Optimizing Thermal Ablation for Colon Cancer Liver Metastases: Rapid Tissue Analysis Allowing for Immediate Retreatment; Metabolic Imaging Biomarker Validation; and Predictive Genetic Signatures

摘要/摘要：结直肠癌(CRC)占所有癌症的8%，生活在110万人以上 仅在美国就有CRC。美国癌症协会估计，2018年将有超过14万新的 在美国，CRC病例和50,000多人死于这种疾病。大约50%的患者患有 结直肠癌发生肝转移(CLM)，这些患者的死亡率最高。热消融是一种 用于治疗慢性粒细胞白血病的微创局部治疗。TA导致的凝固性坏死大于靶肿瘤 为了创造至少5毫米的边缘以减少局部肿瘤进展(LTP)，并具有高度有利的安全性 和治疗潜力。尽管TA的技术在发展，但LTP比率仍然很高，从3%到60%不等 在消融性肝肿瘤的随访中。我们已经证明，微波消融受散热片的影响较小。 在治疗血管周围CLM时，比射频消融更常见的现象；因此，我们将限制这一提议 到使用微波进行热消融以优化结果。较高的LTP速率是其主要限制 TA在癌症治疗中的广泛使用。在之前的工作中，我们证明了可行的(OXPHOS 抗体阳性和/或Ki-67阳性)TA和KRAS突变后消融区(AZ)内的肿瘤，携带 对LTP有显著风险，并影响患者生存。我们假设残留的未被检测到的存活肿瘤 肿瘤生物学是最有可能导致消融失败和最终LTP的机制，即使在 常规解剖成像中所描绘的完全消融边缘的面部。 这项拟议的临床试验旨在克服这些机制，优化TA作为CLM的治疗方法 通过以下三个具体目标：目标1：建立实时细胞病理学和荧光评估 目的2：确定代表肿瘤存活的18F-FDG摄取水平 CLM术后即刻；目的3：识别预测接受CLM移植的患者反应的基因标志 通过消融前活检和对靶区CLM进行基因组分析。 AZ的实时细胞病理学评估(由3D辅助技术和代谢成像引导) 是一种新的方法，可以作为预后的即时生物标志物 在助教之后。更重要的是，将在同一时间提供再次治疗，以治疗已确定的、可见的残留肿瘤。 我们还建议进行消融前活组织检查和下一代测序(这是我们 所有接受TA的CLM的机构)。与KRAS相比，KRAS突变患LTP的风险显著更高 野生型CLM最近被我们小组和其他人记录在案。尽管有这些新发现和之前的 尽管分子特征会影响TA的预后，但目前尚缺乏前瞻性的基因组分析。 因此，全基因组分析被提出用来检测可能构成极端反应者的未知基因。 (估计为队列的10%)。我们的研究有望创造一种消融实践范式的改变，改善 接受TA治疗的大批慢性粒细胞白血病和其他癌症患者的结果。

Summary/Abstract: Colorectal cancer (CRC) represents 8% of all cancers with over 1,100,000 people living with CRC in the US alone. The American Cancer Society estimates that in 2018 there will be over 140,000 new CRC cases and over 50,000 deaths from this disease in the United States. Approximately 50% of patients with CRC develop liver metastases (CLM) and these patients have the highest mortality. Thermal ablation (TA) is a minimally invasive local therapy used to treat CLM. TA causes coagulation necrosis larger than the target tumor to create at least a 5 mm margin to diminish local tumor progression (LTP) with a highly favorable safety profile and curative potential. Despite technological evolution of TA, LTP rates remain high, ranging from 3% to 60% during follow-up of ablated liver tumors. We have shown that microwave ablation is less affected by the heat sink phenomena than radiofrequency ablation, when treating perivascular CLM; therefore, we will limit this proposal to the use of microwave for thermal ablation to optimize outcomes. The high LTP rates are the main limitation of the widespread use of TA in the treatment of cancer. In prior work, we demonstrated that viable (OXPHOS antibody positive and/or KI-67 positive) tumor within the ablation zone (AZ) after TA, and KRAS mutations, carry significant risk for LTP and effect patient survival. We hypothesize that residual undetected viable tumor and tumor biology are the most likely mechanisms leading to ablation failure and eventual LTP, even in the face of complete ablation with margins, depicted in conventional anatomic imaging. This proposed clinical trial is designed to overcome these mechanisms, optimizing TA as a treatment for CLM through the following three specific aims: AIM 1: Establish real time cytopathologic and fluorescent assessment of the AZ by immediate post TA biopsy; AIM 2: Determine the 18F-FDG uptake level representing viable tumor immediately post TA of CLM; AIM 3: Identify gene signatures that predict response in patients undergoing TA of CLM through a pre-ablation biopsy and genomic analysis of the target CLM. Real-time cytopathologic evaluation of the AZ (guided by 3D-assisted technology and metabolic imaging) immediately after TA, is a novel method that can be used as a prognostic immediate biomarker of outcomes after TA. More importantly, retreatment will be offered to treat identified, visible residual tumor at the same sitting. We also propose a pre-ablation biopsy and next-generation sequencing (that is a standard of care in our institution) of all CLM undergoing TA. A significantly higher risk for LTP for KRAS mutant compared to KRAS wild type CLM has been recently documented by our group and others. Despite these new findings and prior knowledge that molecular characteristics impact outcomes of TA, a prospective genomic analysis is still lacking. Whole-genome analysis is thus proposed to detect unknown genes that may underlie extreme responders (estimated 10% of cohort). Our study is expected to create an ablation practice paradigm change, improving outcomes in the large population of patients with CLM and other cancers treated by TA.