Author(s)

Dominic E. Sanford, Matthew R. Porembka, Roheena Z. Panni, Jonathan B. Mitchem, Brian A. Belt, Stacey M. Plambeck-Suess, Goldie Lin, David G. DeNardo, Ryan C. Fields, William G. Hawkins, Steven M. Strasberg, Craig Lockhart, Andrea Wang-Gillam, Simon Peter Goedegebuure, David C. Linehan

Alvin J. Siteman Cancer Center, St. Louis, USA.
Department of Medicine, School of Medicine, Washington University, St. Louis, USA.
Department of Surgery, School of Medicine, Washington University, St. Louis, USA.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by abundant granulocytic myeloid-derived suppressor cells (G-MDSC = CD45⁺/Lin^﹣/CD33⁺/CD11b⁺/CD15⁺), which infiltrate tumors and suppress anti-tumor immunity. We have previously demonstrated in a murine model of PDAC that zoledronic acid (ZA) depletes G-MDSC resulting in decreased tumor growth and improved survival. We report here the results of a phase 1 clinical trial (NCT00892242) using ZA as neo-adjuvant, perioperative therapy in patients with non-metastatic, resectable pancreatic adenocarcinoma. Methods: Eligible PDAC patients received ZA (4 mg) IV 2 weeks prior to surgery. Patients then received 2 additional doses of ZA 4 weeks apart. Blood and bone marrow were obtained from patients prior to treatment with ZA and 3 months after surgery for analysis of G-MDSC by flow cytometry. Results: Twenty-three patients received pre-operative ZA with at least 6 months of follow-up. Only 15 PDAC patients had nonmetastatic PDAC, which was amenable to resection. ZA was well tolerated, and all adverse events were grade 1 or 2. The most common adverse events were fatigue, abdominal pain/discomfort, anorexia, and arthralgia. Of resected PDAC patients treated with ZA, 1- and 2-year overall survival (OS) was 85.7% and 33.3%, respectively, with a median OS of 18 months. This group had a 1- and 2-year progression-free survival (PFS) of 26.9% and 8.9%, respectively, with a median PFS of 12 months. The prevalence of G-MDSC was unchanged in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA. Conclusion: ZA is safe and well tolerated as neo-adjuvant, peri-operative therapy in PDAC patients. In this small study, we did not observe a difference in OS or PFS compared to historical controls. Also, there was no difference in the prevalence of G-MDSC in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA.

Pancreatic Cancer; Zoledronic Acid; Myeloid-Derived Suppressor Cells

D. Sanford, M. Porembka, R. Panni, J. Mitchem, B. Belt, S. Plambeck-Suess, G. Lin, D. DeNardo, R. Fields, W. Hawkins, S. Strasberg, C. Lockhart, A. Wang-Gillam, S. Goedegebuure and D. Linehan, "A Study of Zoledronic Acid as Neo-Adjuvant, Perioperative Therapy in Patients with Resectable Pancreatic Ductal Adenocarcinoma," Journal of Cancer Therapy, Vol. 4 No. 3, 2013, pp. 797-803. doi: 10.4236/jct.2013.43096.