Lloyd RV, et al：WHO Classification of Tumours of Endocrine Organs, 4th Edition. IARC Lyon, 2017.
Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, Capella C, Caplin M, Couvelard A, Doglioni C, Delle Fave G, Fischer L, Fusai G, de Herder WW, Jann H, Komminoth P, de Krijger RR, La Rosa S, Luong TV, Pape U, Perren A, Ruszniewski P, Scarpa A, Schmitt A, Solcia E, Wiedenmann B.
TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study.
J Natl Cancer Inst. 2012 May 16;104(10):764-77. doi: 10.1093/jnci/djs208. Epub 2012 Apr 23.
Abstract/Text
BACKGROUND: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms.
METHODS: The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided.
RESULTS: Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability.
CONCLUSION: Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.
Metz DC, Jensen RT.
Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors.
Gastroenterology. 2008 Nov;135(5):1469-92. doi: 10.1053/j.gastro.2008.05.047. Epub 2008 Aug 12.
Abstract/Text
Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field.
Ito T, Sasano H, Tanaka M, Osamura RY, Sasaki I, Kimura W, Takano K, Obara T, Ishibashi M, Nakao K, Doi R, Shimatsu A, Nishida T, Komoto I, Hirata Y, Nakamura K, Igarashi H, Jensen RT, Wiedenmann B, Imamura M.
Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan.
J Gastroenterol. 2010 Feb;45(2):234-43. doi: 10.1007/s00535-009-0194-8.
Abstract/Text
BACKGROUND: There have been few epidemiological studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Japan.
METHODS: We examined the epidemiology of GEP-NETs [pancreatic endocrine tumors (PETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005 using a nationwide stratified random sampling method.
RESULTS: A total of 2,845 individuals received treatment for PETs. Prevalence was estimated as 2.23/100,000 with an annual onset incidence of 1.01/100,000. Non-functioning tumor (NF)-PET constituted 47.4%, followed by insulinoma (38.2%) and gastrinoma (7.9%). Distant metastases were reported in 21% patients with NF-PETs and occurred more frequently as tumor size increased (>2 cm). Multiple endocrine neoplasia type 1 (MEN-1) was detected in 10% of PETs but only in 6.1% of NF-PETs. NF-PETs were detected incidentally by physical examination in 24% patients. In 2005, an estimated 4,406 patients received treatment for GI-NETs. Prevalence was estimated as 3.45/100,000, with an annual onset incidence of 2.10/100,000. The locations of GI-NETs varied: foregut, 30.4%; midgut, 9.6%; and hindgut, 60.0%. Distant metastases were observed in 6%. Lymph node metastases occurred more frequently as tumor size increased (>1 cm). The frequency of MEN-1 complications was 1%. Physical examination revealed GI-NETs in 44% patients. The frequency of symptomatic GI-NETs was 3.4%. Interestingly, 77.1% of patients with foregut GI-NETs had type A gastritis.
CONCLUSION: Our results show there are large differences in GEP-NETs between Japan and Western nations, primarily due to differences in the presence of MEN-1 in NF-PETs and the location, symptomatic status, and prevalence of malignancy in GI-NETs.
Parker CM, Hanke CW, Madura JA, Liss EC.
Glucagonoma syndrome: case report and literature review.
J Dermatol Surg Oncol. 1984 Nov;10(11):884-9. doi: 10.1111/j.1524-4725.1984.tb01341.x.
Abstract/Text
The glucagonoma syndrome is characterized by dermatitis, glucose intolerance, hypoaminoacidemia, and hyperglucagonemia secondary to an alpha-cell tumor of the pancreas. Other clinical features include anemia, glossitis, and weight loss. A 62-year-old woman with the syndrome sought medical attention for a chronic dermatitis. A skin biopsy was suggestive of necrolytic migratory erythema. A glucagonoma was surgically removed from the tail of the pancreas. Review of the literature indicates that 56 proven and 33 probable cases of glucagonoma syndrome have been reported.
Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, Corrie P, Davar J, Davies AH, Lewington V, Meyer T, Newell-Price J, Poston G, Reed N, Rockall A, Steward W, Thakker RV, Toubanakis C, Valle J, Verbeke C, Grossman AB; UK and Ireland Neuroendocrine Tumour Society.
Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs).
Gut. 2012 Jan;61(1):6-32. doi: 10.1136/gutjnl-2011-300831. Epub 2011 Nov 3.
Abstract/Text
These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.
Jhala D, Eloubeidi M, Chhieng DC, Frost A, Eltoum IA, Roberson J, Jhala N.
Fine needle aspiration biopsy of the islet cell tumor of pancreas: a comparison between computerized axial tomography and endoscopic ultrasound-guided fine needle aspiration biopsy.
Ann Diagn Pathol. 2002 Apr;6(2):106-12. doi: 10.1053/adpa.2002.30613.
Abstract/Text
The objective of the present study is to compare the cytologic features of islet cell tumor (ICT) of pancreas obtained by endoscopic ultrasound guided fine needle aspiration (EUS-FNA) and computed tomography guided FNA (CT-FNA). We also describe the cytologic features associated with malignant ICT. Eleven cytology samples from 121 CT- FNA and 30 EUS- FNA of the pancreas were obtained from nine patients with ICT. Diff-Quik, Papanicolaou, and immunohistochemical stains to determine neuroendocrine differentiation and the hormonal status were evaluated. Cytologic features and specimen adequacy were compared between the two techniques. Cytologic features noted in both benign and malignant ICT were also compared. Nine patients (5 men, 4 women) ranging in age from 29 to 84 years (mean age, 53.8 years). Diagnoses consisted of benign (4) and malignant (5) ICT. EUS-FNA was superior to CT-FNA in obtaining adequate cells (2/2 v 7/9) for the diagnosis and increased cellularity to perform additional immunohistochemical stains (2/2 v 4/7). Single, plasmacytoid cells with finely granular chromatin distribution characterized ICT on cytology. Mitoses (3/5) and necrosis (1/5) were noted in malignant ICT but not in benign ICT. EUS-FNA is superior to CT- FNA for obtaining cells for the diagnosis of ICT. Detection of mitoses and or necrosis from patients with ICT should initiate a search for metastasis.
Copyright 2002, Elsevier Science (USA). All rights reserved.
Roy PK, Venzon DJ, Feigenbaum KM, Koviack PD, Bashir S, Ojeaburu JV, Gibril F, Jensen RT.
Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis--a prospective NIH study of 235 patients and a review of 984 cases in the literature.
Medicine (Baltimore). 2001 May;80(3):189-222. doi: 10.1097/00005792-200105000-00005.
Abstract/Text
We prospectively studied 235 patients with Zollinger-Ellison syndrome (ZES) (205 without and 30 with prior acid-reducing surgery) and compared the results with 984 patients from 182 reports in the literature. The aims of the study were to evaluate the sensitivity of proposed acid secretory criteria for the diagnosis of ZES, propose new criteria, evaluate the variability and methodology of gastric secretory testing, and correlate the symptoms and signs of ZES, tumor extent, and primary tumor size and location with the degree of gastric acid hypersecretion. Multiple endocrine neoplasia-type 1 (MEN1) occurred in 22% of patients. The mean basal acid output (BAO) in patients without and with prior acid-reducing surgery was 41.2 +/- 1.7 mEq/hr (range, 1.6-118.3 mEq/hr) and 27.6 +/- 3.5 mEq/hr (range 5.9-102.9 mEq/hr), respectively. In patients with MEN1, those with female gender, Hispanic, or Asian race had lower BAOs. Diarrhea, esophageal stricture, and pyloric scarring were associated with a higher BAO. Neither other symptoms nor the tumor extent, primary tumor location, or size correlated with the magnitude of acid hypersecretion. ZES diagnosis was delayed a mean of 5.5 +/- 0.4 yr. Patients who were misdiagnosed as having either Crohn or celiac disease had higher BAOs. The sensitivities from our study and the literature review of the proposed BAO criteria for the diagnosis of ZES in patients without previous gastric acid-reducing surgery were 91% and 90% for BAO > or = 15 mEq/hr, 86% and 82% for BAO > or = 18 mEq/hr, 69% and 67% for BAO > 25 mEq/hr, and < 60% for BAO > 31 mEq/hr, respectively. The specificities of all the proposed BAO criteria were high. Both the criterion of BAO > or = 15 mEq/hr and BAO > or = 18 mEq/hr had good specificities and equal sensitivity. With prior acid-reducing surgery, the sensitivities in our study and from the literature review were 100% and 81% for BAO > or = 5 mEq/hr, 73% and 45% for BAO > 14.4 mEq/hr, and 37% and 31% for BAO > 19.2 mEq/hr, respectively. The reported mean specificity for the criterion of BAO > or = 5 mEq/hr was 85%, while it was 100% for the other 2 criteria. The maximal acid output (MAO) criterion of > 70 mEq/hr had sensitivities in the present National Institutes of Health (NIH) study and the literature review of 39% and 31%, respectively, and the criterion of MAO > 100 mEq/hr had a sensitivity of < 15% in patients with no prior acid-reducing surgery. The proposed criterion of BAO/MAO ratio > 0.6 had a low sensitivity. The proposed criterion of the ratio of basal and maximal acid H+ concentration (BAC/MAC ratio) > or = 0.6 had an excellent sensitivity-- > or = 89% in patients with or without previous acid-reducing surgery. The reported specificity for both the BAO/MAO criterion and the BAC/MAC criterion were similar, but BAC/MAC had a better sensitivity. Combination criteria of BAO generally did not improve sensitivity. The criterion of pH < or = 1 was met by only 27% of patients, and pH < or = 0.96 by 21% of patients with previous acid-reducing surgery. For patients with MEN1 with no prior acid-reducing surgery, the sensitivities were lower compared with patients with the sporadic form of ZES. The mean gastric volume in patients without prior acid-reducing surgery was 314 +/- 10 mL/hr and 247 +/- 25 mL/hr in patients with prior acid-reducing surgery. A basal volume criteria of > 160 mL/hr in patients without prior acid-reducing surgery occurred in > 86% of patients, and > 140 mL/hr in 87% of patients with prior acid-reducing surgery; these, thus, are neglected findings that have good sensitivities. Our analysis shows criteria based on MAO, pH, and BAO/MAO ratio do not have high sensitivities and thus are not useful. In patients without prior acid-reducing surgery, the criteria of BAO > or = 15 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 160 mL/hr are useful for the diagnosis of ZES and have good specificities. In patients with prior acid-reducing surgery, the criteria of BAO > or = 5 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 140 mL/hr have high sensitivities. In patients with sporadic ZES without acid-reducing surgery, the criterion of BAO > or = 18 mEq/hr is recommended as it has a similar sensitivity but higher specificity than the criterion of BAO > or = 15 mEq/hr. Only 1 patient in either data set (NIH or the literature) with or without previous acid-reducing surgery had a basal gastric pH > 2, therefore this finding essentially excludes the diagnosis of ZES. Gastric secretory measurements for 30 minutes, but not 15 minutes, give results comparable to those for a full hour. On the basis of these results, a number of gastric secretory criteria are proposed, including some for the first time, and alterations in methodology are proposed that should prove useful in the diagnosis of ZES.
Wada M, Komoto I, Doi R, Imamura M.
Intravenous calcium injection test is a novel complementary procedure in differential diagnosis for gastrinoma.
World J Surg. 2002 Oct;26(10):1291-6. doi: 10.1007/s00268-002-6528-9. Epub 2002 Sep 4.
Abstract/Text
The current study evaluated efficacy of the intravenous calcium injection test as a new diagnostic approach to clarify the existence of gastrinoma, which often goes undetected with routine testing. Twenty-six patients with hypergastrinemia were studied. For the calcium injection test, blood samples were taken from 12 patients with hypergastrinemia (HG), and three healthy volunteers, and one patient with nonfunctioning endocrine tumor in the pancreas (control). We compared results of the calcium injection test with those of the secretin test and the selective arterial secretagogue injection (SASI) test. The SASI test with secretin was performed in 24 of 26 patients with hypergastrinemia, including 22 of 24 patients with Zollinger-Ellison syndrome (ZES). Accuracy in the diagnosis of tumor localization by the SASI test was 95% (21 of 22) in ZES patients. The secretin test was negative in 3 of 21 patients with ZES (14%). Either the secretin test or the SASI test was positive in 22 of 23 patients (96%). The calcium injection test was administered to 12 patients in the HG group and 4 controls. The HG group showed significantly higher serum gastrin levels than those of the control group in the calcium injection test. Eight of 10 ZES patients (80%) had a positive calcium injection test. We could diagnose gastrinomas in 100% of ZES patients by either the calcium injection test or the secretin test. We have thus confirmed the efficacy of the intravenous calcium injection test in the diagnosis of gastrinoma. The calcium injection test could become an adjunct in the diagnosis of gastrinoma, which often goes undetected with routine testing.
Imamura M.
Recent standardization of treatment strategy for pancreatic neuroendocrine tumors.
World J Gastroenterol. 2010 Sep 28;16(36):4519-25. doi: 10.3748/wjg.v16.i36.4519.
Abstract/Text
Recent advances in localization techniques, such as the selective arterial secretagogue injection test (SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors (PNET). For patients with sporadic functioning PNET, curative resection surgery has been established by localization with the SASI test using secretin or calcium. For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1 (MEN 1) which are usually multiple and sometimes numerous, resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test. As resection surgery of PNET has increased, several important pathological features of PNET have been revealed. For example, in patients with Zollinger-Ellison syndrome (ZES), duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma, and in patients with MEN 1 and ZES, gastrinomas have been located mostly in the duodenum, and pancreatic gastrinoma has been found to co-exist in 13% of patients. Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation. The most important prognostic factor in patients with PNET is the development of hepatic metastases. The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit. The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.
Gibril F, Reynolds JC, Doppman JL, Chen CC, Venzon DJ, Termanini B, Weber HC, Stewart CA, Jensen RT.
Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study.
Ann Intern Med. 1996 Jul 1;125(1):26-34. doi: 10.7326/0003-4819-125-1-199607010-00005.
Abstract/Text
OBJECTIVE: To compare the sensitivity of somatostatin receptor scintigraphy done using [111In-DTPA-DPhe1]octreotide with that of other imaging methods in the localization of gastrinomas in patients with the Zollinger-Ellison syndrome.
DESIGN: Prospective study.
SETTING: Referral-based clinical research center.
PATIENTS: 80 consecutive patients with the Zollinger-Ellison syndrome.
INTERVENTIONS: Conventional tumor localization studies (ultrasonography, computed tomography [CT], magnetic resonance imaging [MRI], selective angiography, and bone scanning) and somatostatin receptor scintigraphy done using [111In-DTPA-DPhe1]octreotide with single-photon emission CT imaging at 4 and 24 hours. Patients with possible liver metastases had biopsies done for confirmation, and 15 patients had exploratory laparotomies done to assess primary tumor localization.
RESULTS: Extrahepatic gastrinomas or liver metastases were identified by ultrasonography in 19% of patients, by CT in 38% of patients, by MRI in 45% of patients, by angiography in 40% of patients, and by somatostatin receptor scintigraphy in 70% of patients. Somatostatin receptor scintigraphy was as sensitive as the other tests combined (59%), and when the results of all other tests were added to the somatostatin receptor scintigraphy results, tumors were localized in 75% of patients. Among patients with a possible primary tumor, the results of ultrasonography were positive in 9%, the results of CT were positive in 31%, the results of MRI were positive in 30%, the results of angiography were positive in 28%, and the results of somatostatin receptor scintigraphy were positive in 58%. Somatostatin receptor scintigraphy was as sensitive as all of the other imaging studies combined; when the results of scintigraphy were added to the results of the other studies, possible primary tumors were identified in 68% of patients. In 24 patients who had histologically proven metastatic liver disease, sensitivities for the detection of any metastatic liver lesions were 46% for ultrasonography, 42% for CT, 71% for MRI, 62% for angiography, and 92% for somatostatin receptor scintigraphy. Somatostatin receptor scintigraphy was significantly better than all of the conventional imaging methods in the identification of gastrinomas later found at surgery (P = 0.004), but it still missed 20% of gastrinomas.
CONCLUSIONS: Somatostatin receptor scintigraphy is the single most sensitive method for imaging either primary or metastatic liver lesions in patients with the Zollinger-Ellison syndrome. Because of its sensitivity, simplicity, and cost-effectiveness, it should be the first imaging method used in these patients. For patients with negative results on somatostatin receptor scintigraphy, guidelines about the use of other imaging studies are proposed.
Kirkwood KS, Debas HT.
Neuroendocrine tumors: common presentations of uncommon diseases.
Compr Ther. 1995 Dec;21(12):719-25.
Abstract/Text
In recent decades, isolation of the peptides secreted by gastrointestinal neuroendocrine tumors has greatly advanced our understanding of the pathophysiology of the syndromes resulting from over-production of these biologically active compounds. Early detection of these lesions permits localization and surgical extirpation prior to the development of mestastatic disease. In 1995, early detection of gastrointestinal neuroendocrine tumors hinges on an appropriate index of suspicion on the part of the primary care physician. The prompt recognition of the typical clinical constellations of symptoms associated with these tumors is essential to their timely diagnosis and management.
Jensen RT, Niederle B, Mitry E, Ramage JK, Steinmuller T, Lewington V, Scarpa A, Sundin A, Perren A, Gross D, O'Connor JM, Pauwels S, Kloppel G; Frascati Consensus Conference; European Neuroendocrine Tumor Society.
Gastrinoma (duodenal and pancreatic).
Neuroendocrinology. 2006;84(3):173-82. doi: 10.1159/000098009. Epub 2007 Feb 20.
Abstract/Text
Eldor R, Glaser B, Fraenkel M, Doviner V, Salmon A, Gross DJ.
Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour.
Clin Endocrinol (Oxf). 2011 May;74(5):593-8. doi: 10.1111/j.1365-2265.2011.03967.x.
Abstract/Text
OBJECTIVE: Glucagonoma is a pancreatic neuroendocrine tumour that arises from alpha cells in the pancreas and is often accompanied by a characteristic clinical syndrome.
DESIGN: In this report, we present the cumulative experience and clinical characteristics of six patients diagnosed with glucagonoma and the glucagonoma syndrome and treated at our centre during the past 25 years.
RESULTS: Although the course of the disease was variable, some features were similar. The median age at diagnosis was 53·5 years; the median time from onset of symptoms to diagnosis was 39 months. Presenting symptoms were as follows: weight loss 5/6 (83%), necrotizing migratory erythema (NME) 5/6 (83%), diabetes mellitus 4/6 (66%) and diarrhoea, weakness and thrombosis 2/6 (33%). Plasma glucagon was elevated in all patients upon diagnosis (range 200-10,000 pm; N < 50). Skin biopsy was diagnostic only in 1/6 specimens obtained, even after revision. Metastatic disease developed in all patients; 4/6 initially presented with hepatic metastasis. All patient symptoms responded to somatostatin analogue therapy. In 4/6, the NME responded to amino acid solutions. Other modes of therapy were as follows: surgery in 3/6 patients, peptide receptor radioligand therapy with (90) Y-DOTATOC (PRRT) in 3/6 patients (two responses) and chemotherapy in three patients (two responded). Four out of six patients died of the disease, and median survival time was 6·25 years (range 2-11) from diagnosis and 8 years (range 8-16) from initial symptoms. Five-year survival was 66%.
CONCLUSION: Our data indicate that somatostatin analogues and an aggressive surgical approach offer symptom relief and tumour control. Among other available treatment modalities, PRRT seems to hold the most promise.
© 2011 Blackwell Publishing Ltd.
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group.
Everolimus for advanced pancreatic neuroendocrine tumors.
N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/NEJMoa1009290.
Abstract/Text
BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.
METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.
RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).
CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P.
Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
N Engl J Med. 2011 Feb 10;364(6):501-13. doi: 10.1056/NEJMoa1003825.
Abstract/Text
BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.).
Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG.
Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282.
Ann Oncol. 2001 Aug;12(8):1139-43. doi: 10.1023/a:1011632713360.
Abstract/Text
BACKGROUND: A phase II study of dacarbazine (DTIC), was conducted to determine the response rate, duration of response, toxicity and overall survival of patients with advanced pancreatic islet cell tumors.
PATIENTS AND METHODS: Fifty patients with advanced pancreatic islet cell tumors, having progressive symptoms or evidence of rapidly advancing disease were entered on this study. DTIC was given by IV infusion at a dose of 850 mg/m2, over 60-90 minutes, repeated every four weeks.
RESULTS: The response rate was 33% in 42 patients who had measurable tumor, and 34% in the 50 patients (90% confidence interval (90% CI): 23%-47%). The majority of the responses were seen in patients without prior chemotherapy. Median overall survival was 19.3 months. There were two lethal toxicities on the study, one septic shock and one myocardial infarction. Grade 4 toxicities were, hematological (5 patients), sepsis, neurological (depression and paranoid behavior) and bleeding (1 patient each). The most common toxicity was vomiting, grade 3 in 13% of patients.
CONCLUSIONS: DTIC has activity in advanced previously untreated pancreatic islet cell tumors.
Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L.
First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas.
Cancer. 2011 Jan 15;117(2):268-75. doi: 10.1002/cncr.25425. Epub 2010 Sep 7.
Abstract/Text
BACKGROUND: Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS).
METHODS: Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days.
RESULTS: Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events.
CONCLUSIONS: The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens.
Copyright © 2010 American Cancer Society.
Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators.
Lanreotide in metastatic enteropancreatic neuroendocrine tumors.
N Engl J Med. 2014 Jul 17;371(3):224-33. doi: 10.1056/NEJMoa1316158.
Abstract/Text
BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.).
Shibuya H, Hijioka S, Sakamoto Y, Ito T, Ueda K, Komoto I, Kobayashi N, Kudo A, Yasuda H, Miyake H, Arita J, Kiritani S, Ikeda M, Imaoka H, Ueno M, Kobayashi S, Furuta M, Nagashio Y, Murohisa G, Aoki T, Matsumoto S, Motoya M, Azemoto N, Itakura J, Horiguchi S, Yogi T, Kawagoe T, Miyaoka Y, Imamura F, Senju M, Arioka H, Hara K, Imamura M, Okusaka T.
Multi-center clinical evaluation of streptozocin-based chemotherapy for advanced pancreatic neuroendocrine tumors in Japan: focus on weekly regimens and monotherapy.
Cancer Chemother Pharmacol. 2018 Oct;82(4):661-668. doi: 10.1007/s00280-018-3656-y. Epub 2018 Jul 27.
Abstract/Text
PURPOSE: Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate responses to weekly regimens and to STZ monotherapy, and to identify a predictive marker of a response to STZ.
METHODS: Clinical data regarding STZ-based chemotherapy for pNET were collected between 2015 and 2017 at 25 facilities. We analyzed the effects, safety, progression-free survival (PFS), and factors that correlate with responses to STZ.
RESULTS: The overall objective response rate (ORR) of 110 patients who underwent STZ-based chemotherapy (monotherapy, 81.8%; weekly regimen 46.4%) was 21.8%, and PFS was 9.8 months. The ORR of weekly vs. daily regimens was 21.6 vs. 22.0% (P = 1.000), and that of monotherapy vs. combination therapy was 21.1 vs. 25.0% (P = 0.766). A Ki67 proliferation index (Ki67) of > 5% was a predictive marker of a response to STZ (P = 0.017), whereas regimen type, mono- or combination therapy, treatment line and liver tumor burden were not associated with responses. The frequencies of Grade ≥ 3 nausea and hematological adverse events were significantly lower for monotherapy than combination therapy (P = 0.032).
CONCLUSIONS: The effects of weekly STZ monotherapy on pNET are comparable to those previously reported and the toxicity profile was acceptable. Ki67 > 5% was the sole predictive marker of an objective response.
Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, Sedlackova E, Toumpanakis C, Anlauf M, Cwikla JB, Caplin M, O'Toole D, Perren A; Vienna Consensus Conference participants.
ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas.
Neuroendocrinology. 2016;103(2):186-94. doi: 10.1159/000443172. Epub 2016 Jan 5.
Abstract/Text
Fjällskog ML, Granberg DP, Welin SL, Eriksson C, Oberg KE, Janson ET, Eriksson BK.
Treatment with cisplatin and etoposide in patients with neuroendocrine tumors.
Cancer. 2001 Sep 1;92(5):1101-7. doi: 10.1002/1097-0142(20010901)92:5<1101::aid-cncr1426>3.0.co;2-v.
Abstract/Text
BACKGROUND: Patients with malignant endocrine pancreatic tumors (EPTs) are responsive to combinations of chemotherapy with streptozotocin and 5-fluorouracil/doxorubicin, whereas patients with malignant carcinoids are not. For both categories of patients, alpha-interferon and/or somatostatin analogs can produce long-lasting responses. Cisplatin in combination with etoposide has been suggested to be effective in patients with malignant neuroendocrine carcinomas. The authors used this therapy as second-line or third-line treatment in patients with poorly differentiated and/or rapidly progressing disease.
METHODS: Thirty-six patients with histopathologically verified malignant neuroendocrine tumors were included: Eighteen tumors were of foregut origin, of which 5 were atypical, and 15 tumors were EPTs, of which 4 were poorly differentiated endocrine carcinomas. Three tumors were of midgut origin. The median patient age was 47.5 years. The median duration of disease from the time of diagnosis was 12 months. All patients had metastatic disease. Thirty of 36 patients had received previous treatment. Etoposide was given at a dose of 100 mg/m(2) per day for 3 days, and cisplatin was given at a dose of 45 mg/m(2) on Days 2 and 3 as a continuous intravenous infusion that was repeated every 4 weeks.
RESULTS: Ten of 18 patients with foregut carcinoids (56%) responded radiologically and/or biochemically, with a median duration of 9 months; and 7 of 14 patients with EPTs (50%) responded radiologically and/or biochemically, with a median duration of 9 months. No difference in response was seen between patients with atypical or typical foregut carcinoids or between patients with well differentiated or poorly differentiated endocrine pancreatic carcinoma. Nineteen of 36 patients (53%) experienced World Health Organization (WHO) Grade 1-2 nephrotoxicity, and 23 patients (64%) suffered from WHO Grade 3-4 neutropenia.
CONCLUSIONS: The combination of cisplatin and etoposide can produce significant responses in patients with heavily pretreated and poorly differentiated/rapidly progressing neuroendocrine tumors. The toxicity is considerable, and nephrotoxicity is the dose limiting factor.
Copyright 2001 American Cancer Society.
Kulke MH, Wu B, Ryan DP, Enzinger PC, Zhu AX, Clark JW, Earle CC, Michelini A, Fuchs CS.
A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors.
Dig Dis Sci. 2006 Jun;51(6):1033-8. doi: 10.1007/s10620-006-8001-3.
Abstract/Text
The role of systemic chemotherapy in the treatment of patients with metastatic neuroendocrine tumors is controversial. While combination regimens containing cisplatin and etoposide have activity against more aggressive neuroendocrine tumor variants, such regimens appear to have little efficacy in patients with well-differentiated neuroendocrine tumor subtypes. The combination of irinotecan and cisplatin is active both against small cell lung cancer and in upper gastrointestinal malignancies but has not been prospectively evaluated in patients with metastatic neuroendocrine tumors. We therefore assessed the efficacy of an irinotecan/cisplatin combination in patients with this disease. Eighteen patients with metastatic neuroendocrine tumors (excluding small cell carcinoma) were treated with irinotecan, 65 mg/m2, and cisplatin, 30 mg/m2, administered weekly for 2 of every 3 weeks. Patients were followed for evidence of toxicity, response, and survival. The toxicities associated with this regimen were mild and included myelosuppression, nausea, and diarrhea. Only one radiologic response was observed among four patients with poorly differentiated neuroendocrine tumors. No radiologic responses were observed in 14 patients with well-differentiated tumors. The median overall survival duration of patients treated with this regimen was 11.4 months. We conclude that while the combination of irinotecan and cisplatin may have activity in aggressive neuroendocrine tumor subtypes, this combination is inactive in patients with well-differentiated neuroendocrine tumors.
Arnold R, Wilke A, Rinke A, Mayer C, Kann PH, Klose KJ, Scherag A, Hahmann M, Müller HH, Barth P.
Plasma chromogranin A as marker for survival in patients with metastatic endocrine gastroenteropancreatic tumors.
Clin Gastroenterol Hepatol. 2008 Jul;6(7):820-7. doi: 10.1016/j.cgh.2008.02.052. Epub 2008 Jun 10.
Abstract/Text
BACKGROUND & AIMS: The prognostic role of plasma chromogranin A in patients with neuroendocrine tumors is unclear. We investigated the role of chromogranin A in predicting survival and hypothesized that chromogranin A mirrors tumor burden and that a rapid increase after a phase of stable plasma chromogranin A levels might predict exploding tumor growth.
METHODS: Three hundred forty-four patients with metastatic, well-differentiated neuroendocrine tumors were included. A subsample of 102 patients was investigated to correlate radiologically classified tumor burden with plasma chromogranin A. Hepatic tumor burden (0%, 0%-25%, 25%-50%, >50%) was assessed from computed tomography/magnetic resonance imaging scans. Follow-up information until death was generated in regular intervals.
RESULTS: Plasma chromogranin A levels (U/L) vary between tumor entities (Kruskal-Wallis, P < .001) and were associated with survival time (hazard ratio [hours], 2.14 per one unit in the log10 CgA level scale; 95% confidence interval [CI], 1.75-2.62; P < .001). Chromogranin A levels correlated with hepatic tumor burden (Spearman P = .57; 95% CI, 0.44-0.70; P < .001). Additional extrahepatic tumor load did not relevantly affect plasma chromogranin A. A sudden increase observed in individual patients was paralleled by rapid tumor progress and short survival.
CONCLUSIONS: Increased plasma chromogranin A in patients with metastatic neuroendocrine tumors is predictive for shorter survival. There was a modest correlation between chromogranin A levels and hepatic tumor burden. We hypothesized further that a sudden increase in individual chromogranin A levels indicates unfavorable outcome.
Kimura W, Tezuka K, Hirai I.
Surgical management of pancreatic neuroendocrine tumors.
Surg Today. 2011 Oct;41(10):1332-43. doi: 10.1007/s00595-011-4547-6. Epub 2011 Sep 16.
Abstract/Text
This study outlines the surgical management and clinicopathological findings of pancreatic neuroendocrine tumors (P-NETs). There are various surgical options, such as enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatoduodenectomy, and duodenum-preserving pancreas head resection. Lymph node dissection is performed for malignant cases. New guidelines and classifications have been proposed and are now being used in clinical practice. However, there are still no clear indications for organ-preserving pancreatic resection or lymph node dissection. Hepatectomy is the first choice for liver metastases of well-differentiated neuroendocrine carcinoma without extrahepatic metastases. On the other hand, cisplatin-based combination therapy is performed as first-line chemotherapy for metastatic poorly differentiated neuroendocrine carcinoma. Other treatment options are radiofrequency ablation, transarterial chemoembolization/embolization, and liver transplantation. Systematic chemotherapy and biotherapy, such as that with somatostatin analogue and interferon-α, are used for recurrence after surgery. The precise surgical techniques for enucleation of the tumor and spleen-preserving distal pancreatectomy are described.
