Natural course of small, asymptomatic neuroendocrine pancreatic tumours in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study

Endoscopic ultrasound (EUS) enables detection and localization of pancreatic neuroendocrine tumours. Even small tumours down to a diameter of 1-2 mm can be visualized. Since such small tumours usually cannot be detected by computed tomography (ct), magnetic resonance imaging (mri) and somatostatin receptor scintigraphy (srs), and experience with EUS imaging is limited, there is no clear evidence for clinical management in multiple endocrine neoplasia type 1 (MEN1). Knowledge about the natural course of growth and metastatic distribution is mandatory to come to appropriate clinical decisions and guidelines. This prospective study was aimed to assess the natural course of small (<15 mm) neuroendocrine pancreatic tumours without clinical symptoms due to endocrine activity or mechanical problems and without clear indication for surgical therapy in MEN1 by EUS. A total of 82 asymptomatic tumours<15 mm (5.9+/-3.2 mm diameter at baseline) in 20 patients with MEN1-disease (8 female/12 male, 43+/-13 years) were studied over a period of 20+/-12 months (33.8 patient years, 106.7 tumour years) by EUS. Change in largest diameter of each tumour and annual tumour incidence rate in the patients' cohort were calculated. Increase of largest tumour diameter was found to be 1.3+/-3.2% per month, annual tumour incidence rate 0.62 new tumours per patient year. In one patient, rapid progressive pancreatic manifestation of MEN1 was observed. There was no evidence in ct and/or srs and/or mri for metastatic disease in all patients. Only 4/84 (4.8%) pancreatic tumours could be visualized by computed tomography, 5/79 (6.3%) by somatostatin receptor imaging and 4/39 (10.3%) by magnetic resonance imaging. Small asymptomatic neuroendocrine pancreatic tumours in MEN1 usually seem to grow slowly. Annual tumour incidence rate is low. However, faster growing tumours and patients with rapidly progressive disease can be observed. Risk for obvious metastatic disease from asymptomatic neuroendocrine pancreatic tumours<15 mm in MEN1 seems to be low.     

The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut

The measurement of general and specific biochemical markers in patients with neuroendocrine tumours assists with diagnosis and gives an indication of the effectiveness of treatment and they may be used as prognostic indicators. There is much agreement that chromogranin A is the most universally helpful marker; it is found to be elevated in the circulation of about 90% of patients with metastatic neuroendocrine tumours and there are several excellent commercially available kits which give reliable estimations. Specific markers are useful for diagnosis also, and are helpful indicators of the effectiveness of treatment, particularly where tumour bulk may not change as much as tumour activity. Sporadic pancreatic neuroendocrine tumours may secrete more than one peptide and this indicates a worsening prognosis. Because of the wide variation in the progression of neuroendocrine tumours, a prognostic indicator gives a significant advantage to the clinician in order to facilitate optimum treatment at the optimum stage of disease. Both chromogranin A and neurokinin A have been used as powerful prognostic indicators for midgut carcinoid tumours.     

Severe hypoglycaemia after long-acting octreotide in a patient with an unrecognized malignant insulinoma

Insulinomas are the most common hormone-producing pancreatic neuroendocrine tumours (NETs), and patients usually present with symptoms secondary to hypoglycaemia. Octreotide has been widely used in the symptomatic treatment of patients with pancreatic NETs, including insulinomas. We describe a case of a patient with a metastatic NET, subsequently identified as a malignant insulinoma, who developed severe hypoglycaemia after treatment with long-acting octreotide.     

Multidisciplinary management of refractory insulinomas

Insulinomas are predominantly benign (~90%), pancreatic neuroendocrine tumours characterized by hyperinsulinaemic hypoglycaemia. They usually present as a small (<2 cm), well‐demarcated, solitary nodule that can arise in any part of the organ. Treatment for sporadic insulinomas is generally aimed at curative surgical resection with special consideration in genetic syndromes. Patients with significant hypoglycaemia can pose a difficult management challenge. In isolated cases where the patient is not medically fit for surgery or with metastatic spread, other treatment options are employed. Medical therapy with diazoxide or somatostatin analogues is commonly used first line for symptom control, albeit with variable efficacy. Other medical options are emerging, including newer targeted biological therapies, including everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor) and pasireotide, a multisomatostatin receptor ligand. Pasireotide and everolimus both cause hyperglycaemia by physiological mechanisms synergistic with its antitumour/antiproliferative effects. Minimally invasive treatment modalities such as ethanol ablation are available in selected cases (particularly in patients unfit for surgery), peptide receptor radionuclide therapy (PRRT) can effectively control tumour growth or provide symptomatic benefit in metastatic disease, while cytotoxic chemotherapy can be used in patients with higher‐grade tumours. This review considers the developments in the medical and other nonsurgical management options for cases refractory to standard medical management. Early referral to a dedicated neuroendocrine multidisciplinary team is critical considering the array of medical, oncological, interventional radiological and nuclear medical options. We discuss the evolving armamentarium for insulinomas when standard medical therapy fails.     

Endosonographic and cyst fluid characteristics of cystic pancreatic neuroendocrine tumours: A multicentre case series

BackgroundPancreatic neuroendocrine tumours are uncommon neoplasms which may rarely be cystic. Differentiation from other more common cystic neoplasms may be difficult.AimsTo describe the morphologic, cytologic, and cyst fluid characteristics of cystic pancreatic neuroendocrine tumours.MethodsRetrospective analysis of consecutive patients referred for endosonographic evaluation of pancreatic cysts at four centres.Results27 patients (12 males) with cystic pancreatic neuroendocrine tumours were identified. Prior to endosonography, this tumour was suspected in only 2 patients based on presenting symptoms (7.4%). The median cyst size was 35 mm (range 8–80 mm). Wall thickening was identified in 13 cases. The median carcinoembryonic antigen level was 1.25 (range 0.6–500). Fine needle aspiration cytology in 17 of 24 patients confirmed neuroendocrine tumour (71%). In 8 of 9 patients who had needle targeting of the cyst wall, cytology was consistent with neuroendocrine tumour (88.9%). 18 patients underwent surgical resection.ConclusionsCystic pancreatic neuroendocrine tumour was rarely suspected, including by cross-sectional imaging. Wall thickening was identified in approximately half of cases on endosonography. Cyst fluid was typically non-viscous with very low carcinoembryonic antigen levels. Targeting the wall during fine needle aspiration had a high diagnostic yield and should be performed.     

Cytotoxic treatment including embolization/chemoembolization for neuroendocrine tumours

In patients with advanced neuroendocrine tumours, surgery is curative in only a minority of cases, whilst the anti-tumour effect of somatostatin analogues, despite efficient symptom control, is limited. Systemic chemotherapy has been proved to be effective only in certain tumour types. Although metastatic midgut carcinoids and well-differentiated gastrointestinal carcinoids are relatively insensitive to chemotherapy, pancreatic neuroendocrine tumours show a response rate of around 40% to streptozotocin-based combinations, particularly with fluorouracil and doxorubicin. Poorly differentiated tumours respond even better, especially to a combination of cisplatin and etoposide. In patients with predominant liver disease, ischaemia of tumour lesions induced by vascular occlusion by particle embolization or chemoembolization may be considered. This may have clinical and biochemical responses up to 80%, and objective responses up to 60%, in disease which is progressive despite previous treatments. Potential adverse effects and short duration of response should be taken into account.     

Capsule endoscopy to detect primary tumour site in metastatic neuroendocrine tumours

BackgroundIn patients with metastatic neuroendocrine tumours, primary tumour localisation is often difficult with morphological and/or functional imaging. Although utilised in investigating various small bowel pathologies, evidence for using video capsule endoscopy to identify suspected small bowel primaries in patients exhibiting metastatic neuroendocrine tumours is limited.AimsTo assess the role of video capsule endoscopy in locating primary small bowel neuroendocrine tumours when conventional imaging fails to identify the origin of metastatic disease.MethodsWe retrospectively compared our institutional database of patients presenting with metastatic neuroendocrine tumours between January 2010 and December 2013 with an analogous database of patients undergoing video capsule endoscopy for various indications. Patients whose primary tumours were not located radiologically and also underwent capsule endoscopy were identified.Results390 patients with metastasised neuroendocrine tumours presented within the study period. In 11 (2.8%) the primary tumour was not located radiologically. Video capsule endoscopy identified lesions suggestive of small bowel primary in 8/10 patients in whom it was successful. Small bowel primary was confirmed by histological analysis of surgical specimens.ConclusionsOur study supports the use of video capsule endoscopy as part of the diagnostic work-up in selected patients presenting with metastatic neuroendocrine tumours of unknown primary. The clinical utility of this technology requires clearer definition.     

Pancreatic neoplasm in 2011: an update

Pancreatic cancer still is a significant, unresolved therapeutic challenge with nearly similar incidence and mortality rates. It is the most lethal type of digestive cancer with a 5-year survival rate of 5%. Adjuvant chemotherapy remains to be gemcitabine alone or combined with infusional 5-fluorouracil with radiation therapy. Nevertheless, only a few patients survive for at least 5 years after R0 resection and adjuvant therapy. Most patients need palliative treatment. Once pancreatic cancer becomes metastatic, it is uniformly fatal with an overall survival of typically 6 months from diagnosis. Chemotherapy is an important component of palliative care but must be administered as a part of a multidisciplinary approach, including palliation of pain, managing weight loss, and deterioration in functional status. Gemcitabine has been the standard in both locally advanced and metastatic disease. The addition of the tyrosine kinase inhibitor erlotinib prolongs median survival for only 2 weeks. While gemcitabine-based regimens are currently accepted as the standard first-line treatment of patients with locally advanced or metastatic pancreatic adenocarcinoma, there is no consensus regarding treatment in the second-line setting. It will not be untrue to say that there are no real medical breakthroughs with regards to improving the prognosis of pancreatic cancer as of 2011. On the other hand, we have made some progress in patients with advanced pancreatic neuroendocrine tumors. These patients have a 5-year survival that can range from 97% in benign insulinomas to as low as 30% in non-functional metastatic pancreatic neuroendocrine tumors. Treatment options may include surgery, transarterial chemoembolization of liver metastases, and cytotoxic therapy such as streptozotocin, 5-fluorouracil or doxorubicin. Somatostatin analogues, like octreotide, have been proven to prolong progression-free survival in patients with metastatic neuroendocrine tumors of midgut origin. In 2011, two targeted agents, a tyrosine kinase inhibitor sunitinib and mTOR inhibitor everolimus have been approved by FDA for pancreatic neuroendocrine tumors. With these approvals, U.S. physicians can now offer their patients with progressive pancreatic neuroendocrine tumors. Patients with any stage of pancreatic cancer should be considered candidates for clinical trials.     

Localization of neuroendocrine tumours and insulinomas using radiolabeled somatostatin analogues, 123 I-Try3-octreotide and 111in-pentatreitide

OBJECTIVE A number of neoplasms are known to express somatostatin receptors; the use of somatostatin receptor imaging in their localization has recently been described, but the resolution and discrimination of the isotopes used remains sub-optimal. We have looked at the use of a new” In-labelled analogue of somatostatin, pentatreotide, in the visualization and functional characterization of a number of neoplastic conditions. PATIENTS Thirteen patients with proven neoplasms were scanned using this agent. Planar and single-photon-emission computerized tomographic (SPECT) images of the relevant part of the body were obtained using a gamma-camera at 10 minutes and 4 and 21 hours after injection of the radiopharmaceutical. In six patients (three carcinoid, three insulinomas) scanning was also performed using ¹²³l-Tyr-3-octreotide. RESULTS Primary tumours or metastases were visualized in six of the seven patients with neuroendocrine tumours, and three of six patients with insulinoma. One patient with an insulinoma who had a positive scan showed absent uptake when rescanned after tumour removal. A rise In blood glucose (more than twice basal) in response to octreotide was seen only in those insulinoma patients with positive scans. In cases where both ¹¹¹ln-pentatreotide and ¹²³l-Tyr-3-octreotide scans were performed, both radiopharmaceuticals identified the same 4/ 6 tumours; however, tumour definition (reflecting high tumour to background ratio) was better with pentatreotide on the 21-hour images with minimum biliary and gut activity, allowing better resolution of the tumour image. CONCLUSION It appears that ¹¹¹ln-pentatreotide scintigraphy is a rapid and safe procedure for the visualization of neuroendocrine tumours possessing somatostatin binding sites. A positive scan may be predictive of neuroendocrine responsiveness to octreotide therapy. In addition, it also appears that¹” In-pentatreotide has superior kinetics compared to ¹²³I-Tyr-3-octreotide, typically achieving more satisfactory tumour to background ratios, and may thus be more useful in the localization of endocrine tumours.     

Somatostatin receptor subtype 5 (SSTR5) mRNA expression is related to histopathological features of cell proliferation in insulinomas

Insulinomas are rare endocrine neoplasias that constitute the most frequent islet cell tumours. Somatostatin (SST) analogs are tentatively used to inhibit insulin secretion and control tumour growth in patients with local invasion or inoperative metastasis, but variable responses have been reported. Data regarding somatostatin receptor (SSTR) subtypes expression in insulinomas are conflicting. In this study, we evaluated 16 cases of primary insulinomas (including four primary plurihormonal tumours) and two hepatic metastases. Histopathological and immunohistochemical analysis for some features associated with tumour aggressiveness and semi-quantitative RT-PCR for SSTR1-5 and real-time qPCR for SSTR5 were performed. SSTR subtypes 1, 3, and 5 were expressed in 100%, SSTR2 in 89%, and SSTR4 only in 22% of the insulinomas. SSTR5 mRNA was positively correlated with histopathological features related to tumour aggressiveness (large tumour diameter, well-differentiated endocrine tumour with uncertain behaviour and higher number of cells with nuclear atypia). SSTR5 mRNA expression in primary insulinomas was lower than in primary plurihormonal tumours (P < 0.05). The observed positive correlation between SSTR5 expression and tumour size suggests that the use of SST analogues more specific to SSTR5 in the treatment of insulinomas deserves attention.     

Digestive neuroendocrine tumours: diagnosis and treatment in Italy. A survey by the Oncology study Section of the Italian Society of Gastroenterology (SIGE)

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.     

Parathyroid hormone-related peptide in pancreatic neuroendocrine tumours associated with hypercalcaemia

BackgroundHypercalcaemia is a common paraneoplastic syndrome. In the context of pancreatic neuroendocrine tumours, it is occasionally caused by secretion of parathyroid hormone-related peptide (PTH-rP).Case outlinesTwo patients are reported in whom persistent hypercalcaemia was traced to a large neuroendocrine pancreatic tumour hypersecreting PTH-rP. Resection of the tumour reduced serum levels of calcium and PTH-rP transiently in each case until the patient developed bulky metastatic disease. A 33-year-old woman remained hypercalcaemic after the removal of all four hyperplastic parathyroid glands had rendered circulating parathormone levels undetectable. Radical distal pancreatectomy was followed over the next 4 years by operative debulking of liver metastases, multiple hepatic artery embolisations.octreotide injections and repeated admissions for intravenous fluid and biphosphonate therapy. A 41-year-old man presented with hypercalcaemia as well as features of somatostatinoma syndrome. Symptomatic improvement after radical distal pancreatectomy was short-lived, and hepatic artery embolisation failed to control his rapidly progressive disease.DiscussionMalignant hypercalcaemia associated with a neuroendocrine pancreatic tumour hypersecreting PTH-rP is difficult to treat and can be life-threatening. Aggressive surgical treatment is recommended initially, while somatostatin analogues and hepatic artery embolisation are alternative therapeutic options for metastatic disease.     

Imaging of neuroendocrine gastro-entero-pancreatic tumours using radiolabelled somatostatin analogues

Neuroendocrine tumours of the gastro-entero-pancreatic tract are an uncommon clinical entity and are believed to arise from the endocrine cells of the gastrointestinal tract. Somatostatin receptor imaging is a diagnostic tool which allows visualization of somatostatin receptor bearing tumours. This scintigraphic procedure is performed with indium-111 labelled octreotide, a somatostatin analogue, chelated with diethylene triamine penta-acetic acid. Radionuclide imaging consists in detecting the biodistribution of somatostatin receptors, normally expressed on the cell surface of neuroendocrine gastro-entero-pancreatic tumours. To date, five types of this receptor have been cloned: indium-111-labelled-pentetreotide can visualize tumours expressing type 2 and 5 receptors. The results of our study, which involved 81 neuroendocrine gastro-entero-pancreatic tumour patients, confirm the superior sensitivity of somatostatin receptor imaging (61%) for primary tumour evaluation with respect to conventional imaging modalities such as computed tomography (40%) or ultrasound (28%). Scintigraphic findings in metastatic liver disease proved to have a sensitivity of 89% for somatostatin receptor imaging, versus 81% and 88% for computed tomography and ultrasound, respectively. In 23% of patients, lesions were found with somatostatin receptor imaging which had been missed using the other diagnostic modalities; in 26% of the patients the therapeutic approach was modified after somatostatin receptor imaging.     

Ultrastructural diagnosis of neuroendocrine tumors using fine needle biopsy

Ultrasonic-guided fine-needle-biopsies of primary pancreatic tumours or liver metastasis were performed in 13 patients with neuroendocrine tumours of the gastrointestinal tract (5 carcinoids, 3 gastrinoma, 1 PPoma, 1 calcitoninoma, 1 insulinoma, and 2 non-functional tumours). Specimens obtained were examined on the light- and electronmicroscopic level. In all cases ultrastructural examination sufficiently revealed the correct diagnosis, due to the presence of cytoplasmic neuroendocrine granules within the tumour cells. Additionally performed immunocytochemical investigations at the ultrastructural level enabled the discrimination of gastrinomas, insulinomas, and PPomas. In contrast, light-microscopic examination was less sensitive for tumour classification. It is concluded that ultrastructural investigation of fine needle biopsies represents a valuable method to sufficiently discriminate neuroendocrine neoplasms.     

Hereditary pancreatic endocrine tumours.

The two main types of hereditary pancreatic neuroendocrine tumours are found in multiple endocrine neoplasia type 1 (MEN-1) and von Hippel-Lindau disease (VHL), but also in the rarer disorders of neurofibromatosis type 1 and tuberous sclerosis. This review considers the major advances that have been made in genetic diagnosis, tumour localization, medical and surgical treatment and palliation with systemic chemotherapy and radionuclides. With the exception of the insulinoma syndrome, all of the various hormone excess syndromes of MEN-1 can be treated medically. The role of surgery however remains controversial ranging from no intervention (except enucleation for insulinoma), intervening for tumours diagnosed only by biochemical criteria, intervening in those tumours only detected radiologically (1-2 cm in diameter) or intervening only if the tumour diameter is > 3 cm in diameter. The extent of surgery is also controversial, although radical lymphadenectomy is generally recommended. Pancreatic tumours associated with VHL are usually non-functioning and tumours of at least 2 cm in diameter should be resected. Practice guidelines recommend that screening in patients with MEN-1 should commence at the age of 5 years for insulinoma and at the age of 20 years for other pancreatic neuroendocrine tumours and variously at 10-20 years of age for pancreatic tumours in patients with VHL. The evidence is increasing that the life span of patients may be significantly improved with surgical intervention, mandating the widespread use of tumour surveillance and multidisciplinary team management.     

Tumour markers in neuroendocrine tumours

Most of the neuroendocrine tumours produce and secrete a large number of peptide hormones and amines. Each of these substances cause a specific clinical syndrome: carcinoid, Zollinger-Ellison, hyperglycaemic, glucagonoma and WDHA syndrome. Specific markers for these syndromes are basal and/or stimulated levels of: urinary-5-HIAA, serum or plasma gastrin, insulin, glucagon, and VIP, respectively. About 1/3 of neuroendocrine tumours belong to the so-called "non-functioning" tumours. Therefore, general markers such as chromogranin A, pancreatic polypeptide, serum neuronspecific enolase and subunit of glycoprotein hormones have been used for screening purposes in patients without distinct clinical hormone related syndromes. Among these general tumour markers chromogranin A, although its precise function is not yet established, has been shown to be a very sensitive and specific serum marker for various types of neuroendocrine tumours. This is because it may also be increased in many cases of less well differentiated tumours of neuroendocrine origin that do not secrete known hormones. Then chromogranin A is considered the best general neuroendocrine serum or plasma marker available at the moment and is increased in 50-100% of patients with various neuroendocrine tumours. Chromogranin A serum or plasma levels reflect tumour load and may be an independent marker of prognosis in patients with midgut carcinoids.     

Pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumours are rare tumours ( approximately 1/100,00 population/year) of which 60% are non-functioning. Except for insulinoma all types are malignant in >50% of cases. In multiple endocrine neoplasia (MEN)1, pancreatic neuroendocrine tumours occur in 40-80% of patients and are mostly non-functioning tumours or gastrinomas. Insulinomas are benign in approximately 90%, solitary in 95% of sporadic cases whilst multiple in 90% of MEN1 patients. In contrast approximately 50% gastrinomas and the majority of non-functioning pancreatic neuroendocrine tumours are malignant. Pancreatic neuroendocrine tumours occur in 10-15% of patients with Von Hippel-Lindau (VHL) and are frequently multiple (>30%). Surgical excision is a key aspect of treatment for all cases of sporadic gastrinoma and if >2.5 cm in MEN1. Insulinomas are enucleated if solitary and may require pancreatectomy if multiple. Non-functioning tumours should also be resected if sporadic and if >2 cm in MEN1 or if >2-3 cm in VHL. Tumours <1cm require yearly follow-up by CT or MRI from an early age in VHL. The local treatment for liver metastases is now well established and options include liver resection, chemoembolisation and radiofrequency ablation. Systemic therapies have also been better defined and include radionuclide therapy against somatostatin receptors or MIBG and chemotherapy especially for poorly differentiated tumours. A number of novel agents are currently in clinical development.     

Localization of gastroenteropancreatic tumours by angiography

Neuroendocrine tumours are seen on arteriography as diffusely enhancing masses without tumour vessels and without arteriovenous shunting. In 70 patients with surgically proven tumours, the sensitivity of angiography was 68% for extrapancreatic and 86% for hepatic lesions. Hepatic metastases have always been easier to demonstrate arteriographically than the primary tumour because of the absence of overlying bowel. Portal venous sampling is a sensitive technique for detecting functioning gastroenteropancreatic tumours. Sampling the small veins about the pancreatic head yielded a sensitivity of 62% but this is an invasive procedure in which considerable experience is required. Intra-arterial secretagogue, secretin for gastrinomas and calcium for insulinomas, selectively injected into the pancreatic and the hepatic arteries produce a diagnostic gastrin or insulin gradient respectively. The localization sensitivity of arterial stimulation with venous sampling is 77-89% for gastrinoma and 92% for pancreatic insulinoma. Recently, spiral CT in conjunction with selective intra-arterial rather than intravenous injection of contrast may increase the detection sensitivity of duodenal and pancreatic gastrinomas.     

New treatment strategies in advanced neuroendocrine tumours

Malignant well-differentiated neuroendocrine tumours of the pancreas and the gastrointestinal tract are rare and clinically challenging heterogeneous neoplasms. This review focuses on neuroendocrine tumours grade 1 and grade 2 (new WHO classification 2010), in comparison to the neuroendocrine tumours grade 3 group, corresponding to poorly differentiated neuroendocrine carcinomas. Surgical resection of the primary and metastases remains the only curative treatment, however many patients with neuroendocrine tumours are diagnosed once unresectable metastases have occurred; management of functioning syndromes with somatostatin analogues remains the priority. Pasireotide, a new somatostatin analogue, is currently undergoing evaluation for carcinoid syndrome. Treatment options for advanced neuroendocrine tumours differ from pancreatic gastrointestinal tract neuroendocrine tumours: (a) in pancreatic neuroendocrine tumours, streptozotocin-based chemotherapies are challenged by other cytotoxic agents (dacarbazine, temozolomide and oxaliplatin); two randomized, placebo-controlled phase III studies have demonstrated that everolimus and sunitinib significantly improved progression-free-survival; (b) in midgut neuroendocrine tumours, octreotide improved time-to-progression in patients with a low proliferation index and low liver burden; preliminary data suggesting efficacy of bevacizumab are still to be confirmed; the effect of everolimus associated with octreotide was almost significant on progression-free-survival in a phase III trial. Liver-directed therapies are effective in both tumour types. New techniques of embolization need further evaluation and must be formally compared to other therapies. Finally, peptide receptor radionuclide therapy has shown promising activity in non-comparative studies in advanced neuroendocrine tumours.     

Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil

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.