296 - A Randomized Phase II Study of Hypofractionated Stereotactic Radiotherapy With Concurrent 5-fluorouracil /Capecitabine With or Without Zoledronic Acid in Locally Advanced Pancreatic Ductal Adenocarcinoma
Presenter(s)
C. Lin1, A. J. Lazenby2, A. C. Das3, L. M. Smith4, Q. P. Ly5, K. Klute6, M. Krishnan6, J. C. Padussis5, J. L. Grem6, L. D. Berim7, B. N. Reames8, P. Seshacharyulu9, and S. K. Batra9; 1Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, 2Department of Pathology, University of Nebraska Medical Center, Omaha, NE, 3Novartis Pharmaceuticals, cambridge, MA, 4Department of Biostatistics, university of Nebraska Medical Center, Omaha, NE, 5Department of Surgery, University of Nebraska Medical Center, Omaha, NE, 6Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 7Department of Medical Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 8Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, 9Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE
Purpose/Objective(s):
To translate our preclinical findings that inhibition of farnesyl diphosphate synthase (FDPS) with zoledronic acid (Zometa) radiosensitizes pancreatic cancer, we conducted a randomized phase II trial evaluating Zometa with SBRT and concurrent 5-fluorouracil /capecitabine in locally advanced pancreatic ductal adenocarcinoma (PDAC).Materials/Methods:
After pathologic confirmation and staging, patients with borderline resectable or locally advanced PDAC received induction FOLFIRINOX or gemcitabine/nab-paclitaxel per standard of care. Patients without progression were randomized to SBRT/capecitabine with or without Zometa. Zometa (4 mg IV) was administered 2–4 hours before SBRT on day 1. SBRT was delivered to 40 Gy in 5 fractions with concurrent capecitabine orally (1650 mg/m²/day) or 5-fluorouracil IV (225-250 mg/m²/day) for 4 weeks. Resectable patients underwent pancreaticoduodenectomy afterwards and pathologic response was assessed. OS and DFS were estimated using Kaplan–Meier method.Results:
No dose-limiting toxicities occurred in the first 6 patients per arm. The trial employed a two-stage design and proceeded to stage 2. Forty patients were initially enrolled (20 in each arm); three per arm received gemcitabine/nab-paclitaxel and were planned for replacement. The study closed after 2 of 6 replacement patients were accrued; 42 patients were analyzed (20 Zometa, 22 control). Median follow-up was 62 months (range, 26–64). Seventeen patients underwent resection (9/22 control, 8/20 Zometa). Median pathologic response score (0–9) was 4 in both arms; one complete response occurred in the Zometa arm. No Zometa-associated grade =3 toxicities were observed. At last follow-up, 8/42 patients were alive (5/20 Zometa, 3/22 control). Locoregional failure as first site occurred in 8/42 patients (4 per arm); distant failure in 38/42 (20 control, 18 Zometa). Median DFS and OS were 8 and 26 months with Zometa versus 11 and 23.9 months without. Two-year DFS and OS were 20% and 55% with Zometa versus 22.7% and 50% without. No statistically significant differences were observed, though a greater proportion of patients in the Zometa arm survived beyond 30 months.Conclusion:
SBRT with capecitabine and Zometa is feasible and safe in locally advanced PDAC. While Zometa did not significantly improve locoregional control or survival, a higher proportion of long-term survivors in the Zometa arm warrants further study with the addition of immune checkpoint inhibitors.