Paul N. Maton

Somatostatin and Somatostatin Analogue (SMS 201-995) in Treatment of Hormone-Secreting Tumors of the Pituitary and Gastrointestinal Tract and Non-Neoplastic Diseases of the Gut

Somatostatin is a peptide synthesized in many tissues that can act as a neurotransmitter, a systemic hormone, or a local hormone, and inhibits the secretion of hormones or other cell products. A long-acting synthetic analogue of somatostatin (SMS 201-995) has been developed which when administered subcutaneously has a biologic half-life of 90 to 120 minutes and can be administered 2 or 3 times per day. SMS 201-995 can lower plasma concentrations of growth hormone and somatomedin-C in patients with pituitary acromegaly, but no controlled trials to assess symptomatic response or change in tumor size have been done. In patients with pituitary thyrotropin-producing pituitary tumors, SMS 201-995 has been remarkably effective in producing biochemical and clinical responses and is the drug of first choice in this syndrome when tumor resection is not possible. In patients with the carcinoid syndrome, SMS 201-995 effectively reduces diarrhea, is the best available drug for treatment of carcinoid flush (effective in approximately 90% of cases), and is useful in treating carcinoid crisis. Eighty-five percent of patients with pancreatic islet cell tumors that produce vasoactive intestinal peptide will respond to SMS 201-995 with a reduction in diarrhea that often has been resistant to all other therapy. SMS 201-995 may also be useful in treating the symptoms in some patients with glucagonomas, growth hormone releasing hormone-producing tumors and insulinomas. Whether SMS 201-995 has a significant effect on gut neuroendocrine tumor growth remains uncertain. Certain nonmalignant diseases of the gut respond to somatostatin, including secretory diarrhea and fistulas of unknown cause. In general, SMS 201-995 has proved safe with few significant side effects, but whether the long-term use of the drug will result in an iatrogenic form of the somatostatinoma syndrome is uncertain.

Intraoperative Ultrasonographic Localization of Islet Cell Tumors: A Prospective Comparison to Palpation

The purpose of the present study was to evaluate prospectively the value of intraoperative ultrasound scanning (IOUS) in localizing islet cell tumors by comparing results of IOUS to those of palpation during 44 consecutive laparotomies for gastrinoma (36) or insulinoma (8). All patients had preoperative radiographic imaging studies and selective venous sampling for hormones, which guided the subsequent laparotomy. Any suspicious finding by palpation and/or IOUS was resected. Pathologic evidence of islet cell neoplasm served as the reference standard. Five patients were excluded from analysis because neither palpation nor IOUS had suspicious findings and no islet cell tumor was found. Seven pancreatic insulinomas were found in seven patients. IOUS was as sensitive as palpation at localizing insulinomas. Twenty-three pancreatic gastrinomas were found in 19 patients. IOUS was equal to palpation in the ability to localize gastrinomas. Gastrinomas that were successfully imaged by IOUS were significantly larger than gastrinomas that were not imaged. Twelve extrapancreatic gastrinomas were found in nine patients, and palpation was more sensitive than IOUS at localizing these small duodenal wall tumors. Five patients (11%) had their surgical management changed by IOUS. Two patients had pancreatic tumors (one gastrinoma and insulinoma) enucleated that would not have been found without IOUS, and three patients had resections of pathologically proven malignant islet cell tumors based on sonographic findings. All five patients were cured with short follow-up. The present results demonstrate that palpation and IOUS are complementary because IOUS can image tumors that are not palpable and IOUS can provide additional information concerning malignant potential not detected by palpation.

Secretin and Calcium Provocative Tests in the Zollinger-Ellison Syndrome: A Prospective Study

STUDY OBJECTIVE To evaluate criteria of positivity for and usefulness of both the secretin and calcium gastrin-provocative tests in patients with the Zollinger-Ellison syndrome. DESIGN Prospective trial in consecutive patients. SETTING Referrals to a clinical research center. PATIENTS Consecutive sample of 80 patients with the Zollinger-Ellison syndrome. INTERVENTION Kabi-secretin (2 U/kg body weight) given by intravenous bolus and calcium gluconate (10%) (54 mg/kg.h [5 mg/kg.h of calcium]) given by continuous intravenous infusion for 3 hours. Serum gastrin measured at -15, and -1 minutes before, and 2, 5, 10, 15, 20, and 30 minutes after secretin, or every 30 minutes for 3 hours during the calcium infusion. Serum calcium and serum gastrin were measured simultaneously during the calcium infusion. MEASUREMENTS AND MAIN RESULTS There was no significant difference in the responses of patients with different extents or locations of the tumor, presence or absence of multiple endocrine neoplasia, type-I, or with fasting gastrin less than or greater than 1000 pg/mL. In patients with fasting gastrin of less than 1000 pg/mL, the sensitivity of the secretin test using the criterion of an increase in gastrin of at least 110 pg/mL was 93% (CI, 76% to 99%) and for an increase of 200 pg/mL it was 85% (CI, 66% to 96%), (P greater than 0.05). With the calcium infusion test, the sensitivity using the criterion of an increase of 395 pg/mL was 43%, (CI, 23% to 66%) and for an increase of 50% was 74% (CI, 52% to 90%), (P less than 0.01). The calcium infusion test was positive in 33% of patients with a negative secretin test. With the secretin test, 75% of patients had a positive response by 5 minutes, 95% by 10 minutes, 100% by 15 minutes, and 6% only at 2 minutes. With calcium infusion, patients had positive responses at 120 to 180 minutes. CONCLUSIONS The secretin test is preferred over the calcium test because of its greater sensitivity and simplicity. The recommended criteria are a 200 pg/mL increase for the secretin test and a 395 pg/mL increase for the calcium test. The calcium test should be reserved for patients having a negative secretin test, gastric acid hypersecretion, and a strong clinical suspicion of the Zollinger-Ellison syndrome.

Famotidine, a New, Potent, Long-Acting Histamine H2-Receptor Antagonist: Comparison With Cimetidine and Ranitidine in the Treatment of Zollinger-Ellison Syndrome

Famotidine, a new, potent, long-acting histamine H2-receptor antagonist was compared with cimetidine and ranitidine in 9 patients with Zollinger-Ellison syndrome. The mean minimum daily requirement of famotidine to control gastric acid hypersecretion was 0.24 g (range 0.08-0.48 g) compared with 2.1 g (range 0.6-3.6 g) for ranitidine and 7.8 g (range 1.2-13.2 g) for cimetidine. Equally potent doses of the three drugs had similar onsets of action, but the duration of action of famotidine was 30% longer than the duration of action of either ranitidine or cimetidine (p less than 0.05). Eight patients were treated for up to 9 mo (mean 6 mo) with good control of gastric acid hypersecretion and with no evidence of biochemical or hematologic toxicity. These studies demonstrate that famotidine is nine times more potent than ranitidine and 32 times more potent than cimetidine, has a longer duration of action than ranitidine or cimetidine, and is both safe and effective in the long-term therapy of Zollinger-Ellison syndrome.

Prospective Study of Gastrinoma Localization and Resection in Patients with Zollinger-ellison Syndrome

In 1982, a prospective study was initiated of 52 consecutive patients with proven Zollinger-Ellison syndrome (ZES), involving surgical exploration with the goal of removing the gastrinoma after an extensive protocol to localize the tumor. Each patient underwent ultrasound, computed tomography (CT) with oral/ intravenous (IV) contrast, and selective arteriography. Eighteen patients had metastatic disease identified by imaging studies and confirmed by percutaneous biopsies, and two patients had multiple endocrine neoplasia type I (MEN-I) with negative imaging studies; therefore, these 20 patients did not undergo laparotomy. Each of the remaining 32 patients (3 with MEN-I and positive imaging studies) underwent laparotomy, and gastrinomas were removed in 20 patients. Preoperative ultrasound localized tumors in 20% of patients, CT in 40%, arteriography in 60%, and any of the modalities in 70% of patients. Infusion CT and arteriography were 100% specific. In 18 patients with either negative imaging (17) or false-positive imaging (1 ultrasound), gastrinomas were found and removed in six patients (33%). Twenty-four gastrinomas were found in 20 patients at laparotomy: eight in lymph nodes around the pancreatic head, four in the pancreatic head, one in the pancreatic body, three in the pancreatic tail, three in the pyloric channel, one in the duodenal wall, two in the jejunum at the ligament of Treitz, one in the ovary, and multiple liver metastases in one patient. If one excludes patients with MEN-I or liver metastatic disease, 12/28 (43%) of patients were biochemically “cured” immediately after operation. This result decreased to 7/23 (30%) with greater than 6 months follow-up. No patients with gastrinomas resected have developed recurrent gastrinoma on follow-up imaging studies (longest follow-up: 4 years). This study indicates that 95% of metastatic gastrinoma can be diagnosed before operation and that, by a combination of careful imaging studies and thorough exploration at surgery, 30% of patients with gastrinomas may be curable.

Aggressive resection of metastatic disease in selected patients with malignant gastrinoma.

Fifteen patients with Zollinger-EIlison syndrome followed at the National Institutes of Health with extensive metastatic disease had an actuarial 5-year survival of 20%. Therefore, in 1982 a prospective study to examine the effect and feasibility of removing all gross tumor in selected patients with extensive metastatic disease was instituted. Five patients with extensive metastatic gastrinoma confined to the abdomen in whom imaging studies suggested the possibility of complete surgical resection were entered into this study and underwent attempted complete surgical resection and chemotherapy with streptozotocin, doxorubicin, and 5-fluorouracil. Median follow-up was 24 months. Surgical resection of all gastrinoma was possible in 4/5 patients attempted. In one patient in whom all gross disease could not be resected, the residual tumor progressed and the patient died 19 months after operation. All four patients with all disease resected appeared to benefit since all of them had a significant reduction in antisecretory medications and are enjoying normal activity and work. Three patients have had no detectable tumor on follow-up, and two of these patients are clinically and biochemically “cured” with normal fasting gastrin levels and negative provocative gastrin tests at 14 and 32 months. Therefore, aggressive resection of metastatic disease in selected patients with malignant gastrinoma is recommended.

Cushing's Syndrome in Patients with the Zollinger–Ellison Syndrome

Reports of Cushings syndrome in patients with the Zollinger-Ellison syndrome are rare, although up to 30 percent of gastrinomas contain ACTH-like immunoreactivity. We prospectively examined 75 patients with the Zollinger-Ellison syndrome for Cushings syndrome. Three of 59 patients (5 percent) with the sporadic form of the Zollinger-Ellison syndrome had Cushings syndrome, with severe symptoms due to ectopic production of ACTH. Each of these patients had metastatic gastrinoma, responded poorly to chemotherapy, and died within three years of the diagnosis of both syndromes. Three of 16 patients (19 percent) with the Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1 had Cushings syndrome due to pituitary production of ACTH, and their symptoms were mild. The gastrinoma in these patients was localized, and the prognosis was excellent. Thus, Cushings syndrome is more common in patients with the Zollinger-Ellison syndrome than was previously reported, occurring in 8 percent of all cases. Furthermore, Cushings syndrome in patients with sporadic Zollinger-Ellison syndrome and in those with multiple endocrine neoplasia type 1 differ in incidence, cause, clinical severity, extent of gastrinoma, the need for therapy, and prognosis. All patients with the Zollinger-Ellison syndrome and all patients with multiple endocrine neoplasia type 1 should be screened for Cushings syndrome.

Use of long-acting somatostatin analog SMS 201-995 in patients with pancreatic islet cell tumors.

Natural somatostatin reduces plasma concentrations of many peptides, and is of short term benefit in patients with islet cell tumors, but has to be given as a continuous intravenous infusion. We review the published experience with the long acting synthetic somatostatin analogue SMS 201-995 in patients with islet cell tumors. Fifteen of 18 patients with vasoactive intestinal peptide-producing tumors, 8 of 8 patients with glucagonomas, 7 of 7 patients with unresectable insulinomas, and 3 of 3 patients with growth hormone releasing factor-producing tumors had a good sustained symptomatic response to SMS 201-995. Patients with benign insulinomas responded variably and are best treated by surgery. Patients with gastrinomas are best treated by oral gastric antisecretory agents. In all these syndromes, the clinical response to SMS 201-995 did not necessarily parallel the change in plasma concentration of marker peptide, suggesting that SMS 201-995 may have actions at various sites. The effect of SMS 201-995 on tumor size has been assessed in 46 patients, less than 20% of whom showed a reduction in tumor size. Side effects have been mild, but include steatorrhea and gastrointestinal disturbances. More studies will be required to fully assess the effects of longterm administration of SMS 201-995.

Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: A prospective study

To determine the long-term efficacy, safety, and toxicity of omeprazole, we studied 40 patients with Zollinger-Ellison syndrome given omeprazole for 6-51 mo (median 29). The mean daily dose of omeprazole required to control gastric acid secretion was 82 +/- 31 mg. Thirty-one patients required omeprazole once per day. In 9 patients acid output was not controlled by 120 mg once per day, but was controlled by 60 mg every 12 h. The daily dose of omeprazole correlated with the previous dose of histamine H2-receptor antagonist (r = 0.89, p less than 0.001), basal acid output (r = 0.43, p less than 0.01), and maximal acid output (r = 0.39, p less than 0.02) but not with serum concentration of gastrin (r = -0.32). Increases in the dose of omeprazole were required in 9 patients. Twenty-nine patients had mild peptic symptoms with acid outputs less than 10 mEq/h while taking histamine H2-receptor antagonists. Symptoms resolved completely in 23 patients and partially in 3 when taking omeprazole. Omeprazole prevented mucosal disease in all patients including 17 in whom histamine H2-receptor antagonists had produced only partial resolution despite acid output being less than 10 mEq/h and in those with symptoms during omeprazole therapy. Omeprazole therapy was not associated with any significant side effects, nor with any evidence of hematologic or biochemical toxicity. Serum concentrations of gastrin did not change significantly during therapy. In 6 patients treated with omeprazole for 1 yr there was no change in basal or maximal acid output. In all patients, gastric morphology and histopathology demonstrated no evidence of gastric carcinoid formation. These results demonstrate that with long-term treatment of up to 4 yr, omeprazole is safe, with no evidence of hematologic, biochemical, or gastric toxicity. Furthermore, omeprazole remained effective, with only 23% of patients requiring an increase in dose, and continued to control symptoms in patients who had not been entirely symptom-free despite high doses of histamine H2-receptor antagonists. Omeprazole is now the drug of choice in patients with Zollinger-Ellison syndrome.

Reflux esophagitis in patients with Zollinger-Ellison syndrome

The incidence of ulcers of the stomach and duodenum and their response to medical therapy, in patients with Zollinger-Ellison syndrome is well described. However, reflux esophagitis is less well recognized. In this study we determined the frequency of reflux esophagitis in 122 patients with Zollinger-Ellison syndrome and examined their response to medical therapy. Esophageal symptoms, endoscopic abnormalities, or both were present in 61% of patients. Forty-five percent of patients had esophageal symptoms consisting of heartburn, dysphagia, or both. Forty-three percent of patients had endoscopic abnormalities of the esophagus, and 23% demonstrated moderate or severe disease. When sufficient antisecretory medication was administered to lower gastric acid secretion to less than 10 mEq/h in the last hour before the next dose of drug, 67% of the patients with reflux esophagitis responded with complete disappearance of symptoms and normalization of the endoscopic abnormalities. The other 33% of patients required an increase in medication to lower acid output to less than 5 mEq/h in 7% and less than 1 mEq/h in the other 26% to resolve symptoms and signs completely. We conclude that reflux esophagitis occurs in the majority of patients with Zollinger-Ellison syndrome and responds well to medical therapy, although one third of patients require intensive antisecretory medication.