The Role of Chemotherapy in Neuroendocrine Tumors

The origin of cells and embryologic relation of neuroendocrine tumors (NETs) are major determinants of clinical behavior and treatment strategy. The slow-growing nature and low rate of mitoses in NETs contrast the mechanism of efficacy of cytotoxic drugs. Bulky disease, symptomatic disease with urgent need for alleviation, and aggressively progressive tumors are potential candidates among well-to moderate-differentiated neuroendocrine neoplasms (NENs). Despite the rarity of high-level evidence of activity, cytotoxic drugs remain as an important component of treatment of NETs. Among the cytotoxic drug family, the two groups of drugs are the most active agents for NENs: alkylating agents including streptozocin (STZ), dacarbazine (DTIC), and temozolomide (TEM), and antimetabolites such as 5-fluorouracil (5-FU) and capecitabine (CAP). Topoisomerase inhibitors such as etoposide as well as platinum derivatives have been reported with high response rates in both panNETs and poorly differentiated NEC. There is no definite evidence to guide chemotherapy choice for PanNETs. CAPTEM and STZ/5-FU represent the most used regimens in clinical practice. There is no established systemic treatment for foregut NETs; only STZ combinations have been given with varying results. Besides, the indolent course of midgut NETs even in the presence of advanced tumors creates a chemo-resistant environment. In case of bronchopulmonary NETs (BP-NETs), there is no evidence of survival benefit deriving from chemotherapy. Etoposide-, temozolomide-, and oxaliplatin-containing regimens have demonstrated some activity in patients with BP-NETs. Recently, the mTOR inhibitor everolimus and the tyrosine-kinase inhibitor sunitinib have been approved for the treatment of well-differentiated pancreatic NETs. The combination of new molecular targeted therapies with chemotherapy is an immersing option, which may improve the survival results. With further understanding of importance of neoantigens and emergence of new mutations, the immunotherapy-cytotoxic therapy combination is sure to be popular in the near future.