Surveillance of the Genetic Signature in Circulating Tumor DNA for Guiding Adjuvant Chemotherapy in Urothelial Carcinoma: Protocol for a Pilot Randomized Controlled Trial.

Background: 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).

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: Genetic signature in ctDNA is informative for personalized management of postoperative urothelial carcinomas, including personalized treatment and early detection of disease progression.

Trial Registration: ClinicalTrials.gov NCT06257017; https://clinicaltrials.gov/study/NCT06257017.

International Registered Report Identifier (irrid): DERR1-10.2196/72597.