Pancreatic endocrine tumours, immunotherapy and gene therapy: chemotherapy and interferon therapy of endocrine tumours.

The various pancreatic endocrine tumors (PETs) share histological features with each other and with the carcinoid. The aspects of chemotherapy and/or interferon concern the management of metastatic disease. The value of chemotherapy is difficult to evaluate from the literature because often no distinction is made between the various types of PETs and carcinoids are often also included. Moreover, it has been shown that not each tumor responds equally to chemotherapy, depending on a functioning or non-functioning state of the tumor. In general the response rate to any cytostatic drug, single agents or combinations, is low.

Somatostatin analogue treatment of neuroendocrine tumours.

The long-acting analogues of somatostatin have an established place in the medical treatment of patients with neuroendocrine tumours. They act through binding with specific, high-affinity membrane receptors. Somatostatin analogue therapy is an effective and safe treatment for most growth hormone and thyrothropin-secreting pituitary adenomas. The potential therapeutic consequences of the presence of somatostatin receptors on clinically 'nonfunctioning' pituitary tumours are still uncertain. Somatostatin analogues are not useful in the treatment of patients with prolactinomas, or adrenocorticotropin (ACTH)-secreting adenomas. However, the somatostatin analogue octreotide suppressed pathological ACTH release in some patients with Nelson's syndrome and ACTH and cortisol secretion in several patients with Cushing's syndrome caused by ectopic ACTH secretion. Somatostatin analogues are effective in the sympatomatic treatment of most (metastatic) pancreatic islet cell tumours and most (metastatic) carcinoids. In some of these patients, they also induce tumour stabilisation or reduction. In some patients with (metastatic) medullary thyroid carcinomas, continuous treatment with very high doses of octreotide can be of temporary relief. The clinical effectiveness of somatostatin analogues in patients with small cell lung cancer is currently under investigation. Long-term therapy with somatostatin analogues of catecholamine-secreting (malignant) paragangliomas and phaeochromocytomas has not shown clinical benefits.

Mitoxantrone in metastatic apudomas: a phase II study of the EORTC Gastro-Intestinal Cancer Cooperative Group.

We performed a phase II study with mitoxantrone in patients with carcinoid tumours, islet cell tumours and medullary carcinomas of the thyroid. Thirty-five eligible patients received mitoxantrone 12 mg m-2 i.v. every 3 weeks. Among 18 previously untreated patients, three responded (17%, 95% CI = 4-41%); no responses were achieved in 17 previously treated patients. Of the 21 patients who had carcinoid tumours, 11 were previously untreated and two achieved a response (18%, 95% CI = 2-52%). Overall response rate was 9% (95% CI = 2-23%). At a median follow-up of 43 months, median overall survival was 16 months. The median survival of 21 patients with a normal alkaline phosphatase was 29 months and 9 months for 14 patients with elevated serum levels (P = 0.005). A similar observation was noticed for gamma-glutamyltransferase (P = 0.007). We concluded that mitoxantrone is not active in APUD tumours. Elevated alkaline phosphatase and gamma-glutamyltransferase are associated with a poor prognosis.

A phase II trial of carboplatin in patients with advanced APUD tumors.

BACKGROUND: Chemotherapy remains inadequate for patients with carcinoid tumors, islet cell tumors, and medullary carcinomas of the thyroid. Carboplatin has shown activity in oat cell carcinoma of the lung, another tumor of neuroectodermal origin. METHODS: Forty-two patients with advanced APUD tumors (20 carcinoid tumors, 9 islet cell carcinomas, 5 medullary carcinomas of the thyroid, and 9 neuroendocrine tumors of unknown primary site) were treated with carboplatin in a Phase II study. RESULTS: Carboplatin was inactive in carcinoid and islet cell tumors, with 0 of 20 and 0 of 9 patients responding, respectively. Of the 41 total patients evaluable for response, only 2 (5%) achieved a partial response. Both of these responding patients had neuroendocrine tumors of unknown primary site. No complete responses were seen. Toxicities were those previously noted with carboplatin, with myelosuppression, particularly thrombocytopenia, being dose limiting. CONCLUSIONS: Carboplatin is inactive in carcinoid tumors and did not show evidence of activity in islet cell tumors. Further investigations are needed to identify active agents in the treatment of neuroendocrine malignancies.

Somatostatin analogue therapy in functioning neuroendocrine gut tumors.

The purpose of the workshop was to critically evaluate the use of octreotide in the management of important surgical and gastroenterological conditions. The topics covered included: (1) management of functioning gut neuroendocrine tumors, (2) new approaches to localize these tumors, (3) the place of octreotide in the treatment of variceal bleedings, and (4) the use of octreotide in postoperative conditions. Octreotide therapy has been shown to be effective in the carcinoid syndrome, in which symptom control is achieved in 85% of patients, and reduction in 5-HIAA in 60%. Although tumor regression is rarely seen, prolongation of survival probably occurs. Control of diarrhea has been achieved in 84% of patients with VIPoma treated with octreotide. Similarly, octreotide has been found to provide effective control of the necrolytic, migratory dermatitis seen in glucagonoma. By contrast, insulinomas are more resistant to somatostatin agonist therapy. In the Zollinger-Ellison syndrome, octreotide is effective in alleviating symptoms and in reducing serum gastrin levels. However, its use in this syndrome has been superceded by omeprazole. Radioiodine-labelled octreotide has been very effective in in vivo imaging of neuroendocrine tumors in the abdomen, and is now considered the best available technique for localizing these tumors preoperatively. Intraoperative localization with a hand-held gamma camera is being developed. There is an exciting future possibility to use the technique to deliver therapy to tumors. Octreotide therapy has been shown to be at least as effective as and without the adverse hemodynamic effects of Pitressin in control of variceal hemorrhage. It should be regarded as one of several modalities of therapy in the condition.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacological treatment of gastroenteropancreatic apudomas with an analog of somatostatin, SMS 201-995 (octreotide)]. / Tratamiento farmacológico de los apudomas gastroenteropancreáticos con el análogo de la somatostatina SMS 201-995 (octreotide).

Ten patients with gastro-pancreatic apudomas were prospectively treated with SMS 201-995 at the dose of 25-50 mg/12 h. subcutaneously before breakfast and dinner during two months. The biological and clinical effects were evaluated, as well its possible antitumoral action. When clinical or biological benefit was ascertained, the treatment was continued uninterruptedly. SMS 201-995 was well tolerated. It allows ambulatory treatment. It reduced hormonal levels in 62% of cases and controlled symptoms in 50%. No antitumoral effects were observed in the majority of patients.

[The pharmacological treatment of digestive endocrine tumors with the somatostatin analog SMS 201-995]. / Tratamiento farmacológico de los tumores endocrino-digestivos con el análogo de la somatostatina SMS 201-995.

Eight patients suffering gastroenteropancreatic apudomas were prospectively treated with subcutaneous SMS 201-995 at a dose of 25-50 mg/12 hours, before breakfast and dinner during two months. Biological and clinical effects were evaluated as well as the possible antitumor effect. In those cases that obtained a clinical and/or biological benefit, treatment was continued uninterruptedly. The results showed that SMS 201-995 is a well tolerated drug which permits ambulatory treatment of patients with GI endocrine tumors being the main objective the reduction of hormone levels and symptom control, not finding in most cases an antitumor effect.

APUD update.

Apudomas are a diffuse group of tumors that have interested surgeons for a long time. With recent developments in their radiological localization and pharmacological control, they are now treated in a truly multidisciplinary approach. In this chapter, recent developments in the radiological, surgical, and medical approaches to these tumors are reviewed. Emphasis is placed on how non-surgical developments have affected the surgical treatment of specific apudomas. Resulting changes in surgical philosophy are also reviewed.

Sandostatin and the Belfast experience.

Twenty-four patients with 26 apudomas have been treated with Sandostatin (octreotide) in Belfast. The 2 patients with vipoma showed an excellent response clinically and biochemically. Of 15 patients with carcinoids, Sandostatin improved the diarrhoea in 70%, flush in 58%, and wheeze in 100% of patients. Patients with insulinoma and the Zollinger-Ellison syndrome were unresponsive to Sandostatin. In general, the response to Sandostatin appeared to decline as the tumour size increased and tumour markers rose. Side effects have not been a problem.

Metastatic medullary thyroid carcinoma. Complete response to combination chemotherapy with dacarbazine and 5-fluorouracil.

A 20-year-old woman had a sporadic case of medullary thyroid carcinoma (MTC) metastatic to the lungs. After a transient response to streptozotocin and doxorubicin, new subcutaneous lesions appeared on the left chest wall and there was progression of pulmonary disease. Because MTC is one of the amine precursor uptake and decarboxylation (APUD) tumors, treatment was undertaken with agents active in these diseases. Dacarbazine and 5-fluorouracil, given daily for 5 days every 4 weeks, resulted in complete resolution of pulmonary and subcutaneous lesions and a sharp decrease in tumor marker levels that lasted 10 months. Recurrence of the pulmonary disease lead to her death 21 months after presentation. Thus, the chemo-responsiveness of MTC may be akin to that of other APUD carcinomas (APUDomas) and treatment of metastatic MTC and other APUDomas with the combination of dacarbazine and 5-fluorouracil appears to merit further study.

[Treatment of gastrointestinal neuroendocrine tumors with the somatostatin analog octreotide (Sandostatin)]. / Behandlung gastrointestinaler neuroendokriner Tumoren mit dem 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.

A phase II trial of streptozotocin and adriamycin in advanced APUD tumors.

Thirty-three patients with advanced carcinoid tumors, islet cell carcinomas, or medullary carcinomas of the thyroid were entered into a phase II trial combining streptozotocin (STZ) and Adriamycin. Thirty-one patients are evaluable for response, and 29 are evaluable for survival. Six (19%) patients achieved objective partial responses (95% confidence limits: 5.4-33). The median duration of response for partial responders was 282 days. The median survival for responders and nonresponders was 16.2 months and 7.8 months, respectively, with an overall median survival of 10.9 months. At 10.9 months median follow-up, 4 (14%) of 29 patients are surviving. Toxicity was mild, except that nausea or vomiting occurred in 25 of 31 patients evaluable for toxicity. With this dose and schedule of administration, STZ and Adriamycin produce modest response rates with objective palliation of disease in patients with advanced amine precursor uptake and decarboxylation (APUD) tumors.

Merkel cell tumor. A chemosensitive skin cancer.

The clinical courses of six patients treated with cytotoxic chemotherapy for recurrent Merkel cell tumor of the skin are reported. All patients experienced prompt clinical responses to chemotherapy (five complete response [CR], one partial response [PR]) and three patients (50%) have achieved long-term disease-free remission. The report highlights (1) the aggressive nature of Merkel cell skin cancer, (2) the highly chemosensitive nature of the disease, and (3) some practical problems in administering chemotherapy to elderly patients.

Observations on the effect of a somatostatin analog in the Zollinger-Ellison syndrome: implications for the treatment of apudomas.

Somatostatin is known to inhibit hormone release and gastrointestinal secretion and hence may be useful in the treatment of amine precursor uptake, decarboxylase tumors. Clinical application has been limited by the short half-life, potency, and specificity of the natural hormone. Our study evaluated the effect of a synthetic analog of somatostatin, SMS 201-995 (Sandoz, Inc., E. Hanover, N.J.) on basal and stimulated gastrin release and gastric acid secretion in 10 patients with the Zollinger-Ellison syndrome. In experiment 1, H2-receptor antagonists were discontinued for 48 hours; SMS 201-995, 1 microgram/kg, was given subcutaneously; gastrin and SMS levels in plasma were determined by radioimmunoassay; and gastric secretion was measured and titrated at 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 18 hours. The mean +/- SEM baseline gastrin level (1526 +/- 733 pg/ml) was significantly inhibited for 16 hours (p less than 0.05, paired t test). Gastric secretion was neutralized for as long as 18 hours (p 0.05). In experiment 2, three patients received either a secretin (2 U/kg) or a calcium stimulation test (2 mg/kg) with or without pretreatment with SMS 201-995, 1 microgram/kg, subcutaneously. The mean +/- SEM interpreted change in gastrin (ng X 60 min/ml) without SMS 201-995, 36.8 +/- 11 (secretin), and 129 +/- 30 (calcium) were reduced with SMS 201-995 to -1.1 +/- 0.76 (secretin) and -29 +/- 28 (calcium) (p less than 0.05). In the Zollinger-Ellison syndrome, SMS 201-995 caused significant and long-lasting inhibition of both tumor gastrin release and gastric acid secretion, probably by direct action on both the gastrinoma and the stomach. SMS 201-995 blocks acid secretion and secretin- and calcium-stimulated gastrin release, indicating that SMS 201-995 inhibits peptide secretion by postreceptor mechanisms. SMS 201-995 will be useful in the palliative treatment of apudomas.