ArticlesEverolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study
Introduction
Neuroendocrine tumours, also known as carcinoids, are uncommon tumours arising from various primary sites.1 Nearly 50% of patients with neuroendocrine tumours have metastatic disease, and 65% will die within 5 years of diagnosis.1 The 5 year survival rate for patients with advanced neuroendocrine tumours is greater for patients with well differentiated (low or intermediate grade) versus poorly differentiated tumours and locoregional versus distant disease.1 Survival also varies by primary site; in patients with low-grade or intermediate-grade histology and distant disease, lung and colon are associated with the worst median survival (17 and 7 months, respectively), and jejunum, ileum, and caecum are associated with the best (55–65 months).1
Somatostatin analogues, such as octreotide and lanreotide, improve the hormone-related symptoms associated with neuroendocrine tumours. Furthermore, octreotide long-acting repeatable (LAR) has also shown antitumour activity, prolonging time to disease progression in patients with midgut neuroendocrine tumours.2, 3 No approved antitumour drugs are available for treating progressive disease in patients with gastrointestinal or lung neuroendocrine tumours.
Overactivation of the mammalian target of rapamycin (mTOR), a serine-threonine kinase that regulates cell growth, proliferation, metabolism, and angiogenesis, has been implicated in the pathogenesis of neuroendocrine tumours.4, 5, 6, 7 Autocrine activation of the mTOR signalling pathway, mediated through insulin-like growth factor I, has been associated with neuroendocrine tumour cell proliferation,8 and inhibition of the mTOR pathway has shown antiproliferative effects in cell lines of neuroendocrine tumours9, 10 and primary cultures of human neuroendocrine tumours.11 Everolimus, an oral inhibitor of mTOR, showed promising antitumour activity in advanced neuroendocrine tumours in two phase 2 studies.12, 13 Recently, everolimus showed a 6·4 month increase in progression-free survival compared with placebo in patients with advanced pancreatic neuroendocrine tumours.14 However, the role of everolimus in neuroendocrine tumours of other primary sites or in combination with other drugs has not been studied extensively. Combination therapy with everolimus plus octreotide LAR might enhance antitumour efficacy by simultaneously targeting upstream and downstream components of the mTOR pathway (webappendix p 1).15, 16
We aimed to establish whether 10 mg per day everolimus plus 30 mg octreotide LAR every 28 days compared with placebo plus 30 mg octreotide LAR every 28 days prolongs progression-free survival in patients with well differentiated or moderately differentiated advanced neuroendocrine tumours (carcinoid tumours) and a history of flushing, diarrhoea, or both.
Section snippets
Participants
Between Jan 10, 2007, and April 2, 2010, we did a multicentre, double-blind, phase 3 study in Australia, Belgium, Canada, Czech Republic, Finland, France, Germany, Greece, Israel, Italy, Netherlands, Slovakia, Spain, Sweden, Turkey, and the USA. We judged the participants eligible if they were aged 18 years or older, had low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological
Results
Figure 1 shows the trial profile. 211 patients (98%) assigned to receive everolimus plus octreotide LAR and 204 (96%) assigned to receive placebo plus octreotide LAR had metastatic disease. There were imbalances in baseline demographic and disease characteristics favouring placebo plus octreotide LAR, including lung as primary tumour site, WHO performance status greater than 0, and previous use of chemotherapy (table 1). Both groups were similar with respect to history of previous treatment
Discussion
Our findings show that median progression-free survival was greater in the everolimus plus octreotide LAR group than the placebo plus octreotide LAR group. Treatment of advanced neuroendocrine tumours remains a clinical challenge because of the lack of effective options and the absence of well controlled randomised clinical trial data to support evidence-based practice. With few exceptions, chemotherapeutic drugs are not active in advanced non-pancreatic neuroendocrine tumours and are
References (24)
- et al.
Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and further proposals
Translational Oncol
(2010) - et al.
One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States
J Clin Oncol
(2008) - et al.
Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors
Cancer
(1993) - et al.
Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group
J Clin Oncol
(2009) - et al.
Targeting the mTOR signaling network for cancer therapy
J Clin Oncol
(2009) - et al.
Current development of mTOR inhibitors as anticancer agents
Nat Rev Drug Discov
(2006) - et al.
The TOR pathway: a target for cancer therapy
Nat Rev Cancer
(2004) - et al.
Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells
Cancer Res
(2000) - et al.
Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors
Endocr Relat Cancer
(2008) - et al.
Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway
J Clin Oncol
(2010)
Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids
Endocr Relat Cancer
Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial
J Clin Oncol
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