Safety and Activity of Metronomic Temozolomide in Second-Line Treatment of Advanced Neuroendocrine Neoplasms

Abstract

Background: The front-line treatment of advanced NeuroEndocrine Neoplasms (NENs) depends on clinical and pathological factors but there are no standard second-line therapies. Methods: Metastatic NENs patients were treated at the ENETS (European NeuroEndocrine Tumor Society) center of excellence of Naples (Italy), from 2014 to 2017 with second-line metronomic temozolomide, 75 mg/m2 per os “one week on/one week off”. Toxicity was graded with NCI-CTC criteria v4.0; objective responses with RECIST v1.1 and performance status (PS) according to ECOG. Results: Twenty-six consecutive patients were treated. Median age was 65.5 years. The predominant primary organs were pancreas and lung. Grading was G2 in 11 patients, G3 in 15. Eleven patients presented with PS 1 and 15 with PS 2. The median time-on-temozolomide therapy was 12.2 months (95% CI: 11.4-19.6). No G3/G4 toxicities were registered. Complete response was obtained in 1 patient, partial response in 4, stable disease in 19 (disease control rate: 92.3%), and progressive disease in 2. The median overall survival from temozolomide start was 28.3 months. PS improved in 73% of patients. Conclusions: Metronomic temozolomide is a safe and active treatment for G2 and G3 NENs. Prospective and larger trials are needed to confirm these results.

Metronomic chemotherapy in patients with advanced neuroendocrine tumors: A single‐center retrospective analysis

“…Our data were in line with those reported in previous studies on the activity and tolerance of mCAP 43,44 or 5‐FU as an intravenous continuous infusion in combination with other drugs in the treatment of advanced NETs 27,45 . Metronomic TEM was explored as a “week on/week off” schedule at 75 mg/m 2 /day as second‐line treatment in advanced GEP and lung G2‐G3 neuroendocrine neoplasms (NENs) 24 . In our study, about 30% of patients received mTEM as a second‐line.…”

“…27,45 Metronomic TEM was explored as a "week on/week off" schedule at 75 mg/m 2 /day as second-line treatment in advanced GEP and lung G2-G3 neuroendocrine neoplasms (NENs). 24 In our study, about 30% of patients received mTEM as a second-line. Although our population included also G3 NETs (n = 15; 58%), mTEM did not show significant relationships between response to therapy and patients or tumor characteristics.…”

“…8 The biological characteristics of advanced NETs represents the ideal basis for mCT application, with the aim to integrate the concepts of angiogenesis and angiogenetic machinery, tumoral microenvironment, cancer stem cells, and tumoral immunology. However, to date, most of the published body of evidence in this setting, include case reports, retrospective analyses 23,24 and very few phase II studies. [25][26][27][28] Furthermore, in these studies, mCT is often associated with other concomitant drugs and the patient population is heterogeneous in terms of primary site, biological features and previous treatments.…”

Evaluation of MGMT Gene Methylation in Neuroendocrine Neoplasms

“…Alkylating agents, in particular temozolomide, have been tested for the treatment of NENs unresponsive or resistant to commonly used therapeutic approaches 5–8 . Temozolomide is currently used in the clinical management of different types of tumors, in particular lymphomas and melanomas, and, in addition to surgical resection and radiotherapy, as first-line treatment of glioblastomas 9–13 .…”