the progression of the tumor is slow. However, many patients suffer from endocrine symptoms induced by the hormones produced and released by the tumor cells. For some patients these symptoms can be life- threatening as in midgut carcinoid patients suffering from carcinoid crises with extensive flushes and hypotension or in patients with severe diarrhea induced by tumors producing vasointestinal polypeptide. In many other patients the hormone-induced symptoms interfere with the ability to carry out ordinary daily activities. The introduction of somatostatin analogs in the treatment of these hormone related symptoms has made it possible to control most of them and has added significantly to the quality of life for this group of patients. Unfortunately, the clinical inhibitory effect on tumor growth has not been very good with only 5–10% of the patients showing an objective response. However, stabilization of tumor growth may be achieved in a significant number of patients. In the future, the hope is that development of new somatostatin analogs with broader receptor-binding profiles will give us new analogs which are more efficient with regard to their antiproliferative effect. This possibility will be studied in future trials.     

Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors

Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuro-endocrine tumors (NETs). In recent years, accumul ating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carci-noid and pancreatic endocrine tumors. A phase Ⅲ, ran-domized, placebo-controlled trial has now demonstrated that octreotide long-acting repeatable (LAR) 30 mg can significantly prolo...     

Somatostatin analogue-induced pancreatic exocrine insufficiency in patients with neuroendocrine tumors: results of a prospective observational study

Background: Patients with advanced well-differentiated neuroendocrine tumours (Wd-NETs) are commonly treated with somatostatin analogues (SSAs). Some patients may develop SSA-related side effects such as pancreatic exocrine insufficiency (PEI).

Methods: In this prospective, observational study, the frequency of SSA-induced PEI in 50 sequential patients with advanced Wd-NETs treated with SSAs was investigated. Toxicity was assessed monthly and faecal elastase-1 (FE1) and quality of life (QoL) were assessed 3-monthly.

Results: The median age was 65.8 years, 58% were male and the majority (92%) of patients had metastatic disease; patients received 4-weekly long acting octreotide (60%) or lanreotide (40%). Twelve patients (24%) developed SSA-related PEI after a median of 2.9 months from SSA initiation; FE1 was a reliable screening tool for PEI, especially in symptomatic (abdominal bloating, flatulence and/or diarrhea) patients (risk ratio 8.25 (95% confidence interval 1.15–59.01)). Most of these patients (11/12; 92%) required PERT. Other SSA-related adverse events (any grade) included flatulence (50%), abdominal pain (32%), diarrhoea (30%) and fatigue (20%). Development of PEI did not significantly worsen overall QoL, however gastrointestinal symptoms and diarrhoea were increased.

Conclusion: This study demonstrated that PEI occurs at a higher rate than previously reported; clinicians need to diagnose and treat this SSA-related adverse-event which occurs in 1 in 4 patients with Wd-NETs treated with SSAs. Screening with FE1 in symtomatic patients is recommend.     

Summary and recommendations from the Australasian guidelines for the management of pancreatic exocrine insufficiency

AimBecause of increasing awareness of variations in the use of pancreatic exocrine replacement therapy, the Australasian Pancreatic Club decided it was timely to re-review the literature and create new Australasian guidelines for the management of pancreatic exocrine insufficiency (PEI).MethodsA working party of expert clinicians was convened and initially determined that by dividing the types of presentation into three categories for the likelihood of PEI (definite, possible and unlikely) they were able to consider the difficulties of diagnosing PEI and relate these to the value of treatment for each diagnostic category.Results and conclusionsRecent studies confirm that patients with chronic pancreatitis receive similar benefit from pancreatic exocrine replacement therapy (PERT) to that established in children with cystic fibrosis. Severe acute pancreatitis is frequently followed by PEI and PERT should be considered for these patients because of their nutritional requirements. Evidence is also becoming stronger for the benefits of PERT in patients with unresectable pancreatic cancer. However there is as yet no clear guide to help identify those patients in the ‘unlikely’ PEI group who would benefit from PERT. For example, patients with coeliac disease, diabetes mellitus, irritable bowel syndrome and weight loss in the elderly may occasionally be given a trial of PERT, but determining its effectiveness will be difficult. The starting dose of PERT should be from 25,000–40,000 IU lipase taken with food. This may need to be titrated up and there may be a need for proton pump inhibitors in some patients to improve efficacy.     

Study of the gastrointestinal bioavailability of a pancreatic extract product (Zenpep) in chronic pancreatitis patients with exocrine pancreatic insufficiency

IntroductionThe Food and Drug Administration in 2006 required that all pancreatic enzyme products demonstrate bioavailability of lipase, amylase, and protease in the proximal small intestine.MethodsIn this phase I open-label, randomized, crossover trial, 17 adult chronic pancreatitis (CP) patients with severe exocrine pancreatic insufficiency (EPI) underwent two separate gastroduodenal perfusion procedures (Dreiling tube suctioning and [¹⁴C]-PEG instillation by an attached Dobhoff tube in the duodenal bulb). Patients received Ensure Plus® alone and Ensure Plus with Zenpep (75,000 USP lipase units) in random order. The bioavailability of Zenpep was estimated by comparing the recovery of lipase, amylase, chymotrypsin activity in two treatment conditions. ¹⁴C-PEG was used to correct duodenal aspirates volume. The primary efficacy endpoint was lipase delivery in the duodenum after Zenpep administration under fed conditions. Secondary efficacy endpoints included chymotrypsin and amylase delivery, serum CCK levels, and measuring duodenal and gastric pH.ResultsZenpep administration with a test meal was associated with significant increase in duodenal aspiration of lipase (p = 0.046), chymotrypsin (p = 0.008), and amylase (p = 0.001), compared to the test meal alone, indicating release of enzymes to the duodenum. Lipase delivery was higher in the pH subpopulation (the efficacy population with acid hypersecretors excluded) (p = 0.01). Recovery of [¹⁴C]-PEG was 61%. Zenpep was generally well tolerated. All adverse events were mild and transient.ConclusionsIn CP patients with severe EPI, lipase, chymotrypsin and amylase were released rapidly into the duodenum after ingestion of Zenpep plus meal compared to meals alone. Results also reflected the known pH threshold for enzyme release from enteric coated products.     

Clinicopathological characteristics of non-functioning cystic pancreatic neuroendocrine tumors

Background/objectives

The biological features of cystic pancreatic neuroendocrine tumors (PNETs) remain unclear. The aim of this study was to clarify the clinicopathological characteristics of non-functioning PNETs (NF-PNETs) with a cystic component.

继发于胰腺癌的胰腺外分泌功能不全的研究进展

目前国际上对胰腺外分泌功能不全的诊断和治疗标准尚未完善,胰腺外科医师对继发于胰腺癌的胰腺外分泌功能不全常常忽视或错误估计,使得胰腺外分泌功能不全未得到充分治疗,严重影响了胰腺癌患者的生存质量。对胰腺癌患者胰腺外分泌功能不全的发病机制、典型症状、诊断方法、不同胰腺癌阶段的胰酶替代治疗等方面的最新研究进展进行了归纳总结,分析认为胰酶替代治疗能显著改善不同疾病阶段胰腺癌患者的生存质量。     

Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus

IntroductionExocrine pancreatic insufficiency (EPI) can occur in patients with diabetes mellitus (DM). Incidence of EPI and its clinical significance remain poorly defined. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with DM.Patients and methodsOne hundred and fifty consecutive patients, mean age 59.0 (±12.0 years), with DM lasting at least 5 years were included in the study. We included 50 patients with type 1 DM (DM1), 50 insulin-treated patients DM type 2 (DM2-insulin) and 50 non-insulin treated patients with DM type 2 (DM2 no-insulin). Diagnosis of DM was established from health records, lasting 15.0 ± 9.9 years on average. EPI was diagnosed with a fecal elastase-1 concentration (FE1) of less than 200 μg/g (ELISA).ResultsFE1 was reduced in 8 (5.4%) patients: mildly reduced (100–200 μg/g) in 4 patients (2.7%) and markedly reduced (<100 μg/g) in 4 patients (2.7%). Frequency of EPI was 3 in DM1, 5 in DM2(insulin) and none in DM2 (no-insulin) groups.ConclusionsEPI in DM occurred less frequently than in previous studies, probably due to our strict exclusion criteria (age, alcohol intake).     

Diagnosis and treatment of exocrine pancreatic insufficiency in chronic pancreatitis: An international expert survey and case vignette study

IntroductionDespite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency.MethodsAn online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years.ResultsOverall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency.ConclusionThis survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.     

Three-dimensional remnant pancreatic volume ratio indicates postoperative pancreatic exocrine insufficiency in pancreatic cancer patients after distal pancreatectomy

BackgroundPancreatectomy may cause serious pancreatic exocrine insufficiency (PEI), which can lead to some nutritional problems, including new-onset diabetes mellitus (DM) or non-alcoholic fatty liver disease (NAFLD). Recent studies have reported that remnant pancreatic volume (RPV) significantly influences postoperative PEI. However, the specific correlation between RPV and postoperative PEI remains unclear. Here, we compare various pre-, peri-, and postoperative risk factors in a retrospective cohort to address whether preoperatively measured RPV is a predictor of postoperative PEI in pancreatic cancer patients after distal pancreatectomy (DP).MethodsSixty-one pancreatic cancer patients who underwent DP were retrospectively enrolled. Pancreatic volume was measured using preoperative 3D images, which simulated the actual intraoperative pancreatic parenchymal volume. We obtained the 3D-measured RPV and resected pancreatic volume. We calculated the ratio of the RPV to the total pancreatic volume and then divided the cohort into high- and low-RPV ratio groups based on a cut-off value (>0.35, n = 37 and ≤ 0.35, n = 24). Using multivariate analysis, the RPV ratio as well as pre-, peri- and postoperative PEI risk factors were independently assessed.ResultsThe multivariate analysis revealed that a low RPV ratio (odds ratio [OR], 5.911; p = 0.001), a hard pancreatic texture (OR, 3.313; p = 0.023) and TNM stage III/IV (OR, 3.515; p = 0.031) were strong predictors of the incidence of PEI.ConclusionsThe present study indicates that the RPV ratio is an additional useful predictor of postoperative nutrition status in pancreatic cancer patients.     

Critical examination of therapeutic efficacy of a ph-sensitive enteric-coated pancreatic enzyme preparation in treatment of exocrine pancreatic insufficiency secondary to cystic fibrosis

In an attempt to critically examine the therapeutic efficacy of pH-sensitive entericcoated pancreatic enzyme preparations in patients with pancreatic insufficiency due to cystic fibrosis, postprandial duodenal concentration and recovery of orally administered pancreatic enzymes, duodenal pH, and coefficient of fat absorption were determined in eight cases after ingestion of equivalent dosage of enteric-coated as well as conventional enzyme preparations. Ingestion of a pH-sensitive enteric-coated pancreatic enzyme preparation was accompanied with a significant (P<0.05) reduction in steatorrhea, as well as a lower mean concentration and recovery of lipase and trypsin activity in the postprandial duodenal samples. Furthermore, the intraluminal duodenal pH was noted to be below 4.0 during the postprandial period in all patients. These data suggest that in cystic fibrosis, the greater therapeutic efficacy of pH-sensitive enteric-coated preparations over conventional preparations may be related to the protection of pancreatic enzymes from the highly acidic milieu in the duodenum, allowing for possible bioavailability in the distal small intestine.Supported by the Veterans Administration.     

胰腺外分泌功能与胰腺癌分期、肿瘤大小关系的临床研究

目的 研究胰腺外分泌功能与胰腺癌分期、肿瘤大小的关系.方法 采用NBT-PABA试验测定39例胰腺癌、46例CP患者和20名正常人胰腺外分泌功能,分析其与胰腺癌JPS局部进展度(T因子)及肿瘤大小(Ts)的关系.结果 正常人PABA排泄率平均为(78.9±15.9)%;CP患者平均为(58.6±19.3)%,其中轻、中、重度CP的PABA排泄率分别为(75.5±23.6)%、(57.9±21.5)%、(45.5±16.7)%;胰腺癌患者PABA排泄率平均为(47.6±18.3)%.其中,L3+T4期胰腺癌患者PABA排泄率为(42.2±21.7)%,显著低于Tl+T2期患者的(64.8±11.1)%(P<0.05);TS3+TS4患者PABA排泄率为(34.8±17.2)%,显著低于TS1+TS2患者的(55.6±23.5)%(P<0.05);胰头癌PABA排泄率为(42.5±16.4)%,显著低于胰体尾癌的(71.8±9.6)%(P<0.05);33例胰头癌中,主胰管狭窄患者的PABA排泄率为(54.2±14.1)%,显著高于胰管中断患者的(37.6±14.1)%(P<0.05).胰腺癌与中、重度CP的胰腺外分泌功能无显著差异.结论 胰头癌患者的胰腺外分泌功能减低的程度与胰腺癌分期、肿瘤大小及部位有一定相关性,其中胰管中断为影响判定的因素.胰腺外分泌功能不能鉴别胰腺癌与中、重度CP.     

150例糖尿病患者胰腺外分泌功能检测及相关因素分析

目的探讨糖尿病患者胰腺外分泌功能不全的发生情况及其相关因素。方法选取2009年3月至2010年6月于第四军医大学西京医院内分泌科就诊的糖尿病患者150例,分为1型糖尿病组（T1DM,23例）、2型糖尿病组（T2DM,127例）,对照组为来我院健康体检者及我科医护人员共48人。记录糖尿病患者的年龄、性别、体质指数（BMI）、病程、糖尿病微血管病变发生情况、糖化血红蛋白（HbAle）等指标。收集受试者24h内排出的粪便,应用酶联免疫吸附实验（ELISA）法测定粪便中粪弹性蛋白酶（FE）的含量,对所有受试者的胰腺外分泌功能进行评估。率的比较采用X2检验或Fisher精确概率法。结果1型糖尿病患者、2型糖尿病患者及对照组粪便FE含量差异有统计学意义[分别为（394±237）比（502±194）比（576±170）μg／g,F=6．93,P〈0．01]。以FE〈200μg／g作为胰腺外分泌功能不全的判断标准,结果显示30．4％（7／23）的T1DM患者及7．9％（10／127）的T2DM患者存在胰腺外分泌功能不全,与对照组（0）相比,差异有统计学意义（Fisher检验P〈0．05）。以是否存在胰腺外分泌功能不全对糖尿病患者进行分组分析,结果显示两组间年龄、性别、BMI、病程、胰岛素治疗与否、糖尿病微血管病变发生情况、稳态模型胰岛素分泌指数（HOMA-B）、空腹胰岛素、餐后2h胰岛素及HbAlc等差异均无统计学意义（均P〉0．05）。结论本研究提示与健康对照相比,T1DM和他DM患者胰腺外分泌功能不全的发生率普遍较高。     

Diagnosis and treatment of pancreatic exocrine insufficiency

Pancreatic exocrine insufficiency is an important cause of maldigestion and a major complication in chronic pancreatitis.Normal digestion requires adequate stimulation of pancreatic secretion,sufficient production of digestive enzymes by pancreatic acinar cells,a pancreatic duct system without significant outflow obstruction and adequate mixing of the pancreatic juice with ingested food.Failure in any of these steps may result in pancreatic exocrine insufficiency,which leads to steatorrhea,weight loss and malnutrition-related complications,such as osteoporosis.Methods evaluating digestion,such as fecal fat quantification and the13C-mixed triglycerides test,are the most accurate tests for pancreatic exocrine insufficiency,but the probability of the diagnosis can also be estimated based on symptoms,signs of malnutrition in blood tests,fecal elastase 1 levels and signs of morphologically severe chronic pancreatitis on imaging.Treatment for pancreatic exocrine insufficiency includes support to stop smoking and alcohol consumption,dietary consultation,enzyme replacement therapy and a structured follow-up of nutritional status and the effect of treatment.Pancreatic enzyme replacement therapy is administered in the form of enteric-coated minimicro-spheres during meals.The dose should be in proportion to the fat content of the meal,usually 40-50000 lipase units per main meal,and half the dose is required for a snack.In cases that do not respond to initial treatment,the doses can be doubled,and proton inhibitors can be added to the treatment.This review focuses on current concepts of the diagnosis and treatment of pancreatic exocrine insufficiency.     

Obstructed pancreaticojejunostomy partly explains exocrine insufficiency after pancreatic head resection

Objective. The majority of patients with long-term survival after pancreatic head resection suffer from pancreatic exocrine insufficiency. The objective of this study was to investigate whether this is due to glandular malfunction or obstructed pancreaticojejunal anastomosis. Material and methods. Twenty-six patients (10 M, 16 F, mean age 61 years, range 34–81 years) were re-examined a median of 52 months (range 3–76 months) after pancreatic head resection and end-to-end invaginated pancreaticojejunostomy. Pancreatic exocrine function was measured by fecal elastase-1 assay. The size of the pancreatic remnant, glandular secretion and the flow through the anastomosis were analyzed with secretin-stimulated dynamic magnetic resonance pancreatography (D-MRP). Results. All patients had pancreatic exocrine insufficiency, 24 (92%) of them having severe insufficiency. Eighteen patients (69%) reported moderate to severe diarrhea. Lowest fecal elastase-1 concentrations were associated with the initial diagnosis of chronic pancreatitis or ductal adenocarcinoma, suggesting preoperative primary or secondary chronic pancreatitis as important determinants. The size of the remnant gland did not correlate with the fecal elastase-1 concentrations. D-MRP failed in three patients. Severe glandular malfunctions were found in 7 (30%) of the 23 successful D-MRP examinations. The anastomosis was totally obstructed in 5 patients (22%) or partially obstructed in 6 (26%) but remained perfectly open in 5 patients (22%). The five patients with perfect anastomoses had the highest measured median fecal elastase-1 activity. Conclusions. Although late diarrhea and pancreatic exocrine insufficiency may be partly induced already by the disease treated with resection, at least half may be explained by obstructed anastomosis. To obtain better late functional results, improvements may be required in the surgical techniques.     

血浆嗜铬粒蛋白A对多种神经内分泌肿瘤的诊断价值

目的 探讨血浆嗜铬粒蛋白A(CgA)对神经内分泌肿瘤的诊断价值,同时评价血浆CgA对胃肠胰腺内分泌肿瘤的诊断效力,初步探讨血浆CgA对胃肠胰腺内分泌肿瘤预后的监测作用.方法 应用酶联免疫试剂盒检测56例胃肠胰腺内分泌肿瘤、52例嗜铬细胞瘤和7例小细胞肺癌的血浆CgA浓度,同时以52例健康体检者作为对照,计算血浆CgA诊...     

Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.