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.     

The role of somatostatin analogues in the treatment of neuroendocrine tumours

Neuroendocrine tumours belong to a heterogeneous family of neoplasms, originating in endocrine glands (such as the pituitary, parathyroid or the neuroendocrine adrenal glands), in endocrine islets (within the thyroid or pancreas) as well as in endocrine cells dispersed between exocrine cells throughout the digestive or respiratory tracts. The clinical behaviour of neuroendocrine tumours is variable; they may be functioning or not functioning, ranging from well-differentiated slow growing neuroendocrine tumours to poorly differentiated neuroendocrine tumours, which are highly aggressive malignant tumours. The development of somatostatin analogues as important diagnostic and treatment tools have revolutionised the clinical management of patients with neuroendocrine tumours. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with somatostatin analogues, tumour regression is rare. Development of new somatostatin analogues and new drug combination therapies should further improve the clinical management of these patients.     

New somatostatin analogues for radiotherapy of somatostatin receptor expressing tumours

Among various newly synthesized chelator-linked octreotide analogues 90Y-[DOTA-DPhe1, Thyr3]-octreotide (90Y-SMT 487) was finally selected for clinical development. In vitro, SMT 487 binds selectively with nanomolar affinity to the somatostatin receptor subtype 2 (IC30 = 0.39 nM +/- 0.02). In vivo, 90Y-[DOTA-DPhe1, Thyr3]-octreotide shows a rapid blood clearance (T1/2 alpha < 5 min) and high accumulation in somatostatin subtype 2 receptor expressing tumours. The in vivo administration of 90Y-[DOTA-DPhe1, Thyr3]-octreotide induces a rapid tumour shrinkage in three different somatostatin receptor positive tumour models: CA20948 rat pancreatic tumours grown in normal rats, AR42J rat pancreatic tumours and NCI-H69 human small cell lung cancer both grown in nude mice. The radiotherapeutic efficacy of 90Y-SMT 487 was enhanced in combination with standard anticancer drugs, such as mitomycin C, which resulted in a tumour decrease of 70% of the initial volume. In the CA 20948 syngeneic rat tumour model, a single treatment with 10 microCi/kg 90Y-SMT 487 resulted in the disappearance of 5 out of 7 tumours. Thus the new radiotherapeutic agent showed its curative potential for the selective treatment of SRIF receptor-expression tumours. Clinical Phase I studies with 90Y-SMT 487 were started in September 1997.     

Treatment of neuroendocrine tumors with somatostatin analogs

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

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.     

Systemic chemotherapy of advanced digestive neuroendocrine tumours

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.     

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 type I gastric neuroendocrine tumors with somatostatin analogs

Background and Aim: There are limited data on response and long‐term follow‐up of octreotide therapy in type‐I gastric neuroendocrine tumors. The objective of the present study was to assess the response of type‐I gastric neuroendocrine tumors to octreotide‐long acting, repeatable (LAR) therapy and evaluate long‐term follow up of such patients after therapy. Methods: Three patients with documented type‐I gastric neuroendocrine tumors from a tertiary gastroenterology centre were studied. Octreotide‐LAR therapy 20 mg intramuscularly every 28 days was administered for one year. Serum gastrin and chromogranin levels, gastroscopies and biopsies from tumor nodules at 6 months and one year on therapy and every 6 months after completion of drug therapy were taken. Follow‐up after completion of therapy extended for 3 years in two and 2.5 years in one patient. Results: During octreotide therapy there was normalization of serum gastrin levels and serum chromogranin levels. Tumors in all three patients had regressed at 6 months of treatment. Following cessation of therapy, there was progressive rise of serum gastrin to pre‐treatment levels. Serum chromogranin levels remained within normal limits. Gastroscopic and histologic examination of gastric biopsies did not reveal recurrence of tumors in any patients. All patients tolerated therapy well and became asymptomatic soon after drug therapy. Conclusions: Octreotide‐LAR therapy causes regression of type‐I gastric neuroendocrine tumors. After completion of drug therapy there was no recurrence of tumors even with continued hypergastrinemia. Octreotide therapy should be considered as one of the treatment options in such patients.     

Occurrence of exocrine pancreatic insufficiency in patients with advanced neuroendocrine tumors treated with somatostatin analogs

BackgroundAlthough exocrine pancreatic insufficiency (EPI) has been described in patients with neuroendocrine neoplasia (NEN) treated with somatostatin analogs (SSAs), its role in the therapeutic management of these patients is not well established.AimTo determine the frequency of EPI in patients with NEN long-term treated with SSAs.MethodsThis is a prospective single-center study evaluating 35 patients treated with SSAs for >12 months due to unresectable/advanced nonpancreatic well-differentiated NEN. Clinical evaluation, biochemical parameters, and fecal elastases 1 (FE-1) were assessed to diagnose EPI.ResultsA total of 7 patients (20%) had EPI, given the presence of abdominal symptoms and a median FE-1 value of 180 mcg/g stool (150–198). No patient had severe EPI, defined as FE-1 < 100 mcg/g stool. Elevated glycated Hb levels were a significant predictor for developing EPI (OR 4.81, p = 0.01). No significant difference in terms of duration of SSA treatment was observed between patients with or without EPI diagnosed (84 months and 72 months, respectively; p = 0.950).ConclusionsMild-moderate EPI is a relatively common condition in patients receiving long-term treatment with SSAs. Specific clinical and biochemical evaluations, including FE-1, should be planned in these patients to diagnose this relevant condition early, which may deteriorate quality of life and cause malnutrition.     

Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms

Neuroendocrine tumours (NETs) represent a heterogeneous family of neoplasms, which may develop from different endocrine glands (such as the pituitary, the parathyroid or the neuroendocrine adrenal glands), endocrine islets (within the thyroid or pancreas) as well as from endocrine cells dispersed between exocrine cells throughout the digestive and respiratory tracts. The development of somatostatin analogues (SSA) as important diagnostic and treatment tools has revolutionised the clinical management of patients with NETs. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with SSA, tumour regression is rare. Possible mechanisms when this does occur include antagonism of local growth factor release and effects, probably including activation of tyrosine and serine-threonine phosphatases, and indirect effects via anti-angiogenesis. The development of new SSA, new drug combination therapies and chimaeric molecules should further improve the clinical management of these patients, as should a more complete understanding of their mode of action.     

High-dose treatment with a long-acting somatostatin analogue in patients with advanced midgut carcinoid tumours

OBJECTIVE: High-dose somatostatin analogue treatment has shown an antiproliferative effect in one study including patients with neuroendocrine tumours. To explore this therapeutic strategy further, we have studied the effect of a high-dose formula of octreotide, octreotide pamoate, in midgut carcinoid patients. DESIGN AND METHODS: Twelve patients with advanced midgut carcinoid tumours with a median duration of disease of more than 5 years were included. All were in a progressive state despite several previous treatment modalities. Octreotide pamoate (160 mg) was given as an intramuscular injection every 2 weeks for 2 months and then monthly. Radiological and biochemical responses were monitored. RESULTS: Tumour size and biochemical markers were stabilised for a median of 12 months in 75% of the patients. Ten patients had symptomatic improvement of flush and diarrhoea. CONCLUSION: In this group of patients with advanced midgut carcinoid tumours and progressive disease, octreotide pamoate managed to improve symptoms, and stabilise hormone production and tumour growth in 75% of the patients. We believe that high-dose treatment with somatostatin analogues can be an important addition to the therapeutic arsenal for patients with advanced progressive midgut carcinoid tumours.     

Treatment of gastrointestinal neuroendocrine tumors with the somatostatin analog octreotide (Sandostatin)

Somatostatin, a 14 amino acid peptide hormone, is a potent inhibitor for secretion of gastrointestinal hormones from endocrine cells. The clinical use of somatostatin for treatment of endocrine gastrointestinal tumours was limited due to its short half-life (2-3 min). Octreotide (Sandostatin), a long-acting somatostatin analogue, has been developed for subcutaneous use with an elimination half-life of about 45 min. This offers a new way of long-term treatment for patients with endocrine gastrointestinal tumours. The effect of octreotide in various forms of these diseases and its importance for the possible inhibition of tumour growth are described.     

Liver transplantation and multivisceral transplantation in the management of patients with advanced neuroendocrine tumours

Orthotopic liver transplantation(OLT) represents a generally accepted albeit somewhat controversially discussed therapeutic strategy in highly selected patients with non-resectable hepatic metastases from neuroendocrine tumours(NET). Whilst there are some exclusion criteria, these are not universally followed, and the optimal set of inclusion parameters for deeming patients eligible has not yet been elucidated. This is due to heterogeneity in the study populations, as well differing approaches employed and also divergences in selection criteria between centres. Recent data have suggested that OLT may represent the most efficacious approach in terms of overall and disease-free survival to the management of NET metastatic to the liver when conducted in accordance with the modified Milan criteria. Therefore, a consensus set of selection criteria requires definition to facilitate stringent and fair allocation of deceased-donor organs, as well as consideration for living-donor organs. In the context of classically non-resectable metastatic tumour bulk, multivisceral transplantation with or without the liver may also be indicated, yet experience is very limited. In this review, we discuss the diagnostic work-up of patients in whom the aforementioned transplantation approaches are being considered, critically analyse the published experience and also anticipate future developments in this field, including a discussion of immediate and longer-term research priorities.     

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.     

Imaging neuroendocrine tumours with radionuclide techniques

Neuroendocrine tumours (NETs) are a rare type of tumour that can range from well differentiated slow growing tumours to poorly differentiated aggressive tumours. NETs can arise in different parts of the body. Patients often present with a large spectrum of clinical syndromes, which depend on the presence of hormones secreted by the tumour type or by a mass effect. Several imaging modalities are used in the diagnosis of NETs. Radionuclide imaging plays an important role in diagnosis, staging and treatment of these tumours. Several radiopharmaceuticals are used to image NETs and are based on different cellular uptake mechanisms. This review will focus on the functional imaging of NETs using single photon emission computed tomography and positron emission tomography radiopharmaceuticals.     

Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours

Pituitary tumours express both somatostatin and dopamine receptors. Medical treatment with somatostatin analogues is a cornerstone of GH- and TSH-secreting tumours, while treatment with dopamine agonists is a cornerstone of prolactin-secreting tumours. Dopamine agonists have also demonstrated some efficacy in patients with GH- and TSH-secreting adenomas. Neither ACTH-secreting nor clinically non-functioning tumours have a well-established medical treatment. Nevertheless, some recent results have indicated a potential usefulness of the dopamine agonist cabergoline in patients with pituitary-dependent Cushing's disease. Combination treatment with both somatostatin analogues and dopamine agonists has been poorly investigated. Some studies conducted in small series have documented an additive effect of both drugs in patients with GH-secreting adenomas. Of mention is that none of the studies were randomised and cross-sectional so that the results should be confirmed by other well-designed studies. No data are available in other pituitary tumour histotypes. Preliminary observations in patients with clinically non-functioning adenomas are very promising.