Predicting Non-small Cell Lung Cancer (NSCLC) Lymph Node Metastasis: Integrating Circulating Tumor DNA (ctDNA) Mutation/ Methylation Profiling With Positron Emission Tomography-computed Tomography (PET-CT) Scan

Recruiting

• Conditions: Non-small Cell Lung Cancer; Carcinoma
• Interventions: Procedure: MRD+ methylation (or combined with PET-CT) and Invasive mediastinoscopy /EBUS-TBNA; Procedure: Intraoperative lymph node dissection; Procedure: Blood ctDNA + methylation + PET-CT and Postoperative pathology

• Registration Number: NCT06358222
• Lead Sponsor: Shanghai Chest Hospital

Brief Summary

This is a single center, prospective and observational study conducted in three stages to predict the NSCLC lymph node metastasis based on ctDNA/specific methylation molecular features combined with PET-CT imaging features and intervention study.

Detailed Description

This is a prospective study conducted in three stages. The volume of blood drawn will be 30 mL each time.

Stage 1: We will enroll 200 patients diagnosed with stage I-IIIB NSCLC who are scheduled for lobectomy and systematic lymph node dissection. The prediction of lymph node metastasis will be based on preoperative blood ctDNA mutation and methylation profiling. Specifically, during this stage, we will prospectively establish ctDNA methylation signatures specifically associated with LNMs in NSCLC. These molecular profiles will be combined with PET-CT imaging. Postoperative pathological results will serve as the reference standard for comparison.

Stage 2: A certain number (depending on the Results of Stage 1) of patients requiring invasive mediastinoscopy or EBUS-TBNA, based on the clinical guidelines, will be included for blood ctDNA mutation/methylation profile (or combined PET-CT), and the detection rate of LNMs will be assessed in patients with negative preoperative blood ctDNA mutation/methylation (or combined PET-CT). The accuracy of predicting LNMs will be compared with that of patients with negative or positive preoperative blood ctDNA mutation/methylation (or combined PET-CT).

Stage 3: For patients with negative preoperative blood negative testing (ctDNA mutation/methylation profiles alone or in combination with PET-CT), systematic lymph node sampling/dissection and no lymph node dissection will be grouped and compared. Regular follow-up is performed to investigate the impact on long-term MRD negative duration and prognosis. The primary outcomes: postoperative MRD negative duration and progression-free survival (PFS); The second outcomes: Overall survival (OS).

Study Timeline

• Study Start: 2023-12-15
• Study First Submitted: 2024-03-28
• Study First Submitted QC: 2024-04-06
• Study First Posted: 2024-04-10
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-14
• Last Update Posted: 2025-05-18
• Primary Completion: 2027-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Provision of informed consent prior to study initiation.
2. Age between 18 and 75 years.
3. Preoperative clinical evaluation indicating non-small cell lung cancer (NSCLC) stage I-IIIB (without initial treatment sought).
4. Newly treated patients who have consented to undergo surgery.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1.

Exclusion Criteria

1. Non-small cell lung cancer (NSCLC) histopathologically determined to be other than stage I-IIIB following surgical evaluation.
2. Presence of other active malignant tumor diseases.
3. Evidence of any serious or uncontrolled systemic illness, including uncontrolled hypertension and active bleeding, as assessed by the investigator, which may contribute to reluctance to participate in the trial or decrease adherence to the study regimen. Additionally, active infectious diseases such as hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infection are grounds for exclusion.
4. History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid therapy, or any indication of clinically active ILD.
5. Patients considered by the investigator to be unable to comply with the study protocol, restrictions, and requirements, or those facing circumstances at the investigator's discretion that would impede their participation in the study.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
MRD+ methylation (or combined with PET-CT) vs Invasive mediastinoscopy /EBUS-TBNA	MRD+ methylation (or combined with PET-CT) and Invasive mediastinoscopy /EBUS-TBNA	-
Lymph Node dissection vs no lymph node dissection	Intraoperative lymph node dissection	-
Blood ctDNA + methylation + PET-CT vs Postoperative pathology	Blood ctDNA + methylation + PET-CT and Postoperative pathology	-

Primary Outcome Measures

Name	Time	Method
ctDNA-free interval (CFI)	Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years.	CFI is defined as the duration between a patient's transition from ctDNA negative to ctDNA positive status.
Negative prediction value (NPV) of lymph node metastasis rates	one day for each patient	The primary endpoint will be the negative prediction value (NPV) of LNM rates between groups using preoperative blood ctDNA/methylation alone or in combination with PET-CT. LNMs-specific ctDNA methylation signatures will be developed and the sensitivity and specificity of ctDNA mutation/methylation profiles alone or when combined with PET-CT scans for predicting LNMs will be assessed. Postoperative pathological results will serve as the reference standard for comparison.
Disease-free survival (DFS)	Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years.	DFS is defined as the time from surgical resection to tumor recurrence or death due to tumor progression. DFS will be compared between the ctDNA-positive group and the ctDNA-negative group. DFS will be assessed in stage 3.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years	OS is defined as the time between the start of the patient's surgical resection and any documented death from any cause. OS will be compared between ctDNA-positive and ctDNA-negative groups. OS will be assessed in stage 3.

Trial Locations

Locations (1)

Shanghai Chest Hospital; 🇨🇳 ShangHai, China