Pancreatic Neuroendocrine Tumors - Octreotide Therapy

11/23/2005

Question:  What is the efficacy of Octreotide therapy for pancreatic neuroendocrine tumors?

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<1>

Unique Identifier [PMID]: 15888809

Authors: Ramage JK. Davies AH. Ardill J. Bax N. Caplin M. Grossman A. Hawkins R. McNicol AM. Reed N. Sutton R. Thakker R. Aylwin S. Breen D. Britton K. Buchanan K. Corrie P. Gillams A. Lewington V. McCance D. Meeran K. Watkinson A. UKNETwork for Neuroendocrine Tumours.

Institution: North Hampshire Hospital, Aldermaston Road, Basingstoke, Hants, UK. johnramage1@compuserve.com

Title: Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.

Source: Gut. 54 Suppl 4:iv1-16, 2005 Jun.

Publication Type: Guideline. Journal Article. Practice Guideline.

<2>

Unique Identifier [PMID]: 15545183

Authors: Oberg K. Astrup L. Eriksson B. Falkmer SE. Falkmer UG. Gustafsen J. Haglund C. Knigge U. Vatn MH. Valimaki M. Nordic NE Tumour Group.

Institution: Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. kjell.oberg@medsci.uu.se

Title: Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part II-specific NE tumour types.

Source: Acta Oncologica. 43(7):626-36, 2004.

Abstract: Part II of the guidelines contains a description of epidemiology, histopathology, clinical presentation, diagnostic procedure, treatment, and survival for each type of neuroendocrine tumour. We are not only including gastroenteropancreatic tumours but also bronchopulmonary and thymic neuroendocrine tumours. These guidelines essentially cover basic knowledge in the diagnosis and management of the different forms of neuroendocrine tumour. We have, however, tried to give more updated information about the epidemiology and histopathology, which is essential for the clinical management of these tumours.

Publication Type: Guideline. Journal Article.

<3>

Unique Identifier [PMID]: 15545182

Authors: Oberg K. Astrup L. Eriksson B. Falkmer SE. Falkmer UG. Gustafsen J. Haglund C. Knigge U. Vatn MH. Valimaki M. Nordic NE Tumour Group.

Institution: Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. kjell.oberg@medsci.uu.se

Title: Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I-general overview.

Source: Acta Oncologica. 43(7):617-25, 2004.

Abstract: The incidence of neuroendocrine tumours of the gastroenteropancreatic system seems to have increased during the past decade. New diagnostic and therapeutic procedures have aroused the interest of physicians, though most see very few cases of such diseases. A group of members of the Nordic Neuroendocrine Tumour Group decided to compile some guidelines to facilitate the diagnosis and treatment of patients with these tumours. Part I of these guidelines discusses the principles of histopathology, biochemical and radiological diagnosis as well as therapeutic options.

Publication Type: Guideline. Journal Article.

<4>

Unique Identifier [PMID]: 15471830

Authors: Nguyen C. Faraggi M. Giraudet AL. de Labriolle-Vaylet C. Aparicio T. Rouzet F. Mignon M. Askienazy S. Sobhani I.

Institution: Service de Medecine Nucleaire, Centre Hospitalier et Universitaire de Saint-Antoine, Paris, France. charles.nguyen@sat.ap-hop-paris.fr

Title: Long-term efficacy of radionuclide therapy in patients with disseminated neuroendocrine tumors uncontrolled by conventional therapy.

Source: Journal of Nuclear Medicine. 45(10):1660-8, 2004 Oct.

Abstract: Therapeutic options in patients with advanced-stage gastroenteropancreatic (GEP) neuroendocrine tumors are limited. We compared the efficacy of radionuclide therapy with 111In-pentetreotide and 131I-metaiodobenzylguanidine (MIBG) in 20 patients (group A) with the outcome of similar patients who could not be treated for nonmedical reasons (group B, n = 12). The intent was to treat all patients because of uncontrolled tumor disease (n = 21), contraindication to chemotherapy or surgery (n = 7), or uncontrolled and badly tolerated clinical symptoms (n = 4). METHODS: Group A patients received 3 monthly administrations of 3.7-7.4 GBq of 131I-MIBG (n = 5) or 7 GBq of 111In-pentetreotide (n = 15), according to the best tracer uptake. Clinical evaluation, biologic tests, and conventional imaging were performed at 3, 6, 12, 18, and 24 mo. Therapy was considered beneficial if clinical status improved, laboratory tests for secreting tumors improved by >20%, tumor progression was halted, the size of the most significant localization had decreased by >25%, and the dosage of analgesic and cold somatostatin therapy could be lowered. Pejorative events were defined as side effects due to therapy, relapse in clinical symptoms, tumor progression, tumor laboratory marker increase, and death. RESULTS: The overall survival rate at 3 mo was significantly higher in group A (P = 0.05). Radionuclide therapy was beneficial in 14 patients (73% of group A), with only 1 significant side effect. The average time before relapse was 16.1 +/- 7.8 mo. The overall Kaplan-Meier survival rate and cumulative progression-free and cumulative event-free survival rates during the first 15 mo were significantly higher in patients receiving radionuclide therapy (P = 0.019, P = 0.024, and P = 0.019, respectively). CONCLUSION: Radionuclide therapy is feasible and safe and significantly defers the occurrence of fatal and nonfatal events in patients clinically uncontrolled by conventional therapy.

Publication Type: Clinical Trial. Controlled Clinical Trial. Journal Article. Validation Studies.

<5>

Unique Identifier [PMID]: 15153439

Authors: Pape UF. Bohmig M. Berndt U. Tiling N. Wiedenmann B. Plockinger U.

Institution: Department of Internal Medicine, Charite Universitatsmedizin Berlin, Campus Virchow-Klinikum, Medical Faculty of the Humboldt University, Berlin, Germany. ulrich-frank.pape@charite.de

Title: Survival and clinical outcome of patients with neuroendocrine tumors of the gastroenteropancreatic tract in a german referral center.

Source: Annals of the New York Academy of Sciences. 1014:222-33, 2004 Apr.

Abstract: Neuroendocrine tumors (NETs) are rare neoplasms. Approximately 75% of all cases manifest in the gastroenteropancreatic (GEP) system. Because of the low incidence of NETs, limited data about the clinical outcome and prognostic variables are available. In an attempt to identify prognostic parameters, we investigated the distribution of primary tumors, pattern of metastasis formation, clinical presentation, histological classification, and outcome of therapeutic interventions in a large patient cohort cared for in a German referral center. In 254 patients with GEP-NETs, the primary tumor was of foregut, midgut, or hindgut origin in 44.1% (28.7% pancreas), 43.7% (34.7% jejunoileum), and 4.3%, respectively. No primary tumor was found in 7.9%. Metastases occurred preferentially in lymph nodes and the liver. The overall 5-year survival rate was 57.1%. In the absence or presence of metastases at initial diagnosis the 5-year survival rate was 80.0% and 51.7%, respectively. The 5-year survival rate was related to the localization of the primary and was 75.0% and 42.9% for jejunoileal and pancreatic tumors, respectively. The size of the primary tumor (<2 cm) and histological grading as low-grade malignant were both associated with a significantly longer survival. Surgery with curative intent was attempted in 141 patients. However, an R(0) resection was achieved in only 66.0% of these patients. Five-year survival rate in the latter group was significantly higher (77.3%) as compared with all surgical patients (55.4%). Long-term tumor-free survival was obtained in only 53.7% of successfully resected patients. Palliative medical treatment, either with chemotherapy (i.e., especially for foregut NETs) or biotherapy (especially for midgut NETs), was only moderately effective for both therapeutic regimens.

Publication Type: Journal Article.

<6>

Unique Identifier [PMID]: 15151956

Authors: Oberg K. Kvols L. Caplin M. Delle Fave G. de Herder W. Rindi G. Ruszniewski P. Woltering EA. Wiedenmann B.

Institution: Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. kjell.oberg@medsci.uu.se

Title: Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. [Review] [55 refs]

Source: Annals of Oncology. 15(6):966-73, 2004 Jun.

Abstract: This consensus report gives a detailed description of the use of somatostatin analogs in the management of neuroendocrine tumors of the gastroenteropancreatic system. As background information we have outlined critical aspects of the pathology, the use of tumor markers, a definition of functional and non-functional digestive neuroendocrine tumors, different imaging modalities, surgical considerations, liver embolization and the use of cytotoxic drugs as well as interferon. Included in the report is an overview of somatostatin, somatostatin analogs and its receptor expression in different neuroendocrine tumors. It will also define the binding affinities of different somatostatin analogs to the five different subtypes of somatostatin receptor. We compare the efficacy of octreotide and lanreotide in reducing diarrhea and flushing. Side-effects are described and we provide practical information on somatostatin analog treatment. [References: 55]

Publication Type: Consensus Development Conference. Journal Article. Review.

<7>

Unique Identifier [PMID]: 12860945

Authors: Faiss S. Pape UF. Bohmig M. Dorffel Y. Mansmann U. Golder W. Riecken EO. Wiedenmann B. International Lanreotide and Interferon Alfa Study Group.

Institution: Universitatsklinikum Charite, Campus Virchow Klinikum, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Augustenburger Platz 1, D-13353 Berlin, Germany.

Title: Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group.[see comment].

Comments Comment in: J Clin Oncol. 2004 Feb 1;22(3):573-4; author reply 574-5; PMID: 14752088, Comment in: J Clin Oncol. 2004 Feb 1;22(3):573; author reply 574-5; PMID: 14752089

Source: Journal of Clinical Oncology. 21(14):2689-96, 2003 Jul 15.

Abstract: PURPOSE: Somatostatin analogs and interferon alfa control hormone-active/functional neuroendocrine gastroenteropancreatic tumors. In addition to hormonal control, variable degrees of antiproliferative effects for both agents have been reported. Until now, however, no prospective, randomized studies in therapy-naive patients have compared somatostatin analogs or interferon alfa alone with a combination of the two. METHODS: Eighty therapy-naive patients with histologically verified neuroendocrine tumor disease (primary localization: foregut, n = 36; midgut, n = 30; hindgut, n = 3; unknown, n = 11; functional, n = 29; nonfunctional, n = 51) were randomly treated either with lanreotide (1 mg three times a day administered subcutaneously [SC]) or interferon alfa (5 x 106 U three times a week SC) or both. All patients had disease progression in the 3 months before study entry, verified with imaging procedures. RESULTS: Twenty-five patients were treated with lanreotide, 27 patients were treated with interferon alfa, and 28 patients were treated with the combination. Partial tumor remission was seen in four patients (one patient who received lanreotide, one patient who received interferon alfa, and two patients who received the combination). During the 12 months of therapy, stable disease was observed in 19 patients (seven patients who received lanreotide, seven patients who received interferon alfa, and five patients who received the combination), whereas tumor progression occurred in 14 of 25 patients (lanreotide), 15 of 27 patients (interferon alfa), and 14 of 28 patients (combination). Side effects leading to an interruption of therapy were more frequent in the combination group than in the monotherapy arms. CONCLUSION: This prospective, randomized, multicenter study shows for the first time that somatostatin analogs, interferon alfa, or the combination of the two had comparable antiproliferative effects in the treatment of metastatic neuroendocrine gastroenteropancreatic tumors. Response rates were lower compared with those published in previous, nonrandomized studies. The antiproliferative effect of the tested substances was similar for functional and nonfunctional neuroendocrine tumors.

Publication Type: Clinical Trial. Journal Article. Multicenter Study. Randomized Controlled Trial.

<8>

Unique Identifier [PMID]: 12417506

Authors: Chu QD. Hill HC. Douglass HO Jr. Driscoll D. Smith JL. Nava HR. Gibbs JF.

Institution: Department of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York 14263, USA.

Title: Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas.

Source: Annals of Surgical Oncology. 9(9):855-62, 2002 Nov.

Abstract: BACKGROUND: Neuroendocrine tumors of the pancreas are rare tumors. We identified predictive factors that are associated with long-term survival (> or=5 years). METHODS: Fifty patients with a diagnosis of neuroendocrine tumors of the pancreas were retrospectively evaluated. The following factors were evaluated for disease-specific mortality: age, sex, primary tumor location, functional status, type of primary tumor treatment, presence or absence of liver metastases, timing of liver metastases occurrence, and type of liver metastases treatment. Aggressive treatment of the liver metastases included surgery, chemoembolization, or intrahepatic arterial infusion chemotherapy. RESULTS: Twenty-three patients (47%) had tumor located in the head of the pancreas, and 29 patients (58%) had nonfunctioning tumor. Thirty-nine patients (78%) had liver metastases. The median follow-up for the entire group was 35 months (range,.76-206 months). The median survival for the entire group was 40 months, and the overall 1-, 2-, and 5-year survival rates were 84%, 69%, and 36%, respectively. Factors that had a significant favorable effect on survival included curative resection of the primary tumor, metachronous liver metastases, absence of liver metastases, and aggressive treatment of the liver metastases. CONCLUSIONS: Definitive surgical resection of the primary tumor, absence of liver metastases, metachronous liver metastases, and aggressive treatment of the liver metastases were predictors of long-term survival in patients with neuroendocrine tumors of the pancreas.

Publication Type: Journal Article.

<9>

Unique Identifier [PMID]: 12153595

Authors: Kaltsas GA. Mukherjee JJ. Isidori A. Kola B. Plowman PN. Monson JP. Grossman AB. Besser GM.

Institution: Departments of Endocrinology, St Bartholomew's Hospital, West Smithfield, London, UK.

Title: Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil. [Review] [50 refs]

Source: Clinical Endocrinology. 57(2):169-83, 2002 Aug.

Abstract: OBJECTIVE: Combination chemotherapy with the two agents streptozotocin (SZT), which is a nitrosurea, and 5-fluorouracil (5-FU), an alkylating agent, has a long-established role in the treatment of neuroendocrine tumours; however, it is often accompanied by considerable toxicity, and it has not been assessed in a comparative manner with other current chemotherapy regimens. In order to assess the therapeutic response and adverse effects using an alternative nitrosurea, lomustine (CCNU), which has a different side-effect profile, in combination with 5-FU, we have reviewed all patients with neuroendocrine tumours who received this form of treatment in our department. DESIGN: Retrospective analysis of the case notes of patients with metastatic neuroendocrine tumours who received treatment with the combination of CCNU and 5-FU, and who were followed up according to a defined protocol in a given time frame. PATIENTS: Thirty-one patients with metastatic neuroendocrine tumours (18 with carcinoid tumours, five islet-cell tumours, five chromaffin-cell tumours and three medullary carcinoma of the thyroid) treated with the combination of CCNU and 5-FU, and when necessary additional therapy, over a 22-year period, were included in this analysis. MEASUREMENTS: The symptomatic, hormonal and tumoural responses before and after chemotherapy with the combination of CCNU and 5-FU over a median follow-up duration of 25 months (range 9-348 months) were recorded. Of the 31 patients (16 males; median age 52 years, range 20-86 years), eight (four males; median age 61 years, range 30-74 years) were treated with the combination of CCNU and 5-FU alone (Group 1), whereas the other 23 patients (12 males; median age 47 years, range 20-86 years) received additional therapy with other chemotherapeutic regimens, somatostatin analogues, alpha-interferon or radiolabelled meta-iodobenzylguanidine (131I-MIBG) therapy (Group 2). RESULTS: A total of 121 therapeutic cycles was administered (mean 3.9, range 1-14 cycles). None of the patients obtained a complete tumour response. A partial tumour response (not a complete but a 50% or greater reduction of all measurable tumour) was seen in six out of the 29 patients (21%) (four out of eight in Group 1 and two out of 21 in Group 2, respectively). There was no tumour progression in eight out of the 29 patients (27.5%) (one out of eight in Group 1 and seven out of 21 in Group 2, respectively). The median survival over the period of the study was 48 months (95% confidence interval, CI, 22-74 months). The overall 5-year survival rate was 42% (95% CI, 17-67%) for all patients and 50% (95% CI, 18-83%) for the carcinoid group alone, according to Kaplan-Meier analysis. A complete or partial symptomatic response was obtained in 12 out of 27 (44%) patients who presented with symptoms (four out of eight in Group 1 and eight out 19 in Group 2, respectively) and a complete or partial hormonal response in eight out of 19 patients (42.1%) who presented with hormonally active disease (two out of four in Group 1 and six out of 15 in Group 2, respectively). Nine out of the 15 (60%) patients with carcinoid tumours who presented with symptoms obtained a symptomatic response, five out of 10 patients (50%) a hormonal response, and four out of 16 (25%) patients a partial tumoural response, respectively. The combination of CCNU and 5-FU was safe and well tolerated. Serious side-effects necessitating the termination of CCNU and 5-FU were seen only in two patients, and mainly consisted of reversible bone marrow suppression. No chemotherapy-related death was recorded. CONCLUSIONS: Chemotherapy with CCNU and 5-FU, either alone or in combination with other therapeutic modalities, produces considerable symptomatic and hormonal improvement and moderate tumour regression/stabilization according to currently accepted WHO criteria, particularly in patients with metastatic gastroenteropancreatic neuroendocrine tumours with minimal adverse effects. However, long-term survival was still relatively poor. It may therefore be a valuable additional therapl was still relatively poor. It may therefore be a valuable additional therapeutic option, particularly for well-differentiated carcinoid and islet-cell tumours, but mainly reserved for when there is no response or progression of the disease after currently available first-line treatment with somatostatin analogues or radiopharmaceuticals. [References: 50]

Publication Type: Journal Article. Review. Review, Multicase.

<10>

Unique Identifier [PMID]: 11407665

Authors: Corleto VD. Panzuto F. Falconi M. Cannizzaro R. Angeletti S. Moretti A. Delle Fave G. Farinati F. Oncology Study Section of the Italian Society of Gastroenterology.

Institution: Chair of Gastroenterology, II Faculty of Medicine, La Sapienza University, Rome, Italy.

Title: Digestive neuroendocrine tumours: diagnosis and treatment in Italy. A survey by the Oncology Study Section of the Italian Society of Gastroenterology (SIGE).[see comment].

Comments Comment in: Dig Liver Dis. 2001 Apr;33(3):212-4; PMID: 11407663

Source: Digestive & Liver Disease. 33(3):217-21, 2001 Apr.

Abstract: BACKGROUND: New insights in the diagnosis and treatment of digestive neuroendocrine tumours have prompted a renewed interest in these rare and complex diseases. AIM: To establish how many new cases of digestive neuroendocrine tumours were diagnosed, and how they were treated, at gastroenterological centres across Italy during a two-year period (1997-1998). METHODS: The 12 centres taking part filled in a data collection form reporting type of tumour, methods of diagnosis and therapeutic strategies adopted in each case. Data were collected and analysed by the authors of the present report. RESULTS: Data refer to 98 patients, 22 with functioning and 76 with non-functioning digestive neuroendocrine tumours [50 carcinoids, 48 pancreatic endocrine tumour syndromes]. Primary tumours were localised in 96% (38% with metastases) of non-functioning and 81% (50% with metastases) of functioning tumours. These were surgically removed in >80% of patients in both groups. Somatostatin analogue treatment, with or without interferon, was administered in 35% of patients, while chemotherapy was used in 9% and 23% of functioning and non-functioning tumours, respectively. The imaging study always included a computed tomography scan (20% helical computed tomography). Magnetic resonance and somatostatin receptor scintigraphy were also performed, the former in 41% and 21% of the two (functioning and non-functioning tumour) groups, the latter in 45% and 30%. CONCLUSIONS: The number of functioning digestive neuroendocrine tumours reported was lower than expected. Surgery plays a major role in the treatment of these tumours in all centres. Overall, in only a small number of patients was a multidisciplinary approach applied.

Publication Type: Journal Article.

<11>

Unique Identifier [PMID]: 11376401

Authors: Skogseid B.

Institution: Endocrine Oncology Unit, Department of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden. britt.skogseid@medsci.uu.se

Title: Nonsurgical treatment of advanced malignant neuroendocrine pancreatic tumors and midgut carcinoids.

Source: World Journal of Surgery. 25(6):700-3, 2001 Jun.

Abstract: Neuroendocrine enteropancreatic tumors are relatively uncommon and present variable biologic and clinical features. Surgery at early disease stages is currently the only available cure. Evidenced-based medicine and consensus on systemic treatment of advanced malignant disease is virtually nonexistent, and the various available therapeutic regimens should be considered primarily palliative. Symptomatic treatment of patients with endocrine functioning tumors, however, is of utmost importance and leads to extensive prolongation of survival. Biotherapy by means of somatostatin analogs and interferon-alpha facilitates symptomatic control and offers stabilization of tumor progression for extended periods of time. Pancreatic endocrine tumors metastatic to the liver frequently respond to chemotherapy by means of a significant reduction in tumor volume. Programs including streptozotocin and 5-fluorouracil or doxorubicin are generally regarded as first line treatment for pancreatic endocrine tumors with liver metastases, whereas midgut carcinoid tumors often are resistant to systemic chemotherapy. Treatment attempts in patients with the latter disease may rather include interferon-alpha and somatostatin analogs. Somatostatin receptor-targeted radiotherapy is still investigational. Repeated surgical intervention including various debulking procedures should be considered here and in patients with advanced neuroendocrine pancreatic tumors and midgut carcinoids requiring systemic antitumor treatment.

Publication Type: Journal Article.

<12>

Unique Identifier [PMID]: 11111016

Authors: Desai DC. O'Dorisio TM. Schirmer WJ. Jung SS. Khabiri H. Villanueva V. Martin EW.

Institution: The Neuroendocrine Tumor Clinic at The Ohio State University, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.

Title: Serum pancreastatin levels predict response to hepatic artery chemoembolization and somatostatin analogue therapy in metastatic neuroendocrine tumors.

Source: Regulatory Peptides. 96(3):113-7, 2001 Jan 12.

Abstract: INTRODUCTION: Neuroendocrine tumors often metastasize to the liver and present with disabling hormonal symptoms. Hepatic artery chemoembolization (HACE) combined with somatostatin therapy, pre-embolization, peri-embolization and post-embolization, at doses to control symptoms, is an aggressive approach that can relieve hormonal symptoms with minimal morbidity and mortality. METHODS: Chemoembolization was performed using 30 mg of adriamycin, 50 mg of mitomycin, 12 ml of hexabrix, 10 ml of ethiodol, and 360-500-microm particles. Pancreastatin, a split product of chromogranin A, was measured pre-HACE and post-HACE in all patients. RESULTS: Forty-three chemoebolization procedures were performed in 34 symptomatic patients from December 1995 to August 1999. Seventeen patients had intestinal primaries (50%), seven had pancreatic primaries (20%), five had bronchial primaries (15%), and five had unknown primaries (15%). Systemic pancreastatin levels were improved or stable in 31 patients (78%). Symptoms were improved in these 31 patients (78%). Systemic serotonin levels were improved or stable in 24 patients (60%). Radiographic improvement or stability was seen in 18 patients (45%). Procedural related morbidity included pain, fevers, nausea, vomiting, and transient elevations of liver function studies in 75-100% of patients. There was one procedural related mortality (2%). Less than 20% improvement in pancreastatin levels from baseline was associated with death in five of five patients (100%). This was not observed with serotonin levels. CONCLUSION: Measurement of serum pancreastatin levels is an easy and useful method to predict success in patients who undergo HACE plus somatostatin therapy for metastatic neuroendocrine tumors to the liver. This therapeutic approach is effective in relieving symptoms in 78% of patients, with minimal major morbidity or mortality.

Publication Type: Journal Article.

<13>

Unique Identifier [PMID]: 10626288

Authors: Pape UF. Hocker M. Seuss U. Wiedenmann B.

Institution: Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Universitatsklinikum Charite, Medizinische Fakultat, Humboldt Universitat zu Berlin, Germany.

Title: New molecular aspects in the diagnosis and therapy of neuroendocrine tumors of the gastroenteropancreatic system. [Review] [77 refs]

Source: Recent Results in Cancer Research. 153:45-60, 2000.

Abstract: The nature and biology of neuroendocrine cells and of tumors derived therefrom have been the subject of intense research using cell biological and molecular approaches. Diagnostic procedures for establishing the diagnosis of a neuroendocrine tumor have been improved through the development of new serological markers and imaging procedures. Histopathological diagnosis has been refined by the introduction of a broad spectrum of marker proteins for different subtypes of neuroendocrine neoplasms. The high receptor specificity of somatostatin analogues such as octreotide or lanreotide has made these drugs valuable tools in diagnosis and therapy, and some of the achievements made as well as future directions are reviewed in this article. Another substance in use for therapy of neuroendocrine tumors is interferon-a, whose signal transduction mechanism has been investigated considerably during the past several years. In addition to biotherapy with somatostatin analogues and/or interferon-a, chemotherapy is an accepted strategy in the treatment of advanced neuroendocrine tumor disease derived from the foregut. In this context, streptozotocin has caught some attention due to its somewhat selective toxicity against neuroendocrine tumor cells. Some recent studies on the role of the glucose transporter isoform GLUT2 may provide insight into streptozotocin's action. The multiple endocrine neoplasia type-1 gene has recently been cloned, sequenced and identified as a gene potentially involved in the development of the familial cancer syndrome of multiple endocrine neoplasia type 1 (MEN-1). Mutations of this putative tumor suppressor gene have been described, and the abundance of mutations in MEN-1-related tumors as well as sporadic neuroendocrine tumors at MEN-1 locations have been demonstrated. Whether determination of MEN-1 mutations will be valuable for clinical routine is under investigation. [References: 77]

Publication Type: Journal Article. Review. Review, Tutorial.

<14>

Unique Identifier [PMID]: 10235222

Authors: Frank M. Klose KJ. Wied M. Ishaque N. Schade-Brittinger C. Arnold R.

Institution: Department of Internal Medicine, Philipps University, Marburg, Germany.

Title: Combination therapy with octreotide and alpha-interferon: effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors.

Source: American Journal of Gastroenterology. 94(5):1381-7, 1999 May.

Abstract: OBJECTIVE: We investigated the antiproliferative efficacy of the addition of alpha-interferon to the somatostatin analogue octreotide in patients with metastasized gastroenteropancreatic tumors unresponsive to octreotide monotherapy. METHODS: In an open prospective trial, 21 patients with metastasized neuroendocrine gastroenteropancreatic tumors (nine patients with carcinoid syndrome, eight with nonfunctioning tumors, four with gastrinoma) were treated with 5 x 10(6) IU alpha-interferon tiw in addition to 200 microg of octreotide tid. All patients, including 16 patients with preceding monotherapy with 200 microg of octreotide tid, had tumor progression documented by computed tomography before entering the study. Growth response (computed tomography documented) and biochemical response were assessed at 3-month intervals. RESULTS: Inhibition of tumor growth was observed in 14 patients (67%), 11 of whom had preceding octreotide monotherapy; complete regression was observed in one patient lasting for 49 months and stable disease (stand-still) in 13 patients lasting for 3 to 52 months (median, 12 months). Seven patients failing this combination therapy exhibited a significantly shorter overall survival (median, 23 months; range, 5 to 42 months) than the 14 patients responding to this regimen (median, 68 months; range, 12 to 112 months; p = 0.007). Two patients are still alive. Biochemical response was achieved in 69% of patients with functioning tumors: in three of four patients with gastrinoma and in six of nine patients with carcinoid syndrome. CONCLUSIONS: These data suggest that the addition of alpha-interferon to octreotide has antiproliferative efficacy in a subgroup of patients with advanced metastatic disease unresponsive to octreotide monotherapy. Prolonged survival was seen in the responder group.

Publication Type: Clinical Trial. Journal Article.

<15>

Unique Identifier [PMID]: 10207242

Authors: Mantke R. Manger T. Schulz HU. Ridwelski K. Pross M. Gunther T. Lippert H.

Institution: Department of General Surgery (Director: Prof. Dr. H. Lippert), 'Otto von Guericke' University Magdeburg, Germany.

Title: Multimodal treatment of neuroendocrine tumors of the pancreas and the ampulla of Vater.

Source: Digestive Surgery. 16(2):145-51, 1999.

Abstract: Neuroendocrine tumors are not seen frequently. They are most commonly located in the small bowel including the vermiform appendix. Neuroendocrine tumors of pancreatic origin are extremely rare. Symptoms caused by excessive hormone production by large liver metastases often lead to their diagnosis. Preoperative diagnostics include analysis of specific hormones in serum and urine, ultrasound, CT and somatostatin receptor scintigraphy. Liver metastases of neuroendocrine tumors of the pancreas are common at the time of diagnosis. Curative resection should be performed whenever possible, although patients often benefit from debulking procedures, too. Liver metastases can be subjected to surgical resection, embolization, regional chemotherapy or local procedures such as alcohol injection or cryoablation. As an exception, liver transplantation can be considered in selected cases where radical surgery for the primary tumor could be performed and extrahepatic metastases are not present. Supplementary or alternative options include octreotide and/or interferon-alpha administration. In this article, we report on 6 patients suffering from primary neuroendocrine tumors of the pancreas or the ampulla of Vater who were treated at our department over the past 5 years. In addition, we discuss our own experience with this rare condition in the light of the recent literature.

Publication Type: Journal Article.

<16>

Unique Identifier [PMID]: 9914876

Authors: Venook AP.

Institution: Division of Hematology and Oncology, University of California, San Francisco 94143-0324, USA.

Title: Embolization and chemoembolization therapy for neuroendocrine tumors. [Review] [29 refs]

Source: Current Opinion in Oncology. 11(1):38-41, 1999 Jan.

Abstract: Neuroendocrine tumors, particularly those of gastrointestinal tract origin, have a predisposition for metastasizing to the liver. In such patients, the clinical course is often dominated by the hepatic disease, either because of hormone secretion or because of tumor bulk. Because the liver has a dual vascular supply and hepatic metastases derive the majority of blood from the hepatic artery, the regional delivery of chemotherapy can offer pharmacokinetic advantages over systemic administration. The hepatic artery is also a nonsurgical avenue for inducing selective metastasis ischemia by the embolization of tumor vessels. The combination of these two therapies, or chemoembolization, may provide additive benefits. Such an approach has been demonstrated to reduce tumor bulk, reduce hormone levels, and palliate the symptoms of many patients with liver-dominant neuroendocrine metastases. Embolization or chemoembolization is an appropriate modality for some patients with neuroendocrine tumors. [References: 29]

Publication Type: Journal Article. Review. Review, Tutorial.

<17>

Unique Identifier [PMID]: 10604131

Authors: Rougier P. Ducreux M.

Institution: Service Hepato-gastroenterologie, Hopital Ambroise Pare, Boulogne, France.

Title: Systemic chemotherapy of advanced digestive neuroendocrine tumours. [Review] [30 refs]

Source: Italian Journal of Gastroenterology & Hepatology. 31 Suppl 2:S202-6, 1999 Oct.

Abstract: The efficacy of chemotherapy on digestive neuro-endocrine tumours is not yet fully established and depends on the tumour type and on the differentiation of the neuro-endocrine tumours. Reports have indirectly suggested the superior activity of chemotherapy for pancreatic neuro-endocrine tumours than for metastatic carcinoid tumours (response rates around 60% vs 20%). Neuro-endocrine tumour differentiation is also a major factor and a higher chemotherapy efficacy (tumour responses: 69%) has been suggested in undifferentiated or poorly differentiated neuro-endocrine tumours which respond to chemotherapy, a little like small cell lung carcinomas. The efficacy of interferons has also been reported in phase II trials only, with symptomatic and biological responses in about 50% of the cases and tumour responses in 10 to 15%; some studies have suggested an interesting tumour growth control with prolonged survival but this efficacy has still to be investigated to clearly establish the best indications. The role of chemotherapy has to be discussed with surgeons and, in slowly progressing tumours, after the use of somatostatin analogues. [References: 30]

Publication Type: Journal Article. Review. Review, Tutorial.

<18>

Unique Identifier [PMID]: 10070309

Authors: Zhou Y. Gobl A. Wang S. Jacobsen MB. Janson ET. Haines GK 3rd. Radosevich JA. Oberg K.

Institution: Endocrine Oncology Unit of Internal Medicine, Uppsala University Hospital, Sweden.

Title: Expression of p68 protein kinase and its prognostic significance during IFN-alpha therapy in patients with carcinoid tumours.

Source: European Journal of Cancer. 34(13):2046-52, 1998 Dec.

Abstract: The aim of this study was to evaluate the antiproliferative effects of interferon alpha (IFN-alpha) on neuroendocrine differentiated cell lines and, retrospectively, to assess the prognostic significance of p68 protein kinase (PKR) induction in neuroendocrine gut and pancreatic tumour patients. Archive specimens from 56 patients were studied, 43 before IFN-alpha and 56 during therapy. The tissues were immunostained for p68 protein kinase (PKR) using the monoclonal antibody (MAb) TJ4C4. A significant increase in immunostaining after treatment with IFN-alpha compared with before treatment (3.47 +/- 0.12 versus 2.72 +/- 0.15, P < 0.001) was noted. The p68 score was significantly increased after treatment only in patients with stable disease before = 2.71 +/- 0.19, after = 3.40 +/- 0.14 (P < 0.001) or an objective response before 3.13 +/- 0.22, after = 4.00 +/- 0.24 (P < 0.05) but not in those with progressive disease (before = 2.32 +/- 0.24, after 2.86 +/- 0.26, NS). A low p68 score (< 3.0) during treatment was a predictor of shorter duration of response and overall survival (P = 0.0062 and P < 0.0001, respectively). Furthermore, IFN-alpha showed a significant antiproliferative effect (by [3H]thymidine incorporation) on two carcinoid tumour cell lines in a dose-dependent manner which correlated with a dose-dependent induction of p68 mRNA and protein expression (by Northern and Western blot analysis). We conclude that IFN-alpha can effectively inhibit the in vitro growth of carcinoid tumor cell lines and upregulates the expression of p68 at both mRNA and protein levels in carcinoid tumours. The induction of p68 could be a prognostic indicator of response in patients with carcinoid tumours during IFN-alpha treatment.

Publication Type: Journal Article.

<19>

Unique Identifier [PMID]: 9803143

Authors: van de Loosdrecht AA. van Bodegraven AA. Sepers JM. Sindram JW.

Institution: Department of Internal Medicine, Medisch Centrum Alkmaar, The Netherlands.

Title: Long-term follow-up of two patients with metastatic neuroendocrine tumours treated with octreotide.

Source: Netherlands Journal of Medicine. 53(3):118-23, 1998 Sep.

Abstract: Two patients are described with metastatic neuroendocrine tumours of the pancreas head and region of Vater. After surgery, administration of the long-acting somatostatin analogue octreotide was started. In the first patient we found an IgG-lambda paraproteinaemia and a parathyroid hormone-related protein (PTHrP) driven hypercalcaemia. By increasing the dose of octreotide the paraproteinaemia disappeared. In the second patient with a metastasized somatostatin producing neuroendocrine tumour, octreotide showed a long-term stabilizing effect on symptoms and progression of disease. The role of octreotide in the induction of changes in biological behaviour of malignant neuroendocrine cells is discussed.

Publication Type: Case Reports. Journal Article.

<20>

Unique Identifier [PMID]: 9448967

Authors: Hatton MQ. Reed NS.

Institution: Beatson Oncology Centre, Western Infirmary, Glasgow, UK.

Title: Chemotherapy for neuroendocrine tumors: the Beatson Oncology Centre experience.

Source: Clinical Oncology (Royal College of Radiologists). 9(6):385-9, 1997.

Abstract: The role of chemotherapy in malignant neuroendocrine tumours is difficult to assess because of their rarity and variation in biological behaviour. We present a retrospective review of chemotherapy given to 18 patients with metastatic and one with locally advanced neuroendocrine tumours. There were eight poorly differentiated neuroendocrine tumours, six thyroid medullary carcinomas, two phaeochromocytomas, two pancreatic islet cell tumours and one undifferentiated neuroblastoma. Four patients were given 3-weekly dacarbazine, vincristine and cyclophosphamide (DOC) chemotherapy. In eight patients, this regimen was modified by substituting the dacarbazine and cisplatin and etoposide (OPEC). A further six patients were treated with dacarbazine reintroduced into the 3-weekly regimen (DOPEC). The remaining patient received cisplatin and etoposide. There were two complete responses (both with OPEC) and eight partial responses (two with DOC, three with OPEC and three with DOPEC). Five patients had stable disease and four progressed. Four received further chemotherapy on relapse, producing one complete and one partial response. The median response duration to initial chemotherapy was 10 months (range 3-34). The median survival was 12 months (range 1-42). The main toxicity was haematological, with grade 3-4 neutropenia in 12 patients; eight suffered episodes of sepsis. One death was treatment related. Other toxicity was mild although three patients discontinued vincristine with grade 2 neurotoxicity. The response rate and side effects of these three regimens appear comparable. We conclude that, although these patient numbers are small, combination chemotherapy produces an encouraging response rate (53%; 95% CI 30-75) in malignant neuroendocrine tumours, with acceptable toxicity.

Publication Type: Journal Article.

<21>

Unique Identifier [PMID]: 8813472

Authors: Krenning EP. Kooij PP. Pauwels S. Breeman WA. Postema PT. De Herder WW. Valkema R. Kwekkeboom DJ.

Institution: Department of Nuclear Medicine, University Hospital Rotterdam, The Netherlands.

Title: Somatostatin receptor: scintigraphy and radionuclide therapy.

Source: Digestion. 57 Suppl 1:57-61, 1996.

Abstract: Peptide receptor scintigraphy is more sensitive at the biological than anatomical level, in contrast to conventional imaging, which it complements. Neuroendocrine tumours have the most somatostatin receptors in vitro and their metastases are somatostatin receptor positive in vitro, so that [111In-DTPA-D-Phe1]octreotide (OCT) can be used to image them. OCT was compared with conventional imaging techniques (CON) in a European Multicentre Trial. In 350 evaluable patients, CON detected 88%, and OCT 80% (glucagonomas 100%, VIPomas 88%, carcinoids 87%, non-functioning islet cell tumours 82%, insulinomas 46%) of tumour sites but there was no systematic use of abdominal single-photon-emission computerised tomography. OCT demonstrated multiple tumour sites in 62 of 178 patients in whom CON had found only 1 lesion, with 60% confirmed. 12/16 lesions detected by OCT in 11 patients with no lesions according to CON were also confirmed. The impact of OCT on management was evaluated in 235 patients and affected 40%: it determined 29 surgical decisions, led to octreotide therapy in 47, and modified octreotide dose in 18. Six end-stage patients with neuroendocrine tumours were treated with OCT radionuclide therapy (up to a cumulative dose of 53 GBq per patient) in a phase I trial. There were no major side-effects after up to 2 years treatment, with impressive effects on hormone production and a likely anti-proliferative effect.

Publication Type: Clinical Trial. Journal Article. Multicenter Study.

<22>

Unique Identifier [PMID]: 7710986

Authors: Di Bartolomeo M. Bajetta E. Bochicchio AM. Carnaghi C. Somma L. Mazzaferro V. Visini M. Gebbia V. Tumolo S. Ballatore P.

Institution: Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Title: A phase II trial of dacarbazine, fluorouracil and epirubicin in patients with neuroendocrine tumours. A study by the Italian Trials in Medical Oncology (I.T.M.O.) Group.

Source: Annals of Oncology. 6(1):77-9, 1995 Jan.

Abstract: BACKGROUND: Previous experiences in the treatment of neuroendocrine tumours have demonstrated some activity of single agents such as adriamycin, fluorouracil (FU), streptozotocin and dacarbazine (DTIC). Opinions concerning the usefulness of polychemotherapy in carcinoid tumours are discordant, whereas better results have been achieved in other endocrine pancreatic neoplasms. Based on this background, we used multidrug chemotherapy with DTIC, FU and epirubicin in the treatment of different neuroendocrine tumours. METHODS: The study involved 38 pts with progressive and measurable disease. The treatment schedule was FU 250 mg/m2 i.v., epirubicin 25 mg/m2 i.v., and DTIC 200 mg/m2 i.v. on days 1, 2 and 3 every 3 weeks. RESULTS: The responses achieved by histologic types were carcinoids 2/20, medullary thyroid carcinoma 1/7, neuroendocrine tumours 1/6; and Merkel cell carcinoma 3/5. The median duration of response was 5 months (range 2-11). Stable disease was observed in 13 cases (34%). Out of the 18 cases in progression, 17 had not responded to previous medical treatment. No symptom control was observed in 4 pts with carcinoid syndrome. Treatment toxicity was moderate and included nausea and vomiting, alopecia, leukopenia and mucositis. CONCLUSIONS: Our results document the moderate efficacy of the regimen in all of the histologic types. The major difference in comparison with previous studies was the lower response rate observed in patients with neuroendocrine tumours.

Publication Type: Clinical Trial. Clinical Trial, Phase II. Journal Article. Multicenter Study.

<23>

Unique Identifier [PMID]: 7534331

Authors: Jacobsen MB. Hanssen LE.

Institution: Medical Department A. Rikshospitalet, University of Oslo, Norway.

Title: Clinical effects of octreotide compared to placebo in patients with gastrointestinal neuroendocrine tumours. Report on a double-blind, randomized trial.

Source: Journal of Internal Medicine. 237(3):269-75, 1995 Mar.

Abstract: OBJECTIVES. To compare the effect of octreotide with f placebo on symptoms, tumour marker and quality of life in patients with gastrointestinal neuroendocrine tumours and liver metastases. DESIGN. A blinded, placebo-controlled, cross-over study was performed. The number of flushing epidodes and diarrhoea episodes were registered for 1 week prior to the study and for the 8-week duration of the study. Quality of life and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion were measured before the start, and at 4 and 8 weeks. Quality of life was registered with the Psychosocial Adjustment to Illness Scale (PAIS) and 5-HIAA measured by high-performance chromatography with electrochemical detection. 5-HIAA values exceeding 45 mumol 24 h-1 were considered to be elevated. SETTING. The study was performed in a tertiary referral centre. SUBJECTS. Twelve patients were approached; eleven patients were included, with a mean age of 56.5 (range 30-72) years. The primary tumour originated from the small intestine in nine and from the pancreas in two patients. The main symptoms were diarrhoea, flushing and nausea. The 24-h excretion of 5-HIAA was increased in all patients. INTERVENTIONS. Patients were treated for 4 weeks with octreotide (100 micrograms) subcutaneously, twice daily, and for 4 weeks on placebo (octreotide vehicle) in random starting order. MAIN OUTCOME MEASURES. The main outcome measures were the number of episodes of the main clinical symptom(s) and 24-h 5-HIAA excretion. RESULTS. Octreotide lowered diarrhoea and flushing frequency significantly compared to placebo. 5-HIAA excretion was reduced during treatment with the active drug. Two domains of the PAIS were significantly improved, indicating that the reduction of tumour marker and symptoms were clinically important. CONCLUSIONS. The clinical effect of octreotide on symptoms in patients with neuroendocrine tumours was demonstrated in a controlled, prospective trial.

Publication Type: Clinical Trial. Journal Article. Randomized Controlled Trial.