pasireotide and Carcinoid-Tumor

Neuroendocrine tumors (NETs) are relatively rare neoplasms that often present as diagnostic dilemmas due to obscure or non-specific symptoms. The ability of carcinoid tumors to cause clinical symptoms by secretion of hormones or biogenic amines is best recognised in the form of the carcinoid syndrome. Although generally slow growing, a significant minority demonstrate aggressive tumor growth. Ten-twenty percent of pancreatic NETs may be associated with hereditary disorders such as multiple endocrine neoplasia-1 (MEN-1) and less frequently, Von Hippel Lindau, which should be considered in the investigation and management of these patients. A small percentage of NETs are associated with co-existing synchronous non-carcinoid neoplasm. The aim of this paper was to review the optimal management in patients with NETs. The therapeutic options which are reviewed, including the use of somatostatin analogues, the role of surgery, the use of chemotherapy, biotherapy using interferon, peptide receptor targeted therapy. In addition, the challenging interventional management of liver metastases is discussed, including the role of hepatic-artery embolization, radiofrequency ablation and the place of orthotoptic liver transplantation in selected patients. Authors have focused on the newest therapeutic modalities, e.g., radionuclide peptide receptor targeted therapy with Yttrium-90 and Lutetium-177, the newest somatostatin analogues such as pasireotide and angiogenic inhibitors. In conclusion, with the increasing number of investigative procedures and therapeutic options available to diagnose and treat carcinoid tumors, it is vital to have a multidisciplinary approach. Furthermore, additional scientific research and controlled clinical trials are needed to determine the efficacy of the many treatment options, which for these rare tumors can only be achieved by collaboration.

Topics: Angiogenesis Inhibitors; Biochemistry; Carcinoid Tumor; Embolization, Therapeutic; Gastrinoma; Hepatic Artery; Humans; Insulinoma; Liver Transplantation; Malignant Carcinoid Syndrome; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Patient Selection; Receptors, Peptide; Somatostatin; Vipoma; von Hippel-Lindau Disease

Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue with high binding affinity for somatostatin receptor subtypes sst(1,2,3) and sst(5). Pasireotide potently suppresses GH, IGF-I and ACTH secretion, indicating potential efficacy in acromegaly and Cushing's disease. The prolonged inhibition of hormone secretion by pasireotide in animal models and expression of multiple sst receptors in carcinoid tumors suggests that pasireotide may have clinical advantages over octreotide in patients with carcinoid tumors. Direct and indirect antitumor activity has been observed in vitro with pasireotide, including sst receptor-mediated apoptosis and antiangiogenesis, suggesting a possible role for pasireotide in antineoplastic therapy. In summary, preclinical evidence, as well as preliminary results from clinical studies suggests that pasireotide is a promising new treatment for patients with symptoms of metastatic carcinoid tumors refractory or resistant to octreotide, de novo or persistent acromegaly, and that pasireotide has the potential to be the first directed medical therapy for Cushing's disease.

Topics: Acromegaly; Adrenocorticotropic Hormone; Animals; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Drug Resistance, Neoplasm; Growth Hormone; Humans; Insulin-Like Growth Factor I; Octreotide; Pituitary ACTH Hypersecretion; Receptors, Somatostatin; Somatostatin; Structure-Activity Relationship

There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.. LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.. Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.. The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.. Novartis Pharma AG.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Delayed-Action Preparations; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Everolimus; Female; Humans; Injections, Intramuscular; Lung Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Patient Safety; Prognosis; Prospective Studies; Somatostatin; Survival Analysis; Thymus Neoplasms; Treatment Outcome

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoid Tumor; Delayed-Action Preparations; Digestive System Neoplasms; Disease-Free Survival; Double-Blind Method; Drug Resistance, Neoplasm; Drug Substitution; Female; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Octreotide; Odds Ratio; Proportional Hazards Models; Somatostatin; Time Factors; Treatment Outcome; Tumor Burden

N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing's Syndrome (CS). Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation. This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.

Topics: Adenoma; Adrenocorticotropic Hormone; Carcinoid Tumor; Cushing Syndrome; Humans; Lung Neoplasms; Neuroendocrine Tumors

Therapeutic approaches to gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still not satisfactory. A new direction in treatment options could be the novel aurora kinase inhibitor ZM447439, which was previously reported to interfere with the mitotic spindle integrity checkpoint and chromosome segregation, but does not interfere with other kinases when used up to 5 muM.. We evaluated the antineoplastic effects of ZM447439 on growth and apoptosis of the GEP-NET cell lines BON, QGP-1 and MIP-101, representing the different malignant tumor types, using standard cell biological tests as crystal violet assays, caspase activation, DNA fragmentation and cell cycle analysis.. ZM447439 dose-dependently inhibited proliferation of all three cell lines with IC(50) values in the nanomolar to low micromolar range. Moreover, aurora kinase inhibition by ZM447439 potently induced apoptosis, which was accompanied by DNA fragmentation and caspase 3 and 7 activation. Furthermore, we observed cell cycle arrest at G(0)/G(1) phase as well as a block in G(2)/M transition. In addition, combined treatment with the chemotherapeutic agents streptozocin and cisplatin augmented significantly the antiproliferative effects of those agents.. Aurora kinase inhibition by ZM447439 seems to be a promising new therapeutic approach in GEP-NETs, which should be evaluated in further clinical trials.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Apoptosis; Aurora Kinases; Benzamides; Carcinoid Tumor; Carcinoma, Neuroendocrine; Cell Division; Cell Line, Tumor; Cisplatin; Doxorubicin; Drug Interactions; Drug Therapy, Combination; Fluorouracil; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Octreotide; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Quinazolines; Somatostatin; Streptozocin; Survivin; Synaptophysin

A 56-yr-old woman presented with acromegaly, a pulmonary mass, and elevated levels of GHRH, GH, and IGF-I. Histological examination revealed a bronchial carcinoid with positive staining for GHRH. Somatostatin analogs (SAs) can play an important role in the treatment of neuroendocrine tumors, dependent on the somatostatin receptor subtype (sst) expression pattern. The sst pattern in bronchial carcinoids and effects of SAs have not been extensively investigated, particularly not for the recently developed universal SA SOM230 (Pasireotide) that has high affinity for sst1, 2, 3, and 5.. Our objective was to investigate the in vivo response of a GHRH-producing bronchial carcinoid to octreotide (OCT), its sst-expression profile, and in vitro responses to different SAs, including SOM230.. In vivo, 50 microg OCT was administered, and plasma GH and GHRH responses were determined. In vitro, the expression of ssts was analyzed by quantitative PCR. Furthermore, the effects of SOM230 and OCT on GHRH secretion were evaluated in primary cell cultures of the carcinoid tissue.. In vivo, OCT administration fully suppressed GH and GHRH levels. In vitro, sst1 mRNA was most abundant, followed by sst2 and sst5. Both SOM230 and OCT inhibited GHRH production dose dependently (SOM230 100 nm vs. control, P = 0.01; OCT 110 nm vs. control, P = 0.05).. In this case of a GHRH-producing bronchial carcinoid, we demonstrated that SOM230 was a potent inhibitor of GHRH production in vitro and was at least equally potent compared with OCT. Therefore, SOM230 may be a potential therapeutic agent to control GHRH secretion in ectopic acromegaly.

Topics: Acromegaly; Bronchial Neoplasms; Carcinoid Tumor; Female; Growth Hormone-Releasing Hormone; Hormones, Ectopic; Humans; Middle Aged; Somatostatin; Treatment Outcome; Tumor Cells, Cultured