Optimizing the Treatment of Pancreatic Adenocarcinoma

项目摘要/摘要： 拟议研究的最终目标是改善胰腺导管腺癌(PDAC)患者 存活率和人口死亡率。虽然随着时间的推移，许多癌症的存活率有所提高，但 占胰腺癌绝大多数(90%)的PDAC仍然很差。这在一定程度上 因为大多数PDAC是在其病程晚期被发现的，当时手术切除是不可能的。 然而，即使在可切除的原发肿瘤的病例中，由于早期转移，治愈仍然难以捉摸。 它们通常是微小的，无法检测到。极小肿瘤的早期转移是 提高胰腺癌死亡率。系统化疗可早期治疗看不见的微转移 因此，当作为佐剂或新佐剂使用时，PDAC具有改善患者预后的潜力 手术切除和放疗相结合的治疗。目前只有约20%的被诊断为 PDAC在诊断时是可以手术切除的；然而，有希望的新化疗方案， 当与放射治疗相结合作为新的辅助治疗时，可能会使许多 (30%)现在边界可切除或局部晚期的PDAC。如果证明有效，这些新的治疗方法 策略可能代表着朝着提高PDAC存活率迈出的重要一步，并可能在 覆盖大多数被诊断为PDAC的患者。然而，关于如何最好地应用的问题仍然存在 新辅助和辅助治疗方案，它们都有相当大的毒性。必须小心谨慎地 将临床试验结果应用于相当大比例被诊断为PDAC的老年患者 与试验参与者相比，他们的健康状况(合并症)更差。在这样的场景中，有一些限制 对于临床试验数据的泛化，建模方法可以起到补充作用。一种疾病 PDAC的仿真模型可以为综合和整合各种肿瘤和患者提供一个框架 从而能够全面平衡治疗计划的潜在益处和危害的因素。 研究计划将建立在我们不同团队先前和正在进行的工作的基础上，这些团队包括数学 模型师、人口科学家、癌症生物学家和对PDAC各个方面都有经验的临床医生 管理和治疗。我们的计划是开发一个全面的PDAC治疗模式，将 分析以提供洞察力：提高早期PDAC患者的总体生存率，增强决策 制定个性化治疗计划，优化资源利用，确定优先顺序并告知未来 研究和试验。该项目的目标将是：目标1-完善和验证PDAC模型，重点是 治疗；目标2-根据个别患者的特点设计个性化治疗策略 优化早期PDAC的治疗；目标3-确定新的个性化治疗策略的影响 关于人口死亡率。

Project Summary/Abstract: The ultimate goal of the proposed research is to improve pancreatic ductal adenocarcinoma (PDAC) patient survival and population mortality. While survival for many cancers has improved over time, the survival for PDAC, which constitutes the vast majority (90%) of all cancers of the pancreas, remains poor. This is in part because the majority of PDACs are detected late in their course when surgical resection is not possible. However, even in cases with a resectable primary tumor, cure remains elusive because of early metastases, which are frequently microscopic and undetectable. Early metastasis from very small tumors is a key barrier to improving pancreatic cancer mortality. Systematic chemotherapy can treat unseen micrometastases in early PDAC and thus has the potential to improve patient outcomes when used as an adjuvant or neoadjuvant therapy in conjunction with surgical resection and radiotherapy. At present only about 20% of diagnosed PDACs are surgically resectable at the time of diagnosis; however, promising newer chemotherapy regimens, when combined with radiotherapy as neoadjuvant treatment, may enable the definitive resection of many PDACs (30%) that are now borderline resectable or locally advanced. If proven effective, these new treatment strategies potentially represent a major step toward improving PDAC survival and may bring a cure within reach for the majority of patients diagnosed with PDAC. Yet, questions remain about how best to apply neoadjuvant and adjuvant therapy regimens, which have considerable toxicities. Care must be taken in applying the results of clinical trials to a significant proportion of patients diagnosed with PDAC, who are older and less healthy (comorbidities) than trial participants. In scenarios such as these, where there are limitations to the generalizability of clinical trial data, modeling approaches can serve a complementary role. A disease simulation model of PDAC can provide a framework to synthesize and incorporate various tumor and patient factors thereby allowing for a comprehensive balancing of the potential benefits and harms of treatment plans. The research plan will build upon prior and ongoing work by our diverse team, comprised of mathematical modelers, population scientists, cancer biologists, and clinicians with experience in all aspects of PDAC management and treatment. Our plan is to develop a comprehensive PDAC treatment model that will be analyzed to provide insights to: improve overall survival of patients with early stage PDAC, enhance decision making regarding personalized treatment plans, optimize resource utilization, and prioritize and inform future research and trials. The aims of the project will be: Aim 1-Refine and validate a model of PDAC focused on treatment; Aim 2-Design personalized treatment strategies tailored to individual patient characteristics to optimize treatment of early PDAC; Aim 3-Determine the impact of the new personalized treatment strategies on population mortality.