Standard treatment for locally advanced gastric cancer currently involves surgery combined with chemotherapy administered both before and after the operation. However, post-surgery (adjuvant) chemotherapy often causes severe side effects, and it is unclear if all patients truly benefit from it. Recent research, such as the SPACE-FLOT study, suggests that patients who respond well to pre-surgery treatment might not actually benefit from further aggressive treatment after surgery; in these cases, additional therapy may only increase the risk of side effects without improving survival.
To address this, researchers are investigating circulating tumor DNA (ctDNA) testing, which detects microscopic traces of cancer (Molecular Residual Disease, or MRD) in the blood. The utility of ctDNA is supported by extensive research:
In Colorectal Cancer: The GALAXY study demonstrated that ctDNA status accurately predicts patient survival and identifies who benefits from chemotherapy. Furthermore, the DYNAMIC study showed that using ctDNA to guide treatment decisions significantly reduced the use of unnecessary chemotherapy without compromising patient survival.
In Gastric Cancer: Studies such as MENCA-GC, CRITICS, and PLAGAST have confirmed that post-surgery ctDNA is a strong predictor of patient prognosis. Additionally, the MRD-GATE study provided preliminary evidence that ctDNA-guided strategies can reduce unnecessary chemotherapy in the adjuvant setting.
Building on this evidence, this study applies ctDNA testing to the standard perioperative treatment model for gastric cancer. The primary objective is to determine if a ctDNA-guided strategy can identify patients who can safely forgo post-surgery chemotherapy, thereby reducing treatment toxicity and unnecessary usage, without sacrificing long-term survival outcomes.
Be able to provide a written informed consent form (ICF), and understand, agree to, and comply with the study requirements and assessment schedule.
Male or female aged 18 to 79 years.
Histologically confirmed gastric adenocarcinoma or adenocarcinoma of the gastroesophageal junction (GEJ), with clinical TNM staging (per the 8th edition of the AJCC/UICC Clinical TNM Staging for Gastric Cancer) as clinical Stage cIII to cIVa, and the primary gastric cancer lesion assessed to be amenable to curative resection.
ECOG PS ≤ 2, tolerable to surgical treatment, no surgical contraindications.
Subjects for whom investigators consider that there are obvious contraindications to (neo)adjuvant treatment or who cannot tolerate (neo)adjuvant treatment.
Females of childbearing potential who have not undergone surgical sterilization or do not use adequate contraceptive measures, pregnant or lactating females, and males who plan to impregnate their partners in the near term.
Any severe or uncontrolled systemic disease, including but not limited to uncontrolled hypertension, active bleeding, diabetes mellitus, and others.
Severe chronic or active infections that require systemic antibacterial, antifungal, or antiviral therapy, including but not limited to tuberculosis (TB), human immunodeficiency virus (HIV) infection, and others.
Parallel
Standard neoadjuvant therapy
DrugParticipants will receive 4 cycles of neoadjuvant therapy based on CSCO/NCCN guidelines. The specific regimen is determined by molecular characteristics and clinical practice: 1. Chemotherapy: Options include SOX, DOS, FLOT, XELOX (CapeOx), or FOLFOX. 2. HER2-Positive: Trastuzumab combined with chemotherapy, with or without immunotherapy. 3. Immunotherapy: PD-(L)1 inhibitors may be administered as monotherapy or in combination with chemotherapy. Dosages and administration follow standard pharmaceutical labeling and institutional protocols.
Radical gastrectomy
Procedure/SurgeryRadical gastrectomy with standard D2 lymphadenectomy will be performed.
Standard adjuvant therapy
DrugPostoperative adjuvant therapy for the control group is determined by an experienced clinician based on standard clinical guidelines (e.g., CSCO, NCCN) and the patient's clinical status. The decision to administer adjuvant therapy, along with the specific regimen, is made at the discretion of experienced clinicians. If indicated, therapy typically begins 4-6 weeks post-surgery and consists of 4 cycles. The regimen generally mirrors the neoadjuvant therapy received and may include: 1. Chemotherapy: Options include SOX, DOS, FLOT, XELOX (CapeOx), or FOLFOX. 2. HER2-Positive: Trastuzumab combined with chemotherapy, with or without immunotherapy. 3. Immunotherapy: PD-(L)1 inhibitors may be administered as monotherapy or in combination with chemotherapy. Dosages and administration follow standard pharmaceutical labeling and institutional protocols. Patients deemed unsuitable for adjuvant therapy by experienced clinicians will undergo observation.
ctDNA-MRD-guided adjuvant therapy
DrugParticipants in the Experimental Arm will initially receive 4 cycles of neoadjuvant therapy followed by D2 radical gastrectomy. Postoperative management is strictly guided by ctDNA MRD status assessed at 4 weeks post-surgery: 1. ctDNA MRD-Negative Subgroup: Participants will not receive adjuvant therapy and will undergo active surveillance (observation). 2. ctDNA MRD-Positive Subgroup: Participants will receive 4 cycles of adjuvant therapy, initiating 4-6 weeks after surgery. The regimen generally mirrors the neoadjuvant therapy and is selected based on clinical guidelines (e.g., CSCO/NCCN). Options include: Chemotherapy: SOX, XELOX (CapeOx), FLOT, DOS, or FOLFOX . Targeted/Immunotherapy: Agents such as Trastuzumab (for HER2+) or PD-(L)1 inhibitors may be included if clinically indicated.
Recurrence-Free Survival (RFS)
RFS is defined as the time from the date of radical gastrectomy to the date of the first documented disease recurrence or death from any cause.
Overall Survival (OS)
OS is defined as the time from the date of radical gastrectomy to the date of death from any cause.
ctDNA Clearance Rate
Defined as the proportion of patients whose ctDNA status converts from positive to negative.
The time point of ctDNA conversion from negative to positive and the time difference from the time point of radiological diagnosis of tumor recurrence
After peripheral blood collection, ctDNA detection is performed using a tumor-informed strategy based on NGS (Next-Generation Sequencing) and WES (Whole-Exome Sequencing) technologies.
Pathological Complete Response (pCR) Rate
Pathological examination performed on gastric cancer surgical specimens
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