Everolimus for advanced pancreatic neuroendocrine tumors.

BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

Gemcitabine and oxaliplatin combination chemotherapy for metastatic well-differentiated neuroendocrine carcinomas: a single-center experience.

BACKGROUND: Beyond the usual regimens based on streptozocin and doxorubicin or 5-fluorouracil, no second-line therapy of metastatic neuroendocrine tumor has gained wide acceptance. Gemcitabine and oxaliplatin are generally well tolerated and have shown activity against a wide range of malignancies. The authors assessed the efficacy of gemcitabine-oxaliplatin combination (GEMOX) in the treatment of patients with metastatic neuroendocrine tumors. METHODS: Twenty consecutive patients with progressive disease were treated with GEMOX, in most cases after failure of other chemotherapy regimens (median=2). Patients were followed for evidence of toxicity, response, and survival. Two patients were chemotherapy-naive at treatment initiation and were excluded from the efficacy analysis. RESULTS: Toxicity was manageable overall; however, 6 (30%) patients had to discontinue treatment because of oxaliplatin-induced neurotoxicity (grade 2). Three (17%) of 18 patients had a partial response, median progression-free survival was 7.0 months, and median overall survival was 23.4 months. CONCLUSIONS: Gemcitabine-oxaliplatin combination shows interesting activity and is well tolerated in pretreated patients with neuroendocrine tumors.