Metastatic pancreatic neuroendocrine tumors (PNET) are generally not curable; however, some patients may have prolonged survival. Until recently, metastatic PNET were primarily managed with somatostatin-analogs. New developments demonstrating therapeutic value of temozolomide (TMZ) in these patients resulted in its off-label use in National Comprehensive Cancer Network guidelines. Given alone, or in combination with other therapies, TMZ is associated with improved clinical outcomes. However, serious hematologic adverse events (AEs) like agranulocytosis, lymphopenia and aplastic anemia are not uncommon. At the University of Kansas Cancer Center (KUCC), 3 patients with history of TMZ-treated metastatic PNET developed hematologic malignancies. The purpose of this study is to determine the incidence of secondary malignancies (SM) in this patient population.
A systematic review of all known clinical trials, case reports, and other relevant literature regarding PNET and TMZ published before September 2017 was conducted using PubMed, Embase, Cochrane Library, and the FDA Adverse Event Reporting System (FAERS).
We analyzed 38 publications and 8,215 cases reported from FAERS. AEs ranged from agranulocytosis to myelodysplastic syndrome. No publications reported any SM. The 3 patients identified at KUCC are as follows: 1) 29-year-old female with TMZ-treated metastatic PNET developed acute myeloid leukemia with cytogenetics consistent with therapy-related leukemia. 2) 80-year-old male with TMZ-treated metastatic PNET developed diffuse large B-cell lymphoma. 3) 12-year-old male with TMZ-treated metastatic PNET developed high-grade T-cell lymphoblastic lymphoma. All these patients succumbed to their hematologic malignancies, and not the underlying PNET.
Although we observed 3 cases at KUCC, this retrospective review did not find any cases of SM in TMZ-treated metastatic PNET. We believe that the leukemogenic potential of TMZ is underreported. It is important for treatment guidelines to address this risk in the decision to pursue TMZ treatment.
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All authors have declared no conflicts of interest.