PurposeNo established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs.Patients and MethodsThis open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed.ResultsBy central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus.ConclusionDaily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.

BACKGROUNDGemcitabine has broad activity in a variety of solid tumors including biliary tract carcinomas. The authors evaluated 6‐month survival, response, and toxicity associated with a combination of gemcitabine, 5‐fluorouracil (5‐FU), and leucovorin (LV) in patients with unresectable or metastatic biliary tract or gallbladder adenocarcinoma (ACA).METHODSA 4‐week course included 1000 mg/m2 gemcitabine by intravenous infusion over 30 minutes on Days 1, 8, and 15, 25 mg/m2 LV by intravenous push, and 600 mg/m2 5‐FU by intravenous push after LV.RESULTSForty‐two patients were enrolled in 6 months, 35 of whom had metastatic disease. Patients with biliary tract ACA included 24 with hepatic disease (19 patients had intrahepatic disease and 5 patients had extrahepatic disease) and 4 with disease in the ampulla of Vater. All patients were evaluable and received a median of 4 courses of treatment (range, 1–21 courses). Commonly occurring severe toxicity (NCI CTC Grade 3 or worse) included: dyspnea (four patients), nausea (four patients), fatigue (seven patients), thrombocytopenia (six patients), emesis (four patients), and diarrhea (four patients). Five partial responses (9.5%) occurred, 3 of which were sustained for ≥ 8 weeks. No treatment‐related deaths occurred. Thirty‐two patients had disease progression and 38 died after a median follow‐up of 20 months (range, 1.4–24 months). The median time to disease progression was 4.6 months (95% confidence interval [95% CI], 2.4–6.6%). The median survival period was 9.7 months (95% CI, 7–12%).CONCLUSIONSThis combination regimen was manageable in patients with advanced biliary tract and gallbladder ACA. Of 42 patients, 24 (57%) survived ≥ 6 months, satisfying the primary end point of the trial. The length of survival suggested that gemcitabine, 5‐FU, and LV had benefit equivalent to gemcitabine alone. Cancer 2005. © 2004 American Cancer Society.