Alkylating Agents in Pancreatic Neuroendocrine Tumors

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A number of studies have suggested that pancreatic neuroendocrine tumors (pNETs) are sensitive to chemotherapy, despite traditionally being considered chemo-resistant. Given this accumulation of data, Diane Reidy-Lagunes, MD, MS, believes chemotherapy is a reasonable option, particularly for patients with metastases in greater than 75% of their liver when embolization can be very toxic.

At this point, a clear advantage has not been demonstrated for the administration of systemic or targeted therapies in the adjuvant setting for patients with pNETs, notes Rodney F. Pommier, MD. To investigate this further, an ongoing phase II study investigating the effectiveness of everolimus in patients with pNETs following the surgical resection of liver metastases is enrolling patients with results expected in 2-3 years (NCT02031536).

A collection of data from phase II studies suggests that certain alkylating regimens are very active for patients with pNETs, notes Jonathan Strosberg, MD. Traditionally, streptozocin-based combinations were utilized; however, more recently, the oral agent temozolomide has emerged as a promising new option. In one study that combined capecitabine and temozolomide, the frontline response rate for patients with advanced pNETs was 70% with a median progression-free survival of 18 months, notes Strosberg.

The identification of more exact prognostic factors for the selection and sequencing of therapies requires further refinement, Strosberg believes. In general, patients with high-volume, progressive disease with Ki-67 in excess of 5% are ideal candidates for chemotherapy. Moreover, patients with a Ki-67 index in the range of 50% to 60% respond well to temozolomide-based chemotherapy, Strosberg suggests. Patients with very aggressive disease with a very high Ki-67 index respond best to platinum-based chemotherapy.

For patients with unresectable disease, the combination of capecitabine and temozolomide elicits a high response that can convert some patients into candidates for debulking, Pommier notes. These therapies are demonstrating exciting results for patients with pNETs, Reidy-Lagunes states. However, alkylating agents can increase the risk of bone marrow complications, warranting caution. As a result, a 12-month course of treatment may be ideal, Reidy-Lagunes believes.