Preventing an Incurable Disease: The Prevention of Progression to Pancreatic Cancer Trial (The 3P-C Trial)

项目摘要 2019年，美国将有大约55，000人被诊断出胰腺癌。几乎所有这些 患者将死于这种疾病，因为在诊断和目前的无效阶段 全身治疗。目前的诊断和治疗策略的缺点体现在以下事实： 即使当患者在可识别的转移性疾病发展之前被诊断时（<15%的 患者），并接受手术切除和辅助全身治疗，五年的概率 存活率约为10%。因此，迫切需要新的策略来改善患者的预后。 疾病 胰腺导管内乳头状黏液性肿瘤是胰腺导管内唯一的囊性肿瘤， 放射学可识别的胰腺癌前病变。IPMN是一个“全腺体”的过程， 已知接受部分胰腺切除术治疗IPMN的患者患癌症的风险增加 在胰腺残留物中正因为如此，建议接受部分 非侵入性IPMN的胰腺切除术是对他们的胰腺进行连续的放射学和/或内窥镜监视， 残留物我们小组最近的数据显示，大约25%的患者会出现放射学检查异常。 IPMN在切除后3 - 4年内进展的迹象。我们的四个中心（杜克大学 医院、约翰霍普金斯大学医院、马萨诸塞州总医院、纪念斯隆凯特琳）我们是 目前随访了450多名因IPMN接受切除术的患者。这些病人非常适合 进行化学预防试验 这项多机构研究工作的目标是进行首次人体化学预防试验， 胰腺癌接受过部分胰腺切除术的患者，并发现 有高风险IPMN，将有资格参加这项随机双盲安慰剂对照II期试验（100 患者/手臂）。该试验将使用选择性考克斯抑制剂舒林酸，已证明其 在临床前模型中高度有效地预防胰腺癌的进展。我们的临床数据 研究小组和其他人已经证明了炎症和患者进展之间的密切联系， 与IPMN，舒林酸已被证明可以减少这些囊性前体患者的IPMN的大小 病变主要终点是3年后的放射学进展率。患者将 密切监测，每六个月交替进行CT成像和内窥镜超声/液体抽吸。 次要终点将包括：（1）评估这种治疗对囊液炎性反应的影响。 标记物，和先前开发的囊液生物标志物面板，和（2）一种新的方法， 评估（放射组学），用于早期发现恶性进展。

PROJECT SUMMARY Pancreatic cancer will be diagnosed in approximately 55,000 people in the U.S. in 2019. Nearly all of these patients will die from this disease because of the late stage at diagnosis and the ineffectiveness of current systemic therapies. The shortcomings of current diagnostic and therapeutic strategies is exemplified by the fact that even when patients are diagnosed prior to the development of identifiable metastatic disease (<15% of patients) and are treated with operative resection and adjuvant systemic therapy, the probability of five-year survival is approximately 10%. There is an urgent need for novel strategies to improve patient outcomes for this disease. Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are cystic tumors that represent the only radiographically identifiable precursor lesion of pancreatic cancer. IPMN is a “whole-gland” process, and it is known that patients who undergo partial pancreatectomy for IPMN have an increased risk of developing cancer in the pancreatic remnant. Because of this, recommendations for patients who have undergone partial pancreatectomy for non-invasive IPMN is serial radiographic and/or endoscopic surveillance of their pancreatic remnant. Recent data from our group has shown that approximately 25% of patients will develop radiographic signs of IPMN progression within three to four years of resection. Between our four centers (Duke University Hospital, Johns Hopkins University Hospital, Massachusetts General Hospital, Memorial Sloan Kettering) we are currently following over 450 patients who have undergone resection for IPMN. These patients are ideally suited for a chemoprevention trial. The goal of this multi-institutional research effort is to perform the first-in-human chemoprevention trial for pancreatic adenocarcinoma. Patients who have undergone partial pancreatectomy, and have been found to have high-risk IPMN, will be eligible for this randomized double-blind placebo controlled Phase II trial (100 patients/arm). This trial will utilize the selective COX inhibitor sulindac, which has been demonstrated to be highly effective in preventing progression to pancreatic cancer in pre-clinical models. Clinical data from our group and others have demonstrated a strong association between inflammation and progression in patients with IPMN, and sulindac has been shown to decrease the size of IPMN in patients with these cystic precursor lesions. The primary endpoint will be the rate of radiographic progression after three years. Patients will be closely monitored, with alternating CT imaging and endoscopic ultrasound/fluid aspiration every six months. Secondary endpoints will include: (1) assessment of the effects of this treatment on cyst fluid inflammatory markers, and a previously developed cyst fluid biomarker panel, and (2) a novel approach to radiographic assessment (radiomics) for early detection of progression to malignancy.