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Background: alfa-interferon exerts antiangiogenic effects on neuroendocrine tumors. Preclinical studies showed that different interferon doses and schedules resulted in different antiangiogenic impact. In particular, low, twice-daily, and protracted dosage was most active. We studied the changes of the serum level of Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), and Vascular Cell Adhesion Molecule (VCAM-1) during treatment with very low doses of alfa-2b-interferon (INTRON-A®) combined with Sandostatin-LAR® to verify the correlations with the clinical activity. Patients and methods: 16 consecutive patients with histologic diagnosis of neuroendocrine carcinoma were included. Two are not evaluable because too early. Fourteen are evaluable for objective and twelve for biochemical response. The therapy consisted of INTRON-A®, 500.000-600.000 I.U. twice daily over five days q1w + Sandostatin LAR® 20 mg i.m. q4w. All patients signed an informed consent. Baseline evaluation: CT-scan, Octreoscan, and circulating markers. Objective response was evaluated after 4 months with CT-scan and/or Octreoscan. Treatment was confirmed in responders until progression. All patients had serum assessment of VEGF, bFGF, and VCAM-1. Results: two patients had midgut carcinoid, three pancreatic endocrine carcinoma, two type III gastric carcinoid, two typical bronchial carcinoid, one medullary carcinoma of the thyroid, and six unknown primary site. All patients had metastatic slow-growing and well differentiated carcinoma. Eleven patients had functioning and five non-functioning disease at the beginning of our treatment. Median age was 61 (range 33-74). Seven patients were pre-treated and nine untreated. Previous treatments were chemo-embolization, systemic chemotherapy, radiotargeted therapy, surgery, interferon and somatostatin analog. Median follow-up was 10 months (range 1-49). Subjective response occurred in all of the 11 symptomatic patients, and biochemical response in seven. Two patients had a partial response (PR) and seven stable disease (SD). One of the two PRs has been lasting for more than four years and is ongoing. No toxicity was observed. VEGF, FGF, and VCAM-1 evaluation is ongoing and the results will be presented at Conference. Conclusion: very low, multi-fractionated, protracted doses of INTRON-A® combined with Sandostatin-LAR® 20 mg are active and very well tolerated in patients with metastatic slow-growing neuroendocrine carcinoma. Ongoing angiogenic analysis will verify if the trend of VEGF, bFGF, and VCAM-1 under therapy is associated with treatment outcome.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]