CHARM 2: Chemotherapy for ablation and resolution of mucinous pancreatic cysts: a prospective, randomized, double-blind, multi-center clinical trial

胰腺癌前病变的特征和治疗都很困难， 在过去的二十年里，由于成像技术的进步和衰老， 人口随着美国高致命性胰腺癌发病率的上升， 胰腺囊肿具有恶性潜能，以安全有效的方式治疗是一项重大的公共卫生 关心虽然患者在历史上一直局限于放射学监测或潜在的 危险的手术作为不可取的方法管理这些囊肿，内镜超声 引导细针注射（EUS-FNI）已成为一种微创，安全和有效的 早期干预的方法。目前，对于胰腺囊肿的EUS引导治疗， 包括用乙醇灌洗。然而，专家一致认为，观察到的不良事件（AE） 在治疗过程中，由于使用乙醇。最近，基于对周围安全问题的担忧， 乙醇的使用，以及与紫杉醇输注相关的有希望的治疗发现，我们 研究小组创造了一种无乙醇（EF）的联合化疗疗法， 紫杉醇和吉西他滨混合物-专为靶向胰腺囊性病变而设计 通过EUS引导注射的瘤形成。我们的团队完成了对这种新型治疗策略的测试 在2017年作为初步随机试验，显示EF灌洗（即，生理盐水） 化疗是有效的，而且比同样的化疗更安全， 包括乙醇灌洗（EL）。在这项建议中，我们的目标是扩大我们试点研究的规模， 进行一项大型和确定性的多中心试验，这将是第一个资助的随机对照试验， EL治疗至无乙醇（EF）治疗联合化疗药物输注 剂.所有受试者将进行合格的囊性病变抽吸和清除，并接受 3个月时进行随访，12个月时进行最终成像。我们将随机分配100名 成人胰腺囊肿患者分为两个研究组：（1）乙醇灌洗（EL）：EL，然后 输注紫杉醇-吉西他滨混合物，或（2）无乙醇（EF）：盐水灌洗，然后 通过输注相同的紫杉醇-吉西他滨混合物。我们假设EF治疗将 导致不良事件显著减少，并将具有完全的囊肿消融解决率 不低于EL治疗。如果EF干预被证明不劣于，且 它比EL治疗安全得多，将验证EUS-FNI作为一种可行的治疗方式 用于干预癌前囊肿，并将改变胰腺囊肿的护理标准 管理重要的是，如果EF治疗成功，它可能会改变治疗决定， 患者可以选择和改变卓越中心提供的治疗方案。

Pre-malignant pancreatic cysts that are difficult to characterize and treat are increasingly discovered in the US over the last two decades due to advances in imaging and an aging population. With the incidence of highly lethal pancreatic cancer rising in the US, intervening on pancreatic cysts with malignant potential in a safe and effective way is a major public health concern. While patients have been historically limited to radiographic surveillance or potentially hazardous surgery as undesirable methods of managing these cysts, endoscopic ultrasound guided fine needle injection (EUS-FNI) has emerged as a less-invasive, safe and effective method of early intervention. For EUS-guided treatment of pancreatic cysts today, care typically includes lavage with ethanol. However, experts agree that adverse events (AEs) observed during treatment are due to ethanol use. Recently, based on the safety concerns surrounding ethanol use, as well as the promising treatment findings linked to the infusion of paclitaxel, our team created an ethanol-free (EF), combination chemotherapy treatment consisting of an admixture—paclitaxel and gemcitabine—specifically designed to target pancreatic cystic neoplasia by EUS-guided injection. Our team completed testing of this novel treatment strategy in 2017 as a preliminary randomized trial, showing that EF lavage (i.e., saline) with combination chemotherapy was as effective, and far safer, than the same chemotherapy treatment with the inclusion of ethanol lavage (EL). In this proposal, our aim is increase the scale of our pilot study, conducting a large and definitive multi-center trial that will be the first funded RCT to compare treatment with EL to ethanol-free (EF) treatment with combination infusion of chemotherapeutic agents. All subjects will have qualifying cystic lesions aspirated and evacuated, and undergo a follow-up procedure at 3 months and final imaging at 12 months. We will randomly assign 100 adult patients with pancreatic cysts to two study arms: (1) Ethanol lavage (EL): EL, followed by infusion of a paclitaxel-gemcitabine admixture, or (2) Ethanol Free (EF): saline lavage, followed by infusion of the same paclitaxel-gemcitabine admixture. We hypothesize that EF treatment will result in significantly fewer adverse events and will have complete cyst ablation resolution rates that are not inferior to EL treatment. If the EF intervention proves to be non-inferior to, and significantly safer than, treatment with EL, it will validate EUS-FNI as a viable treatment modality for intervening on pre-malignant cysts and will change the standard of care for pancreatic cyst management. Critically, if EF treatment is successful, it may alter the treatment decisions that patients make and change the treatment options that centers of excellence offer.