Continuous 5-fluorouracil infusion plus long acting octreotide in advanced well-differentiated neuroendocrine carcinomas. A phase II trial of the Piemonte oncology network

Maria P Brizzi, Alfredo Berruti, Anna Ferrero, Enrica Milanesi, Marco Volante, Federico Castiglione, Nadia Birocco, Sebastiano Bombaci, Davide Perroni, Benedetta Ferretti, Oscar Alabiso, Libero Ciuffreda, Oscar Bertetto, Mauro Papotti, Luigi Dogliotti, Maria P Brizzi, Alfredo Berruti, Anna Ferrero, Enrica Milanesi, Marco Volante, Federico Castiglione, Nadia Birocco, Sebastiano Bombaci, Davide Perroni, Benedetta Ferretti, Oscar Alabiso, Libero Ciuffreda, Oscar Bertetto, Mauro Papotti, Luigi Dogliotti

Abstract

Background: Well-differentiated neuroendocrine carcinomas are highly vascularized and may be sensitive to drugs administered on a metronomic schedule that has shown antiangiogenic properties. A phase II study was designed to test the activity of protracted 5-fluorouracil (5FU) infusion plus long-acting release (LAR) octreotide in patients with neuroendocrine carcinoma.

Methods: Twenty-nine patients with metastatic or locally advanced well-differentiated neuroendocrine carcinoma were treated with protracted 5FU intravenous infusion (200 mg/m2 daily) plus LAR octreotide (20 mg monthly). Patients were followed for toxicity, objective response, symptomatic and biochemical response, time to progression and survival.

Results: Assessment by Response Evaluation Criteria in Solid Tumors (RECIST) criteria showed partial response in 7 (24.1%), stable disease in 20 (69.0%), and disease progression in 2 patients. Response did not significantly differ when patients were stratified by primary tumor site and proliferative activity. A biochemical (chromogranin A) response was observed in 12/25 assessable patients (48.0%); symptom relief was obtained in 9/15 symptomatic patients (60.0%). There was non significant decrease in circulating vascular epithelial growth factor (VEGF) over time. Median time to progression was 22.6 months (range, 2.7-68.5); median overall survival was not reached yet. Toxicity was mild and manageable.

Conclusion: Continuous/metronomic 5FU infusion plus LAR octreotide is well tolerated and shows activity in patients with well-differentiated neuroendocrine carcinoma. The potential synergism between metronomic chemotherapy and antiangiogenic drugs provides a rationale for exploring this association in the future.

Trial registration: NCT00953394.

Figures

Figure 1
Figure 1
Time to progression (1a and 1b) and overall survival (1c and 1d) according to Ki67 expression at the cutoff of 2% positive cells and mitosis count.

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