Efficacy and safety of aranoza-based therapy in neuroendocrine neoplasms. Prognostic role of O6-methylguanine DNA methyltransferase expression in tumor tissue

Abstract

Aranoza (3-a-L-arabinopyranosyl-1-methyl-nitrosourea) is nitrosourea derivative, as streptozotocin STZ. O6-methylguanine DNA methyltransferase (MGMT) is an enzyme involved in chemotherapy resistance to alkalyting agents. Material and methods. There were observed 117patients with neuroendocrine neoplasms (NENs) received Aranoza-based therapy. They included 52 cases with pancreatic neuroendocrine tumors (P-NETs), 52 patients with non-pancreatic (notP-NETs, 13 NET patients with metastases without revealed primary tumor focus). There was investigated the radiologic response to the treatment according to Response Evaluation Criteria In Solid Tumors (RECIST) Score, version 1.0), biochemical response, median progression-free survival (PFS) by Kaplan-Meier estimator), toxicity (according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0) and the impact of MGMT expression (immunohistochemistry method) in tumor tissue on the efficacy of the treatment. Results. Objective response rate (ORR) in PNET cases accounted for 39% (20/52) whereas in nonP-NETpatients - 12% (6/52) (p = 0.0032). Median PFS accounted for 15.3 months in PNET patients and 16.6 months in non-PNET cases (p = 0.78). The most common types of the toxicity grade III-IV included thrombocytopenia (17from 871 courses) and neutropenia (11 from 871 courses). In samples of the tumor tissue the lack of MGMT expression was observed in 29 out of 35 P-NET cases, 12 out of 31 non-PNET cases (p = 0,0006). Objective response was recorded in 20 of 44 patients with MGMT-deficient tumors and in 1 out of 27patients with MGMT intact tumors (p = 0.0001). In the lack and presence of the MGMT expression in the tumor tissue median PFS accounted for 20.6 months and 14.4 months correspondingly (p = 0,022). Conclusion. Aranoza-based therapy demonstrated an antitumor activity and good safety profile in NENpatientss. MGMT deficiency in PNETs was more common than in non-PNETs and explained the susceptibility of some PNETs to treatment.