Total Neoadjuvant Therapy (TNT) for Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma

项目摘要/摘要--RP1 手术是治疗胰腺导管腺癌(PDAC)的唯一有效方法，但 只有20%的患者可以使用。对于20%-30%的交界性可切除或局部晚期患者 (BR/LA；累及腹部大血管)PDAC，诱导化疗的新辅助治疗， 或不接受放射治疗，是新兴的标准。这种预先进行化疗的序列提供了 有机会将肿瘤降级，以便进行根治性切除。重要的是，微转移的早期治疗 疾病帮助选择可能从手术中受益的患者，并免除这些患者不必要的手术 不会从中受益的人。 到目前为止，有证据支持新辅助疗法，但需要一种更有结构、更全面的方法， 这需要严格的前瞻性评估。此外，目前还没有生物标志物可以可靠地预测 治疗反应或抗药性。这一知识对于恰当地选择将受益的患者是必不可少的 从特定的治疗方案和针对个别患者的调整治疗。 我们将评估完全新辅助治疗(TNT)结合新三联化疗和 消融剂量放射治疗(AD-XRT)，手术前给予，II期试验(目标1)。这场审判将评估 5-氟尿嘧啶/亚叶酸钙+脂质体-伊立替康+奥沙利铂(NALIRIFOX)方案 完全预付4个月，然后进行AD-XRT(生物当量剂量为100Gy15-25次 以卡培他滨为放射增敏剂)。主要终点是无事件生存，并定义了事件 如进展、手术后复发或死亡。 对于TNT后治疗反应的生物标志物的开发，我们将评估(AIM)的潜力 2a)CT图像和(Aim 2B)功能性FDG-PET和新型免疫PET的放射组学分析 识别肿瘤抗原19-9(CA19-9)的HuMab-5b1监测治疗反应，评估手术 可切除性，并预测存活率。使用在试验中收集的血液样本，我们还将评估循环 用于相同目的的肿瘤DNA(通过MSK-Access靶向测序)和血清CA19-9(AIM 3)。 这项临床试验旨在将TNT定义为BR/LA PDAC的新治疗标准。计划中的关联性 研究承诺识别TNT术后的非侵入性生物标志物，这些标志物可能会迅速转化为 诊所，以允许适应性疾病管理。由于BR/LA PDAC患者将从以下方面受益 改善治疗和监测，因为有机会进行根治性切除，该项目 可能会对整个PDAC的结果产生重大影响。

PROJECT SUMMARY/ABSTRACT – RP1 Surgery is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC) but is available to only <20% of patients. For the 20%-30% of patients with borderline resectable or locally advanced (BR/LA; involving major abdominal vasculature) PDAC, neoadjuvant therapy with induction chemotherapy, with or without radiotherapy, is the emerging standard. This sequence with chemotherapy up-front provides the opportunity to downstage tumors to allow curative resection. Importantly, early treatment of micrometastatic disease helps select patients who are likely to benefit from surgery and spares unnecessary surgery in those who would not benefit. Evidence to date supports neoadjuvant therapy, but a more-structured, comprehensive approach is needed, which requires rigorous prospective evaluation. Moreover, there are currently no biomarkers that reliably predict treatment response or resistance. This knowledge is essential to appropriately select patients who will benefit from specific treatment regimens and to modulate treatment for individual patients. We will evaluate the efficacy of total neoadjuvant therapy (TNT) combining novel triplet chemotherapy with ablative-dose radiotherapy (AD-XRT), given before surgery, in a phase II trial (Aim 1). This trial will assess the promising 5-fluorouracil/leucovorin + liposomal-irinotecan + oxaliplatin (NALIRIFOX) regimen, administered entirely up-front for 4 months, followed by AD-XRT (biological equivalent dose of 100 Gy, delivered in 15-25 fractions, with capecitabine as radiosensitizer). The primary endpoint is event-free survival, with events defined as progression, recurrence after surgery, or death. Toward the development of biomarkers of treatment response after TNT, we will assess the potential of (Aim 2A) radiomics analysis of CT images and (Aim 2B) functional FDG-PET and novel immunoPET using 89Zr- HuMab-5B1 that recognizes cancer antigen 19-9 (CA19-9) to monitor treatment response, assess surgical resectability, and predict survival. Using blood samples collected on the trial, we will also evaluate circulating tumor DNA (measured by MSK-ACCESS targeted sequencing) and serum CA19-9 for the same purpose (Aim 3). This clinical trial aims to define TNT as a new treatment standard for BR/LA PDAC. The planned correlative studies promise to identify noninvasive biomarkers of response after TNT that may be rapidly translated to the clinic to allow adaptive disease management. As patients with BR/LA PDAC stand to benefit greatly from improvements in treatment and monitoring, because of the opportunity to enable curative resection, this project will likely have a major impact on outcomes in PDAC overall.