Systemic chemotherapy with FOLFOX in metastatic grade 1/2 neuroendocrine cancer

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies with various clinical presentations and evolution. NETs are often diagnosed at a late stage, when they are already metastatic. Treatment is currently based on traditional chemotherapies, such as streptozocin, with serious side effects. The favorable toxicity profile of the combination of 5-fluorouracil with oxaliplatin, together with its significant antitumor activity in several gastrointestinal malignancies, led to the evaluation of its efficacy and tolerability in patients with advanced grade 1/2 (G1/G2) NETs. The endpoints of the study were tumor response (according to the Response Evaluation Criteria in Solid Tumors 1.1), overall survival (OS), progression-free survival (PFS) and symptom improvement. From January, 2013 to January, 2015, during our Regional Multidisciplinary Tumor Board dedicated to NETs (RENATEN network), FOLFOX was recommended for the treatment of metastatic NETs as first-line therapy or after failure of other therapies. The inclusion criteria were metastatic, well-differentiated G1/G2 NETs, progressing within the last 3 months. Cases with previous antitumor therapy were allowed. The patients received modified FOLFOX-6 and were assessed every 3 months by computed tomography or magnetic resonance imaging examinations. A total of 31 patients were included. The median follow-up was 20 months [95% confidence interval (CI): 15-27]. Nine patients (29%) exhibited a partial response, and 13 (41%) achieved stable disease; the disease control rate was 70%. A total of 9 patients exhibited disease progression. The control rate was 78% for pancreatic and 65% for extrapancreatic NETs. The median OS was not reached; the 1- and 2-year OS rates were 89 and 70%, respectively (Fig. 1). No significant difference in OS was observed between the <5 and 5-20% Ki-67 subgroups (P=0.41) (Fig. 2A) or according to primary tumor location (P=0.71) (Fig. 2B). The median PFS was 14.1 months (95% CI: 9.3-24.1), with no significant difference in PFS between the Ki-67 subgroups (P=0.26) (Fig. 3A) or by primary tumor location (P=0.995) (Fig. 3B). The median time to treatment failure was 14.72 months (95% CI: 10.0-not estimable). No unusual toxicity or toxicity-related deaths were reported. Finally, 7 of 9 patients who achieved a partial response benefited from a break in treatment of ≥3 months. The median duration of this break was 9.2 months (range, 3-42 months). Of the 13 patients with stable disease, 12 may have also benefited from a chemotherapy break. The median break duration was 10 months (range, 0.5-26 months).