A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
British Journal of Cancer (Impact Factor: 4.82). 12/2006; 95(9):1148-54. DOI: 10.1038/sj.bjc.6603419
Source: PubMed

ABSTRACT Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

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    ABSTRACT: Pancreatic neuroendocrine tumors (NETs) are uncommon disease, about which little is known. Pancreatic NETs are usually slow growing and their malignant potential are often underestimated. The management of this disease poses a challenge because of the heterogeneous clinical presentation and varying degrees of aggressiveness. Recently, several guidelines for the management of pancreatic NETs have been established and help to devise clinical strategy. In the treatment algorithms, however, a lot of uncertain points are included. Practical treatment decisions of pancreatic NETs are still sometimes made in a patient- and/or physicians-oriented manner. The tumor grading system proposed by the European Neuroendocrine Tumor Society (ENETS) gives important prognostic information, however, the implication of grading regarding medical treatment strategies to choose has not yet been clarified. Moreover, the place of surgical treatment is unclear in the overall management course of advanced pancreatic NETs. In some cases, practical management and treatment have to be individualized depending on predominant symptoms, tumor spread, and general health of the patients. Current issues and a few points to make a strategy in the management of pancreatic NETs would be reviewed.

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