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

结直肠癌（CRC）占所有癌症的8%，有超过1，100，000人生活在 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病例和超过50，000例死于这种疾病。大约50%的患者 结直肠癌发生肝转移（CLM），这些患者的死亡率最高。热消融（TA）是一种 用于治疗CLM的微创局部疗法。TA导致凝固性坏死大于靶肿瘤 创建至少5 mm的边缘，以减少局部肿瘤进展（LTP），并具有非常有利的安全性特征 和治疗潜力。尽管技术援助不断发展，但长期培训率仍然很高，从3%到60%不等 在消融的肝肿瘤的随访期间。我们已经表明，微波消融受热沉的影响较小 在治疗血管周围CLM时，射频消融的现象;因此，我们将限制该建议 使用微波进行热消融以优化结果。高LTP率是主要的限制， TA在癌症治疗中的广泛应用。在以前的工作中，我们证明了可行的（OXPHOS 抗体阳性和/或KI-67阳性）肿瘤，以及KRAS突变，携带 LTP和影响患者生存的显著风险。我们假设残留的未检测到的存活肿瘤和 肿瘤生物学是导致消融失败和最终LTP的最可能机制，即使在 在常规解剖成像中描绘的完全消融面和边缘。 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：建立真实的时间细胞病理学和荧光评估 目的2：确定代表存活肿瘤的18F-FDG摄取水平 CLM TA后立即; AIM 3：确定预测接受CLM TA患者反应的基因特征 通过消融前活检和靶CLM的基因组分析， AZ的实时细胞病理学评价（由3D辅助技术和代谢成像引导） TA后立即检测是一种新的方法，可用作预后的直接生物标志物 TA之后更重要的是，将提供再治疗，以在同一部位治疗已确定的可见残留肿瘤。 我们还提出了消融前活检和下一代测序（这是我们的护理标准）。 机构）的所有CLM进行TA。与KRAS相比，KRAS突变的LTP风险显著更高 野生型CLM最近已经被我们的小组和其他人记录。尽管这些新的发现和先前的 分子特征影响TA结果的知识，仍然缺乏前瞻性的基因组分析。 因此，全基因组分析被提出来检测可能导致极端反应的未知基因 （估计为10%）。我们的研究有望创造一个消融实践范式的变化，提高 在大量CLM患者和接受TA治疗的其他癌症患者中的结果。

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.