Zhan Yongle, Ruan Xiaohao, Wu Yishuo, Chun Tsun Tsun Stacia, Yao Chi, Shi Ruofan, Liu Jiacheng, Ali Salida, Ma Ruochen, Huang Da, Gao Yi, Xu Ying, Chen Lu, Du Qijun, Ng Ada Tsui-Lin, Li Cho Wing Bryan, Xu Danfeng, Na Rong
Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China (Hong Kong).
Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
JMIR Res Protoc. 2025 Aug 26;14:e72597. doi: 10.2196/72597.
Urothelial carcinoma is one of the most commonly diagnosed cancers worldwide, with a poor 5-year survival rate. As genomics is the backbone of the precision medicine paradigm, the genetic signature in circulating tumor DNA (ctDNA) is emerging as a pivotal biomarker for detecting early-stage cancer and molecular residual disease (MRD).
We aim to evaluate the feasibility and preliminary effects of a ctDNA-based sequencing approach for detecting MRD and guiding adjuvant chemotherapy in postoperative urothelial carcinomas.
We will perform a stratified 2-arm pilot randomized controlled trial in 2 tertiary hospitals in Hong Kong, involving patients with urothelial carcinomas (pT2-4a N0-2 M0) undergoing radical resection. We plan to recruit 20 patients and determine stratification according to their MRD status before randomization. Patients in each stratum (MRD-positive and MRD-negative groups) will be randomly allocated to either a 4-cycle gemcitabine plus cisplatin chemotherapy arm or a standard management arm in a 1:1 ratio. ctDNA MRD will be tested using a personalized next-generation sequencing panel, which is designed based on the individual's whole exome sequencing results from the operation specimen. The primary outcome is the feasibility of this trial (ie, recruitment, retention, adherence, and completeness). The secondary outcome is treatment-related adverse events. Exploratory outcomes include radiographic disease-free survival, cancer-specific survival, overall survival, ctDNA clearance in patients with ctDNA MRD-positive status, quality of life, fear of cancer recurrence, and cost-effectiveness. Benchmarks for feasibility evaluation are set as (1) ≥20% recruitment response rate, (2) ≤20% loss to follow-up or withdrawal, (3) ≥80% intervention adherence, and (4) ≤20% missing value rate. Each benchmark will be assigned one score, and a total score of 4, 2 to 3, and 0 to 1 will be deemed high, medium, and low feasibility, respectively. Safety evaluations will be presented as numbers and proportions of the adverse events. ANOVA and the Kruskal-Wallis test will be used for continuous outcome variables, whereas the chi-square test and the Fisher exact test will be used for categorical outcome variables. Hazard ratios will be calculated to compare the preliminary treatment effect of the gemcitabine plus cisplatin arm against the standard management arm on survival within each MRD group.
This project was funded in February 2024. Patient recruitment started on May 2, 2024. Recruitment and data collection for the trial are ongoing. Data analysis will be performed in mid-2025 and the results of this study are expected to be published in late 2025.
Genetic signature in ctDNA is informative for personalized management of postoperative urothelial carcinomas, including personalized treatment and early detection of disease progression.
ClinicalTrials.gov NCT06257017; https://clinicaltrials.gov/study/NCT06257017.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/72597.
尿路上皮癌是全球最常被诊断出的癌症之一，5年生存率较低。由于基因组学是精准医学模式的核心，循环肿瘤DNA（ctDNA）中的基因特征正逐渐成为检测早期癌症和分子残留病灶（MRD）的关键生物标志物。
我们旨在评估基于ctDNA的测序方法在检测MRD及指导术后尿路上皮癌辅助化疗方面的可行性和初步效果。
我们将在香港的两家三级医院开展一项分层双臂试点随机对照试验，纳入接受根治性切除术的尿路上皮癌患者（pT2-4a N0-2 M0）。我们计划招募20名患者，并在随机分组前根据其MRD状态进行分层。每个分层（MRD阳性和MRD阴性组）的患者将以1:1的比例随机分配至4周期吉西他滨联合顺铂化疗组或标准治疗组。将使用基于个体手术标本全外显子测序结果设计的个性化二代测序panel检测ctDNA MRD。主要结局是本试验的可行性（即招募、留存、依从性和完整性）。次要结局是与治疗相关的不良事件。探索性结局包括影像学无病生存期、癌症特异性生存期、总生存期、ctDNA MRD阳性状态患者的ctDNA清除情况、生活质量、对癌症复发的恐惧以及成本效益。可行性评估的基准设定为：（1）招募响应率≥20%，（2）失访或退出率≤20%，（3）干预依从性≥80%，（4）缺失值率≤20%。每个基准将赋予一个分数，总分4分、2至3分和0至1分将分别被视为高、中、低可行性。安全性评估将以不良事件的数量和比例呈现。对于连续结局变量将使用方差分析和Kruskal-Wallis检验，而对于分类结局变量将使用卡方检验和Fisher精确检验。将计算风险比以比较吉西他滨联合顺铂组与标准治疗组在每个MRD组内对生存的初步治疗效果。
该项目于2024年2月获得资助。患者招募于2024年5月2日开始。本试验的招募和数据收集正在进行中。数据分析将于2025年年中进行，本研究结果预计于2025年末发表。
ctDNA中的基因特征对术后尿路上皮癌的个性化管理具有指导意义，包括个性化治疗和疾病进展的早期检测。
ClinicalTrials.gov NCT06257017；https://clinicaltrials.gov/study/NCT06257017。
国际注册报告识别码（IRRID）：DERR1-10.2196/72597。
