Improving Outcome in Patients with Advanced Intrahepatic Cholangiocarcinoma: A Randomized Phase II Study of Gemcitabine and Oxaliplatin With or Without Regional Floxuridine (FUDR)

总结 肝内胆管癌（IHC）是胆道腺癌的一种亚型，预后不良， 发病率上升。SEER数据最近记录了过去十年平均增长4.4%。同样， 18年的分析报告，发病率每年增加7%，是所有胆道亚型中最高的。 两项研究都强调了IHC患者的生存率极低，后者报告的中位数约为6 个月大多数IHC患者在诊断时患有不可切除的疾病，即使是那些少数幸运的患者， 接受切除术通常会复发。对于这些患者，治疗选择有限，全身 化疗代表了标准，在大多数情况下，是唯一的方法。联合治疗 吉西他滨（GEM）和铂剂是目前的金标准，但其效益有限，提供了一个中位数 总生存期约为12个月。最近，我们小组完成了一项II期单组研究， 肝动脉持续灌注尿嘧啶核苷联合吉西他滨区域化疗 和奥沙利铂（OX）。中位总生存期为25个月，4名患者对以下治疗有充分反应： 接受切除术。基于这些有希望的结果，本提案的主要目标是确定疗效 HAI FUDR添加到最有效的全身方案（GEM/OX）中，用于治疗不可切除的IHC， 多中心随机II期研究，主要终点为无进展生存期。 IHC管理的进一步改进在很大程度上受到以下因素的阻碍： 疾病的生物学IHC是基因组异质性最强的实体瘤之一，由肿瘤的生长和分化引起。 一系列的危险因素和多种潜在的起源细胞。不仅显示出显著的异质性， 从一个病人到另一个病人，甚至在同一个肿瘤内。这一特点妨碍了对 分子发病机制，使其难以确定有效的靶向治疗，并导致不准确的 基于单个活检时的突变景观评估。拟议的临床试验提供了一个 这是弥补这些差距的理想机会。我们将使用靶向外显子组评估肿瘤内异质性（ITH） 对来自大队列患者的多个肿瘤活检和无细胞DNA（cfDNA）进行测序，并使用这些 根据反应和生存率对患者进行分层。对于那些进展的患者， 入组试验，我们将在进展时获得肿瘤活检和血液，以阐明机制 通过肿瘤DNA和cfDNA测序确定治疗抗性。利用这些样本，我们将建立 患者源性类器官模型，用于治疗反应的遗传预测因子的功能评价。最后， 我们将使用放射基因组学，或定量成像与分子分析的结合，来探索非 根据突变模式对患者进行侵入性分层，并量化异质性程度。使用 作为一种综合分析方法，这些研究将为IHC的多模式风险分层提供基础。

SUMMARY Intrahepatic cholangiocarcinoma (IHC) is a subtype of biliary tract adenocarcinoma with a poor prognosis and rising incidence. SEER data recently documented an average 4.4% rise over the past decade. Similarly, an analysis spanning 18 years reported a 7% annual increase in incidence, the highest of any biliary tract subtype. Both studies highlight the abysmal survival of patients with IHC, the latter reporting a median of approximately 6 months. Most patients with IHC have unresectable disease at diagnosis, and even those few fortunate enough to undergo resection recur commonly. For these patients, treatment options are limited, with systemic chemotherapy representing the standard, and in most cases, the only approach. Combination therapy with gemcitabine (GEM) and a platinum agent is the current gold standard, but its benefit is limited, offering a median overall survival of approximately 12 months. Recently, our group completed a phase II single-arm study of regional chemotherapy using continuous infusion hepatic arterial (HAI) floxuridine (FUDR) combined with GEM and oxaliplatin (OX). The median overall survival was 25 months, with four patients responding sufficiently to undergo resection. Based on these promising results, the primary goal of this proposal is to establish the efficacy of HAI FUDR added to the most active systemic regimen (GEM/OX) for the treatment of unresectable IHC in a multi-center randomized phase II study, with the primary endpoint of progression-free survival. Further improvements in the management of IHC have been hindered in large part by a poor understanding of the biology of the disease. IHC is among the most genomically heterogeneous solid tumor, resulting from the wide array of risk factors and multiple potential cells of origin. Significant heterogeneity has been shown not only from patient to patient, but even within the same tumor. This feature has precluded precise characterization of molecular pathogenesis, made it difficult to identify effective targeted therapies, and results in inaccurate assessment of the mutational landscape when based on a single biopsy. The proposed clinical trial provides an ideal opportunity to address these gaps. We will evaluate intratumoral heterogeneity (ITH) using targeted exome sequencing of multiple tumor biopsies and cell-free DNA (cfDNA) from a large cohort of patients and use these findings to stratify patients with respect to response and survival. For the subset of patients that progress while enrolled in the trial, we will obtain tumor biopsies and blood at the time of progression to elucidate mechanism(s) of treatment resistance by tumor DNA and cfDNA sequencing. Using these same samples, we will establish patient-derived organoid models for functional evaluation of genetic predictors of treatment response. Finally, we will use radiogenomics, or the merger of quantitative imaging with molecular analyses, to explore non- invasive stratification of patients based on mutational patterns and to quantify the degree of heterogeneity. Using an integrated analysis approach, these studies will provide a foundation for multimodal risk stratification for IHC.