Laparoscopic versus open distal gastrectomy with D2 lymphadenectomy following neoadjuvant chemotherapy for locally advanced gastric cancer (CLASS-03b): protocol for a multicentre, randomised, controlled, non-inferiority trial

Abstract

Introduction

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with most Chinese patients diagnosed at a locally advanced stage. Neoadjuvant chemotherapy (NAC) is increasingly used to improve resectability and survival. Laparoscopy-assisted distal gastrectomy (LADG) provides short-term recovery benefits compared with open distal gastrectomy (ODG), but its safety and oncologic efficacy following NAC remain uncertain. This trial aims to determine whether LADG is non-inferior to ODG in terms of long-term survival outcomes in patients with locally advanced distal gastric cancer (LAGC) after NAC.

Methods and analysis

This is a multicentre, randomised, controlled, non-inferiority trial conducted at high-volume GC centres in China. Eligible patients (aged 18–75 years; cT3–4a, N0/+, M0) with histologically confirmed distal gastric adenocarcinoma who have completed standard NAC will be randomised 1:1 to LADG or ODG with D2 lymphadenectomy. Surgical quality will be standardised through operative manuals, intraoperative video recording and central auditing. The primary endpoint is 3-year disease-free survival. Secondary endpoints are 3- and 5-year overall survival. A total of 998 patients (499 per arm) will be enrolled, providing 80% power to test non-inferiority with an absolute 8% margin, accounting for 15% attrition. Analyses will follow the intention-to-treat principle, with Cox models used for survival comparisons and subgroup analyses according to nodal status, tumour size and pathological response.

Ethics and dissemination

This trial has been reviewed and approved by the Biomedical Ethics Committee of West China Hospital, Sichuan University (Approval No. 2025 (865), 16 July 2025). Written informed consent will be obtained from all participants. The results will be disseminated through peer-reviewed journals and international conferences, providing high-level evidence to guide the surgical management of LAGC after NAC.

Trial registration number

Chinese Clinical Trial Registry, ChiCTR2500109677; registered on 23 September 2025. Protocol V.2.1, dated 29 June 2025.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This multicentre, randomised, controlled, non-inferiority trial in China is designed to rigorously evaluate laparoscopic vs open distal gastrectomy following neoadjuvant chemotherapy for locally advanced gastric cancer.

• Surgical quality is strictly standardised, with mandatory D2 lymphadenectomy, operative video recording, central auditing and surgeon eligibility criteria, thereby ensuring methodological rigour and consistency across centres.

• The large sample size (n=998) is powered to detect clinically meaningful differences in long-term oncologic outcomes, providing robust evidence to guide clinical practice.

• Blinding of patients and surgeons is not feasible due to the nature of surgical interventions, which may introduce bias in perioperative management, although outcome assessment and statistical analysis will remain blinded.

• Variability in adjuvant chemotherapy compliance after surgery may affect long-term survival outcomes, despite efforts to standardise postoperative care across participating centres.

Introduction

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and remains among the top three malignancies associated with cancer-related deaths in China.^{1 2} Due to the low rate of early detection, fewer than 20% of GC patients in China are diagnosed at an early stage and are eligible for curative surgery. Consequently, the majority present with locally advanced gastric cancer (LAGC), for which multimodal treatment strategies centred on surgery are recommended.³

Emerging evidence indicates that neoadjuvant chemotherapy (NAC) provides survival benefits for patients with LAGC.^{4 5} The primary goals of NAC are to eradicate micrometastases, downstage the tumour and thereby increase the likelihood of achieving an R0 resection. According to the National Comprehensive Cancer Network guidelines, NAC is recommended for patients with clinical stage T2–T4, any N.⁶ Although the Japanese Gastric Cancer Treatment Guidelines (V.6) do not advocate NAC as a routine standard of care, they acknowledge potential survival benefits in chemotherapy-responsive patients.⁷

Based on these guidelines, prospective clinical trials of NAC are considered appropriate for selected high-risk patients, including those with anticipated R0 resection but a high likelihood of recurrence (eg, T4N+M0 or stage IIIa–IIIc) or those with poor prognostic features (eg, extensive lymph node metastasis or large Borrmann type III–IV tumours).⁸ The Japanese phase II JCOG0210 trial demonstrated the feasibility and safety of NAC followed by gastrectomy in patients with Borrmann type III–IV tumours,⁹ while the subsequent phase III JCOG0501 trial confirmed the safety of NAC but failed to demonstrate a survival benefit for type IV and large type III GCs.¹⁰

Laparoscopy-assisted distal gastrectomy (LADG) has been shown to improve short-term postoperative recovery compared with open distal gastrectomy (ODG).¹¹ LADG is associated with reduced intraoperative blood loss, shorter hospital stay and faster return of gastrointestinal function. Accordingly, laparoscopic approaches have been widely adopted as part of enhanced recovery after surgery (ERAS) protocols in GC management.12,14 Although current evidence suggests comparable long-term survival outcomes between laparoscopic and open gastrectomy,¹⁵ most trials have focused on early-stage disease, and there remains a paucity of high-quality randomised trials evaluating the oncologic safety of LADG for LAGC.

In recent years, multicentre randomised controlled trials (RCTs) in East Asia have compared laparoscopic and open gastrectomy for LAGC.^{16 17} The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS)-01 trial demonstrated the short-term safety and feasibility of LADG in this population,¹⁸ and its long-term results confirmed non-inferiority in overall survival (OS) compared with ODG.^{19 20} In patients with LAGC who have undergone NAC, surgical tolerance and the ability to cope with surgical stress may be compromised. Whether minimally invasive laparoscopic surgery following NAC can reduce surgical trauma and promote postoperative recovery remains unclear, as relevant evidence is limited. Some reports suggest that the combination of XELOX-based chemotherapy with laparoscopy-assisted D2 gastrectomy is safe and feasible for LAGC and may achieve higher R0 resection rates and improved 3-year disease-free survival (DFS) compared with XELOX adjuvant chemotherapy alone following laparoscopy-assisted D2 gastrectomy.²¹

Currently, three RCTs are ongoing to compare laparoscopic and open gastrectomy following NAC for LAGC,^{22 23} but their results are pending. High-quality evidence addressing this combined treatment strategy is still lacking. Therefore, this trial is designed as a multicentre, randomised, non-inferiority study to compare LADG and ODG after NAC in patients with LAGC, with the aim of providing robust evidence to guide clinical practice.

Objectives

Building on our previous single-arm CLASS-03a study, which demonstrated the safety and feasibility of LADG following NAC in patients with locally advanced GC, this trial aims to provide higher-level evidence through a multicentre randomised controlled design. Specifically, we seek to compare the long-term survival outcomes of LADG versus ODG after NAC in patients with locally advanced distal gastric adenocarcinoma (cT3–4a, N0/+, M0).

Methods and analysis

Trial design

This study is designed as a multicentre, randomised, controlled, non-inferiority trial conducted at high-volume GC centres across China. Eligible patients will be randomised in a 1:1 ratio to undergo either LADG or ODG, both with D2 lymphadenectomy performed according to standardised oncologic principles. The primary aim is to evaluate whether LADG after NAC is non-inferior to ODG in terms of long-term survival outcomes. The reporting of this study protocol conforms to the Standard Protocol Items: Recommendations for Interventional Trials statement.²⁴ The study workflow and participant timeline are summarised in table 1 and figure 1, respectively.

Table 1. Schedule of assessments and interventions for participants in the CLASS-03b trial.

Trial period	Enrolment and allocation	Pre-op (≤4 weeks)	Operation	Post-op (≤30 days)	Follow-up (months)
Timepoint					1	3	6	12	24	36	48	60
Eligibility and consent	✔
Randomisation	✔
NAC		✔
Post-NAC assessment		✔
LADG/ODG			✔
Pathology			✔
Complications (early/late)				✔
Clinical and laboratory assessment				✔	✔	✔	✔	✔	✔	✔	✔	✔
Blood test				✔(d1/3/5)
Tumour markers				✔	✔	✔	✔	✔	✔	✔	✔	✔
Imaging (CT/MRI)								✔	✔	✔	✔	✔
Ultrasound							✔	✔	✔	✔	✔	✔
Endoscopy								✔	✔	✔	✔	✔

LADG, laparoscopy-assisted distal gastrectomy; NAC, Neoadjuvant chemotherapy; ODG, open distal gastrectomy.

Figure 1. Flowchart illustrating the overall design of the trial, including participant screening, enrolment, randomisation, intervention and follow-up assessments. LADG, laparoscopy-assisted distal gastrectomy; ODG, open distal gastrectomy.

Trial oversight

The coordinating site (West China Hospital, Sichuan University) oversees overall trial management, site coordination and data integrity. A steering committee, composed of principal investigators from participating centres, supervises trial conduct and approves protocol amendments. A central quality committee (CQC) ensures adherence to standardised ‘gold-standard’ oncologic procedures for both open and laparoscopic distal gastrectomy. All operative videos and intraoperative photographs, including lymphadenectomy fields and resected specimens, will be reviewed by the CQC to verify procedural quality. The CQC will also verify the total number of retrieved lymph nodes, station-specific dissections, circumferential resection margins and D2 lymphadenectomy compliance to ensure histopathologic comparability between the two groups, following quality assurance frameworks used in high-quality randomised trial of gastrointestinal surgery.²⁵ An independent Data Monitoring Committee (DMC) monitors safety and interim analyses and may recommend continuation, modification or early termination. The data management team handles secure data entry, quality checks and database maintenance.

Participating centres

The trial will be conducted at multiple high-volume GC centres in China. These centres were selected because they are recognised referral hospitals with established GC programmes, extensive experience in D2 gastrectomy and the ability to perform both laparoscopic and open radical gastrectomy at high volumes annually. Participating surgeons must meet the following criteria: the centre performs ≥300 GC surgeries/year, can perform both open and laparoscopic D2 gastrectomy, PI performs ≥50 laparoscopic D2 gastrectomies per year and proficiency is confirmed via blinded video review. This approach ensures that all procedures are performed by experienced surgeons at high-volume centres, following quality-assurance measures implemented in high-level randomised trials of complex upper gastrointestinal surgery to maintain procedural consistency and reliability.^{25 26} A complete list of participating hospitals and investigators will be provided in online supplemental appendix 1.

Eligibility criteria and recruitment

Inclusion criteria

Eligible patients are aged 18–75 years with histologically confirmed primary gastric adenocarcinoma (papillary, tubular, mucinous, signet-ring cell or poorly differentiated) located in the middle or distal stomach, suitable for distal gastrectomy. Pre-neoadjuvant clinical stage must be cT3-4a, N-/+, M0. Staging laparoscopy before neoadjuvant chemotherapy is not mandatory and may be performed according to the surgeon’s discretion and institutional practice, particularly to avoid unnecessary laparotomy if peritoneal dissemination is suspected. Patients must have completed standardised neoadjuvant chemotherapy (XELOX three cycles, SOX three cycles, FLOT4 four cycles or DOS three cycles) with an interval of 4–6 weeks before surgery. Post-neoadjuvant stage must be T≤ycT4 a, N-/+, M0 without distant metastasis. Treatment response may be complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) if R0 distal gastrectomy with D2 lymphadenectomy is feasible. Eastern Cooperative Oncology Group (ECOG) 0–1, American Society of Anesthesiologists (ASA) I–III, adequate organ function (hemoglobin≥90 g/L, neutrophils≥1.5×10⁹/L, platelets≥80×10⁹/L, total bilirubin<1.5×upper limit of normal [ULN], alanine/aspartate aminotransferase [ALT/AST]<2.5× ULN, creatinine≤1×ULN) and willingness to participate are required.

Exclusion criteria

Patients are excluded for prior upper abdominal surgery (except laparoscopic cholecystectomy), gastric endoscopic submucosal dissection/endoscopic mucosal resection (ESD/EMR), acute pancreatitis, preoperative need for total gastrectomy, pre- or post-neoadjuvant lymph nodes>3 cm, other malignancy within 5 years, recent cardiovascular/cerebrovascular events within the past 6 months, ongoing systemic corticosteroids within the past 1 month, need for concurrent surgery (except cholecystectomy), urgent surgery for bleeding/perforation, pyloric obstruction, forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC)<50%, pregnancy/breastfeeding, severe psychiatric disorder or withdrawal of consent.

Intraoperative exclusion

Patients will be removed if intraoperative findings reveal peritoneal or distant metastasis, unresectable tumour or inability to perform a distal gastrectomy. Treatment decisions will follow institutional practice. Excluded patients will continue follow-up and be included in analyses.

Interventions

All procedures will follow standardised oncologic principles. Patients in the experimental arm will undergo LADG with D2 lymphadenectomy, and those in the control arm will undergo ODG with D2 lymphadenectomy. For patients assigned to the open group, staging laparoscopy before laparotomy is not required but may be performed at the surgeon’s discretion to exclude peritoneal dissemination, considering that peritoneal spread is often underestimated by imaging techniques. Peritoneal lavage cytology will be obtained at the beginning of surgery. Following cytology collection, the abdomen will be explored for liver, peritoneal, mesenteric and pelvic metastases, as well as gastric serosal involvement. D2 lymphadenectomy will include nodal stations 1, 3, 4d, 4sb, 5, 6, 7, 8a, 9, 11p and 12a, according to the Japanese Gastric Cancer Treatment Guidelines (sixth edition).⁷

Perioperative management will follow enhanced recovery after surgery (ERAS) protocols. Conversion from LADG to ODG, or modification of the surgical plan, will be allowed in cases of intraoperative complications or technical challenges. To ensure adherence and quality control, all operative procedures will be video-recorded and reviewed by the CQC.

Standard perioperative care and postoperative adjuvant chemotherapy will be permitted in both groups in accordance with national guidelines. Other investigational therapies or additional GC surgeries are prohibited during the trial.

Outcomes

The primary endpoint is a 3-year DFS, defined as the time from randomisation to recurrence, metastasis or death from any cause. Secondary endpoints are 3-year OS and 5-year OS.

DFS was selected as the primary endpoint because it is a robust surrogate for OS in GC trials, particularly in multimodal treatment strategies.

Sample size

Based on the CLASS-01 trial, the expected 3-year DFS after NAC followed by surgery and adjuvant chemotherapy is approximately 77.8%. This trial is designed as a non-inferiority study to test whether LADG after NAC is not inferior to ODG in terms of survival outcomes.

Sample size was calculated using PASS 2021 (V.21.0.3). Assuming a control arm 3-year DFS rate of 77.8% and an absolute non-inferiority margin of 8% at 3 years, with two-sided α=0.05 and power=80% (β=0.20) and allowing for 15% attrition (5% perioperative exclusion, 10% loss to follow-up), the required total sample size is 998 patients, with 499 in each arm.

Randomisation and blinding

Eligible patients who meet the inclusion and exclusion criteria and provide written informed consent will be consecutively registered in the study database. Prior to surgery, the principal investigator at each centre will complete a Surgical Eligibility Confirmation Form, which will be reviewed by the CLASS-03 Research Committee. On approval, patients will be randomised centrally via a secure, third-party web-based platform using a centre-stratified block randomisation design. Stratification factors will include pre-chemotherapy stage, post-chemotherapy stage and the type of neoadjuvant chemotherapy regimen, in order to minimise potential bias due to treatment heterogeneity. Randomisation results will be communicated to investigators in written form.

This is an open-label trial; neither patients nor surgeons will be blinded. Outcome assessors, statisticians and data analysts will remain blinded. Data will be coded, and analysts will handle blinded datasets to minimise bias. Emergency unblinding is permitted only for patient safety and must be approved by the coordinating site; the event, reason and time of unblinding will be documented and reported to the DMC.

Data collection and management

Clinical data will be collected prospectively using standardised case report forms and entered into a secure electronic database. Data quality will be ensured through double data entry, automated range checks and regular on-site monitoring.

Follow-up visits will be scheduled every 3 months for the first 2 years and every 6 months thereafter until 5 years post-surgery or death. Data on survival, recurrence, complications, adjuvant therapy and quality of life will be collected.

Statistical analysis

All analyses will follow the intention-to-treat principle, with per-protocol analyses performed as sensitivity analyses. Kaplan–Meier estimates will be used for survival, with log-rank tests for group comparisons. Hazard ratios and 95% CIs will be estimated using Cox proportional hazards models.

Prespecified subgroup analyses will be conducted by nodal status, tumour size and pathological response. Missing data will be handled with multiple imputation.

Data monitoring and safety

An independent DMC will oversee trial conduct, reviewing safety data and interim analyses. The DMC may recommend continuation, modification or termination of the study.

All adverse events and serious adverse events will be documented and graded according to the Clavien–Dindo classification and the Common Terminology Criteria for Adverse Events V.4.0, supplemented by the Accordion Severity Grading System.

Patient and public involvement

Patients and the public are not directly involved in the design, conduct, reporting or dissemination of this trial. However, the research question was formulated based on unmet clinical needs observed in practice, particularly the lack of high-quality evidence regarding the safety and efficacy of LADG following NAC in patients with LAGC.

Ethics and dissemination

The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. This trial has been reviewed and approved by the Biomedical Ethics Committee of West China Hospital, Sichuan University (Approval No. 2025 (865), 16 July 2025). Written informed consent will be obtained from all patients prior to enrolment. An example of the informed consent form is provided in the online supplemental appendix 2 (see online supplemental appendix 3 for an English-language version).

The trial was registered with the Chinese Clinical Trial Registry (ChiCTR; http://www.chictr.org.cn) on 23 September 2025 (ChiCTR2500109677). Personal information will be anonymised, securely stored and protected throughout the study.

Ancillary or post-trial care beyond standard clinical practice will not be provided; patients who suffer trial-related harm will receive appropriate compensation in accordance with institutional policy.

Any modifications to the study protocol will require approval from the relevant ethics committees and will be updated in the trial registry.

The study results will be disseminated through peer-reviewed publications and presentations at scientific conferences. No patient-identifiable data will be disclosed.

Discussion

This trial addresses an important gap in the treatment of LAGC. Although LADG is widely accepted for early-stage GC, its safety and efficacy after NAC remain unclear. Prior randomised trials such as CLASS-01 and KLASS-02 demonstrated comparable survival between LADG and ODG,^{17 20} but few patients in these studies received NAC. As NAC becomes increasingly adopted worldwide, robust evidence is needed to evaluate the role of minimally invasive surgery in this setting.

Our trial builds on the single-arm CLASS-03a study, which confirmed the feasibility of LADG after NAC, but lacked a control group. By using a multicentre randomised non-inferiority design, this study aims to directly compare long-term outcomes between LADG and ODG following NAC. Surgical quality will be ensured by restricting participation to high-volume centres and mandating standardised D2 lymphadenectomy in accordance with Japanese guidelines.⁷

DFS was chosen as the primary endpoint because it is a reliable surrogate for OS in GC and reflects the impact of multimodal strategies.²⁷ Secondary endpoints, including 3-year and 5-year OS together with perioperative outcomes, will provide a more comprehensive evaluation of potential benefits such as reduced surgical trauma and improved postoperative recovery.

We acknowledge several challenges. First, NAC can induce tissue oedema and fibrosis, potentially complicating laparoscopic procedures.²⁸ Second, as this is an open-label study, bias in perioperative care is possible, though outcome assessment and analysis will remain blinded. Finally, variability in adjuvant therapy compliance may influence survival outcomes, underscoring the importance of strict protocol monitoring.

Despite these limitations, this trial is designed to generate high-level evidence on whether LADG after NAC is non-inferior to ODG in terms of oncologic safety. If confirmed, the findings may support broader adoption of minimally invasive approaches in the multimodal management of LAGC, offering patients faster recovery without compromising long-term outcomes.

Trial status

This protocol is V.2.1, dated 29 June 2025. Patient recruitment is scheduled to begin on 30 September 2025 and is expected to be completed by 30 April 2028. The 3-year follow-up, data analysis and reporting will take place from October 2028 to April 2031. The 5-year follow-up, final data analysis and dissemination of results are planned from October 2031 to April 2033.

Data availability statement

De-identified trial data will be available from the corresponding author on reasonable request and with appropriate ethical approval, following the completion of follow-up, data analysis and publication of the study results.