Sanford Dominic E, Porembka Matthew R, Panni Roheena Z, Mitchem Jonathan B, Belt Brian A, Plambeck-Suess Stacey M, Lin Goldie, Denardo David G, Fields Ryan C, Hawkins William G, Strasberg Steven M, Lockhart A Craig, Wang-Gillam Andrea, Goedegebuure Simon Peter, Linehan David C
Department of Surgery, Washington University - School of Medicine.
J Cancer Ther. 2013 May;4(3):797-803. doi: 10.4236/jct.2013.43096.
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.
Eligible PDAC patients received ZA (4mg) 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.
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 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.
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.
胰腺导管腺癌（PDAC）是一种侵袭性恶性肿瘤，其特征是有大量粒细胞性髓源性抑制细胞（G-MDSC = CD45/Lin/CD33/CD11b/CD15）浸润肿瘤并抑制抗肿瘤免疫。我们之前在PDAC小鼠模型中证明，唑来膦酸（ZA）可减少G-MDSC，从而导致肿瘤生长减缓并提高生存率。我们在此报告一项1期临床试验（NCT00892242）的结果，该试验使用ZA作为非转移性、可切除胰腺腺癌患者的新辅助围手术期治疗。
符合条件的PDAC患者在手术前2周静脉注射ZA（4mg）。然后患者每隔4周再接受2剂ZA。在患者接受ZA治疗前及术后3个月采集血液和骨髓，通过流式细胞术分析G-MDSC。
23例患者接受了术前ZA治疗，随访至少6个月。只有15例PDAC患者为非转移性PDAC，适合进行切除。ZA耐受性良好，所有不良事件均为1级或2级。最常见的不良事件是疲劳﹑腹痛/不适﹑厌食和关节痛。接受ZA治疗的切除PDAC患者中，1年和2年总生存率（OS）分别为85.7%和33.3%，中位OS为18个月。该组1年和2年无进展生存率（PFS）分别为26.9%和8.9%，中位PFS为12个月。PDAC患者在接受ZA治疗前后，血液和骨髓中G-MDSC的患病率没有变化。
ZA作为PDAC患者的新辅助围手术期治疗是安全且耐受性良好的。在这项小型研究中，与历史对照相比，我们未观察到OS或PFS有差异。此外，PDAC患者在接受ZA治疗前后，血液和骨髓中G-MDSC的患病率也没有差异。
