Somatostatin Analogues In Patients Research Articles

Pre-surgical treatment with somatostatin analogues in patients with acromegaly: The case against

Pre-surgical treatment with somatostatin analogues in patients with acromegaly: The case against

Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly

To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly. This is a cross-sectional study in two tertiary referral centers in The Netherlands. One hundred and eight patients with acromegaly, in whom transsphenoidal (n=101, 94%) or transcranial (n=7, 6%) surgery was performed. Subsequently, 46 (43%) received additional radiotherapy and 41 (38%) were on postoperative treatment with SSTA because of persistent or recurrent disease at the time of study. All subjects filled in standardized questionnaires measuring HR-QoL. Disease control at the time of study was assessed by local IGF1 SDS. IGF1 SDS were slightly higher in patients treated with SSTA in comparison with patients without use of SSTA (0.85±1.52 vs 0.25±1.21, P=0.026), but the percentage of patients with insufficient control (IGF1 SDS >2) was not different (17 vs 9%, P=0.208). Patients using SSTA reported poorer scores on most subscales of the RAND-36 and the acromegaly QoL and on all subscales of the multidimensional fatigue inventory-20. A subgroup analysis in patients with similar IGF1 levels (SSTA+, n=26, IGF1 SDS 0.44±0.72 vs SSTA-, n=44, IGF1 SDS 0.41±0.65) revealed worse scores on physical functioning, physical fatigue, reduced activity, vitality, and general health perception across all HR-QoL questionnaires in patients treated with SSTA. QoL is impaired in association with the need for prolonged postoperative therapy by SSTA in patients with acromegaly despite similar IGF1 levels.

New Perspectives on Diagnostics, Prognosis, and Therapy in Aggressive Endocrine Tumours

New Perspectives on Diagnostics, Prognosis, and Therapy in Aggressive Endocrine Tumours

Safety review: Dose optimization of somatostatin analogs in patients with acromegaly and neuroendocrine tumors

Patients with either acromegaly or neuroendocrine tumors (NET) can be treated with somatostatin analogs to relieve symptoms and improve disease control. However, there is an absence of large clinical trials specifically designed to document the safety when increases in somatostatin analog dosing are needed in patients who do not achieve their treatment goals. To fully explore and communicate any potential risks, we conducted a literature review and present a summary of the studies documenting the safety and tolerability of dose optimization with somatostatin analogs in patients with acromegaly and NET. A literature search was undertaken to find clinical studies specifically reporting the effects of dose titration using the depot formulations of the somatostatin analogs, octreotide long-acting repeatable (LAR) or lanreotide, in patients with acromegaly and NET. Publications that described the treatment and management of patients with acromegaly and NET were reviewed. The rationale for dose optimization, including high-dose treatment in patients who are inadequately controlled on conventional doses and the safety and tolerability of somatostatin analogs, is discussed. A review of published clinical studies demonstrates that dose optimization provides additional biochemical control in patients with acromegaly and NET who are inadequately controlled with conventional starting doses of octreotide LAR and lanreotide ATG. The benefits of dose optimization include improved efficacy without a significant change in the recorded adverse events and the tolerability of the treatment. Therefore, patient response to treatment should be routinely monitored and their somatostatin analog dose increased or decreased thereafter according to their individual response.

Efficacy of adding high-dose In-111 octreotide therapy during Sandostatin treatment in patients with disseminated neuroendocrine tumors: clinical results of 14 patients

This study aimed to assess the outcome of high-dose In-111 octreotide treatment and efficacy of long-acting Sandostatin LAR in patients with disseminated neuroendocrine tumors. A total of 14 patients (mean age 51.8±13.2years; 10 female, 4 male) receiving high-dose In-111 octreotide in our centre for the treatment of neuroendocrine tumors were included in the study. Monthly treatment with long-acting somatostatin analogue [Sandostatin long-acting release (Novartis Pharmaceuticals)] was continued in nine cases. During a 3-year period, a total of 45 courses of high-dose In-111 octreotide treatment were delivered to 14 patients. In seven patients receiving an average of four treatment courses (6 carcinoid tumors, 1 thymoma, patients: 2, 4, 5, 11-14) stable disease was achieved (50%). In two patients with carcinoid tumors (patients 1 and 3) who received four treatment courses, partial response was observed (14%). Five patients (36%; 4 NET, 1 gastrinoma; patients 6-10) died due to progressive disease following on average two treatment courses. On average, deaths occurred 2months after the last treatment dose. No complete responses were seen. Partial response was achieved in two of the nine patients receiving Sandostatin LAR, while four had stable disease. Both treatments were associated with acceptable tolerability. High-dose In-111 octreotide can be safely administered in conjunction with somatostatin analogue in patients with disseminated NET and this treatment may help to stabilize the disease.

New Treatment Options for Patients with Advanced Neuroendocrine Tumors

Well- to moderately differentiated neuroendocrine tumors (NET) are a heterogeneous group of malignancies for which a range of therapeutic options have been employed. For patients with localized NET, surgical resection remains the mainstay of treatment. Surgical resection of hepatic metastases or hepatic artery embolization may also be beneficial in patients with hepatic-predominant metastatic disease. Symptoms of hormonal excess, such as carcinoid syndrome and syndromes associated with functional pancreatic NET, can be effectively treated with somatostatin analogs. Systemic treatment options for patients with advanced NET have been limited. Treatment with the somatostatin analog octreotide has been shown to improve progression-free survival in patients with advanced midgut carcinoid tumors, and the potential antiproliferative effect of somatostatin analogs in patients with other NET subtypes is currently under investigation. Patients with advanced pancreatic NET may also respond to treatment with streptozocin or temozolomide-based therapy. In patients with advanced pancreatic NET, randomized, placebo-controlled studies have recently demonstrated that treatment with the tyrosine kinase inhibitor sunitinib or with the mTOR inhibitor everolimus is associated with improved progression-free survival. Based on these studies, sunitinib or everolimus should now be considered as therapeutic options in patients with advanced pancreatic NET. Initial phase II studies have also suggested activity associated with VEGF pathway and mTOR inhibitors in patients with advanced carcinoid tumors. Future studies will likely further define the role of these agents in the advanced carcinoid patient population.

Role of Somatostatin Receptors in Normal and Tumoral Pituitary Corticotropic Cells

Normal and tumoral pituitary corticotropic cells express sst₂ and sst₅, of which sst₅ is the predominantly expressed receptor subtype. Somatostatin (SS) inhibits pituitary adrenocorticotropin hormone (ACTH) secretion in vitro, but the sensitivity to SS is strongly regulated by glucocorticoids. In pathological conditions of a low endogenous cortisol level, i.e. in patients with adrenal insufficiency and in patients with Nelson’s syndrome, SS and sst₂-preferring SS analogs (SSA), such as octreotide, are able to lower circulating ACTH and cortisol levels. On the other hand, sst₂-preferring SSA seem not effective in lowering ACTH and cortisol levels in patients with untreated Cushing’s disease (CD), in which circulating cortisol levels are high. This is likely due to the downregulation of sst₂ receptors by glucocorticoids. sst₅ receptor expression is more resistant to the inhibitory effect of glucocorticoids. In recent years, novel sst subtype-selective and universal SSA have been developed. In particular, SSA with a high sst₅-binding affinity are potent inhibitors of ACTH secretion by pituitary corticotropic adenoma cells. This knowledge has initiated clinical trials evaluating the efficacy of these novel SSA in patients with CD, with the aim to lower circulating ACTH and cortisol levels by targeting multiple ssts on the corticotropic adenoma cells. In this minireview, the effects of SS in the regulation of normal and tumoral ACTH secretion, the role of sst subtypes involved herein, as well as the potentials of novel SSA in the treatment of patients with recurrent or persisting CD are discussed.

Magnetic Resonance Imaging as a Predictor of Response to Somatostatin Analogs in Acromegaly after Surgical Failure

Transsphenoidal surgery is considered first-line therapy for acromegaly; however, there is often a need for adjunctive therapy. Somatostatin analogs (SSA) have greatly improved the effectiveness of medical treatment, but one third of patients are resistant. The aim was to evaluate whether magnetic resonance imaging (MRI) signal could predict long-term response to SSA in patients with active acromegaly after neurosurgery. Sixty-two patients who were active acromegalic after surgery were included in this retrospective study. Remaining pituitary tumor was classified as hyper-, iso-, or hypointense by evaluating T2-weighted MRI signal. Treatment with SSA at maximal effective doses was prescribed and evaluated at 6 and 12 months by monitoring IGF-I, GH, and T2 MRI. Complete response to SSA treatment (defined as normal IGF-I) at 6 months was observed in 30%, partial response (defined as IGF-I between 2 and 3 sd score) in 15%, and no response in 55% of patients. At 12 months, 28, 20, and 52% were observed, respectively. MRI signal was hypointense in 40%, hyperintense in 48%, and isointense in 12%. At 6 months, complete response to SSA was observed in 71% of cases having hypointense MRI signal and in 20% of hyperintense (P = 0.04). At 12 months, 62% of hypointense remained well controlled, whereas in the hyperintense group, good, partial, or no response results did not change from that observed at 6 months (P = 0.04). In active acromegalic patients after surgery, a hypointense T2-weighted MRI signal is associated with a better response to SSA treatment at 6 and 12 months.

Long-term effects of somatostatin analogs in patients with acromegaly

Long-term effects of somatostatin analogs in patients with acromegaly

Genetic abnormalities of somatostatin receptors in pituitary tumors

Somatostatin exerts antisecretive and antiproliferative effects on different endocrine cells by acting through a family of G protein-coupled receptors that includes five subtypes (SST1-5). Normal human pituitary and pituitary adenomas have been shown to express almost all SST subtypes, with the exception of SST4. Consistent with the observation that octreotide and other somatostatin analogs bind to SST2 and SST5 with high affinity, these genes have been screened for quantitative/qualitative abnormalities in tumors removed from patients with poor responsiveness to somatostatin analogs treatment. Data obtained in GH-secreting adenomas suggested that resistance to octreotide was frequently associated with low expression of SST2 mRNA, although other authors failed to confirm this finding. To date, the only mutational change involving SST2 and SST5 is the Arg to Trp substitution in codon 240 of the SST5 gene that was found in one acromegalic patient resistant to octreotide. Similarly, loss of heterozygosis at SST5 gene locus in pituitary adenomas has been described in individual tumors. In recent years, molecular studies investigated the possible association of gene polymorphisms and susceptibility to diseases and/or resistance to drugs. As far as polymorphic variants of SST genes are concerned, a possible role of SST5 C1004T and T-461C alleles in influencing GH and IGF-I levels in patients with acromegaly has been proposed. Nevertheless, polymorphic variants in SST2 and SST5 genes seem to have a minor, if any, role in determining the different responsiveness to somatostatin analogs in patients with acromegaly.

Presurgical treatment with somatostatin analogs in patients with acromegaly: effects on the remission and complication rates

Presurgical treatment with somatostatin analogs in patients with acromegaly: effects on the remission and complication rates

Presurgical treatment with somatostatin analogs in patients with acromegaly: effects on the remission and complication rates

The question of whether preoperative therapy with somatostatin analogs can improve surgical outcome in acromegaly has not been definitively answered. In this paper, the authors report the effects of preoperative treatment with somatostatin analogs in a large sample of patients with acromegaly. Between 1990 and 2003, 399 consecutive patients with acromegaly underwent surgery at the Istituto Scientifico San Raffaele. Thirty-three patients who had previously undergone surgery or radiation treatment, 48 patients treated with somatostatin analogs for fewer than 3 months, and patients who had stopped therapy for too long a time before surgery were excluded from the study. One hundred forty-three patients who had received somatostatin analogs prior to surgery (Group 1) were randomly matched to 143 patients who had never been treated with somatostatin analogs (Group 2). Matching criteria were tumor size and invasiveness into the cavernous sinus. Before surgery, Group 1 patients showed reduction of growth hormone levels to less than 50% of baseline in 64% of cases, but insulin-like growth factor-I was normalized in only 19.5%. Surgical remission occurred in 81 Group 1 patients (56.6%) and in 91 Group 2 patients (63.6%; p = 0.28). No significant difference in the remission rate was observed when cases were analyzed according to tumor size or invasiveness. Logistic regression analysis confirmed that pretreatment with somatostatin analogs was not associated with surgical outcome. Surgical morbidity was mild and similar in Group 1 and Group 2 patients (7 and 5.6%, respectively; p = 0.81). Surgical remission and complication rates in patients with acromegaly who received treatment with somatostatin analogs prior to surgery were not significantly different from those of matched patients who did not receive these agents. At present, the routine use of presurgical therapy with somatostatin analogs for patients with acromegaly cannot be recommended.

Pre-therapeutic dosimetry with radiolabelled somatostatin analogues in patients with advanced neuroendocrine tumours

Pre-therapeutic dosimetry with radiolabelled somatostatin analogues in patients with advanced neuroendocrine tumours

The value of an acute octreotide suppression test in predicting long‐term responses to depot somatostatin analogues in patients with active acromegaly

The long-acting depot somatostatin analogues [octreotide LAR (LAR) and lanreotide (LAN)] are among the most effective available medical therapies for acromegaly. However, published data on a biochemical test suitable for predicting the responsiveness to these depot agents are lacking. To investigate the value of an acute octreotide suppression test (OST) in predicting the responses to treatment with long-acting somatostatin analogues in patients with active acromegaly. Thirty patients with active acromegaly [mean GH in GH day curve (GHDC) > 5 mU/l] were subjected to an OST [hourly GH measurements for 6 h following 100 microg subcutaneous (s.c.) octreotide]. Subsequently, 14 patients were treated with LAR, 10 with LAN and 6 received both drugs at different times. The final response to treatment was evaluated when the subjects had achieved 'safe' GH levels (mean GH < 5 mU/l) or after receiving the maximal dose of each drug (maximum duration of treatment 6 months). The nadir GH values during the OST were 2.6 +/- 2.5 mU/l (mean +/- SD, range 0.2-8.7) with a percentage fall of 84.8 +/- 15.7% (mean +/- SD, range 26-99%) from the baseline levels (26.2 +/- 31.5 mU/l, mean +/- SD). All the patients except one showed a decrease of greater than 50%. The mean time to achieve the nadir GH value was 3.8 +/- 1.6 h (mean +/- SD, range 1-6). The nadir GH levels showed a positive correlation with both pre-treatment (i.e. before commencing LAN or LAR) GH values during the GHDC (r = 0.63, P < 0.01) and IGF-I levels (r = 0.56, P < 0.05). The nadir GH values during the OST showed a positive correlation with the achieved mean GH levels in patients treated with LAR (r = 0.66, P < 0.01) but not in the ones treated with LAN. The criterion of GH < 5.25 mU/l during the OST had sensitivity 100%, specificity 80%, positive predictive value (PPV) 94% and negative predictive value (NPV) 100% in predicting achievement of 'safe' GH levels in patients treated with LAR. A less optimal prognostic profile was obtained for subjects treated with LAN with the criterion of GH < 6.05 mU/l during the OST providing sensitivity 92%, specificity 67%, PPV 92% and NPV 67%. The above cut-off GH levels had a PPV of only 77% and 60% in predicting normalization of IGF-I on treatment with LAR or LAN, respectively. The OST is a reliable tool for the selection of patients with active acromegaly who will achieve 'safe' GH levels on therapy with LAR. Its prognostic profile is less optimal for patients treated with LAN. If GH values during the test fall < 5.25 mU/l (in case of LAR treatment) or < 6.05 mU/l (in case of LAN treatment), there is a 92-94% chance of subsequently achieving 'safe' GH levels after up to 6 months treatment with either of these agents.

Different responses to chronic somatostatin analogues in patients with central hyperthyroidism

Central hyperthyroidism is mainly due to two different causes, TSH-secreting pituitary adenoma (TSH-oma) and resistance to thyroid hormone in its pituitary variant, i.e. patients presenting with signs and symptoms of hyperthyroidism (PRTH). Because therapeutic approach and the clinical follow-up are extremely different in these two disorders, a correct differential diagnosis is mandatory. Unfortunately, no definite pathognomonic tool is presently available and an extensive biochemical and instrumental workup is frequently needed in order to reach the correct diagnosis. Aim of the present study was to investigate the use of somatostatin analogues in the differential diagnosis between TSH-omas and PRTH, as well as the possible treatment of PRTH with these analogues. Eight patients with TSH-oma and four with PRTH underwent the acute test with somatostatin analogue Octreotide (0.1 mg subcutaneously), as well as long-acting Octreotide-LAR (30 mg intramuscularly every 28 days) for two months. Serum TSH, FT3 and FT4 were evaluated in basal condition, at time 0 and every hour for 6 h during acute test, and every 15 days for 2 months during chronic treatment. During acute test, in both patients with PRTH and TSH-oma, a similar reduction in immunoreactive TSH and FT3 levels was observed, while no variations were found in FT4 concentrations. In contrast, during the administration of Octreotide-LAR, no significant variations of all tested parameters were observed in PRTH group, whereas FT3 and FT4 concentrations normalized or presented a significant reduction (> 30% of pretreatment values) in seven of eight patients with TSH-oma, despite minor variation of immunoreactive TSH levels. Chronic administration of long-acting somatostatin analogues in patients with central hyperthyroidism caused a marked decrease of FT3 and FT4 levels in all patients but one with TSH-oma, while patients with PRTH did not respond at all. Thus, administration of long acting somatostatin analogues for at least 2 months can be useful in the differential diagnosis in problematic cases of central hyperthyroidism. Furthermore, the present findings exclude the possibility of a beneficial effect of chronic administration of somatostatin analogues in controlling thyrotoxic symptoms in PRTH patients.

Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours

A few studies have suggested an antitumour activity of somatostatin analogues in neuroendocrine tumours (NET). The aim of this study was to evaluate the antitumour efficacy of somatostatin analogues in patients with documented progressive tumours. 35 consecutive patients with documented tumour progression were treated with somatostatin analogues. Patients were classified into two groups. In Group 1, tumours were progressing rapidly (an increase of 50% or more in the lesion surface area in 3 months) and in Group 2, tumours were progressing more slowly (an increase of less than 50% in the lesion surface area in 3 months but greater than 25% in 6 months). Treatment consisted of subcutaneous (s.c.) octreotide, 100 μg thrice daily for 17 patients, intramuscular lanreotide, 30 mg/every 14 days for 11 patients and for 7 patients both somatostatin analogues were used successively during the follow-up. Primary tumour sites were the small intestine (n=12), pancreas (n=13), lungs (n=5), and other sites (n=5). 18 patients had the carcinoid syndrome with flushing and/or diarrhoea. The median duration of treatment was 7 months. Treatment was discontinued in 3 patients due to side-effects. One patient (3%) achieved a partial response and the disease was stabilised in 20 patients (57%) for a median duration of 11 months (6–48 months). Stabilisation of patients in Group 1 was significantly less frequent at 6 months than that of patients in Group 2 (4/12 and 13/17 respectively, P<0.02). Somatostatin analogue treatment resulted in one partial response (3%) and 20 cases of stabilisation (57%) in 35 patients with progressive NET. A slow tumour growth rate before treatment is predictive of a good response to somatostatin analogues which could be considered an option for first-line treatment.

Somatostatin receptor scintigraphy before and after treatment with somatostatin analogues in patients with thyroid eye disease.

Octreotide, a potent synthetic long-acting somatostatin analogue, has been shown to have a beneficial effect in thyroid eye disease (TED). Orbital scintigraphy using ocetreoscan-111 is a useful study, which can be used to visualize somatostatin-receptor-bearing cells and also to select patients who might benefit from octreotide therapy. One major limitation of this therapy is that the drug must be administered parenterally and used several times daily. Lanreotide, a new somatostatin analogue, has a much longer duration of action in comparison with octreotide, and has recently been found to have a beneficial effect in the treatment of thyroid eye disease. The aim of this study was to investigate the orbital Indium-111-pentetreotide activity after treatment with octreotide and lanreotide in patients with thyroid ophthalmopathy. Fourteen patients were studied. 12 with bilateral and 2 with unilateral thyroid eye disease, (10 females and 4 males) and all with moderately severe symptoms of ophthalmopathy. All were treated with antithyroid drugs and were euthyroid at the time of the study. All patients were investigated with orbital scintigraphy using octreoscan-111 and selected for study on the basis of a positive octreoscan. Five patients received 30 mg lanreotide intramuscularly once every 2 weeks over a period of 3 months, and 5 patients received octreotide 100 microg subcutaneously thrice daily for 3 months. Four patients served as controls and received no treatment. The octreoscan-111 scintigraphy was repeated in all patients 3 months after the first examination. The NOSPECS classification and the clinical activity score (CAS) of thyroid ophthalmopathy were also evaluated before and 3 months after the initiation of treatment. All patients who received treatment had a negative follow-up octreoscan while controls had a positive octreoscan. NOSPECS score and CAS were improved with treatment, but unchanged in control patients. The reduced uptake of octreoscan may be the result of blocking of somatostatin receptors, or reduction in receptor-expressing tissues, downregulation of somatostatin receptors in target tissues, or a combination of these factors.

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.

Comparative in vitro and in vivo studies with four radiolabelled somatostatin analogues in patients with endocrine tumours

Li, S. R.; Yang, Q.; Leimer, M.; Raderer, M.; Kurtaran, A.; Angelberger, P.; Niederle, B.; Scheithauer, W.; Valent, P.; Virgolini, I. Author Information

Classification of Eye Changes of Graves' Disease

Classification of Eye Changes of Graves' Disease