A Phase II Trial of Cetuximab, Gemcitabine, 5-Fluorouracil, and Radiation Therapy in Locally Advanced Nonmetastatic Pancreatic Adenocarcinoma.

Background: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. A minority of patients present with localized disease and surgical resection still offers patients the only hope for long-term survival. Locally advanced pancreatic cancer is defined as surgically unresectable, but has no evidence of distant metastases. The purpose of this study is to evaluate the efficacy and safety of cetuximab in combination with gemcitabine and 5-FU along with radiation therapy in locally advanced non-resectable, pancreatic adenocarcinoma, using progression free survival as the primary end point.

Methods: This was a prospective, single arm, open label pilot phase II study to evaluate the anti-tumor activity of gemcitabine (200 mg/m(2) per week) and cetuximab (250 mg/m(2) per week after an initial 400 mg/m(2) loading dose) with continuous infusion 5-FU (800 mg/m(2) over 96 hours) and daily concurrent external beam radiation therapy (50.4 Gy total dose) for six weeks (cycle 1) in patients with non-metastatic, locally advanced pancreatic adenocarcinoma. Following neoadjuvant treatment, subjects were re-evaluated for response and surgical candidacy with restaging scans. After resection, or also if not resected; subjects received further therapy with four 28-day cycles (cycles 2-5) of weekly gemcitabine (1000 mg/m(2)) and cetuximab (250 mg/m(2)) on days 1, 8, and 15.

Results: Between 2006 and 2011, twenty-six patients were screened and eleven of them were enrolled in the study. Most common reasons for screen failures were having resectable disease, metastatic disease or co-morbidity. Ten patients were able to tolerate and complete cycle 1 of chemoradiotherapy. One patient stopped the study prematurely due to grade III diarrhea. All except this one patient received planned radiation therapy. The response evaluation after cycle 1 showed one Partial Response, eight Stable Disease and two Progressive Disease. Four patients subsequently underwent surgical resection of the tumor. All patients had R0 resections. There was one preoperative mortality due to multiple organ failure. Median progression free survival (PFS) for four resected patients was 9.0 months while for unresected patients median PFS was 7.1 months. Median overall survival (OS) for four resected patients was 47.4 months and for unresected patients median OS was 17.0 months. Most common adverse events were hematologic (27%). Only two patients developed grade 3 neutropenia. Most common treatment related non-hematologic adverse events were diarrhea (10 of 11), nausea (8 of 11) and skin rash (10 of 11 patients). Only 9.5% of all reported non-hematologic adverse events were grade 3 or higher.

Conclusions: The combination of cetuximab, weekly gemcitabine and continuous infusion of 5-FU with radiotherapy was quite well tolerated with intriguing clinical benefit and survival results in carefully selected patients with locally advanced pancreatic adenocarcinoma. A trial with larger sample size will be necessary to confirm these results.