The Role of Cytotoxic Chemotherapy in Advanced Pancreatic Neuroendocrine Tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms accounting for less than 5% of all pancreatic malignancies. These tumors are characterized by clinical and prognostical heterogeneity and are predominantly diagnosed in a metastatic stage. Cytotoxic chemotherapy, along with alkylating agents and antimetabolites as well as molecular targeted agents (everolimus, sunitinib), is used in the treatment of advanced PNETs. After the approval of lanreotide for unresectable PNETs, an additional therapeutic option has become available; however, the best sequence of therapies and patient stratification to different treatments remains challenging. Furthermore, no randomized phase-3 trials or head-to-head comparisons are available to support treatment decisions.

SUMMARY: The publication of 3 large single-center retrospective studies on streptozocin-(STZ)-based chemotherapy in advanced PNETs in 2015 confirmed the effectiveness of this treatment as described in previously reported trials. All studies investigated markers for progression-free and overall survival and strongly supported the value of the Ki-67 index as a robust prognostic marker. Interestingly, chemotherapy consistently displayed antitumor efficacy in different therapeutic lines. Moreover, a recent study of dacarbazine (DTIC) in a cohort of patients predominantly with PNETs demonstrated that a once monthly infusional DTIC schedule was well tolerated and yielded similar response rates (RR) as STZ-based schedules. Given the overall good tolerability of a monthly infusion and RR similar to STZ schedules, DTIC thus represents a feasible alternative or additional treatment option for PNETs. In this article, we review the current standard and summarize the most recent advances in the field of cytotoxic chemotherapy for PNET patients. Key Messages: (1) Despite the lack of phase3 trials, cytotoxic chemotherapy offers efficacy for patients with advanced PNETs; (2) the best therapeutic option and sequence remain open since comparable randomized studies are lacking; (3) careful patient selection and treatment stratification may increase overall outcome; and (4) currently, no biomarkers for clinical routine exist to predict response to chemotherapy.