Disease response did not change when the patients were stratified by primary disease site, mitotic count and Ki67

Disease response did not change when the patients were stratified by primary disease site, mitotic count and Ki67. In the 11 patients with circulating VEGF assessed before and after treatment, there was a non significant trend of progressive marker reduction over time (mean VEGF levels 147, 96, and 67 pg/ml at baseline, 3 and 6 months, respectively, P = 0.33). 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 == Background == Well-differentiated neuroendocrine carcinomas are a group of rare malignancies generally characterized by low aggressiveness [1-4]. Surgery is the only curative modality. In unresectable disease, somatostatin analogues effectively reduce hormonal hypersecretion, but tumor shrinkage is only rarely seen (0%-6% of patients) [5,6]. Because of their low proliferative activity, conventional chemotherapy for these tumors is not recommended [7-9]. Metronomic chemotherapy, i.e., the frequent administration of cytotoxic drugs at low doses [10], has demonstrated antiangiogenetic properties [11-13]. Since well-differentiated neuroendocrine carcinomas are highly vascular [14,15], there is a rationale for testing metronomic chemotherapy in this clinical setting [16]. Five-fluorouracil (5FU) is frequently employed in the treatment of advanced neuroendocrine carcinoma [17-19]. The combination of protracted 5FU infusion and alfa 2b interferon has been tested in the treatment of well-differentiated neuroendocrine carcinomas of the gastroenteropancreatic tract, and a disease response obtained in more than 40% of patients [20]. Moreover, concomitant administration of somatostatin analogues to enhance the effect of the antiproliferative activity of 5FU has been reported in severalin vitroandin vivopreclinical studies [21]. On these grounds, the Piemonte Region Oncology Network conducted a multicenter phase II trial to assess the activity and safety profile of a combination regimen of protracted 5FU infusion and long-acting release (LAR) octreotide in patients with advanced well-differentiated neuroendocrine carcinomas. The primary study aim was to assess response to treatment; the secondary aims were to evaluate toxicity, biochemical and symptomatic response, MDM2 Inhibitor time to progression and survival. == Methods == == Study population == Eligibility criteria included histological diagnosis of well-differentiated neuroendocrine carcinoma according to the World Health Organization (WHO) classification [1], locally advanced or metastatic disease not amenable to surgery with radical intent, at least one measurable target lesion, radiological documentation of progressive disease, somatostatin receptor scintigraphy, Eastern MDM2 Inhibitor Cooperative Oncology Group (ECOG) performance status grade 2, life expectancy 12 weeks, adequate bone marrow reserve (WBC count 3.5 109/L, platelets 100 109/L, hemoglobin 10 g/dL), adequate hepatic and renal function (hepatic enzymes and bilirubin < 2 upper limit of normal, serum creatinine < 1.4 mg/dl). Exclusion CD340 criteria were non-malignant systemic MDM2 Inhibitor disease or conditions that precluded patients from receiving the study therapy, second primary malignancies, and previous systemic antineoplastic treatment including somatostatin analogues. Diagnostic work-up included physical examination, screening chemistry, circulating chromogranin A (CgA), abdominal, chest and pelvis computed tomography (CT), and somatostatin receptor scintigraphy. The study was approved by the local ethic committee of each participating center. Written informed consent was obtained from all patients before starting treatment. == Histology and immunohistochemical analysis == The histological diagnoses performed at each center were centrally reviewed by two experienced pathologists using the proposed morphological criteria for well-differentiated neuroendocrine carcinoma [1]. In addition, immunohistochemical analysis of the Ki-67 proliferation index (DakoCytomation, Glostrup, Denmark, clone MIB-1, diluted 1/300), type 2 somatostatin receptor expression (BioTrend, Cologne, Germany, code SS-800, diluted 1/3000) and VEGF marker levels (NeoMarkers, Fremont, CA, USA, polyclonal, diluted 1/250) was performed. == Treatment plan and toxicity assessment == LAR octreotide acetate at a dose of 20 mg was administered intramuscularly every 4 weeks. The first administration was matched to an induction treatment of octreotide (0.1 mg subcutaneous every 8 h) for 14 days; 5FU was given as a protracted continuous infusion without interruption at a daily dose of 200 mg/m2of body-surface area through an MDM2 Inhibitor elastomeric pump connected to a central venous access. 5FU treatment was planned to be administered for 6 months, however, prolonged 5FU administration beyond 6 months was permitted. LAR octreotide administration was continued until disease progression. Toxicity was assessed according to National Cancer Institute Common Toxicity Criteria (NCI CTC) [22]. 5FU dose modifications were performed as follows: if WBC count was < 2500/mL and/or platelet.