Daily Oral Everolimus Activity in Patients With Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial
ABSTRACT PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.
- SourceAvailable from: Francoise Borson-Chazot
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- "Par la suite, 9 % de réponses objectives et une survie sans progression de 9,7 mois ont été rapportées dans une étude de phase II évaluant l'évérolimus chez 115 patients ayant une TNE du pancréas en progression ou non . Enfin, l'association évérolimus–octréotide retard a été étudiée dans deux études objectivant respectivement 27 et 4 % de réponses morphologiques dans 30 et 45 TNE du pancréas, en progression ou non, donnant une survie sans progression égale à 16 mois pour la deuxième étude  . Plus récemment, une étude de phase III randomisée, en double aveugle, testant l'efficacité de l'évérolimus contre placebo dans des TNE du pancréas bien différenciées en progression a démontré un bénéfice statistiquement significatif en termes de survie sans progression dans le bras traité par évérolimus (11,4 mois) en comparaison du bras placebo (4,6 mois) . "
ABSTRACT: Insulinoma are malignant in 4 to 14 % of cases. Their rarity and the sparse data available in the literature have limited publication of specific guidelines for their management. The following review aim to provide up-to-date recommendations on initial evaluation including pathologic grading, measures to control hypoglycemia, antitumor strategies and long term follow-up. Will be discussed in detail respective indications of surgery, diazoxide, somatostatin analogs, everolimus, sunitinib, liver directed treatments including arterial embolization, chemotherapy and radiometabolic therapy. A Medline search using terms “insulinoma”, “neuroendocrine pancreatic tumors”, “islet cell carcinoma”, “malignant insulinoma” was performed limiting the selection to English language articles and adult age cases, along with cross referencing.La Presse Médicale 05/2014; 43(6). DOI:10.1016/j.lpm.2013.08.007 · 1.17 Impact Factor
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- "The median progressionfree survival (PFS) was 60 weeks; 1-, 2-and 3-year survival rates were 83%, 81% and 78%, respectively. The international, multicenter, open-label, Phase II study (RAD001 in advanced NET: RADIANT) evaluating the effect of everolimus and octreotide LAR as a combination therapy in patients with advanced pancreatic NET resistant to cytotoxic chemotherapy reported reduction in tumor volume in 84.2% of patients receiving combination therapy (everolimus 10 mg/day plus octreotide LAR ≤30 mg) versus 59.3% of patients receiving everolimus monotherapy (10 mg/day) (Yao et al., 2010). The median PFS was prolonged with combination therapy (16.7 months) compared with everolimus monotherapy (9.7 months) (Figure 3) and the clinical benefit rate, defined as overall response rate plus stable disease, was also better with combination therapy (84.4%) compared with everolimus monotherapy (77.4%). "
ABSTRACT: Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and have a wide expression pattern in both normal tissues and solid tumors. Investigating the function of each SSTR in several tumor types has provided a wealth of information about the common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis. This provided the rationale for developing multireceptor-targeted somatostatin analogs and combination therapies with signaling-targeted agents such as inhibitors of the mammalian (or mechanistic) target of rapamycin (mTOR). The ability of SSTR to internalize and the development of rabiolabeled somatostatin analogs have improved the diagnosis and treatment of neuroendocrine tumors.Frontiers in Neuroendocrinology 07/2013; 34(3). DOI:10.1016/j.yfrne.2013.07.005 · 7.58 Impact Factor
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- "Side eff ects were moderate including stomatitis, diarrhea, rash, fatigue, nausea and asthenia. Th ese data suggest that the combination of everolimus and SST-A might be benefi cial ; however, this was a stratifi ed patient cohort and not a randomised trial . "
ABSTRACT: Neuroendocrine tumours (NETs) are rare tumours with their clinical behaviour depending on the location of the primary and grade of differentiation. Recently, a number of randomised studies have been published focussing on pancreatic NETs which have demonstrated the efficacy of new therapeutic approaches including thyrosin-kinase inhibition and targetting the mTOR pathway. The objective of this review is to briefly sum up systemic treatment options in well differentiated pancreatic neuroendocrine tumours which are currently available.memo - Magazine of European Medical Oncology 04/2012; 5(1). DOI:10.1007/s12254-012-0339-y