Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects

Abstract

Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the O⁶-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response.

Appendiceal neuroendocrine neoplasms: diagnosis and management

“…Loco-regional therapies with embolisation and/or radiofrequency ablation could be utilised in patients with predominant hepatic metastases; the administration of molecular targeted therapies and radiopharmaceuticals could be also employed (Pape et al 2012). Although traditionally GI-NENs other than pancreatic NENs are not considered to be chemosensitive, recent data have suggested that they may also respond to temozolomide-based chemotherapy (Koumarianou et al 2015). Interestingly, a 25-year-old woman with aNEN was treated with intraperitoneal cisplatin for peritoneal recurrence after a fertility-sparing cytoreductive procedure; 5 years after her procedure, she had a successful second pregnancy implying a good long-term outcome (Smaldone et al 2007).…”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…Temozolomidebased chemotherapy, either as monotherapy or in combination with capecitabine or bevacizumab may produce response rates of 30-70% based on a limited number of mostly retrospective studies and represents an alternative approach in pNET (Koumarianou et al 2015). Pending data from a prospective trial of temozolomide vs temozolomide + capecitabine in progressive pNET (NCT01824875, www.clinicaltrials.gov) will provide more evidence for its use in the near future.…”

The effect of ascorbic acid over the etoposide and temozolomide mediated cytotoxicity in glioblastoma cell culture: a molecular study

“…The therapeutic benefit of temozolomide depends on its ability to alkylate/ methylate DNA, which most often occurs at the N (nitrogen) 7 and O (oxygen) 6 positions of guanine residues, causing a base pair mismatch. This methylation damages the DNA, and when mismatch repair (MMR) enzymes attempt to remove the 8-oxo-dGuo adduct, they produce single and double-strand breaks in the DNA and trigger cell death (11,13). Removing the methyl guanine adducts causes a decrease in the guanine residue concentrations.…”