Abstract
The role of lymph node dissection in gastric cancer (GC) patients undergoing immune checkpoint inhibitor (ICI) therapy remains unclear. While extensive lymph node dissection has been a cornerstone of GC surgery, its impact on the efficacy of ICIs, which rely on immune functionality, warrants investigation. This retrospective study analyzed 218 GC patients treated with ICIs and compared their outcomes based on the number of lymph nodes dissected. Propensity score matching and multivariate Cox regression analyses were conducted to minimize confounding factors and identify independent prognostic variables. Subgroup analyses were performed based on lymph node metastasis status to explore potential interactions. Patients with fewer lymph node dissections demonstrated significantly longer progression-free survival (χ2 = 4.714, P = .030) and overall survival (χ2 = 5.826, P = .009) compared to those with extensive dissections. Subgroup analyses revealed that this association persisted in patients with positive lymph node metastasis but was less evident in those without metastasis, likely due to group imbalance. Propensity score matching analysis further supported the association between fewer lymph node dissections and improved survival outcomes. However, multivariate analysis indicated that the number of lymph nodes dissected was not an independent prognostic factor. This study revealed that a lower number of lymph node dissections is associated with improved recurrence-free survival and overall survival in GC patients receiving ICIs, suggesting a potential benefit of preserving immune-active lymph nodes.
Keywords: gastric cancer, immune checkpoint inhibitors, lymph node dissection, prognosis, surgery
1. Introduction
Gastric cancer (GC) is one of the leading causes of cancer-related morbidity and mortality worldwide, particularly in East Asia, where its incidence is notably high.[1] According to recent global statistics, GC ranks as the 5th most common malignancy and the 3rd leading cause of cancer death.[2] The survival rates for GC remain low, especially in advanced stages, due to late diagnosis and metastasis.[3] While surgery remains the primary treatment for localized GC, the role of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has become a promising adjunct in the treatment of advanced or metastatic cases.[4] ICIs, which target immune checkpoint proteins such as programmed cell death protein 1/programmed death-ligand 1 (PD-L1) and cytotoxic t-lymphocyte-associated protein 4, work by enhancing the body’s immune response against tumor cells, thereby improving outcomes in various cancers, including GC.[5] The combination of surgery and ICIs has shown to provide a significant survival benefit, particularly in patients with advanced stages of the disease.
The extent of lymph node dissection during GC surgery is a critical factor in determining patient outcomes, particularly regarding the risk of recurrence and survival.[6] Compared to the sentinel lymph node biopsy technique used in breast cancer, GC tends to favor more extensive lymph node dissection. This is due to the larger number of lymph nodes surrounding the stomach and the higher tendency for lymph node metastasis in GC. Standardized procedures, such as D2 lymphadenectomy, are widely used to remove regional lymph nodes, which are potential sites for metastatic spread.[7] However, the number of lymph nodes removed, and the areas targeted can vary, even when the same surgical approach is employed. This variability is often influenced by the patient’s unique anatomy, tumor characteristics, and the surgeon’s judgment.[8] While the extent of lymph node dissection is generally guided by established protocols, certain regions may be prioritized based on the perceived risk of metastasis, the presence of lymph node involvement, and the surgeon’s experience.[9] It is important to note that these differences in lymph node dissection are not due to surgeon inexperience, but rather reflect the adaptability required in clinical practice to optimize outcomes for individual patients.
Traditionally, the focus of lymph node dissection has been on removing all potentially metastatic nodes to reduce the risk of recurrence. With the introduction of ICIs, which rely on immune function to target and eliminate tumor cells, this approach may need to be reconsidered. It is now hypothesized that preserving certain lymph nodes, particularly those that are immune-active and free from metastasis, may enhance the efficacy of ICIs by maintaining a supportive immune microenvironment. This study aims to investigate the impact of lymph node dissection on prognosis in GC patients treated with ICIs. By exploring this relationship, the study could contribute to the advancement of more precise lymph node biopsy techniques, ultimately leading to improved personalized treatment strategies and optimized outcomes for GC patients.
2. Patients and materials
2.1. Patients
This study was designed as a retrospective cohort study. Patients with pathologically confirmed gastric adenocarcinoma who underwent curative-intent surgery at our hospital between August 2016 and December 2022 were retrospectively screened. Eligible patients had received at least 3 cycles of adjuvant ICI therapy or conventional chemotherapy following surgery. The inclusion and exclusion criteria are detailed below.
Age ≥ 18 years.
Pathological confirmation of gastric adenocarcinoma.
Completion of curative surgical resection (R0 resection).
Receipt of at least 3 cycles of postoperative ICIs or chemotherapy.
Availability of complete clinical and follow-up data.
The exclusion criteria were as follows:
History of other malignancies.
Prior chemotherapy, immunotherapy, or radiotherapy before surgery.
Presence of distant metastasis at diagnosis.
Incomplete surgical resection (R1 or R2 resection).
Severe postoperative complications or comorbidities interfering with treatment or follow-up.
Incomplete medical records or loss to follow-up.
This study adhered to the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of our hospital (approval number: 2019-57-IIT). Written informed consent was obtained from all patients before their inclusion in the study.
2.2. Indications for ICIs
In this study, ICIs therapy was administered as adjuvant treatment following curative gastrectomy. Standard indications were determined according to contemporary clinical guidelines and recommendations from the institutional multidisciplinary tumor board. Eligible patients typically had stage II–III GC with high-risk features, including lymph node metastasis, poor tumor differentiation, or microsatellite instability-high status. Additionally, patients with PD-L1-positive tumors (combined positive score ≥ 1) were considered suitable candidates for immunotherapy. Importantly, a subset of patients without established indications elected to undergo ICI therapy voluntarily, after comprehensive clinical consultation and provision of written informed consent. These cases were guided by individualized clinical judgment and the patient’s willingness to pursue immunotherapy despite the absence of formal guideline-based criteria or predictive biomarkers.
2.3. Data collection and follow-up
Data were collected through regular telephone follow-ups and a comprehensive review of electronic medical records. Follow-up assessment includes clinical examination results, imaging reports, and treatment progress. It is conducted every 3 months for the first 2 years after surgery and every 6 months thereafter until the last follow-up date or death. Recurrence-free survival (RFS) was defined as the time from curative surgery to the first documented tumor recurrence or death from any cause, whichever occurred first. Overall survival (OS) refers to the time from surgery to death for any reason.
2.4. Statistical analysis
Continuous variables were expressed as mean ± standard deviation and compared using independent sample t-tests, while categorical variables were presented as frequencies and percentages and analyzed using the chi-square test or Fisher exact test, as appropriate. Kaplan–Meier survival curves and log-rank tests were used to compare survival differences between groups. Univariate and multivariate Cox regression analyses were performed to adjust for confounding factors and identify independent prognostic factors. Additionally, propensity score matching (PSM) analysis was conducted to further minimize potential confounding effects and ensure comparability between groups. Statistical analyses were performed using Statistical Package for the Social Sciences 29.0 (IBM Corp.), and survival curves were generated using GraphPad Prism 8.0 (GraphPad Software). A 2-tailed P value of <.05 was considered statistically significant.
3. Results
3.1. Patients characteristics
Between August 2016 and December 2022, a total of 550 patients who underwent gastrectomy for pathologically confirmed gastric adenocarcinoma were retrospectively screened. After excluding 123 patients due to incomplete clinical data (n = 38), non-adenocarcinoma pathology (n = 22), fewer than 3 cycles of adjuvant therapy (n = 41), or loss to follow-up within 6 months (n = 22), a total of 427 patients were included in the final analysis. Of these, 218 patients received adjuvant ICI therapy and 209 received postoperative chemotherapy. The patient selection process is illustrated in Figure 1. The mean age was 58.60 years (standard deviation: 10.30 years). All patients underwent radical resection, with 51 undergoing D1 lymph node dissection and 376 undergoing D2 lymph node dissection. Due to the limited number of stage I patients, stages I and II were combined for analysis, resulting in 124 patients classified as stage I + II and 303 patients as stage III. Furthermore, the cutoff value for the number of dissected lymph nodes, determined using the receiver operating characteristic curve, was 26. Based on this threshold, patients were categorized into the low lymph node dissection group (n = 290) and the high lymph node dissection group (n = 137). Notably, as ICIs have not yet been integrated into the treatment guidelines for GC, patients receiving ICIs exhibited significantly poorer differentiation (P < .001), larger tumor size (P < .001), and more advanced tumor-node-metastasis (staging system) (TNM) stage (P < .001) (Table 1).
Figure 1.
Flowchart of patient selection and group allocation.
Table 1.
Patient characteristics.
| Items | ICIs | Chemotherapy | P |
|---|---|---|---|
| n = 218 | n = 209 | ||
| Age (yr), mean (SD) | 58.22 (9.76) | 59.00 (10.84) | .432 |
| BMI (kg/m2), mean (SD) | 21.92 (3.64) | 22.36 (3.27) | .186 |
| Sex, n (%) | .687 | ||
| Male | 150 (68.8) | 140 (67.0) | |
| Female | 68 (31.2) | 69 (33.0) | |
| Number of lymph nodes, mean (SD) | 26.35 (11.83) | 28.09 (11.94) | .112 |
| Number of lymph node dissection, n (%) | .052 | ||
| Low | 134 (61.5) | 149 (71.3) | |
| High | 84 (38.5) | 60 (28.7) | |
| Lymph node range, n (%) | |||
| D1 | 20 (9.2) | 31 (14.8) | .072 |
| D2 | 198 (90.8) | 178 (85.2) | |
| Lymph node metastasis, n (%) | .250 | ||
| Positive | 170 (78.0) | 153 (73.2) | |
| Negative | 48 (22.0) | 56 (26.8) | |
| Differentiation, n (%) | <.001 | ||
| Poorly differentiated | 178 (81.7) | 78 (37.3) | |
| Moderately differentiated | 34 (15.6) | 114 (54.5) | |
| Well differentiated | 6 (2.7) | 17 (8.2) | |
| Tumor size, n (%) | <.001 | ||
| <30 mm | 31 (14.2) | 74 (35.4) | |
| 30–50 mm | 91 (41.7) | 62 (29.7) | |
| >50 mm | 96 (44.1) | 73 (34.9) | |
| TNM stage, n (%) | <.001 | ||
| I + II | 56 (25.7) | 68 (32.5) | |
| III | 162 (74.3) | 141 (67.5) |
BMI = body mass index, SD = standard deviation, TNM = tumor-node-metastasis (staging system).
3.2. Survival analyses for number of lymph nodes
The survival curves for different treatment modalities indicated that patients receiving ICIs had slightly longer survival compared to those undergoing chemotherapy. The median RFS for patients receiving ICIs was 47.9 months, and the median OS was not reached, while the median RFS for chemotherapy patients was 32.0 months and the median OS was 51.2 months. However, the log-rank test revealed no statistically significant differences in RFS (χ2 = 2.377, P = .124) or OS (χ2 = 1.981, P = .159) between the 2 groups (Fig. 2A, B). Among patients receiving ICIs, 134 were in the low lymph node dissection group, and 84 were in the high lymph node dissection group. The median RFS and OS for the low dissection group was both not reached, while the high dissection group had median RFS of 24.4 months and OS of 60.1 months. Patients in the low dissection group exhibited significantly longer RFS (χ2 = 4.714, P = .030) and OS (χ2 = 5.826, P = .009) (Fig. 2C, D). In contrast, among chemotherapy patients, 149 were in the low lymph node dissection group, and 60 in the high lymph node dissection group. The median RFS for the low dissection group was 55.9 months, and the median OS was not reached, while the median RFS and OS of high dissection group were both not reached. No significant differences in RFS (χ2 = 1.767, P = .185) or OS (χ2 = 2.171, P = .141) were observed between the 2 groups (Fig. 2E, F).
Figure 2.
Survival analysis of RFS and OS for different treatments and lymph node dissection groups. (A, B) RFS and OS comparisons between ICIs and chemotherapy treatments. (C, D) RFS and OS for ICIs patients stratified by lymph node dissection groups. (E, F) RFS and OS for chemotherapy patients stratified by lymph node dissection groups. ICI = immune checkpoint inhibitor, OS = overall survival, RFS = recurrence-free survival.
3.3. Survival analyses for number of lymph nodes in ICIs and chemotherapy
In the ICIs cohort, among patients with negative lymph node metastasis, 34 were assigned to the low lymph node dissection group, and 14 to the high lymph node dissection group. The median RFS and OS in the low dissection group and high dissection group were both not reached. Patients in the low dissection group exhibited significantly longer RFS (χ2 = 5.714, P = .010), whereas there was no significant difference in OS (χ2 = 6.826, P < .001) (Fig. 3A, B). In contrast, for patients with positive lymph node metastasis, 100 were in the low lymph node dissection group, and 70 in the high lymph node dissection group. The median RFS and OS for the low dissection group were 43.6 months and 52.1 months, respectively, while the median RFS and OS for the high dissection group were 24.6 and 32.2 months, respectively. Patients in the low dissection group demonstrated significantly better RFS (χ2 = 7.323, P < .001) and OS (χ2 = 6.591, P < .001) (Fig. 3C, D).
Figure 3.
Survival analysis of RFS and OS in ICIs patients stratified by lymph node status and dissection groups. (A, B) RFS and OS for patients with negative lymph node metastasis, comparing low and high lymph node dissection groups. (C, D) RFS and OS for patients with positive lymph node metastasis, comparing low and high lymph node dissection groups. ICI = immune checkpoint inhibitor, OS = overall survival, RFS = recurrence-free survival.
Among chemotherapy patients with positive lymph node metastasis, 48 were in the high lymph node count group, and 105 were in the low lymph node count group. The median RFS and OS for the high lymph node count group were 7.2 and 16.5 months, while the low lymph node count group had median RFS and OS of 6.8 and 15.0 months, respectively. No significant differences in (χ2 = 0.482, P = .598) and OS (χ2 = 0.433, P = .658) were observed between the 2 groups (Fig. 4A, B). For patients with negative lymph node metastasis, there were 56 patients, with 12 in the high lymph node count group and 44 in the low lymph node count group. The median RFS and OS for the high lymph node count group were 14.6 months and 30.2 months, while in the low lymph node count group, they were 13.4 months and 28.5 months, respectively. Similarly, no significant differences in RFS (χ2 = 0.171, P = .870) and OS (χ2 = 0.203, P ≤ 0.740) were found between these 2 groups (Fig. 4C, D).
Figure 4.
Survival analysis of RFS and OS in chemotherapy patients stratified by lymph node status and dissection groups. (A, B) RFS and OS for patients with negative lymph node metastasis, comparing low and high lymph node dissection groups. (C, D) RFS and OS for patients with positive lymph node metastasis, comparing low and high lymph node dissection groups. OS = overall survival, RFS = recurrence-free survival.
3.4. Cox survival analysis in ICIs
To minimize the impact of confounding factors, a Cox regression analysis was performed on patients receiving ICIs. The results revealed that age, the number of lymph nodes dissected, lymph node metastasis, tumor size, and TNM stage were associated with both RFS and OS (P all < 0.05). Additionally, patients with poorer differentiation (P = .025) had shorter RFS. Multivariate analysis identified lymph node metastasis (hazard ratio, HR = 0.459, P < .001 for RFS; HR = 0.449, P < .001 for OS), tumor size (HR = 1.802, P < .001 for RFS; HR = 1.997, P < .001 for OS), and TNM stage (HR = 2.834, P < .001 for RFS; HR = 3.120, P < .001 for OS) as independent prognostic factors for both RFS and OS (Table 2).
Table 2.
Cox survival analysis of PFS and OS in ICIs.
| Items | Univariate analysis | P | Multivariate analysis | P |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| PFS | ||||
| Age | 1.021 (1.006–1.036) | .007 | 1.013 (0.997–1.0029) | .114 |
| BMI | 0.973 (0.930–1.017) | .218 | ||
| Sex (male vs female) | 0.812 (0.582–1.134) | .222 | ||
| Number of lymph node dissection (low vs high) | 2.560 (1.890–3.467) | <.001 | 1.072 (0.863–1.331) | .530 |
| Lymph node metastasis (positive vs negative) | 0.411 (00.299–0.566) | <.001 | 0.459 (0.328–0.643) | <.001 |
| Differentiation (poorly vs moderately vs well) | 0.749 (0.582–0.965) | .025 | 0.894 (0.682–1.173) | .419 |
| Tumor size (<30 vs 30–50 vs > 50) | 2.992 (1.463–4.032) | <.001 | 1.802 (1.310–2.478) | <.001 |
| TNM stage (I + II vs III) | 3.432 (2.242–5.253) | <.001 | 2.834 (1.801–4.447) | <.001 |
| OS | ||||
| Age | 1.027 (1.004–1.043) | .003 | 1.012 (0.996–1.029) | .146 |
| BMI | 0.989 (0.947–1.033) | .609 | ||
| Sex (male vs female) | 0.849 (0.608–1.186) | .338 | ||
| Number of lymph node dissection (low vs high) | 2.386 (1.764–3.228) | <.001 | 1.137 (0.919–1.408) | .237 |
| Lymph node metastasis (positive vs negative) | 0.429 (0.312–0.590) | <.001 | 0.449 (0.322–0.626) | <.001 |
| Differentiation (poorly vs moderately vs well) | 0.792 (0.582–1.018) | .069 | ||
| Tumor size (<30 vs 30–50 vs >50) | 2.297 (1.057–4.153) | <.001 | 1.997 (1.403–2.565) | <.001 |
| TNM stage (I + II vs III) | 3.669 (2.397–5.616) | <.001 | 3.120 (1.998–4.871) | <.001 |
BMI = body mass index, CI = confidence interval, HR = hazard ratio, ICI = immune checkpoint inhibitor, OS = overall survival, PFS = progression-free survival, TNM = tumor-node-metastasis (staging system).
3.5. PSM analysis for the number of lymph node dissections in ICIs
To further minimize confounding factors and ensure comparability between groups, a PSM analysis was conducted for the number of lymph node dissections in patients receiving ICIs. Propensity scores were calculated using a logistic regression model based on factors identified as significant in the multivariate analysis, including lymph node metastasis, tumor size, and TNM stage. A 1:1 nearest-neighbor matching method without replacement was employed, with a caliper width set to 0.02 to maximize the balance between the groups. After matching, a total of 108 patients were included in the final analysis (Table 3). Before PSM, significant differences were observed between the groups in terms of gender (P = .014), lymph node metastasis (P < .001), tumor differentiation (P < .001), and TNM stage (P < .001). After PSM, these baseline characteristics were well balanced, and no significant differences were detected between the low and high lymph node dissection groups (P all > 0.05).
Table 3.
PSM analysis.
| Items | Before PSM | P | After PSM | P | ||
|---|---|---|---|---|---|---|
| Low | High | Low | High | |||
| n = 134 | n = 84 | n = 54 | n = 54 | |||
| Age (yr), mean (SD) | 57.42 (10.21) | 59.50 (8.90) | .063 | 49.37 (9.08) | 49.45 (9.24) | .717 |
| BMI (kg/m2), mean (SD) | 21.97 (4.24) | 21.83 (2.41) | .782 | 24.44 (4.26) | 24.28 (3.72) | .608 |
| Sex, n (%) | .014 | .086 | ||||
| Male | 84 (62.7) | 66 (78.6) | 35 (64.8) | 43 (79.6) | ||
| Female | 50 (37.3) | 18 (21.4)) | 19 (35.2) | 11 (20.4) | ||
| Lymph node metastasis, n (%) | <.001 | .142 | ||||
| Positive | 34 (25.4) | 14 (16.7) | 48 (88.9) | 52 (96.3) | ||
| Negative | 100 (74.6) | 70 (83.3) | 6 (11.1) | 2 (3.7) | ||
| Differentiation, n (%) | <.001 | .54 | ||||
| Poorly | 104 (77.6) | 74 (88.1) | 44 (81.5) | 45 (83.3) | ||
| Moderately | 26 (19.4) | 8 (9.5) | 10 (18.5) | 8 (14.8) | ||
| Well | 4 (3.0) | 2 (2.4) | 0 (0.0) | 1 (1.9) | ||
| Tumor size, n (%) | .424 | .644 | ||||
| <30 mm | 58 (43.3) | 34 (40.5) | 23 (42.6) | 22 (40.7) | ||
| 30–50 mm | 34 (25.4) | 28 (33.3) | 11 (20.4) | 15 (27.8) | ||
| >50 mm | 42 (31.3) | 22 (26.2) | 20 (37.0) | 17 (31.5) | ||
| TNM stage, n (%) | <.001 | .188 | ||||
| I + II | 48 (35.8) | 18 (21.4) | 17 (31.5) | 11 (20.4) | ||
| III | 86 (64.2) | 66 (78.6) | 37 (68.5) | 43 (79.6) | ||
BMI = body mass index, PSM = propensity score matching, SD = standard deviation, TNM = tumor-node-metastasis (staging system).
3.6. Survival analyses for number of lymph nodes after PSM
After PSM, the receiver operating characteristic curve for the number of lymph node dissections was plotted, yielding an area under the curve of 0.599 (Fig. 5A). Both the low and high lymph node dissection groups included 54 patients each, and the median RFS for the low group was 41.9 months, compared to 23.5 months for the high group. patients in the low lymph node dissection group demonstrated significantly longer RFS (χ2 = 2.951, P = .012) (Fig. 5B). Additionally, the median OS for the low group was 34.0 months, while it was not reached in the high group. Patients in the low dissection group also exhibited significantly longer OS (χ2 = 3.441, P = .007) (Fig. 5C).
Figure 5.
PSM analysis for the number of lymph node dissections. (A) ROC curve for the number of lymph node dissections. (B) RFS curves for low and high lymph node dissection groups. (C) OS curves for low and high lymph node dissection groups. ICI = immune checkpoint inhibitor, OS = overall survival, PSM = propensity score matching, RFS = recurrence-free survival, ROC = receiver operating characteristic.
4. Discussion
With the ongoing advancements in research, ICIs have demonstrated powerful therapeutic potential in solid tumors, including GC and liver cancer.[10,11] Numerous studies have found that the efficacy of ICIs is significantly correlated with factors such as tumor immunogenicity, programmed cell death protein 1/PD-L1 expression, and nutritional status.[12] The tumor-killing ability of ICIs relies on the patient’s immune function, and lymph nodes, as critical immune-related structures, may also influence the effectiveness of immunotherapy. This study explores the potential impact of lymph node dissection on the efficacy of ICIs through a series of analyses.
In the survival analysis of treatment modalities, we did not observe a significant survival advantage for patients receiving ICIs, which aligns with our previous research findings. In 2022, an analysis of 146 GC patients revealed that those receiving ICIs had a significantly lower survival rate compared to those undergoing chemotherapy.[13] This can be attributed to the fact that the use of ICIs in GC is still in the exploratory phase and has not yet become a routine treatment option. As a result, patients receiving ICIs tend to have poorer physical conditions, larger tumor volumes, and more advanced tumor stages, all of which negatively impact their survival. While ICIs are increasingly being accepted in cancer treatment, patients in this study who received ICIs had worse clinical and pathological statuses compared to those receiving chemotherapy, which likely explains why no survival difference was observed between the 2 treatment groups. However, in clinical trials that control for confounding factors and minimize selection biases, the superior efficacy of immunotherapy has been clearly demonstrated. For instance, a 2016 clinical trial involving 24 countries analyzed the efficacy of pembrolizumab versus docetaxel in treating advanced non-small cell lung cancer.[14] By recruiting 1034 patients and dividing them into multiple treatment groups, the study revealed the significant role of ICIs in extending long-term survival for patients with advanced non-small cell lung cancer. Similarly, a clinical trial involving advanced GC, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma produced similar findings.[15] This trial, which involved 2687 patients, compared the outcomes of immunotherapy plus chemotherapy versus chemotherapy alone. The results showed that nivolumab combined with chemotherapy demonstrated superior OS and PFS benefits compared to chemotherapy alone in patients with advanced GC, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma.
In subsequent analyses, we found that the number of lymph nodes dissected had no significant impact on the survival of chemotherapy patients. However, in ICIs patients, a lower number of lymph node dissections was associated with longer RFS and OS. To minimize the influence of confounding factors, we performed subgroup analysis based on different lymph node metastasis statuses. The results showed that, except for patients with negative lymph node metastasis – whose results may not be reliable due to the imbalance in the number of patients between the groups – all other findings were consistent with the previous analysis. Patients with fewer lymph node dissections had better RFS and OS in the ICIs group. Further PSM analysis in ICIs patients confirmed the association between fewer lymph node dissections and improved survival, after minimizing the impact of confounding factors. However, multivariate analysis revealed that the number of lymph nodes dissected was not an independent prognostic factor for ICIs patients. The impact of the number of lymph nodes dissected on the prognosis of GC patients remains a subject of debate. Some studies have indicated that the total number of dissected lymph nodes is not significantly associated with patient survival. In 2023, a study from Spain analyzed the influence of the total number of lymph nodes dissected and the number of negative lymph nodes on the prognosis of GC patients. After analyzing data from 315 patients, the researchers concluded that in GC patients undergoing surgery in Spain, negative total lymph nodes did not appear to have prognostic significance.[16] Similarly, our study observed that the number of lymph nodes dissected did not significantly impact survival in patients receiving chemotherapy. In contrast, numerous previous studies have suggested that a higher number of dissected lymph nodes is associated with improved survival outcomes. An Asian medical team analyzed data from 2662 GC patients across 2 institutions. They found that examining a greater number of lymph nodes was linked to longer survival and that harvesting at least 21 lymph nodes might represent a threshold for radical total gastrectomy, leading to better prognosis.[17] Another study further demonstrated that this effect was particularly evident in patients without lymph node metastasis.[18] The inconsistency in findings may be attributed to the heterogeneity of study populations, variations in analytical methods, and differences in regional treatment strategies. These factors likely contribute to the discrepancies observed across studies, making it challenging to establish a unified conclusion on this topic.
In this study, we were the first to investigate the potential impact of lymph node dissection numbers on the prognosis of patients receiving ICIs and found that a lower number of dissected lymph nodes was associated with longer RFS and OS. This finding may be closely related to the mechanisms underlying the efficacy of ICIs, which depend on a functional and intact immune system to mount effective anti-tumor responses.[19–21] Lymph nodes play a critical role in immune surveillance and activation, serving as sites where immune cells interact and are primed to combat tumor cells.[22–25] Excessive lymph node dissection may disrupt this delicate immune microenvironment, reducing the availability of immune-active nodes necessary for the full therapeutic benefits of ICIs. By preserving a larger number of functional lymph nodes, patients may retain a more robust immune system, enhancing the anti-tumor efficacy of ICIs. Moreover, extensive lymph node dissection is associated with increased surgical trauma and systemic inflammatory responses, which can lead to postoperative immunosuppression.[26] This transient immunosuppression may impair the ability of ICIs to activate the immune system effectively during the critical post-surgical period.[27] In contrast, patients undergoing less extensive dissection are less likely to experience these adverse effects, allowing ICIs to work more effectively. Furthermore, non-metastatic lymph nodes that are preserved during surgery may act as reservoirs for immune cells, supporting the immune-modulatory effects of ICIs and sustaining long-term anti-tumor immunity.[28] Additionally, patients requiring fewer lymph node dissections may have biologically less aggressive tumors with lower metastatic burdens, making them inherently more responsive to ICIs.[29] This suggests that the interplay between tumor biology, surgical intervention, and immunotherapy is complex and highly individualized. Preserving lymph nodes in these patients not only maintains immune functionality but may also reduce the risk of complications such as infections, lymphatic leakage, and prolonged systemic inflammation, all of which could negatively impact ICIs’ efficacy.
This study holds significant clinical value as it explores the interplay between lymph node dissection and the efficacy of ICIs in GC, an area that has been largely unexplored. With ICIs emerging as a promising therapeutic option, understanding the factors that influence their effectiveness is crucial for optimizing patient outcomes. Traditionally, extensive lymph node dissection has been a cornerstone of GC surgery, aiming to improve tumor control and staging accuracy. However, ICIs rely heavily on the patient’s immune functionality, necessitating a reevaluation of surgical strategies. In this context, the concept of sentinel lymph node biopsy, widely adopted in breast cancer, offers a potential alternative to extensive lymph node dissection. By selectively identifying and removing lymph nodes most likely to harbor metastases, sentinel lymph node biopsy could preserve immune-active nodes, maintaining the immune microenvironment and potentially enhancing the efficacy of ICIs.[30–33] This study’s findings on the impact of lymph node dissection on survival outcomes in ICIs-treated patients highlight the possible for integrating precision techniques, such as sentinel lymph node biopsy, into GC treatment protocols. This approach could optimize both surgical and immunotherapy outcomes, advancing the personalization of GC treatment and improving long-term survival for patients.
However, this study has several notable limitations that may restrict the generalizability of its findings. First, as a single-center retrospective study, the inherent nature of its design poses challenges in eliminating all potential biases. While statistical methods, such as PSM and multivariate analysis, were employed to minimize the influence of confounding factors, residual biases cannot be completely ruled out. Factors such as selection bias, variability in clinical practice, and unmeasured confounders may still have impacted the results. Second, the sample size of this study was relatively limited, which constrained the ability to conduct a more detailed analysis of the effects of different treatment modalities. For instance, the study could not fully stratify the impact of lymph node dissection numbers across various subgroups of patients, such as those receiving combination therapies or differing in baseline characteristics like tumor stage or immunogenicity. A larger cohort would have allowed for more robust subgroup analyses and a better understanding of how lymph node dissection interacts with specific clinical or pathological factors. Lastly, the conclusions of this study require further validation through larger, multicenter prospective clinical trials. Such trials are necessary to confirm the observed associations and to explore the underlying mechanisms in a broader and more diverse population. Expanding the scope of investigation to include patients from multiple institutions with varied clinical practices would enhance the reliability and external validity of the findings. Additionally, prospective trials could provide insights into the dynamic interactions between lymph node dissection, ICIs, and the immune microenvironment, further advancing our understanding of personalized treatment strategies in GC.
5. Conclusion
This study revealed that a lower number of lymph node dissections is associated with improved RFS and OS in GC patients receiving ICIs, suggesting a potential benefit of preserving immune-active lymph nodes.
Author contributions
Data curation: Qi Huang.
Funding acquisition: Yuehua Xu.
Investigation: Qi Huang.
Methodology: Zhidong Yin.
Project administration: Yuehua Xu.
Supervision: Zhidong Yin.
Software: Yuehua Xu.
Writing – original draft: Wei Zhang, Limin Zhang.
Writing – review & editing: Wei Zhang, Limin Zhang.
Abbreviations:
- GC
- gastric cancer
- ICI
- immune checkpoint inhibitor
- HR
- hazard ratio
- OS
- overall survival
- PD-L1
- programmed death-ligand 1
- PSM
- propensity score matching
- RFS
- recurrence-free survival
- TNM
- tumor-node-metastasis (staging system)
This study was approved by the ethics committee of Harbin Medical University Cancer Hospital (Number: 2019-57-IIT). Due to the retrospective character of this study, the Ethics Committee of Harbin Medical University Cancer Hospital decided to waive informed consent.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Zhang W, Zhang L, Huang Q, Yin Z, Xu Y. Impact of lymph node dissection on survival outcomes in gastric cancer patients receiving immune checkpoint inhibitors. Medicine 2026;105:21(e48746).
WZ and LZ contributed to this work equally.
The employer of this study was Limin Zhang, who was also involved in the manuscript editing and the decision to publish.
All methods were carried out in accordance with relevant guidelines and regulations.
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