S. Faiss

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

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.

Endoscopic Ultrasonography of Neuroendocrine Tumours

Neuroendocrine tumours (NETs) of the upper gastrointestinal tract are mainly located in the pancreas, stomach or duodenum. The aims of preoperative work-up are the localization of primary tumour(s), determination of local tumour invasion, of lymph node metastases and of the hormones secreted by the tumour. Endoscopic ultrasonography (EUS) offers ideal conditions to localize and stage NETs of the foregut. We report our results in localizing and staging NETs of the foregut in 40 patients examined between 1990 and 1997 by EUS, somatostatin receptor scintigraphy (SRS), computed tomography (CT), magnetic resonance imaging (MRI) and transabdominal ultrasound (US). EUS shows the highest sensitivity in localizing insulinomas compared with SRS, US, CT and MRI. US and EUS should be the first-line diagnostics if insulinoma has been proven by a fasting test. Further diagnostic procedures are unnecessary in most cases. Further diagnostics such as CT or MRI to search for distant metastases are necessary in large tumours or local invasive tumours. EUS shows the highest accuracy to detect or exclude pancreatic gastrinomas, but fails to detect extrapancreatic gastrinomas in about 50%. The combination of EUS and SRS gives additional information. First-line diagnostics in gastrinoma patients should be SRS and CT or MRI. If no metastases are detected, EUS should be the next preoperative imaging procedure. In nonfunctional NETs, EUS provides the best information on local tumor invasion and regional lymph node involvement.

Ultra-High-Dose Lanreotide Treatment in Patients with Metastatic Neuroendocrine Gastroenteropancreatic Tumors

Background: Symptomatic control and occasionally even tumor regression of functional neuroendocrine tumors (NET) of the gastroenteropancreatic (GEP) system can be achieved by somatostatin analogues. Assuming a dose-dependent antiproliferative effect of somatostatin analogues, we performed a study with the somatostatin analogue lanreotide in ultra-high dosages in patients with progressive, metastatic GEP NET. Patients and Methods: 30 patients with metastatic GEP NET, progressive during treatment with somatostatin analogues (≤1.5 mg/day) and/or interferon-α, underwent ultra-high-dose lanreotide therapy (5 mg lanreotide s.c. three times a day). Tumor growth was evaluated every 3 months. Serum chromogranin A, serum serotonin as well as urinary 5-hydroxyindoleacetic acetic acid levels were also determined at 3-month intervals. In patients with functional tumors, tumor-related symptoms were documented. Results: After a 1-year treatment period with ultra-high-dose lanreotide, 1 complete and 1 partial remission were observed in patients with functional midgut NET. Eleven patients had stable disease and 11 patients showed continuing tumor growth after 3–12 months of treatment. Symptoms decreased significantly during therapy. Conclusions: Our data show that ultra-high-dose lanreotide treatment in patients with metastatic GEP NET can lead to control of both symptoms and proliferation in at least some patients refractory to conventional therapies.

Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human esophageal cancer cells

Esophageal cancer is the most markedly increasing tumor entity in Western countries. Due to very poor 5‐year‐survival, new therapeutic approaches are mandatory. Peripheral benzodiazepine receptors (PBR) have been implicated in growth control of various tumor models, but they have not been studied yet in esophageal cancer. We used esophageal cancer cell lines and primary cell cultures of human esophageal cancers and evaluated (i) expression and localization of PBR; (ii) PBR‐ligand‐induced inhibition of cell growth; (iii) induction of apoptosis; and (iv) alterations in cell cycle. Expression of PBR was detected both in cell lines and in primary cell cultures of human esophageal cancers. PBR was localized in the mitochondria. The PBR‐specific ligands FGIN‐1‐27 and PK 11195, but not the centrally acting benzodiazepine clonazepam or the indolacetamide FGIN‐1‐52, neither of which displaying any affinity to the PBR, inhibited cell proliferation. FGIN‐1‐27 and PK 11195, but not clonazepam, potently induced apoptosis. FGIN‐1‐27 was shown to sequentially decrease the mitochondrial membrane potential, then to activate caspase‐3 and finally to cause DNA fragmentation. In addition, PBR‐specific ligands induced cell cycle arrest in the G1/G0 phase. Our data qualify PBR‐specific ligands as innovative proapoptotic and antiproliferative substances. They might prove suitable for the treatment of esophageal cancer.

Expression of dopamine receptors and transporter in neuroendocrine gastrointestinal tumor cells.

C-11- or F-18-DOPA positron emission tomography (DOPA PET) is a new sensitive imaging technique for small neuroendocrine gastrointestinal tumors which evaluates the decarboxylase activity. To further characterize the dopaminergic system in neuroendocrine gastrointestinal tumor cells, we investigated the expression of both dopamine receptors and the transmembrane dopamine transporter (DAT) in the human neuroendocrine pancreatic cell line BON and in the neuroendocrine gut cell line STC-1. Both BON and STC-1 cells expressed mRNA of the dopamine receptors D2-D5 and DAT. mRNA of the dopamine receptor D1 was detected in BON cells only. Both in BON and STC-1 cells, expression of D2 and D5 receptors and DAT was also demonstrated immunocytochemically. For functional receptor characterization intracellular cAMP levels ([cAMP]i) were determined. Whereas in STC-1 cells dopamine and the D1-like (D1/D5) receptor agonist SKF 38393 increased [cAMP]i, [cAMP]i was decreased by dopamine or the D2-like (D2-D4) receptor agonist quinpirole in BON cells. Functional DAT activity was, however, not detected in either cell line. The presence of both dopamine receptors and of the DAT suggests an autocrine and/or paracrine function of dopamine in neuroendocrine gastrointestinal tumor cells. Yet neither the transmembrane dopamine transporter nor dopamine receptors are likely to contribute to positive DOPA PET imaging of neuroendocrine gastrointestinal tumors. However, these molecules may be of diagnostic importance when applying other dopaminergic system tracers.

Drug Therapy in Metastatic Neuroendocrine Tumors of the Gastroenteropancreatic System

Successful treatment of neuroendocrine tumor disease of the gastroenteropancreatic system requires a multimodal approach. Radical tumor surgery is required before other therapies are initiated. So far, only surgery has proven to be curative. If surgical intervention is not possible or a tumor-free state cannot be achieved, biotherapy with the somatostatin analogues octreotide or lanreotide should then be preferably carried out in patients with functional tumors. Interferon-alpha can alternatively be given. In patients with gastrinoma, therapy with proton pump inhibitors (e.g., omeprazol) is the initial treatment of choice. In patients with nonfunctional tumors, indication for treatment is only given in cases of documented tumor progress. In case of progressive tumor disease or functionality under the above-mentioned therapies, treatment with somatostatin analogues can be intensified by dose escalation or alternatively by a combination therapy with interferon-alpha and a somatostatin analogue. On the basis of the less favorable response of neuroendocrine foregut tumors to biotherapy, chemotherapy should be initiated after failure of biotherapy in documented tumor progression. A combination of streptozotocin and 5-fluorouracil, possibly combined with D,L-folinic acid, is the treatment of choice, considering the response and side effect rates. In case of predominantly anaplastic neuroendocrine tumors in advanced stages, good tumor response rates with a chemotherapeutic scheme consisting of cisplatin and etoposide can be achieved. Since the chemotherapy scheme is less effective in patients with midgut or hindgut tumors, chemoembolization of liver metastases should follow biotherapy. The response to chemoembolization may be increased by simultaneous systemic chemotherapy. Attention should always be paid to an adequate analgesic drug administration.

Interferon-α versus Somatostatin or the Combination of Both in Metastatic Neuroendocrine Gut and Pancreatic Tumours

Neuroendocrine tumours of the gastroenteropancreatic system represent a therapeutic challenge. Current therapeutic strategies will be presented and discussed with especial consideration given to biotherapeutic regimens in metastatic tumour disease.

Neuroendocrine Tumors of the Gastroenteropancreatic System: I. Diagnostic Advances

Neuroendocrine tumors of the gastroenteropancreatic system present both a diagnostic and therapeutic challenge. Even in a patient presenting with a clinical hypersecretion syndrome such as the carcinoid syndrome, the Zollinger-Ellison syndrome or the hypoglycemia syndrome the primary tumor is often difficult to localize. Recently, tumor imaging has been improved by two new powerful techniques, the endosonography and the somatostatin-receptor scintigraphy. In addition, the new arterial secretin or calcium injection tests may guide surgery in patients with gastrinoma or insulinoma, respectively. The recently introduced positron emission tomography with nC-5-hydroxytryptophan can provide information about biochemical and metabolic changes in neuroendocrine tumors. Patients with the hereditary form of neuroendocrine tumor disease of the foregut suffer from the multiple endocrine neoplasia type 1 syndrome. The genetic defect of this autosomal dominant disease has been assigned to chromosomal region 11 q13. Current investigations aim to detect the multiple endocrine neoplasia 1 gene and thus to allow early diagnosis of hereditary neuroendocrine tumor disease of the foregut.