A Study of Zoledronic Acid as Neo-Adjuvant, Perioperative Therapy in Patients with Resectable Pancreatic Ductal Adenocarcinoma


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.

Share and Cite:

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.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] 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
[2] 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
[3] 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
[4] 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
[5] 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
[6] 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
[7] 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.
[8] 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
[9] 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
[10] 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
[11] Novartis Pharma, “Zometa Product Information,” Author, Basel, 2013.
[12] J. R. Brahmer, S. S. Tykodi, L. Q. Chow, W. J. Hwu, S. L. Topalian, P. Hwu, C. G. Drake, L. H. Camacho, J. Kauh, K. Odunsi, et al., “Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer,” The New England Journal of Medicine, Vol. 366, No. 26, pp. 2455-465. doi:10.1056/NEJMoa1200694
[13] F. S. Hodi, S. J. O’Day, D. F. McDermott, R. W. Weber, J. A. Sosman, J. B. Haanen, R. Gonzalez, C. Robert, D. Schadendorf, J. C. Hassel, et al., “Improved Survival with Ipilimumab in Patients with Metastatic Melanoma,” The New England Journal of Medicine, Vol. 363, No. 8, 2010, pp. 711-723. doi:10.1056/NEJMoa1003466
[14] J. R. Berenson, R. A. Vescio, L. S. Rosen, J. M. VonTeichert, M. Woo, R. Swift, A. Savage, E. Givant, M. Hupkes, H. Harvey, et al., “A Phase I Dose-Ranging Trial of Monthly Infusions of Zoledronic Acid for the Treatment of Osteolytic Bone Metastases,” Clinical Cancer Research, Vol. 7, No. 3, 2001, pp. 478-485.
[15] J. M. Winter, J. L. Cameron, K. A. Campbell, M. A. Arnold, D. C. Chang, J. Coleman, M. B. Hodgin, P. K. Sauter, R. H. Hruban, T. S. Riall, et al., “1423 Pancreaticoduodenectomies for Pancreatic Cancer: A Single-Institution Experience,” Journal of Gastrointestinal Surgery, Vol. 10, No. 9, 2006, pp. 1199-1210.
[16] B. G. Smaglo and M. J. Pishvaian, “Postresection Chemotherapy for Pancreatic Cancer,” The Cancer Journal, Vol. 18, No. 6, 2012, 614-623. doi:10.1097/PPO.0b013e31827459d8
[17] H. Eidtmann, R. de Boer, N. Bundred, A. Llombart-Cussac, N. Davidson, P. Neven, G. von Minckwitz, J. Miller, N. Schenk and R. Coleman, “Efficacy of Zoledronic Acid in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole: 36-Month Results of the ZOFAST Study,” Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO, Vol. 21, No. 11, 2010, pp. 2188-2194.
[18] M. Gnant, B. Mlineritsch, H. Stoeger, G. Luschin-Ebengreuth, D. Heck, C. Menzel, R. Jakesz, M. Seifert, M. Hubalek, G. Pristauz, et al., “Adjuvant Endocrine Therapy plus Zoledronic Acid in Premenopausal Women with Early-Stage Breast Cancer: 62-Month Follow-Up from the ABCSG-12 Randomised Trial,” The Lancet Oncology, Vol. 12, No. 7, 2011, pp. 631-641. doi:10.1016/S1470-2045(11)70122-X
[19] R. E. Coleman, H. Marshall, D. Cameron, D. Dodwell, R. Burkinshaw, M. Keane, M. Gil, S. J. Houston, R. J. Grieve, P. J. Barrett-Lee, et al., “Breast-Cancer Adjuvant Therapy with Zoledronic Acid,” The New England Journal of Medicine, Vol. 365, No. 15, 2011, pp. 1396-1405. doi:10.1056/NEJMoa1105195
[20] P. Tassone, P. Tagliaferri, C. Viscomi, C. Palmieri, M. Caraglia, A. D’Alessandro, E. Galea, A. Goel, A. Abbruzzese, C. R. Boland, et al., “Zoledronic Acid Induces Antiproliferative and Apoptotic Effects in Human Pancreatic Cancer Cells in Vitro,” British Journal of Cancer, Vol. 88, No. 12, 2003, pp. 1971-1978. doi:10.1038/sj.bjc.6600986

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.