A Study of Zoledronic Acid as Neo-Adjuvant, Perioperative Therapy in Patients with Resectable Pancreatic Ductal Adenocarcinoma
- 1 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 2 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 3 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 4 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 5 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 6 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 7 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 8 Department of Medicine, School of Medicine, Washington University, St. Louis, USA
- 9 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 10 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 11 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 12 Alvin J. Siteman Cancer Center, St. Louis, USA
- 13 Alvin J. Siteman Cancer Center, St. Louis, USA
- 14 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
- 15 Department of Surgery, School of Medicine, Washington University, St. Louis, USA
Abstract
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 tu mors 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 sur gery. Patients then received 2 additional doses of ZA 4 weeks apart. Blood and bone marrow were obtained from pa tients 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 non metastatic 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 me dian 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.
- A. Jemal, R. Siegel, J. Xu and E. Ward, “Cancer Statistics, 2010,” CA: A Cancer Journal for Clinicians, Vol. 60, No. 5, 2010, pp. 277-300. doi:10.3322/caac.20073
- R. Delcore, F. J. Rodriguez, J. Forster, A. S. Hermreck and J. H. Thomas, “Significance of Lymph Node Metastases in Patients with Pancreatic Cancer Undergoing Curative Resection,” The American Journal of Surgery, Vol. 172, No. 5, 1996, pp. 463-468. doi:10.1016/S0002-9610(96)00237-1
- A. Richter, M. Niedergethmann, J. W. Sturm, D. Lorenz, S. Post and M. Trede, “Long-Term Results of Partial Pancreaticoduodenectomy for Ductal Adenocarcinoma of the Pancreatic Head: 25-Year Experience,” World Journal of Surgery, Vol. 27, No. 3, 2003, pp. 324-329. doi:10.1007/s00268-002-6659-z
- H. M. Karpoff, D. S. Klimstra, M. F. Brennan and K. C. Conlon, “Results of Total Pancreatectomy for Adenocarcinoma of the Pancreas,” Archives of Surgery, Vol. 136, No. 1, 2001, pp. 44-47. doi:10.1001/archsurg.136.1.44
- P. Goedegebuure, J. B. Mitchem, M. R. Porembka, M. C. Tan, B. A. Belt, A. Wang-Gillam, W. E. Gillanders, W. G. Hawkins and D. C. Linehan, “Myeloid-Derived Suppressor Cells: General Characteristics and Relevance to Clinical Management of Pancreatic Cancer,” Current Cancer Drug Targets, Vol. 11, No. 6, 2011, pp. 734-751. doi:10.2174/156800911796191024
- D. I. Gabrilovich and S. Nagaraj, “Myeloid-Derived Suppressor Cells as Regulators of the Immune System,” Nature Reviews Immunology, Vol. 9, No. 3, 2009, pp. 162-174. doi:10.1038/nri2506
- M. R. Porembka, J. B. Mitchem, B. A. Belt, C. S. Hsieh, H. M. Lee, J. Herndon, W. E. Gillanders, D. C. Linehan and P. Goedegebuure, “Pancreatic Adenocarcinoma Induces Bone Marrow Mobilization of Myeloid-Derived Suppressor Cells Which Promote Primary Tumor Growth,” Cancer Immunology, Immunotherapy: CII, Vol. 61, No. 9, 2012, pp. 1373-1385.
- B. Zhang, Y. Zhang, N. A. Bowerman, A. Schietinger, Y. X. Fu, D. M. Kranz, D. A. Rowley and H. Schreiber, “Equilibrium between Host and Cancer Caused by Effector T Cells Killing Tumor Stroma,” Cancer Research, Vol. 68, No. 5, 2008, pp. 1563-1571. doi:10.1158/0008-5472.CAN-07-5324
- L. Yang, L. M. DeBusk, K. Fukuda, B. Fingleton, B. GreenJarvis, Y. Shyr, L. M. Matrisian, D. P. Carbone and P. C. Lin, “Expansion of Myeloid Immune Suppressor Gr+ CD11b+ Cells in Tumor-Bearing Host Directly Promotes Tumor Angiogenesis,” Cancer Cell, Vol. 6, No. 4, 2004, pp. 409-421. doi:10.1016/j.ccr.2004.08.031
- C. Melani, S. Sangaletti, F. M. Barazzetta, Z. Werb and M. P. Colombo, “Amino-Biphosphonate-Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor Stroma,” Cancer Research, Vol. 67, No. 23, 2007, pp. 11438-11446. doi:10.1158/0008-5472.CAN-07-1882