National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
Nihon Medi-Physics Co., Ltd., Chiba, Japan; and.
J Nucl Med. 2019 Oct;60(10):1437-1443. doi: 10.2967/jnumed.118.225045. Epub 2019 Mar 8.
Pancreatic cancer (PC) has a very poor prognosis. Surgery is the primary treatment for patients with resectable PC; however, local recurrence, hepatic metastasis, and peritoneal dissemination often occur even after extensive surgery. Adjuvant chemotherapy, typically with gemcitabine, has been used clinically but with only a modest survival benefit. To achieve a better outcome, we investigated the efficacy of Cu-intraperitoneal radioimmunotherapy (ipRIT) with Cu-labeled antiepidermal growth factor receptor antibody cetuximab as an adjuvant treatment after PC surgery using an orthotopic xenografted mouse model. The efficacy of adjuvant Cu-ipRIT was investigated in a human PC mouse model harboring orthotopic xenografts of xPA-1-DC cells. To reproduce the clinical situation, PC xenografts were surgically resected when pancreatic tumors were readily visible but not metastatic tumors. Increasing doses of Cu-cetuximab were intraperitoneally injected, and the mice were monitored for toxicity to determine the safe therapeutic dose. For adjuvant Cu-ipRIT, the day after tumor resection, the mice were intraperitoneally administered 22.2 MBq of Cu-PCTA-cetuximab and the survival was compared with that in surgery-only controls. For comparison, adjuvant chemotherapy with gemcitabine was also examined using the same model. The mouse model not only developed primary tumors in the pancreas but also subsequently reproduced local recurrence, hepatic metastasis, and peritoneal dissemination after surgery, which is similar to the manifestations that occur with human PC. Adjuvant Cu-ipRIT with Cu-labeled cetuximab after surgery effectively suppressed local recurrence, hepatic metastasis, and peritoneal dissemination in this model. Significant improvement of the survival with minimal toxicity was achieved by adjuvant Cu-ipRIT compared with that in control mice that underwent surgery only. Adjuvant chemotherapy with gemcitabine nominally prolonged the survival, but the effect was not statistically significant. Cu-ipRIT with cetuximab can be an effective adjuvant therapy after PC surgery.
胰腺癌(PC)预后极差。手术是可切除 PC 患者的主要治疗方法;然而,即使进行了广泛的手术,局部复发、肝转移和腹膜播散仍经常发生。辅助化疗,通常使用吉西他滨,已在临床上使用,但仅能带来适度的生存获益。为了获得更好的结果,我们使用原位异种移植小鼠模型研究了 Cu 腹腔内放射免疫治疗(ipRIT)联合 Cu 标记的表皮生长因子受体抗体西妥昔单抗作为 PC 手术后辅助治疗的疗效。在携带 xPA-1-DC 细胞原位异种移植的人 PC 小鼠模型中研究了辅助 Cu-ipRIT 的疗效。为了重现临床情况,当胰腺肿瘤可见但无转移性肿瘤时,通过手术切除 PC 异种移植。将递增剂量的 Cu-西妥昔单抗腹腔内注射,并监测小鼠的毒性以确定安全的治疗剂量。对于辅助 Cu-ipRIT,在肿瘤切除后第 1 天,向小鼠腹腔内给予 22.2 MBq 的 Cu-PCTA-西妥昔单抗,并将其与仅手术对照组的存活情况进行比较。为了进行比较,还使用相同模型检查了辅助吉西他滨化疗。该小鼠模型不仅在胰腺中形成了原发性肿瘤,而且在手术后还随后再现了局部复发、肝转移和腹膜播散,这与人类 PC 的表现相似。手术后使用 Cu 标记的西妥昔单抗进行辅助 Cu-ipRIT 可有效抑制该模型中的局部复发、肝转移和腹膜播散。与仅接受手术的对照小鼠相比,辅助 Cu-ipRIT 显著改善了生存且毒性最小。辅助吉西他滨化疗名义上延长了生存时间,但无统计学意义。西妥昔单抗联合 Cu-ipRIT 可作为 PC 手术后的有效辅助治疗方法。