Pancreatic neuroendocrine neoplasms

MINERVA GASTROENTEROL DIETOL 2012;58:401-26

Pancreatic neuroendocrine neoplasms D. HÖRSCH 1-2, T. BERT 1-2, J. SCHRADER 3, M. HOMMANN D. KAEMMERER 1-4, A. PETROVITCH 1-5, J. ZAKNUN 1-6, R. P. BAUM

Pancreatic neuroendocrine tumors originate from the diffuse neuroendocrine system in the pancreatic region. These tumors exhibit a rising incidence despite their rareness and due to their benign behavior a considerable prevalence. Pathogenesis of pancreatic neuroendocrine tumors is characterized by common pathways of hereditary and sporadic tumors. Pancreatic neuroendocrine tumors may secrete peptide hormones or biogenic amines in an autonomous fashion as functional active tumors. Pathological grading and staging by TNM systems has been established in recent years classifying well and moderately differentiated pancreatice neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Chromogranin A and less so pancreatic polypeptide are suitable tumor markers for pancreatic neuroendocrine tumors. Expression of receptors for somatostatin is the basis of treatment of pancreatic neuroendocrine tumors with somatostatin analogues as antisecretive and antiproliferative agents. In addition, somatostatin scintigraphy or PET/ CT allows comprehensive diagnosis of pancreatic neuroendocrine tumors, which should be supported by (endoscopic and contrast enhanced) ultrasound, CT and MRI. Therapy of pancreatic neuroendocrine tumors consists of somatostatin analogues, chemotherapy, targeted therapy and peptide receptor radionuclide therapy. Two molecular substances hav been registered for pancreatic neuroenCorresponding author: D. Hörsch MD, Department of Gastroenterology and Endocrinology, Center of Neuroendocrine Tumors Bad Berka - ENETS Center of Excellence, Bad Berka GmbH Central Clinic, Robert-Koch-Allee 9, D 99437 Bad Berka, Germany. E-mail: [email protected]

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1Center

for Neuroendocrine Tumors Bad Berka ENETS Center of excellence Bad Berka, Germany 2Department of Internal Medicine Gastroenterology and Endocrinology Central Clinic, Bad Berka GmbH, Bad Berka Germany 3First Department of Internal Medicine Hamburg-Eppendorf Clinical University Hamburg, Germany 4General and Visceral Surgery Central Clinic, Bad Berka GmbH, Bad Berka Germany 5Department of Interventional Radiology Central Clinic, Bad Berka GmbH, Bad Berka Germany 6Clinic for Molecular Radiotherapy/Center of Molecular Imaging Central Clinic, Bad Berka GmbH, Bad Berka Germany

docrine tumors recently, sunitinib (Sutent®) and everolimus (Afinitor®). Predominant tumor load in the liver may be treated by local ablative therapy or liver transplantation. These treatment options have been included in guidelines of several professional societies and weighted for sequential therapy of patients with pancreatic neuroendocrine tumors according to effects and side effects. Key words: Neuroendocrine tumors - Pancreatic neoplasms - Molecular targeted therapy.

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ancreatic neuroendocrine tumors originate from the diffuse neuroendocrine system in the pancreatic region. These tumors exhibit a rising incidence despite their

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HÖRSCH

Pancreatic neuroendocrine neoplasms

rareness and due to their benign behavior a considerable prevalence. Predominant tumor load in the liver may be treated by local ablative therapy or liver transplantation. These treatment options have been included in guidelines of several professional societies and weighted for sequential therapy of patients with pancreatic neuroendocrine tumors according to effects and side effects. Ontogenesis of pancreatic neuroendocrine cells The diffuse neuroendocrine system comprises dispersed endocrine cells consisting of more than 15 cell types differentiated by their content of hormones or transmitters. These cells are active as single or grouped cells and by autocrine, paracrine or endocrine regulation of physiological functions such as blood glucose regulation, peristalsis, secretion of bile and pancreatic juice and appetite. A number of markers are commonly expressed by neuronal and endocrine cells such as chromogranin A, synapthophysin and neureon specific enolase and have thus contributed to the term neuroendocrine. However, only a minority of neuroendocrine cells are derived of the neural crest as neuronal cells.1 Pancreatic neuroendocrine cells stem from buds of the endoderm. During organogenesis of the pancreas, the first endocrine cells are glucagon-producing cells which may switch to insulin producing cells. The majority of pancreatic neuroendocrine cells develops during the second transition and multipotent precursors express Ptfla, c-myc and carboxypeptidase a1 2 and a few days later Ngn-3, which leads to the development of all pancreatic endocrine cell types such as insulin, glucagon, somatostatin and pancreatic polypeptide which then form the islets of Langerhans.3-6 In contrast to neuroendocrine cells of the gut which derive constantly from stem cells at the base of intestinal crypts, neuroendocrine cells of the pancreas are rather stationary with slow proliferation and neogenesis.

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Pathogenesis of pancreatic neuroendocrine neoplasms Most pancreatic neuroendocrine tumors develop sporadically. In a minority of patients, hereditary syndromes such as multiple endocrine neoplasia type 1, VonHippel-Lindau disease, tuberous sclerosis and neurofibromatosis type 1predispose development of pancreatic neuroendocrine tumors. However, recent studies indicate a close relationship between sporadic and hereditary pancreatic neuroendocrine tumors. Jiao et al.7 sequences about 18000 genes coding for proteins in 10 sporadic pancreatic neuroendocrine tumors and detected a distinct gene signature compared to pancreatic ductal adenocarcinomas. The mutated genes were validated in a large cohort of 58 additional sporadic pancreatic neuroendocrine tumors. Results indicated common pathogenic pathways of sporadic and hereditary pancreatic neuroendocrine tumors. Mutations in tumor suppressor gene menin causing multiple neuroendocrine neoplasia syndrome type 1, characterized by hyperparathyroidism, hypothalamic adenomas and pancreatic neuroendocrine tumors, was found to be mutated in 44% of sporadic pancreatic neuroendocrine tumors. Likewise, mutations in pathways responsible for development of neurofibromatosis 1 or tuberous sclerosis such as phosphatidylinositol 3-kinase and serine/threonine kinase mTOR are altered in 17.5% of sporadic pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors with mutations in menin gene and genes of the DAXX/AXTR telomerase complex show a more benign biological behavior than tumors without these mutations. Sporadic pancreatic neuroendocrine tumors do not share common mutations with the more aggressive ductal adenocarcinomas of the pancreas such as p53 or ras, which may explain the more indolent behavior of pancreatic neuroendocrine tumors.7 Epidemiology and prognosis Pancreatic neuroendocrine tumors account for about 1.3% of pancreatic cancers with


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an incidence of about 1.2 to 5 per 1 million with an estimated prevalence ten times higher representing almost 10% of all living patients with pancreatic cancer.8-13 Incidence has been rising, mainly accounted for by improved pathological detection methods. However, most tumors are still discovered in advanced or metastasized stages. Median age at diagnosis is in the mid-fifties with a slight male predominance.8, 10 In a series of the Surveillance, Epidemiology, and End Results database encompassing 1274 patients with pancreatic neuroendocrine tumors from 1973 to 2003, median survival was 38 months. Survival depended upon tumor stage. Localized, regional and distant pancreatic neuroendocrine tumors survived in median 124 months, 70 months and 23 months, respectively. These data were collected at times of limited diagnostic and therapeutic modalities.8 A series from Sweden with a total of 324 patients with pancreatic neuroendocrine tumors analyzed at a tertiary referral center between 1967 and 2005 reported median survival times of approximately 230 months in stage 1, 120-180 months in stage 3 a and 3b and 230 months in stage 1 which are roughly comparable to distant, regional and localized stages in the the Surveillance, Epidemiology, and End Results database database.10 Improved survival may reflect a center effect, different treatment methods or both. Progression-free survival has been recently evaluated for advanced low-grade to intermediate-grade pancreatic neuroendocrine tumors in two placebo-controlled trials involving 85 14 and 203 patients 15 in the placebo arms depicting progression-free survival times of 5.5 and 4.6 months, respectively. Generally, incidence rates appear to be grossly underestimated and are expected to rise. Autopsy series reported high rates of miniscule pancreatic neuroendocrine tumors, which are however, clinically insignificant. Still, these data indicate that endocrine cells of the pancreas tend to dysplasia and proliferation with growing age.16 Grading, WHO classification, TNM systems and staging Biology of neuroendocrine tumors of the pancreas is determined by their differentia-

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tion and grading. Differentiation describes similarities between tumor cells and their non-neoplastic counterparts. Well-differentiated pancreatic neuroendocrine tumors are uniform and express neuroendocrine markers such as chromogranin A or synaptophysin whereas poorly differentiated ones express less neuroendocrine markers. Grade describes primarily proliferation rate of neuroendocrine tumors by rate of mitosis and/or Ki67 index by application of monoclonal antibody Kiel67 labeling proliferating cells by immunohistochemistry.17 Whereas Ki67 index is commonly used in Europe, its application in other parts of the world remains controversial.18 According to recommendations of the European Neuroendocrine Tumor Society (ENETS), a full pathological report for pancreatic neuroendocrine tumors should contain immunohistochemistry for chromogranin A, synaptophysin, Ki67 or MIB-1 and possibly other hormones or nuclear receptors such as insulin, gastrin, TTF-1 and complete staging employing a TNM system.19 In 2010, a new WHO classification replaced the one of 2000. Here, all neuroendocrine tumors or carcinomas are depicted as neuroendocrine neoplasms (NEN) and stratified into two groups; the neuroendocrine tumors with grade 1 and 2 and neuroendocrine carcinomas grade 3. Grading is performed due to mitotic rate and Ki67 index. Grade 1 (Ki67 index 20

a10

HPF: high power field=2 mm2, at least 40 fields (at 40× magnification) evaluated in areas of highest mitotic density antibody; % of 2,000 tumor cells in areas of highest nuclear labeling (Adopted from Klöppel G 17, Rindi G 19) bMIB1

Table II.—TNM Systems of ENETS and AJCC/UICC. Different T Stages of ENETS suggestion of 2006 and AJCC/UICC classification of 2010. ENETS TNM (2006)

T1 T2

AJCC/UICC TNM (2010)

Confined to pancreas, 4 cm, or invasion of duodenum or bile duct Peripancreatic spread with invasion of large vessels or adjacent organs

T3 T4

Confined to pancreas, 1.5 mg/ dL; shunts to the gut or a lung-shunt >20%). For NET with hepatic dominant disease under SIRT-therapy high-rate and long lasting remissions are reported.53 However this method should be done only in specialized centres with expertise in treatment and also in management of possible complications like RILD (radiation induced liver disease). Another type of local treatment-options are thermal procedures like cryotherapy (CRYO), radiofrequency thermal ablation (RFTA), laser-induced interstitial thermal ablation (LITT) or microwaves (MW). The best known and mostly used type is the RFTA. Tumor masses are destroyed by electromagnetic energy deposition in the target volume. Over an alternating electromagnetic field within the tissues (with relatively high electrical resistance) an agitation of ions in the target volume is induced which


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Figure 12.—B) Same patient as in Figure 11 – CT-Scan pre (upper row) and 4 weeks post TACE (lower row). Dissapearance of lower mts and remining gas bubbles as results of tissue necrosis.

results in frictional heat. At temperatures of 60-110 °C a thermal coagulation of the tissue is induced, with secondary damages of surrounding tissues by thermal induced apoptosis. The heat, induced by the process is correlated with intensity and duration of RF-energy. Tissues cannot be heated to temperatures greater than 110 °C, due to gas production by the process, that retards the ability to establish a stable electric field. This effect and the cooling effect of circulating blood flow will limit effective thermocoagulation to a diameter of 5 cm of the treated tumor metastasis. Good treatment follows the so called “rule of five”: not more

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than 5 metastases, diameter of metastases lower than 5 cm. Effectivity of RFTA-treatment could be improved by combination with embolization (TACE) prior to RFTA, or by temporarily occlusion of portal vein (Pringle manoeuvre) by ballon catheter.55, 56 RFTA can be used where a surgery could not be done, or in combination with it, if a complete destruction of metastases seems to be possible. The procedure can be done by percutaneous or laparascopic approach and has a low morbidity by itself.55 For the RFTA in small tumor masses of pNET until now the clinical benefit has not been established clearly, so this treatment option


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should be chosen carefully.56 An overview on local treatment options in relation to different stages of disease is given in Table III. Somatostatin analogues Treatment with somatostatin analogues or congeners is termed biotherapy although is it basically a molecular targeted therapy activating an inhibitory G-protein coupled receptor and inducing intracellular signaling cascades hampering hormone secretion and proliferation of neuroendocrine tumor cells. Short half-life of naturally occurring somatostatin-14 and somatostatin-28 lead to development of cyclic octapeptides as longer acting somatostatin-analogues such as octreotide, vapreotide or lanreotide.56 These peptides were initially administered as subcutaneous or intravenous application. Octreotide and lanreotide have been further modified to allow 4-weekly application as octreotide-LAR or lanreotide-autogel. Due to their inhibitory function on hormone secretion, somatostatin analogues are the method of choice to treat functional active tumors except for gastrinomas, which are effectively treated by proton pump inhibitors. Uncontrolled studies indicated that somatostatin

analogues may also act antiproliferatively on pancreatic neuroendocrine tumors. Butturini et al.57 treated 21 consecutive patients harboring pancreatic neuroendocrine tumors by monthly octreotide-LAR 20 mg and reported a median progression free survival of 48 months. Patients without abdominal pain, weight loss and a low proliferation index showed the best response indicating that somatostatin analogues treatment is effective in patients with slowly growing tumors and low tumor mass.57 A number of other studies indicated benefit of somatostatin analogues in patients with pancreatic neuroendocrine tumors, however, results are inconsistent and difficult to compare.18, 42, 56 It is astonishing that despite its widespread use, there are no prospective and comparative data on antiprilferative effects of somatostatin analogues in patients with pancreatic neuroendocrine tumors while current guidelines citing frequently review articles and sparse or inappropriate original data. Altogether, clinical trials were not performed nor powered to answer the question whether somatostatin analogues retarde growth of pancreatic neuroendocrine tumors. However, pancreatic origin of neuroendocrine tumors is frequently labeled as a negative prognostic factor in tri-

Table III.—Local therapeutic options in the treatment of non-resectable liver metastases. Type of disease

Strategy

Single spots “rule of five” 55% responded better to platinum-based chemotherapy than patients with a lower index, however, prognosis was still worse in patients with a proliferation rate of more than 55%. Negative prognostic factors were poor performance status, elevated lactate dehydrogenase levels and elevated platelets. Reponse rates were similar with respect to different platincompounds (cisplatin or carboplatin) and subtypes of neuroendocrine carcinomas.71 Well differentiated pancreatic neuroendocrine tumors respond to streptozotocinbased combination chemotherapies. The glucosamine-nitrosurea compound streptozotocin acts as an alkylating agent and binds to the glucose transporter GLUT2, highly expressed on insulin producing beta cells. Initial reports by Moertel et al. in 1980 72 reported increased response rates of a combination chemotherapy with streptozotocin in combination with 5-FU versus streptozotocin alone (overall response rate 63% versus 36%, with response duration of 17 months in both arms and longer survival of streptozotocin/5-FU of 26 months versus 17 months). A comparative trial of streptozotocin/doxorubicin versus streptozotocin/5FU 73 showed advantages of combination with doxorubicin than with 5-FU (69% overall response rate, a time to progression of 17 months and overall survival of 26 months compared to streptozotocin/5FU (overall response rate 45%, progression free survival 14 months and overall survival 18 months). However, response rate in this early trial did not include stringent radiological control of tumor progression and response rates in following trials declined. A smaller trial in 12 patients treated with a combination of streptozotocin with doxorubicin and 5-FU yielded a response rate of 55%, response duration of 15 months and overall survival of 21 months.74 A larger study with 176 patients and stringent ra-

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diological response follow up according to WHO standards compared streptozotozin in combination with either doxorubicin or 5-FU. Although response rated and duration of response was similar in both arms, there was a considerable survival advantage in the streptozotocin/5-FU arm (24.3 months versus 15.7 months).75 A small and uncompleted trial on pancreatic and bronchial neuroendocrine tumors (ENET-1 trial) compared chemotherapy with streptozotozin/5FU with octreotide treatment (octreotideLAR 30 mg/every 4 weeks). An interim analysis published in abstract form 76 reports a higher rate of response by chemotherapy with a similar time to tumor progression. Adding cisplatin to streptozotocin-based chemotherapy regimens does not increase response rates.77 Dacarbazine and its oral derivative temozolomide are alkylating cytotoxic drugs. Dacarbazine as a monotherapy is effective in patients with pancreatic neuroendocrine tumors with a reported response rate of 33% but limited overall survival of 19 months.78 The usage of dacarbazine as single agent is not recommend for second line treatment after combination chemotherapy. A recently published trial with temozolomide alone or in combination with capecitabine reported high response rates in patients with pancreatic neuroendocrine tumors that were associated with low levels of methylguanine DNA methyl transferase.79 Adding thalidomide to temozolomide yields a high response rate of 45% and a median response duration of 13 months in patients with pancreatic neuroendocrine tumors.80 A recent examination of temozolomide in combination with VEGF-antibody bevacizumab (Avastin®) in 15 patients with locally advanced or metastatic pancreatic neuroendocrine tumors, 5 patients had a response which lasted in median for 14.3 months and a median survival of 41.7 months.81 A long lasting response rate of 70% was reported in a retrospective series on 30 patients with pancreatic neuroendocrine tumors treated with a combination of temozolomide and capecitabine. Median progression free survival was 18 months and rate of survival at


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2 years 92%.82 These data indicate that combination chemotherapy with temozolomide is an effective treatment for patients with pancreatic neuroendocrine tumors, however, results should be corrobated in controlled prospective clinical trials. We have not been able to affirm reported response rates 82 in pretreated patients with pancreatic neuroendocrine tumors. Few clinical trials evaluating chemotherapy regimens are ongoing. The NET01 trial is testing streptozotozin with capecitabine with or without cisplatin in 84 patients with unresectable gastroenteropancreatic tumors (NET01; http://www.ukinets.org/clinical/ docs/NET1-Trial.pdf assessed 18. July 2012). Another study is testing FOLFOX polychemotherapy with the addition of anti-angiogenic antibody bevacizumab is ongoing. A large controlled and prospective trial was initiated by R. Salazar/Spain to compare chemotherapy (streptozotozin/5-FU) with everolimus (Afinitor®) in patients with advanced or metastatic pancreatic neuroendocrine tumors and will hopefully start soon. Peptide receptor radiotherapy Somatostatin receptors expressed on pancreatic neuroendocrine tumor cells may not only be used for treatment with somatostatin analogues or visualization by somatostatin scintigraphy or PET/CT but also for treatment by internal radiation using betaand gamma emitting radionuclides such as Yttrium-90 or Lutetium-177, which is termed peptide receptor radionuclide therapy. Suitable patients are selected by high somatostatin receptor expression, low proliferation index (