Sc Octreotide Research Articles

THU014 Post-surgical Remission After Resection Of Solitary Mediastinal Lymph Node In A Metastatic Occult Ectopic ACTH Syndrome Patient

Abstract Disclosure: I.P. de Magalhães: None. C.P. Oliveira: None. L.P. Lins: None. N.X. Andrade: None. M.S. Lima: None. S.A. Siqueira: None. J.S. Fonini: None. E.C. Assis Filho: None. A.W. Mariani: None. M.C. Machado: None. BACKGROUND: The prevalence of occult cases has been increasing in the most recent series of Ectopic ACTH syndrome (EAS) maybe due to the small size of pulmonary neuroendocrine tumors. We present an atypical and very rare case of EAS with initial presentation of a single metastatic mediastinal lymph node that evolved with remission after your resection with no defined primary tumor. CASE REPORT: A 15-year-old female patient presented a clinical feature of Cushing’s syndrome (CS) with a 1-year evolution. Hormonal evaluation confirmed ACTH-dependent CS: urinary free cortisol of 819 µg/24h (3-43), late night salivary cortisol of 409 ng/dL (<274) and ACTH of 105 pg/mL (<63.3). Noninvasive methods for differential diagnosis of ACTH-dependent CS did not clarify the etiology (conflicting results): pituitary MRI negative, suppression of 59.6% of cortisol after high dose dexamethasone suppression test, positive response of ACTH and cortisol at desmopressin test, suppression of 81% of ACTH at acute octreotide SC test, negative serum tumor markers (gastrin, calcitonin, CEA, CA125, alpha-fetoprotein, CA19.9 and bhCG), negative cervical and pelvic ultrasound, negative computed tomography of thorax and negative abdominal MRI. Bilateral and simultaneous petrosal inferior sinus sampling with desmopressin confirmed EAS due to negative central to peripheral ACTH gradient, even after normalized PRL/ACTH gradients. Finally, PET/CT with Ga68-DOTATATE revealed a single infracarinal nodule of 1.5x0.6 cm with high capture of radioligand, SUVmax of 23.2, suggestive of affected mediastinal lymph node. The patient was submitted to thoracic surgery and the infracarinal lymph node was dissected and removed. Anatomopathological and immunohistochemical analyses disclosed a lymph node metastatic of a well-differentiated grade neuroendocrine tumor ACTH positive, Ki-67 2%. After surgery, the patient exhibited CS improvement and impressive drop of hormones at 5th postsurgical day (serum cortisol <1.0 µg/dL and ACTH of 2.2 pg/mL) confirming remission of CS. CONCLUSION: To our knowledge, approximately 36 cases of EAS due to neuroendocrine tumor of unknown primary origin were reported. However, previous cases commonly exhibited no remission after only removal of metastasis. Our case presented initial remission even with no primary tumor identified (occult primary tumor non-functioning?). Follow up with clinical, hormonal and imaging methods are necessary due to recurrence risk. Presentation: Thursday, June 15, 2023

Combination of pasireotide and octreotide: effects on GH and IGF-I secretion and glucose metabolism in healthy volunteers.

To assess the pharmacokinetics, pharmacodynamics and tolerability of different doses of octreotide and pasireotide (subcutaneous [sc] and long-acting release [LAR]) when co-administered in healthy volunteers. This was an exploratory, Phase I, single-centre study. Healthy adults were enrolled in a staggered approach into seven cohorts to receive octreotide and pasireotide (sc and LAR formulations), alone or in combination. Plasma drug concentrations, growth hormone (GH), insulin-like growth factor I (IGF-I), and plasma glucose were assessed at baseline, immediately after sc treatment, and 21 and 28 days after LAR treatment. Of 88 enrolled subjects, 52 and 82 participated in sc and LAR dosing phases, respectively. There were no relevant pharmacokinetic interactions between octreotide and pasireotide. In combination, pasireotide sc (150 µg) and octreotide sc (100/300 µg) resulted in numerically greater reductions in insulin levels and a higher incidence of AEs than either single agent; the rapid (within 1 h) increase in plasma glucose after pasireotide was delayed with combination treatment. Octreotide sc and pasireotide sc, alone or in combination, reduced IGF-I levels and led to undetectable GH levels in most subjects. During the LAR phase, addition of a low dose of pasireotide (5 mg) to a standard dose of octreotide (20 mg) resulted in an ~2-fold reduction in median IGF-I versus octreotide 20 mg 21 days post-dose; this effect was numerically greater than seen for pasireotide 20 mg alone. Peak plasma glucose was substantially lower after LAR than sc dosing. Interestingly, glucose levels were also numerically lower in the pasireotide 5 mg plus octreotide 20 mg group than for 20 mg of octreotide or pasireotide alone. AEs were less frequent after LAR than sc dosing. Combined low doses of pasireotide LAR (5 mg) and octreotide LAR (10-30 mg) provided greater suppression of IGF-I than either single agent and did not increase blood glucose or incidence of AEs versus either agent alone.

Management and Outcome of Chylous Ascites in Children: A CARE compliant Case Series

Background: Chylous ascites (CA) is accumulation of lipid rich lymph in peritoneal cavity. CA is rare among children. In pediatric age, causes of CA varies according to the age group, leading primary causes include congenital malformation of lymphatic system, and less likely lymphatic obstruction such as intestinal malrotation, gastroschisis, infections or trauma of thoracic duct. Aim of the work: We aim to report outcome of congenital CA in a pediatric cohort. Material and Methods: Retrospective analysis of data of 4 children (4 boys) who presented by CA to New Children Hospital, Cairo University during 2010- 2018. Results: Duration of follow up of the boys was 6.5, 5, 2.5, and 0.25 years respectively. All presented by abdominal distention and diagnostic tapping of ascitic fluid revealed triglyceride level more than 200 mg%, protein more than 2 g% and/or a cell count greater than 500 /cmm with a predominance of lymphocytes (> 80%). Lymphatic scintigraphy in 3 of them revealed no abnormality in lymph drainage. The course of disease was punctuated by chylothorax, and chylous hydrocoele in all 4 cases. All 4 did not respond to medium chain triglyceride based diet. One child underwent peritenovenous shunt, and the other 3 responded to somatostatin analogue octreotide SC injections during hospital stay and maintenance therapy. Last child was lost to follow up. All other 3 are fine with minimal complications and living with mild peritoneal ascites. Conclusion: Somatostatin analogue therapy provided well-tolerated non-invasive control of congenital CA in our studied pediatric cohort. Surgical intervention should be restricted to those with underlying surgical cause and in those failing to respond to medical treatment.

Lanreotide for the prolonged control of carcinoid syndrome (CS) in somatostatin analog (SSA)-naïve or experienced patients.

347 Background: In the ELECT study, mean percentage of days with rescue octreotide (OCT) use was significantly lower in lanreotide depot/autogel (LAN) 120 mg vs. placebo (PBO) group during 16-week double blind (DB) phase. We examined prospective data on use of subcutaneous (sc) OCT or other medications as rescue during DB and initial open label (IOL) treatment periods of the ELECT trial to evaluate the direct impact of LAN on patients’ relief of CS symptoms for prolonged periods. Methods: Adults with neuroendocrine tumors (NETs) and CS history, with/without prior SSA use, were randomized to 16 weeks DB LAN 120 mg sc or PBO every 4 weeks, followed by a 32-week IOL LAN phase. Prospectively collected data recorded via Interactive Voice (Web) Response System on the use of sc OCT or other rescue medications during screening, DB and IOL treatment periods was analyzed. Results: During the 16-week DB phase, treatment with LAN was associated with less frequent rescue sc OCT use (least squares mean percentage of usage days (MPUD): 33.7% LAN vs. 48.5% PBO; p = 0.02). Through the 32-week LAN IOL period, rescue sc OCT use in the DB LAN group further decreased to 27.1% MPUD. Following crossover from PBO to active treatment, sc rescue OCT MPUD in the DB PBO group decreased from 48.5% to 20.9% during the IOL period. MPUD of other rescue medications at baseline were: 12.9% LAN; 8.3% PBO and no significant decreases were observed with LAN treatment during the DB phase (8.9% LAN vs. 6.3% PBO). MPUD of the DB LAN group remained relatively unchanged through the IOL phase (8.9% LAN DB; 8.8% LAN IOL). Following crossover from PBO to active treatment, the PBO group exhibited a decrease in MPUD of other rescue medications from 6.3% to 3.1% during the IOL period. Stratified by prior SSA therapy cohorts (naïve vs. prior SSA therapy), no apparent differences were observed in the use of sc OCT or other rescue medications between the two cohorts. Trends in MPUD of rescue medications of the individual cohorts were also similar to the overall group. Conclusions: The results of this study demonstrated that LAN is effective for the prolonged control of CS symptoms in SSA-naïve or experienced patients with NETs. Clinical trial information: NCT00774930.

Initiation of Patients onto Long-Acting Somatostatin Analogue Therapy for Neuroendocrine Tumors: A Single-Center Review of Practice

Neuroendocrine tumors (NETs) are being seen increasingly frequently, and recent data show that long-acting somatostatin analogues have become a major initial treatment, regardless of whether the tumors are functioning or not. However, test dosing with subcutaneous (sc) octreotide is usually advised to assess longer-term tolerability, although this advice is mainly based on results with functioning tumors. The aim of the study was to assess the value of an initiating test dose of sc octreotide on the prediction of subsequent adverse events after treatment with the long-acting analogue. In a single, large Centre of Excellence for NETs, a first cohort of patients (n = 24) was admitted overnight after an sc injection of octreotide, and then administered the analogue; a subsequent group (n = 53) had the test dose performed on an outpatient basis. Side effects were recorded after the test dose and subsequent treatment with the long-acting analogue. The test dose injection was of little value in predicting adverse events following the long-acting somatostatin analogue. Unless there are serious symptoms associated with a functioning NET, it is unnecessary to carry out a test dose; a change to this procedure will improve resource allocation and should enhance early initiation onto maintenance therapy. CLARINET = Controlled study of lanreotide antiproliferative response in neuroendocrine tumors LAR = long-acting repeatable NET = neuroendocrine tumor PROMID = Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with meta-static neuroendocrine midgut tumors.

Lanreotide depot (LAN) for symptomatic control of carcinoid syndrome (CS) in neuroendocrine tumor (NET) patients previously responsive to octreotide (OCT): Subanalysis of patient-reported symptoms from the phase III elect study.

4088 Background: In ELECT, LAN significantly reduced the need for short-acting OCT rescue therapy for symptomatic control of CS in NET patients (pts) vs placebo (PBO) (primary result). Here we present flushing and diarrhea symptom data and biochemical response for pts with or without prior OCT use from ELECT. Methods: Adults with histopathologically-confirmed NET and history of stable CS (diarrhea and/or flushing) who were OCT-naive or responsive to OCT long-acting release (LAR) (≤30 mg q4W) or short-acting OCT (≤600 μg daily) were randomized to LAN 120 mg (SC q4W) or PBO for 16 wks. Pts administered SC OCT if needed and recorded daily frequency and severity of symptoms using Interactive Voice/Web Response System for 1 month pre-randomization and throughout the study. 24-hr urinary 5-hydroxindoleacetic acid (5HIAA) and plasma chromogranin A (CgA) were assessed at baseline and wk 12. Results: Of 115 pts randomized, 51 were OCT-naive and 64 received prior OCT. The least squares (LS) mean percentages of days with moderate/severe diarrhea and/or flushing were lower in both naive and prior OCT LAN pts vs naive and prior OCT PBO pts; LS mean difference (LAN-PBO) was significant in the naive group (Table). By week 12, 5HIAA and CgA levels dropped by ≥30% to normal in 35.3% and 15.8% of naive LAN pts and 28.6% and 4.5% of prior OCT LAN pts; 5HIAA and CgA reductions were seen in 15.4% and 21.4% of naive PBO pts and 5HIAA in 7.1% of prior OCT PBO pts. Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN regardless of prior OCT use. Transition from OCT to LAN was well tolerated among prior OCT pts in ELECT. Clinical trial information: NCT00774930. [Table: see text]

Quality of Life (Qol) Associated with Lanreotide Autogel (Lan) Treatment for Carcinoid Syndrome (Cs) in Gastroenteropancreatic Neuroendocrine Tumour (Gepnet) Patients: Results of the Elect Study

ABSTRACT Aim: QoL is an important consideration for CS treatment. This analysis evaluated QoL in GEP-NET patients treated for CS in the ELECT study. Methods: ELECT was a 16-week, randomised, double-blind (DB) phase III study (NCT00774930). Patients with GEP-NETs and a history of CS were treated with LAN 120 mg (n = 59) or placebo (n = 56) every 4 weeks. It was followed by 32-week and ≥2-year open-label extensions (OLEs). The primary endpoint was % of days of rescue medication use (SC octreotide) during DB study. Safety evaluations focused on adverse events (AEs). QoL was assessed using the EORTC QLQ-C30 and the EORTC QLQ-GI.NET21. Scores for global health status score (QLQ-C30) and endocrine and gastrointestinal subscales (QLQ-GI.NET21) were secondary endpoints; other scores were exploratory. Results: Mean [95% CI] % of days of rescue medication use was significantly lower with LAN (34% [25, 42%]) than placebo (49% [40, 57%]); difference –15% [–27, –3%], p = 0.02. Treatment-related AEs occurred in 15 (26%) LAN vs. 11 (19%) placebo patients: most common AEs were gastrointestinal. The global health status score (QLQ-C30) remained similar after 12 weeks of DB treatment with LAN and placebo. Treatment differences in endocrine and gastrointestinal subscale scores are shown in the table. For all functional scales of the QLQ-C30, scores remained stable/slightly improved in the LAN group, while there were small deteriorations in the placebo group; however CIs were wide. For the other subscales of the QLQ-GI.NET21, changes in scores were similar in both treatment groups. Conclusions: LAN 120 mg treatment for CS symptoms was not associated with a deterioration in QoL in GEP-NET patients. In fact, despite the relatively short duration of the study, there was evidence of initial improvements in some aspects of QoL. Results of QoL scores in OLE may provides more information. Table: Effect of LAN on QoL secondary endpoints. Values are mean (SD) unless otherwise stated. P-value tested at a significance level of 0.05. A hierarchical testing procedure was applied for secondary endpoints. Data shown are for the transformed scores, which can range from 0 to 100. A higher transformed score for global health status represents a better QoL. A higher transformed score for Endocrine and GI symptoms represents a higher level of symptomatology/problems Lanreotide Autogel Placebo LS mean treatment difference in change from baseline [95% CI] p-value QLQ-C30 Global health status/QoL Baseline 59.89 (20.15) [n = 59] 62.58 (20.28) [n = 55] 4.05 [–2.09, 10.20] 0.1931 Week 12 64.93 (19.37) [n = 48] 61.19 (18.07) [n = 35] 4.05 [–2.09, 10.20] 0.1931 QLQ-GI.NET21 Endocrine symptoms Baseline 25.89 (22.83) [n = 59] 33.54 (23.92) [n = 53] –7.04 [–14.80, 0.73] 0.0750 Week 12 18.06 (20.06) [n = 48] 29.84 (22.51) [n = 35] –7.04 [–14.80, 0.73] 0.0750 QLQ-GI.NET21 Gastrointestinal symptoms Baseline 22.40 (16.95) [n = 59] 24.84 (20.09) [n = 53] –4.68 [–9.63, 0.26] 0.0632 Week 12 17.64 (14.32) [n = 48] 23.62 (15.45) [n = 35] –4.68 [–9.63, 0.26] 0.0632 Disclosure: E. Gomez-Panzani: Ipsen: employee; A.I. Vinik: Ipsen: Research grant, advisory board member; E.M. Wolin: Research grant from Ipsen. Advisory board member for Ipsen, Novartis and Celgene; H. Audry: Received consulting fee (contract statistician) from Ipsen.

Oral Octreotide Absorption in Human Subjects: Comparable Pharmacokinetics to Parenteral Octreotide and Effective Growth Hormone Suppression

Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. Four single-dose studies were conducted in 75 healthy volunteers. Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 μg octreotide were administered. We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.

Octreotide

Octreotide

The effect of acute application of pegvisomant alone and in combination with octreotide on endogenous GH levels during a 6-h test in patients with acromegaly on constant pegvisomant treatment

Objective Co-treatment with somatostatin analogues and growth hormone receptor antagonists in acromegaly might be a new treatment option abolishing the negative effects of monotherapy. Nevertheless, little is known about the acute effect of the combined treatment on endogenous GH and pegvisomant levels. Design Ten acromegalic patients on constant pegvisomant therapy were included. Two 6-h GH secretion profiles were performed once after pegvisomant alone (P), the other after an additional 100 μg octreotide sc injection (PO). After 180 min, all patients received a standardized light mixed meal. Endogenous serum GH and pegvisomant levels were measured by special in-house assays. In addition, insulin and glucose were measured. Results In the combined profile PO, a significant decrease of median endogenous GH was seen ( p < 0.01, median percentage decline 75.2%, range 23.7–88.2), which was not seen in profile P. Seven of 10 patients had a decline >70% and might be seen as responders. After meal, endogenous GH significantly decreased only in profile P ( p < 0.01). Pegvisomant levels did not differ significantly between profiles and did not change significantly during the tests. After meal, glucose levels rose higher and later and insulin levels lower and later in profile PO than in profile P. Conclusion During pegvisomant treatment, endogenous GH can be reduced significantly by acute application of a somatostatin analogue. Therefore, in acromegalic patients on pegvisomant therapy GH regulation due to somatostatin analogues seems to be preserved.

Octreotide in Palliative Treatment of Hepatic Metastases: Is it Effective for Clinical Stabilization?

Octreotide in Palliative Treatment of Hepatic Metastases: Is it Effective for Clinical Stabilization?

LAR octreotide vs SC octreotide in dumping syndrome

LAR octreotide vs SC octreotide in dumping syndrome

Partial Surgical Removal of Growth Hormone-Secreting Pituitary Tumors Enhances the Response to Somatostatin Analogs in Acromegaly

Surgery is a cornerstone in the treatment of acromegaly, but its efficacy in large, invasive tumors is scant. The objective of this study was to investigate whether partial surgical removal of GH-secreting pituitary tumors enhances the response rate to somatostatin analogs (SSA; sc octreotide, slow-release octreotide, and lanreotide). This was a multicenter, open, retrospective study. The study was performed at university hospitals. Eighty-six patients (42 women and 44 men; age, 42 +/- 14 yr) with acromegaly were studied. Patients underwent two courses of octreotide, lanreotide, or slow-release octreotide treatments before and after surgery of at least 6 months. The main outcome measure was normal IGF-I levels for age. Presurgical SSA treatment significantly decreased GH and IGF-I levels in all patients. GH levels were less than 2.5 microg/liter in 12 patients (14%); IGF-I levels normalized in nine (10%). After surgery, GH and IGF-I levels further decreased in all patients; tumor removal was greater than 75% in 50 (58%), 50.1-75% in 21 (24%), 25.1-50% in 10 (12%), and less than 25% in five patients (6%). Preoperatively, pituitary function was impaired in 12 patients (14%). Postsurgical SSA treatment lowered GH levels to less than 2.5 microg/liter in 49 (56%) and normalized IGF-I levels in 48 patients (55%). The success rate was significantly increased compared with that before surgery (P < 0.0001). GH (r = -0.48; P < 0.0001) and IGF-I levels (r = -0.38; P = 0.0003) after postsurgery SSA treatment correlated with the amount of tumor surgically removed. After surgery, pituitary function was impaired in 28 patients (32.6%) and was improved in 12 patients (13.9%). The cumulative prevalence of pituitary deficiency did not change during the study (normal function from 40 to 42%; deficiency from 60 to 58%). Surgical tumor removal (>75%) enhances the response to SSAs without impairing pituitary function. Our data indicate that surgical debulking has a significant place in the treatment algorithm of acromegaly.

Long-Acting Somatostatin Analog Therapy of Acromegaly: A Meta-Analysis

Although considerable data exist on the use of long-acting somatostatin analogs to treat acromegaly, their reported efficacy differs substantially among trials. We conducted a meta-analysis to derive definitive estimates of their efficacy for biochemical control and tumor shrinkage. A search of literature was conducted through 2003, primarily via PubMed. Inclusion criteria, met in 44 trials, included at least 3 months of secondary octreotide long-acting release (LAR) or lanreotide slow release (SR) therapy or of primary octreotide LAR, lanreotide SR, or sc octreotide therapy and clearly reported data on biochemical efficacy and/or tumor shrinkage. Fifty other trials screened did not meet analysis inclusion criteria. Data were extracted by three independent observers. Among subjects not selected for somatostatin analog responsiveness before study entry, both GH efficacy criteria and IGF-I normalization were met in a greater proportion of those treated with octreotide LAR vs. lanreotide SR (GH: B = 0.2310, P = 0.016; IGF-I: B = 0.2325, P = 0.007). Prestudy selection for somatostatin analog responsiveness was not a significant predictor of meeting GH efficacy criteria (B = 0.0992; P = 0.12). Preselection was a positive predictor of IGF-I normalization rate (B = 0.1213; P = 0.04), which was greater among preselected than unselected subjects (B = 0.1472; P = 0.0475). IGF-I normalization occurred in a greater proportion of secondary octreotide LAR- vs. primary octreotide-treated subjects (B = 0.2056; P = 0.009). The odds of tumor shrinkage more than 10% were lower in the unselected vs. preselected subjects. However, the effect of drug type was an important predictor of shrinkage; such that regardless of preselection or not, the odds of shrinkage with lanreotide SR were lower than with octreotide LAR (P = 0.003). Shrinkage greater than 10% occurred in a higher percentage of primary octreotide LAR-treated vs. primary octreotide sc-treated subjects (odds ratio = 9.4; P < 0.0001). The overall rate of tumor increase was 1.4%. In this meta-analysis, we have shown that the efficacy of octreotide LAR is greater than lanreotide SR among subjects unselected for prior somatostatin analog responsiveness. Preselection is a significant positive predictor of IGF-I normalization and is associated with increased odds of tumor shrinkage, which is also greatest with octreotide LAR. Biochemical efficacy is similar, but tumor shrinkage is greater when these drugs are given as primary vs. secondary therapy.

Octreotide for palliative treatment of hepatic metastases from non-neuroendocrine primary tumours: evaluation of quality of life using the EORTC QLQ-C30 questionnaire.

While octreotide has been used in palliative treatment of hepatocellular carcinoma and neuroendocrine tumours with good results, little is known about the possible role of this in palliative treatment of hepatic metastases. We present our experience from the use of octreotide in palliative treatment of symptomatic liver metastases in 16 patients (11 males, five females, age ranged 43-69 years) with proven hepatic metastases from different primary tumours (six with non-small lung cancer, four with colon carcinoma, two with primary pancreatic head carcinoma, two with prostate cancer and two with adenocarcinoma of the stomach). All patients were administered 20 mg long-acting octreotide IM (octreotide LAR) once the first day, octreotide SC 0.5 mg three times daily on days 2-14 and then 20 mg long-acting octreotide IM every month. Quality of life was assessed by using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30). Tumour response was evaluated by using ultrasonography. One month after baseline, octreotide resulted in significant (P < 0.01, Wilcoxon test) improvement and stabilization of all major related EORTC QLQ-C30 parameters such as global quality of life, pain, fatigue, insomnia, appetite loss as well as physical, emotional, cognitive, social and role functioning. Except for mild hyperglycaemia in six out of 16 patients and mild gastrointestinal complications in one patient, no other severe side effect due to octreotide was reported. Two patients died two months after the initiation of the study due to generalized metastatic disease, while the remaining 14 patients were still alive seven months after the initiation of the study. The hepatic metastases were stabilized and no new lesions were detected by ultrasonography. Although further studies are warranted, we consider the use of octreotide a good alternative in palliative treatment of symptomatic liver metastases in patients with end-stage malignant disease.

Effects of Octreotide Pretreatment in Experimental Acute Pancreatitis

Background: Severity of systemic lesions and mortality of experimental acute pancreatitis (AP) are reduced after pancreatic enzyme content reduction induced by cerulein administration. Octreotide has been used both prophylatically and therapeutically in AP. The possible effects of octreotide on pancreatic enzyme content and its influence on pulmonary lesions of experimental AP were assessed in this study. Methods: Wistar male rats were divided in two branches: Branch I – Animals divided into three groups: Group Sa (n = 10) intravenous saline infusion; Group Ce (n = 10) intravenous cerulein infusion, (0.133 µg/kg^–1·h^–1) and Group Oc (n = 10) SC octreotide (10 µg/kg^–1). Trypsin, elastase and amylase pancreatic contents as well as serum amylase were determined thereafter in all three groups; Branch II – Rats treated as in branch I, were submitted to sodium taurocholate AP (Groups Sa+AP, Ce+AP and Oc+AP). Two hours thereafter amylase and TAP assays were performed in serum, ascites and pancreatic tissue in eight animals of each group. Pulmonary histology was studied by morphometry 24 h after AP in the remaining animals. Results: Increased serum amylase and pancreatic enzyme contents were observed in octreotide-treated animals when compared to animals receiving saline or cerulein. After AP increases of serum and ascitic fluid amylase and of pancreatic TAP were observed in octreotide pre-treated animals when compared to saline and cerulein groups. Pulmonary interstitial and alveolar edema after AP was significantly increased in rats receiving octreotide as compared to the cerulein group. Conclusion: Octreotide administration acutely increases the enzymatic content of the pancreas and thus may have a potential deleterious influence in the evolution of AP.

Somatostatin analogs in the treatment of medullary thyroid carcinoma.

The medical therapy for advanced or metastatic medullary thyroid carcinoma has not been fully established. Somatostatin analogs have been used with variable success in the therapy of a few patients with medullary thyroid carcinoma. In the present study, we evaluated the effects of somatostatin analog therapy on calcitonin (ct) and carcinoembryonic antigen in patients with advanced medullary thyroid carcinoma. Five patients (2 men and 3 women, aged 35-57 yr) with post-operative recurrent medullary thyroid carcinoma received somatostatin analog therapy for 12 weeks. All had been previously treated with total thyroidectomy and lymphadenectomy. Four of them showed positive uptake in (111)In-pentetreotide scanning. One patient was treated with sc octreotide (100 microg/8 h), 3 patients received im slow release lanreotide (30 mg/14 days), and a further one received im octreotide LAR (30 mg/28 days). Serum samples for ct and carcinoembryonic antigen were obtained at 0, 1, 2, 4, 8 and 12 weeks of therapy. Therapy was well-tolerated in general, with minimal side-effects. One patient died after the first month of therapy because of advanced disease. Another patient showed normalization of his ct and carcinoembryonic antigen concentrations at the second week of therapy, maintaining elevated values thereafter. No clinically relevant changes in serum concentrations of ct and carcinoembryonic antigen were observed in the rest of the patients. One patient with positive (111)In-pentetreotide scan, showed no uptake after somatostatin analog therapy. No significant decrease in the size of metastases was evident in the remaining patients. In conclusion, therapy with different formulations of octreotide and lanreotide does not seem to modify serum concentrations of ct and carcinoembryonic antigen in patients with recurrent medullary thyroid carcinoma.

Efficacy of the long-acting octreotide formulation (octreotide-LAR) in patients with thyrotropin-secreting pituitary adenomas.

The presence of somatostatin receptors on TSH-secreting pituitary adenomas allows treatment of central hyperthyroidism with somatostatin analogs. Six women and 5 men (mean +/- SEM age, 43 +/- 3 yr) presented TSH-secreting pituitary adenomas (micro, n = 2; macro, n = 9). Seven patients had previously been treated with partial surgical removal (n = 6) and/or external radiation (n = 4) of their adenoma at least 1 yr before the study, whereas 4 patients had not been treated before somatostatin analog therapy. TSH, free T(4), and free T(3) levels were in the normal range during treatment with sc injections (n = 9) or continuous infusion (n = 2) of octreotide (280 +/- 25 microg/day). Mean thyroid hormone levels increased (P < 0.01) after the washout period (34 +/- 6 days). The patients received monthly im injections of 20 mg Octreotide-LAR. In patients with an elevated free T(4) level after 3 months (n = 1) the Octreotide-LAR dose was increased to 30 mg. After 3 months of Octreotide-LAR treatment, TSH, free T(4)/T(3), and alpha-subunit levels decreased, and 10 patients were euthyroid with normal free T(4) levels. These results remained at the same level over the next 3 months. There were no statistically significant differences in the TSH and free T(4) responses to sc octreotide or im Octreotide-LAR between previously untreated patients and patients who had undergone surgical resection and/or pituitary radiation before somatostatin analog treatment. During Octreotide-LAR treatment, minor digestive problems or moderate discomfort at the injection site, lasting less than 48 h, were reported in 6 and 5 patients, respectively. Gallbladder echographies did not reveal new gallstones during Octreotide-LAR treatment. In conclusion, this study shows that monthly im Octreotide-LAR is as effective as daily sc octreotide in controlling hyperthyroidism in patients with TSH-secreting pituitary adenomas, in both previously untreated patients and patients treated with surgery and/or pituitary radiotherapy. Octreotide-LAR is well tolerated, except for minor digestive problems or mild pain at the injection site. Therefore, Octreotide-LAR appears to be a useful therapeutic tool to facilitate medical treatment of TSH-secreting pituitary adenomas in patients who need long-term somatostatin analog therapy.

Is the acromegalic cardiomyopathy reversible? Effect of 5-year normalization of growth hormone and insulin-like growth factor I levels on cardiac performance.

Acromegalic patients are considered to be exposed to a doubled mortality rate, mostly for cardiovascular diseases. This open prospective study was designed to evaluate whether the impairment of cardiac performance could be reversed by the long-term suppression of GH and insulin-like growth factor I (IGF-I) levels. Eighteen patients with active acromegaly were studied before and 5 yr after surgery, followed by sc octreotide in 11 patients. Disease control (GH levels < or =1 microg/L after glucose load or < or =2.5 microg/L after fasting, respectively, together with normalized IGF-I levels for age) was achieved in seven patients after surgery and in six patients after 0.3--0.6 mg/day sc octreotide. Five patients were not controlled during the 5-yr follow-up. Cardiac performance at rest and at peak exercise was assessed by equilibrium radionuclide angiography at study entry and 5 yr after surgery alone or plus octreotide. Thirty-six sex- and age-matched healthy subjects served as controls. At study entry, patients had a lower left ventricular ejection fraction (LVEF) at peak exercise and LVEF exercise-induced changes, exercise duration, and capacity than controls (P < 0.001). After 5 yr of treatment, a significant decrease of resting heart rate (P = 0.03) and a significant increase of LVEF at peak exercise (P = 0.003) was found in patients achieving disease control. LVEF response at peak exercise worsened in none of the patients with controlled disease and in three patients with uncontrolled disease (60%) (chi(2) = 5.5; P = 0.02). Diastolic filling, exercise duration, and workload did not significantly change during the 5-yr follow-up. No difference was found between patients controlled by surgery alone or by surgery plus octreotide. This 5-yr prospective study demonstrated that the LVEF response at peak exercise improved in all patients achieving disease control, while it was worsened in 60% of uncontrolled ones. These results strengthen the need of a stable suppression of GH and IGF-I hypersecretion to restore a normal cardiac performance in acromegaly.

Treatment of Orthostatic Hypotension with Midodrine and Octreotide1

The purpose of this study was to compare two treatments for orthostatic hypotension, midodrine (an alpha adrenergic agonist), and octreotide (an SRIH analogue) to each other and to combination therapy. Sixteen patients participated. Our hypothesis was that the 2 drugs together would be more effective than either drug alone. The effect of the drugs on the hemodynamic response to food ingestion was evaluated while patients were sitting. Midodrine (5 mg orally, 30 min before breakfast) increased mean blood pressure slightly (5-10 mm Hg, over 30 min) before the patients started eating, but it only partially reversed the hypotensive effect of food ingestion. The nadir in postprandial blood pressure after midodrine was 69 +/- 4 mm Hg, not different from placebo (63 +/- 5). Nevertheless, midodrine accentuated the response to sc octreotide (0.5 microgram/kg). Fifteen minutes after octreotide administration to midodrine-pretreated patients, the average mean blood pressure was 115 +/- 9 mm Hg, higher (P = .0095) than after octreotide given alone (102 +/- 7). Drug effects on orthostatic hypotension were assessed by measuring standing time (minutes before symptoms of hypotension or definite hypotension). In the absence of treatment, standing time was 3.5 +/- 7 min; 1 h after 10 mg midodrine, 8.4 +/- 2.7 min (P = .11); after 1.0 microgram/kg octreotide, 13.2 +/- 3.9 min (P = .0034 vs. no treatment); and after both drugs, 21.2 +/- 5.5 min (P = .0002 vs. no treatment, P = .036 vs. octreotide only). The combination of midodrine and octreotide is more potent than either drug alone.