In patients with midgut neuroendocrine tumors that progressed during octreotide analogue therapy, the addition of
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Lu-Dotatate to octreotide resulted in an 18% response rate and a significantly ...higher rate of progression-free survival at 20 months than high-dose octreotide alone.
Neuroendocrine tumors of the midgut (which is defined as the jejunoileum and the proximal colon) commonly metastasize to the mesentery, peritoneum, and liver and are frequently associated with the carcinoid syndrome.
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Neuroendocrine tumors of the midgut represent the most common type of malignant gastrointestinal neuroendocrine tumors and are associated with 5-year survival rates of less than 50% among persons with metastatic disease.
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First-line systemic therapy usually consists of a somatostatin analogue for control of both hormonal secretion and tumor growth.
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With the exception of everolimus for the treatment of nonfunctional neuroendocrine tumors,
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no standard second-line systemic treatment . . .
To the Editor:
In the Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET), Caplin et al. (July 17 issue)
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report that lanreotide prolonged progression-free ...survival in patients with grade 1 and selected grade 2 neuroendocrine tumors (hazard ratio for progression or death, 0.47; 95% confidence interval, 0.30 to 0.73).
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Somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are expressed in 70 to 90% of neuroendocrine tumors. The result on somatostatin-receptor scintigraphy is the most important factor that predicts the effectiveness of somatostatin analogue therapy.
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For a long time, indium-111–labeled diethylenetriaminepentaacetic acid (DTPA)–octreotide scintigraphy (octreoscan) has been the standard . . .
As compared with placebo, extended-release lanreotide (120 mg every 28 days) was associated with delayed disease progression in patients with nonfunctional, slowly progressing neuroendocrine tumors. ...Progression-free survival at 24 months was 65% with lanreotide and 33% with placebo.
Neuroendocrine tumors are rare neoplasms,
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with an annual incidence of 5 cases per 100,000 people in the United States.
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More than 50% of cases involve tumors originating in the gastrointestinal system or pancreas, and patients commonly have distant metastases at diagnosis.
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Since many of these patients have inoperable disease, medical therapy is often initiated to control disease progression. Treatment may also be required to relieve symptoms arising from the overproduction of amines or peptide hormones in functioning tumors.
Few medical treatments for advanced neuroendocrine tumors have been approved on the basis of their antiproliferative effects (i.e., efficacy in inhibiting . . .
Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled ...phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.
Carcinoid heart disease is a frequent occurrence in patients with carcinoid syndrome and is responsible for substantial morbidity and mortality. The pathophysiology of carcinoid heart disease is ...poorly understood; however, chronic exposure to excessive circulating serotonin is considered one of the most important contributing factors. Despite recognition, international consensus guidelines specifically addressing the diagnosis and management of carcinoid heart disease are lacking. Furthermore, there is considerable variation in multiple aspects of screening and management of the disease. The aim of these guidelines was to provide succinct, practical advice on the diagnosis and management of carcinoid heart disease as well as its surveillance. Recommendations and proposed algorithms for the investigation, screening, and management have been developed based on an evidence-based review of the published data and on the expert opinion of a multidisciplinary consensus panel consisting of neuroendocrine tumor experts, including oncologists, gastroenterologists, and endocrinologists, in conjunction with cardiologists and cardiothoracic surgeons.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Somatostatin analogs (SA) are the standard of care for controlling symptoms of patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). SA control symptoms in more than 70% ...of patients with carcinoid syndrome. Similar results are obtained in patients with functional, hormone-secreting, pancreatic NETs. The use of SA as antiproliferative agents has been established only recently. Retrospective studies have shown stabilization of tumor growth in >50% of patients with progressive disease. The results of a recent randomized phase III trial (PROMID) demonstrated that the median time to progression in patients with midgut carcinoid tumors treated with octreotide LAR (Long-Acting-Repeatable, Novartis, Basel, Switzerland) was more than twice as long compared to that of patients treated with placebo. The results of a phase III study of lanreotide versus placebo in nonfunctional NETs are not yet available. More studies are needed to determine whether combining SA with novel targeted treatments will result in enhanced antiproliferative activity compared to treatment with a SA alone. Studies are ongoing using pan-receptor agonists (eg, pasireotide) and chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins) and are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors). Somatostatin receptor antagonists are also currently being developed for clinical use. Peptide receptor radionuclide therapy (PRRT), consisting of yttrium-90 and lutetium-177 isotopes conjugated with SA appear to be efficacious in advanced NETs. Randomized studies are needed to definitively establish the safety and efficacy of this strategy compared to other available treatments, and to determine which radiolabeled isotopes or combinations are most effective.
Somatostatin receptor PET tracers such as (68)Ga-DOTA,1-Nal(3)-octreotide ((68)Ga-DOTANOC) and (68)Ga-DOTA,Tyr(3)-octreotate ((68)Ga-DOTATATE) have shown promising results in patients with ...neuroendocrine tumors, with a higher lesion detection rate than is achieved with (18)F-fluorodihydroxyphenyl-l-alanine PET, somatostatin receptor SPECT, CT, or MR imaging. (68)Ga-DOTANOC has high affinity for somatostatin receptor subtypes 2, 3, and 5 (sst2,3,5). It has a wider receptor binding profile than (68)Ga-DOTATATE, which is sst2-selective. The wider receptor binding profile might be advantageous for imaging because neuroendocrine tumors express different subtypes of somatostatin receptors. The goal of this study was to prospectively compare (68)Ga-DOTANOC and (68)Ga-DOTATATE PET/CT in the same patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to evaluate the clinical impact of (68)Ga-DOTANOC PET/CT.
Eighteen patients with biopsy-proven GEP-NETs were evaluated with (68)Ga-DOTANOC and (68)Ga-DOTATATE using a randomized crossover design. Labeling of DOTANOC and DOTATATE with (68)Ga was standardized using a fully automated synthesis device. PET/CT findings were compared with 3-phase CT scans and in some patients with MR imaging, (18)F-FDG PET/CT, and histology. Uptake in organs and tumor lesions was quantified and compared by calculation of maximum standardized uptake values (SUVmax) using volume computer-assisted reading.
Histology revealed low-grade GEP-NETs (G1) in 4 patients, intermediate grade (G2) in 7, and high grade (G3) in 7. (68)Ga-DOTANOC and (68)Ga-DOTATATE were false-negative in only 1 of 18 patients. In total, 248 lesions were confirmed by cross-sectional and PET imaging. The lesion-based sensitivity of (68)Ga-DOTANOC PET was 93.5%, compared with 85.5% for (68)Ga-DOTATATE PET (P = 0.005). The better performance of (68)Ga-DOTANOC PET is attributed mainly to the significantly higher detection rate of liver metastases rather than tumor differentiation grade. Multivariate analysis revealed significantly higher SUVmax in G1 tumors than in G3 tumors (P = 0.009). This finding was less pronounced with (68)Ga-DOTANOC (P > 0.001). Altogether, (68)Ga-DOTANOC changed treatment in 3 of 18 patients (17%).
The sst2,3,5-specific radiotracer (68)Ga-DOTANOC detected significantly more lesions than the sst2-specific radiotracer (68)Ga-DOTATATE in our patients with GEP-NETs. The clinical relevance of this finding has to be proven in larger studies.
To determine the prognostic significance of circulating tumor cells (CTCs) in patients with neuroendocrine cancer.
In this single-center prospective study, 176 patients with measurable metastatic ...neuroendocrine tumors (NETs) were recruited. CTCs were measured using a semiautomated technique based on immunomagnetic separation of epithelial cell adhesion molecule-expressing cells.
Overall, 49% patients had ≥ one CTC, 42% had ≥ two CTCs, and 30% had ≥ five CTCs in 7.5 mL blood. Presence of CTCs was associated with increased burden, increased tumor grade, and elevated serum chromogranin A (CgA). Using a 90-patient training set and 85-patient validation set, we defined a cutoff of < one or ≥ one as the optimal prognostic threshold with respect to progression-free survival (PFS). Applying this threshold, the presence of ≥ one CTC was associated with worse PFS and overall survival (OS; hazard ratios HRs, 6.6 and 8.0, respectively; both P < .001). In multivariate analysis, CTCs remained significant when other prognostic markers, grade, tumor burden, and CgA were included. Within grades, presence of CTCs was able to define a poor prognostic subgroup. For grade 1, HRs were 5.0 for PFS (P = .017) and 7.2 for OS (P = .023); for grade 2, HRs were 3.5 for PFS (P = .018) and 5.2 for OS (P = .036).
CTCs are a promising prognostic marker for patients with NETs and should be assessed in the context of clinical trials with defined tumor subtypes and therapy.
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