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![Effect of somatostatin analog in neuroendocrine tumors. Somatostatin analogs bind to G-protein–linked receptors on the cell surface and cause decreased hormonal secretion by inhibiting cyclic adenosine monophosphate, increased apoptosis by activating the protein tyrosine phosphatase SHP1, decreased growth and proliferation through mitogen-activated protein kinase, inhibition of insulin- like growth factor receptor 1 signaling, and inhibition of protein synthesis caused by decreased transcription [12]. Abbreviations: cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; IGF, insulin-like growth factor; IGF-1R, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; NET, neuroendocrine tumor; NF B, nuclear factor- B; SHP1, Src homology phosphatase-1; sst, somatostatin.](profile/Pierre-Dube/publication/225043969/figure/fig1/AS:302728292126728@1449187457847/Effect-of-somatostatin-analog-in-neuroendocrine-tumors-Somatostatin-analogs-bind-to.png)
Effect of somatostatin analog in neuroendocrine tumors. Somatostatin analogs bind to G-protein–linked receptors on the cell surface and cause decreased hormonal secretion by inhibiting cyclic adenosine monophosphate, increased apoptosis by activating the protein tyrosine phosphatase SHP1, decreased growth and proliferation through mitogen-activated protein kinase, inhibition of insulin- like growth factor receptor 1 signaling, and inhibition of protein synthesis caused by decreased transcription [12]. Abbreviations: cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; IGF, insulin-like growth factor; IGF-1R, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; NET, neuroendocrine tumor; NF B, nuclear factor- B; SHP1, Src homology phosphatase-1; sst, somatostatin.
Source publication
For decades, somatostatin analogs (including octreotide and lanreotide) have been indicated for relief of the symptoms of flushing, diarrhea, and wheezing associated with secretory neuroendocrine tumors (NETs). Recently, it has been suggested that somatostatin analogs may provide direct and indirect antitumor effects in secretory and nonsecretory N...
Context in source publication
Context 1
... [2], most patients (60%) have nonfunctioning tumors. Although most pNETs are nonsecreting, many GI-NETs are associated with symptoms of flushing, diarrhea, and wheezing [2]; the constellation of these symptoms is called carcinoid syndrome. Secreting pNETs occur, in decreasing frequency, as insulinomas (causing hypoglycemia), gastrinomas (causing Zollinger-Ellison syndrome), glucagonomas (causing weight loss, diabetes, and/or skin lesions), VIPomas (i.e., Verner-Morrison syndrome; causing profuse diarrhea, hypokalemia, and flushing), and others (e.g., somatostatino- mas) [2, 5]. Most NETs express G-protein– coupled transmembrane somatostatin receptors (SSTRs) [6]. There are five subtypes of SSTRs, and different NETs have differing proportions of SSTR expression [6]. Somatostatin inhibits the release of neuroendocrine hormones, including those released from NETs. However, somatostatin has a short half-life in vivo [6], making it unsuitable for therapeutic use; thus, synthetic somatostatin analogs were developed for NET symptom control [7–11]. A subcutaneous (SC) formulation of octreotide was approved in New Zealand (1987), followed by octreotide long-acting repeatable (LAR) some years later; both are approved in more than 90 countries worldwide for the control of hormonal symptoms in patients with GI-NETs and pNETs [10]. Lanreotide SC first became available in 1988 in Europe; lanreotide long- acting microparticle formulation (LA) was approved for relief of NET symptoms in 1995 in France, and lanreotide Autogel was approved in 2001 in the European Union [9]. Like somatostatin, octreotide and lanreotide bind to the SSTR and produce a range of effects, including decreased hormonal secretion, decreased growth and proliferation, increased apoptosis, inhibition of cell signaling, and inhibition of protein synthesis; they may also have direct antiproliferative activity (Fig. 1) [12, 13]. There are 25 years of evidence that octreotide controls the symptoms of severe diarrhea and flushing in patients with carcinoid syndrome [14 –16]. Analysis of the Sur- veillance, Epidemiology, and End Results (SEER) database found that patients with metastatic NETs who were diagnosed between 1988 and 2004 had significantly greater median survival times than patients with metastatic NETs who were diagnosed between 1973 and 1987 (39 vs. 18 months, respectively; hazard ratio [HR]: 0.73; 95% confidence interval [CI]: 0.69 – 0.77; p Ͻ .001) [3]. Notably, this improvement coincides with the introduction of octreotide in 1987. Before the introduction of somatostatin analogs, many patients may have died from the effects of associated secretion syndromes (e.g., long-term diarrhea, ultimately resulting in severe ...
Citations
... However, some studies suggest chemotherapy with cisplatin, etoposide, ifosfamide, and epirubicin in lymph node or other site metastasis cases. 2,[7][8][9][10][11] In conclusion, because of the rarity of the TNET, there are many controversial issues in the treatment, especially in cases with metastatic TNET. Determining whether TNET is primary or metastasis from another origin is crucial. ...
Key Clinical Message
A 32‐year‐old male with painful scrotal swelling who underwent radical orchiectomy and was diagnosed with a testicular neuroendocrine tumor. Determining whether testicular neuroendocrine tumor is primary or metastasis from another origin is crucial.
Abstract
Testicular neuroendocrine tumors (TNET) are one of the rarest human neoplasms, with about 132 identified cases until 2015. Testicular neuroendocrine tumors are frequently manifest with painless scrotal swelling or mass. In this study, we present a 32‐year‐old male with a chief complaint of painful progressive swelling of the right testicle without any history of trauma. All laboratory tests were within the normal range. Ultrasound revealed two hyper‐vascular masses in the right testicle. Computed tomography was performed, and patients had no evidence of metastases. The patient underwent right radical orchiectomy, and a histopathological examination diagnosed the specimen with a well‐differentiated testicular neuroendocrine tumor. Because of the rarity of TNET, there are many controversial issues in the treatment, especially in cases with metastatic TNET. Determining whether testicular neuroendocrine tumor is primary or metastasis from another origin is crucial. Further studies are required to achieve optimum treatment for TNET.
... et al37 ). In the randomized CLARINET trial, 67 of 101 patients (66%) treated with LAN remained alive without progression within 12 months of treatment vs 49% of patients on placebo. ...
Background
In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs.
Materials and Methods
SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN.
Results
Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication.
Conclusions
LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile.
... Chemotherapy based on temozolomide or capecitabin is considered for functional tumor, but they do not have long-standing effect on hypercalcemia [29][30][31]. The analog of somatostatin, such as octreotide or lanreotide, is considered for decreased tumor burden, not only in resectable lesion, but also in metastatic lesion, to decrease both symptoms and tumor growth [32][33][34]. However, this medical treatment sometimes is not sufficient and efficacy decreases over time as result of tachyphylaxis [25]. ...
Background
Hypercalcemia of malignancy, as a paraneoplastic syndrome, is the most common metabolic disorder that accounts for 30% of malignancies and usually has a poor prognosis. Neuroendocrine tumors are uncommon and arise from neuroendocrine cells throughout the body. Actually, paraneoplastic hypercalcemia in neuroendocrine tumors is unusual and mostly associated with parathyroid hormone-related protein (PTHrP) secretion.
Case presentation
We report a 51-year-old Iranian man who presented with nausea, vomiting, and significant weight loss for 1 month. Laboratory data revealed calcium of 26 mg/dl, accompanied by low level of PTH. Octreotide scan revealed a large donut-shaped octreotide avid lesion in the epigastric region at the right side of the mid-abdomen, with multiple varying size foci of abnormally increased radiotracer uptake in the epigastric region and both lobes of the liver. Endoscopic ultrasonography demonstrated a large heterogeneous mass lesion with irregular outline and good demarcation in the body of the pancreas with diffuse foci of calcification. Percutaneous biopsy of the liver mass demonstrated a well-differentiated neuroendocrine tumor (low grade) confirmed by immunohistochemistry with strongly positive chromogranin and synaptophysin stain. Hypercalcemia was treated with hydration, few sessions of hemodialysis, calcitonin, and denosumab injection. However, the patient developed symptomatic hypocalcemia. Oncology consultation led to prescription of long-acting octreotide 30 mg monthly and everolimus daily.
Conclusion
Pancreatic neuroendocrine tumor could lead to malignant hypercalcemia; secretion of PTHrP is the most common cause, and signs and symptoms are usually milder than paraneoplastic syndrome due to hematologic and solid tumor. Generally, survival is better; however, its treatment is challenging, and primary debulking surgery is often required. A team approach to management is important at all points.
... Radiation therapy has little effect on metastatic NETs [6]. Octreotide, a somatostatin analog, showed symptomatic improvement in 80% of patients diagnosed with metastatic disease and can stop tumor growth, according to a meta-analysis that studied the effect of somatostatin analogs on NETs [10]. ...
Testicular neuroendocrine tumors (TNETs) are extremely rare. We report a case of a primary TNET and discuss the clinical and histological characteristics, treatment, and prognosis of this tumor. A 47-year-old man had a painless right testicular mass. All tumor markers were negative. The patient underwent a high inguinal radical orchidectomy. Histopathology revealed a well-differentiated neuroendocrine tumor. Radiological investigations showed multiple prominent axillary, supraclavicular, mediastinal, and hilar lymph nodes and no bowel or mesenteric lesions suggesting carcinoid. Once a TNET is diagnosed, it is necessary to rule out the secondary origin in the gastrointestinal tract and lungs. Radical orchiectomy is the treatment of choice for TNETs. Somatostatin analogs can be useful in patients with carcinoid syndrome, induce symptomatic improvement, and control disease progression. As this case highlights, physicians should consider TNETs in the differential diagnosis of testicular masses, as early diagnosis and treatment are crucial for good patient outcomes.
... 14 SSA are the mainstay of symptomatic management, demonstrating tumour stabilising effects in up to 60% of pNET. 15,16 Therefore, they are recommended for antiproliferative purposes in non-resectable, slowly progressive, low-grade NET. 17 Our patient had an excellent response to SSA therapy, with rapid resolution of secretory diarrhoea and associated electrolyte derangements. ...
A 35‐year‐old man with known human immunodeficiency virus experienced chronic diarrhoea for 18 months. He presented to multiple hospitals with profuse secretory diarrhoea and life‐threatening electrolyte disturbances. Infectious and non‐infectious aetiologies were considered, with focussed history and investigations ultimately leading to a diagnosis of VIPoma. Initiation of somatostatin analogue therapy followed by surgical resection led to complete resolution of symptoms and markedly improved quality of life.
... Se utilizan para el control de síntomas en TNEs bien diferenciados en estadios avanzados, sin embargo, recientemente se han reconocido sus efectos antitumorales y su beneficio en sobrevida libre de progresión (SLP) 33 . El primero en desarrollarse fue el octreótide 34 que requería múltiples dosis diarias. ...
Neuroendocrine Tumors (NETs) encompass a wide variety of tumors arising from neuroendocrine cells, which produce bioactive substances. The incidence of NETs increased significantly lately, becoming one of the most common tumors of the digestive tract. Their clinical presentation is as diverse as their capacity for hormone production. Carcinoid syndrome is the most common hormonal syndrome produced by NETs and is characterized by diarrhea, flushing and cardiac valvular lesions. New research brought multiple changes in the classification of these neoplasms and a new understanding about their diagnosis and treatment, promoting a multidisciplinary approach. Somatostatin analogues, radiation, biological, and cytotoxic drugs have improved the prognosis of these patients, which entails a great challenge for healthcare providers.
... The direct antitumor effects of SSTR agonists include SSTR activation, phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibition and downregulation of the mitogen-activated protein kinase (MAPK) pathway (12)(13)(14). In addition, some of the indirect effects of this class of drugs include inhibition of angiogenesis, alterations of the tumor immunity and suppression of growth factors (14,15). ...
Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors. In this review, we summarize the results of various clinical trials that have been conducted to investigate the efficacy and safety of various therapeutic options for NENs. Based on the encouraging results obtained from these trials, various therapeutic options have been established for the treatment of NENs, including somatostatin analogs (SSAs), molecularly targeted drugs and cytotoxic agents. In addition, peptide receptor radionucleotide therapy has recently been evaluated for the treatment of various NENs. We also discuss the approach for selecting the appropriate drugs and sequence of treatment with the various drug classes, as recommended by different treatment guidelines. Finally, we discuss the scope for future research in this field, especially into the merits of combination therapy with molecularly targeted drugs plus SSAs, along with ongoing studies.
... Our study reported that most patients receiving LAN-ATG experienced a reduction in tumor size, which was maintained during long-term LAN-ATG. SSAs have a potential antitumor effect by suppressing proliferation [4,15,26], and a clinical trial of octreotide LAR reported a reduction in tumor size [10]. While the doses of LAN-PR evaluated in previous studies might not be high enough to elicit an antitumor effect [8,9], the doses of LAN-ATG administered in our study could have been sufficient to inhibit cell proliferation and then reduce the tumor size. ...
Somatostatin analogs are recommended for pharmacotherapy of TSH-secreting pituitary adenoma (TSHoma). A multicenter clinical trial was conducted to evaluate the efficacy and safety of lanreotide autogel treatment for TSHoma. A total of 13 Japanese patients with TSHoma were enrolled from February to December 2018 and treated with lanreotide autogel 90 mg every 4 weeks, with dose adjustments to 60 mg or 120 mg. Analysis was performed on data from patients receiving preoperative treatment (n = 6) up to 24 weeks and from those receiving primary or postoperative treatment (n = 7) up to 52 weeks. The primary efficacy endpoints were serum concentrations of TSH, free triiodothyronine (FT3), and free thyroxine (FT4). The secondary efficacy endpoints were pituitary tumor size and clinical symptoms. The serum concentrations of TSH, FT3, and FT4 decreased with treatment, and euthyroid status was maintained until final assessment. FT4 at final assessment was within reference ranges in 10/13 patients. The median (interquartile range) percent change in pituitary tumor size from baseline at final assessment was –23.8% (–38.1, –19.8). The clinical symptoms were also improved. The patients receiving preoperative treatment did not develop perioperative thyroid storm. Regarding safety, adverse events were observed in 12/13 patients, but none discontinued treatment. The common adverse events were gastrointestinal disorders (12/13 patients) and administration site reactions (5/13 patients). Lanreotide autogel may be effective for controlling thyroid function and reducing the pituitary tumor size, and is tolerable in patients with TSHoma (Japic Clinical Trials Information; JapicCTI-173772).
... Although the response rate of SSA therapy remains low, treatment with these agents leads to disease stabilization in approximately two thirds of patients [4,5]. There is, however, a subset of patients who demonstrate early disease progression on SSA therapy [6]. Previous studies for characterization of such patients identified several factors predictive of early treatment failure, including pancreatic primary tumor or fast tumor growth rate [7,8], but none of the factors was specific enough to describe more than a tendency toward lack of response [6]. ...
... There is, however, a subset of patients who demonstrate early disease progression on SSA therapy [6]. Previous studies for characterization of such patients identified several factors predictive of early treatment failure, including pancreatic primary tumor or fast tumor growth rate [7,8], but none of the factors was specific enough to describe more than a tendency toward lack of response [6]. ...
... Interestingly, lack of prior SSA therapy also predicted early failure on SSA therapy on univariate analysis. This finding is likely attributed to The most notable clinical implication of the present study is prediction of treatment failure with very high specificity, which has not been possible with previously known predictive factors [6]. With increasing integration of 68 Ga-DOTATATE PET/CT into the initial workup of patients with well-differentiated GEP-NET, SUVmax for a given patient can be easily obtained without demand for additional resources. ...
Background:
Somatostatin analogs (SSAs) are the frontline antitumor therapy in advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A subset of patients demonstrate early disease progression on SSA therapy, yet the currently known predictors for treatment failure lack specificity to affect therapeutic decision. SSAs target tumor somatostatin receptors, the level of which can be quantitatively assessed with 68 Ga-DOTATATE PET/CT. We investigated the ability of 68 Ga-DOTATATE PET/CT to predict response to SSA therapy.
Materials and methods:
The records of 108 consecutive patients with well-differentiated grade 1-2 GEP-NETs on SSA monotherapy who received 68 Ga-DOTATATE PET/CT scans were retrospectively reviewed to obtain baseline characteristics, 68 Ga-DOTATATE SUVmax, and progression-free survival (PFS) data. The optimal SUVmax cutoff for patient stratification was obtained with ROC curve analysis. PFS in the high vs. low SUVmax groups was compared with Kaplan-Meier survival analysis. The effects of baseline characteristics and SUVmax on PFS were examined with univariate and multivariate Cox regression.
Results:
68 Ga-DOTATATE SUVmax predicted therapeutic failure with sensitivity and specificity of 39% and 98%, respectively. SUVmax of <18.35 was associated with shorter PFS, which was reproduced in the subgroup analysis of SSA naive patients. Low SUVmax was the only predictor of early treatment failure (HR=6.85) in multivariate analysis, as well as in the subgroup analysis of grade 2 GEP-NETs.
Conclusion:
Low SUVmax on 68 Ga-DOTATATE PET/CT independently predicts early failure on SSA monotherapy in well-differentiated grade 1-2 GEP-NET patients. Patients with lack of expected benefit from SSA therapy can be readily identified using routine 68 Ga-DOTATATE PET/CT with very high specificity.
Implications for practice:
Based on 68 Ga-DOTATATE PET/CT imaging, clinicians can better inform patients on the expected benefit of somatostatin analog therapy for gastroenteropancreatic neuroendocrine tumors, especially when access to the therapy is difficult, and offer proactive discussion on alternative management options.
... In cases diagnosed with oligometastatic disease, the national comprehensive cancer network guidelines recommend debulking surgery whenever possible; however, in certain cases the extent of disease make surgery with curative intent impossible (8,9). Therefore, in such cases neoadjuvant treatment followed by surgery might be needed; moreover, in cases in which association of gastrin synthesis is demonstrated, somatostatin analogues might be used in order to decrease the risk of recurrence (10,11). ...
Background/aim:
Gastroenteropancreatic neuro-endocrine carcinomas represent poorly differentiated neoplasms with a high capacity of spreading inducing the development of distant metastases. In such cases debulking surgery seems to offer a good chance for survival especially in well and moderately differentiated lesions. The aim of this study was to report the case of a 48-year-old patient submitted to surgery for moderately differentiated neuroendocrine gastric carcinoma with distant metastases.
Case report:
The patient was initially investigated for hematemesis and weight loss and was diagnosed with a lesser curvature gastric tumor in association with liver and peritoneal metastases. Due to the extent of the disease, the patient was initially submitted to neoadjuvant chemotherapy followed by surgery with radical intent. At the time of surgery subtotal gastrectomy en bloc with total omentectomy, peritonectomy, cholecystectomy and atypical liver resection were performed. Moreover, the two ovaries presented large tumoral masses so total hysterectomy with bilateral adnexectomy was performed. The histopathological studies confirmed the presence of a moderately differentiated neuroendocrine gastric carcinoma with negative resection margins.
Conclusion:
Multiple visceral resections might be needed in order to maximize the debulking effort in metastatic gastric neuroendocrine carcinomas.
