5-fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors

BACKGROUND. For patients with surgically untreatable neuroendocrine tumors (NETs), the optimal therapeutic approach remains undefined. Somatostatin analogs and interferons have failed to control neoplastic growth, and chemotherapy has been only moderately more effective. The authors' previous study of the combination of 5-fluorouracil (FU), dacarbazine (DTIC), and epirubicin (EPI) (the FDE regimen) documented good tolerability, but the results for tumor growth control were disappointing. In an attempt to improve these results, the authors conducted a preliminary trial of an intensified FDE regimen (FU 500 mg/m² administered intravenously [i.v.], DTIC 200 mg/m² i.v., and EPI 30 mg/m² i.v. on Days 1, 2, and 3 every 3 weeks). METHODS. Thirty NET patients (15 male, 15 female; median age, 55 years; age range, 19-72 years) were enrolled, none of whom had previously been given chemotherapy. The histologic types of disease were gastroenteropancreatic (GEP) tumors (n = 21, 6 carcinoid tumors and 15 pancreatic NETs), other carcinoid tumors (n = 3), other NETs (n = 4), medullary thyroid carcinoma (MTC) (n = 1), and Merkel cell carcinoma (n = 1). Six patients had a syndrome related to endocrine hypersecretion. One hundred fifty-four therapy cycles were delivered (median, six per patient), and all patients could be evaluated for response on the basis of intent-to-treat analysis. RESULTS. There were 9 objective responses: 2 complete responses (in 1 patient with Merkel cell carcinoma and 1 with pancreatic NET) and 7 partial responses (in 3 patients with pancreatic NETs, 2 with other NETs, 1 with GEP carcinoid tumor, and 1 with MTC). The median duration of response was 10 months (range, 5+ to 24+ months). No reduction in symptoms was achieved among the six patients with endocrine hypersecretion syndrome. Levels of urinary 5- hydroxyindoleacetic acid and serum chromogranin A were decreased in 50% and 14% of patients, respectively, who presented with abnormal baseline values. Treatment toxicity was acceptable and included nausea and vomiting, alopecia, leukopenia, and mucositis. CONCLUSIONS. This trial demonstrated that the FDE regimen may be at least as effective as other systemic regimens. Comparison of this experience with the authors' previous trial revealed a noteworthy increase in the activity of the intensified regimen, especially in GEP NETs (the most chemoresistant tumors). Continued clinical research to improve these results is highly justified.