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Cheng ZW, Wei M, Zhang Y, Liang YZ, Cao WB, Zhao RD, Yan ZB, Sun GR, Cui XH, Yu WB. Surgical safety and efficacy of neoadjuvant immunotherapy plus apatinib and chemotherapy in locally advanced gastric cancer. World J Gastroenterol 2027; 33(2): 122397 [DOI: 10.3748/wjg.122397]
Author contributions: Cheng ZW and Yu WB participated in the conception and design of the study and were involved in the acquisition, analysis, or interpretation of data; Cheng ZW wrote the original draft and managed the project administration; Yu WB and Zhang Y accessed and verified the study data; Zhang Y performed the formal analysis, data curation, statistical analysis, and validation; Wei M, Liang YZ, Cao WB, Zhao RD, Yan ZB, Sun GR, and Cui XH were involved in the investigation, resources, data collection, and writing - review & editing. All authors critically reviewed and provided final approval of the manuscript, and were responsible for the decision to submit the manuscript for publication.
Supported by Horizontal Project of Shandong University, No. 6010123193, No. 6010121066, and No. 6010125120.
Institutional review board statement: This investigation was approved by the Institutional Ethics Committee of Qilu Hospital of Shandong University, No. KYLL-202111-094-1.
Informed consent statement: All involved persons (subjects or legally authorized representative) gave their informed consent prior to study inclusion.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Corresponding author: Wen-Bin Yu, MD, PhD, Professor, Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan 250012, Shandong Province, China. wenbin_yu2003@163.com
Received: April 17, 2026 Revised: May 10, 2026 Accepted: June 10, 2026 Published online: January 14, 2027 Processing time: 207 Days and 20.2 Hours
Abstract
BACKGROUND
Neoadjuvant chemotherapy remains the standard for locally advanced gastric cancer (LAGC), yet outcomes remain suboptimal. Programmed cell death protein-1 inhibitors and apatinib have been used individually with chemotherapy for the treatment of LAGC, but the clinical benefit of programmed cell death protein-1 inhibitors plus apatinib and chemotherapy (PAC) as a neoadjuvant strategy requires comprehensive evaluation.
AIM
To evaluate the surgical safety and efficacy of PAC vs preoperative chemotherapy for LAGC.
METHODS
This retrospective study included 292 patients with LAGC who received either PAC (n = 92) or preoperative chemotherapy (n = 200) followed by radical gastrectomy between January 2019 and December 2022. Tumor regression, surgical outcomes, postoperative recovery, and survival were compared between groups. Subgroup analysis was performed to evaluate the role of indocyanine green (ICG) fluorescence guidance. Overall survival, progression-free survival, and disease-free survival were estimated using Kaplan-Meier method, and independent prognostic factors were identified by the Cox proportional hazards regression model.
RESULTS
The PAC group demonstrated significantly higher pathological complete response rates (28.3% vs 6.5%, P < 0.001) and major pathological response rates (45.7% vs 27.5%, P = 0.002). Despite the PAC regimen increased intraoperative blood loss (100 mL vs 80 mL, P < 0.001), R0 resection rates (92.4% vs 91.0%, P = 0.693) and postoperative complications (23.9% vs 28.0%, P = 0.463) were comparable. ICG fluorescence guidance in the PAC group reduced the open conversion rate (0% vs 19.4%, P = 0.015) and increased the lymph node yield (32 vs 24, P = 0.004). The PAC regimen was significantly associated with prolonged survival outcomes (log-rank P < 0.001) and was an independent prognostic predictor in multivariate analyses (P < 0.05).
CONCLUSION
The PAC regimen significantly improved the pathological response and survival of patients with LAGC, without compromising surgical safety. ICG fluorescence guidance along with the PAC regimen may further optimize surgical outcomes.
Core Tip: This retrospective study of 292 patients with locally advanced gastric cancer demonstrated that programmed cell death protein-1 inhibitors plus apatinib and chemotherapy (PAC) significantly improved tumor regression response and survival outcomes compared with preoperative chemotherapy as a neoadjuvant therapy. The PAC regimen increased intraoperative blood loss, but did not compromise other surgical outcomes or postoperative recovery. Indocyanine green fluorescence guidance in the PAC group reduced the open conversion rate and enhanced lymph node yield. The PAC regimen was an independent prognostic predictor on multivariate analyses. Overall, PAC appears to be a promising neoadjuvant treatment option for locally advanced gastric cancer.
Citation: Cheng ZW, Wei M, Zhang Y, Liang YZ, Cao WB, Zhao RD, Yan ZB, Sun GR, Cui XH, Yu WB. Surgical safety and efficacy of neoadjuvant immunotherapy plus apatinib and chemotherapy in locally advanced gastric cancer. World J Gastroenterol 2027; 33(2): 122397
Gastric cancer (GC) is one of the most common digestive malignancies and a leading cause of cancer-related mortality worldwide[1]. Radical resection remains the standard curative treatment for locally advanced GC (LAGC). Nonetheless, surgery alone often fails to yield a satisfactory prognosis, even after radical dissection of the primary tumors and regional lymph nodes[2]. Currently, the mainstream therapeutic strategy for LAGC is perioperative multidisciplinary treatment centered around surgery[3]. The 2006 MAGIC trial demonstrated that neoadjuvant chemotherapy improved the prognosis of LAGC[4]. However, conventional chemotherapy regimens are less effective against LAGC because of the heterogeneity of GC. Therefore, novel therapies with favorable safety and efficacy profiles are urgently required.
Programmed cell death protein-1 (PD-1) inhibitors exert antitumor effects by blocking the binding of PD-1 to its ligands. Multiple phase III clinical trials and retrospective cohort studies have confirmed that the combination of PD-1 inhibitors and chemotherapy achieves higher pathological response rates and superior survival outcomes than chemotherapy alone in patients with advanced GC compared with chemotherapy alone[5-7]. Vascular endothelial growth factor (VEGF) is overexpressed in GC and serves as a pivotal therapeutic target in the treatment of GC[8]. Apatinib is an original and effective receptor tyrosine kinase inhibitor that selectively targets the VEGF receptor. It inhibits VEGF-mediated endothelial cell migration and proliferation and reduces tumor microvascular density[9]. Numerous clinical studies have found that apatinib combined with chemotherapy yields promising efficacy with acceptable tolerability[10,11] and is superior to chemotherapy alone for patients with LAGC[12,13].
A prospective clinical trial (NCT04195828) revealed that the addition of apatinib to immune checkpoint blockers and chemotherapy conferred clinical benefits in patients with immune desert-type GC[14]. Mechanistically, apatinib plus oxaliplatin reshapes the tumor immune microenvironment by counteracting β-catenin-driven immune exclusion, thereby sensitizing tumor cells to PD-1 inhibitors[15]. Although PD-1 inhibitors plus apatinib and chemotherapy (PAC) have demonstrated notable tumor regression in patients with LAGC[16-18], the safety and efficacy of this neoadjuvant regimen remain unclear, particularly concerning surgical outcomes and long-term survival[19]. Accordingly, we designed this study to evaluate the surgical safety and efficacy of gastrectomy following the PAC regimen compared with those of preoperative chemotherapy (PC) alone in patients with LAGC.
MATERIALS AND METHODS
Study population
This single-center retrospective study was conducted at the First Department of General Surgery, Qilu Hospital of Shandong University. We identified consecutive patients with LAGC (clinically staged T3-4b, N0-3, M0) who underwent radical gastrectomy following neoadjuvant therapy (PAC or PC) between January 2019 and December 2022. Inclusion criteria were as follows: (1) Histological confirmation of gastric or gastroesophageal junction carcinoma; (2) Receipt of at least two cycles of neoadjuvant therapy and subsequent radical gastrectomy; (3) Age 18-80 years; (4) Complete clinicopathological and follow-up data; and (5) Preoperative multidisciplinary team assessment confirming technical resectability. Exclusion criteria were as follows: (1) Underwent emergency surgery for acute complications; (2) Had severe comorbidities precluding safe administration of systemic therapy or major surgery; (3) Had evidence of distant metastasis or recurrence prior to surgery; (4) Underwent palliative or exploratory surgery without curative intent; or (5) Had a history of other active malignancies within 5 years. After applying these criteria, 292 patients were included in the final analysis (Figure 1). This study protocol was approved by the Institutional Ethics Committee of Qilu Hospital of Shandong University, No. KYLL-202111-094-1.
Figure 1 Flow diagram of the patient in the study.
LAGC: Locally advanced gastric cancer; PD-1: Programmed cell death protein-1; PAC: Programmed cell death protein-1 inhibitors plus apatinib and chemotherapy; PC: Preoperative chemotherapy.
Treatments and follow-ups
All patients received SOX (oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks; S-1, 40 mg/m2 orally twice daily for 2 weeks every 3 weeks) as backbone chemotherapy. Patients were treated with one of two neoadjuvant strategies based on recommendation of the multidisciplinary team and patient choice during different periods: Those in the PAC group received a triple combination of a PD-1 inhibitor (sintilimab or camrelizumab, 200 mg intravenously every 3 weeks), apatinib (250 mg orally once daily), and SOX, whereas those in the PC group received neoadjuvant therapy with SOX alone. To ensure safety, radical gastrectomy with D2 lymphadenectomy was scheduled after the following minimal washout periods: At least 2 weeks after the last dose of chemotherapy or apatinib and at least 4 weeks after the last dose of PD-1 inhibitor. The safety of neoadjuvant therapy was assessed by recording all treatment-related adverse events, graded according to the CTCAE v5.0.
Prior to surgery, a comprehensive preoperative assessment was conducted to evaluate patients’ fitness for major resection. This included anesthetic risk stratification using the American Society of Anesthesiologists Physical Status Classification, evaluation of functional status via the Eastern Cooperative Oncology Group Performance Status scale, and nutritional risk screening using the Nutritional Risk Screening 2002 tool. Surgery proceeded only after restaging evaluations confirmed tumor resectability and the absence of active treatment-related toxicities. Indocyanine green (ICG) is a fluorescent dye that enables real-time intraoperative visualization of lymphatic drainage, especially for patients after neoadjuvant therapy with tissue fibrosis and edema. For patients in the ICG group, endoscopy was performed 12-24 hours before surgery. Using a “sandwich injection method”, 0.5 mL normal saline, 0.5 mL ICG solution (0.625 mg/mL), and 0.5 mL normal saline were sequentially injected into the submucosa at four peritumoral sites. All injections were administered by experienced endoscopists to ensure accuracy. All patients underwent standardized radical gastrectomy with D2 lymphadenectomy. Resection extent was determined by tumor location and the goal of achieving negative microscopic margins. All surgeries were performed by experienced surgeons at the First Department of General Surgery, Qilu Hospital of Shandong University. Postoperative complications that occurred within 30 days were documented and classified according to the Clavien-Dindo system.
Administration of postoperative therapy was individualized based on a multidisciplinary review of the pretreatment clinical stage (cTNM) and final pathological stage (ypTNM). Patients were followed prospectively according to a standardized protocol: Clinical and imaging assessments were performed every 3 months for the first 2 years, every 6 months for years 3-5, and annually thereafter. Follow-up began on the date of surgery and continued until death, loss to follow-up, or administrative censoring date of January 2026. The survival endpoints were overall survival (OS), defined as the time from the date of initial pathological diagnosis to death from any cause; progression-free survival (PFS), defined as the time from the initiation of neoadjuvant therapy to disease progression or death from any cause; and disease-free survival (DFS), defined as the time from the date of curative gastrectomy to disease recurrence or death from any cause, whichever occurred first.
Patient evaluation and response assessment
Clinical staging was established at diagnosis through a multidisciplinary evaluation incorporating endoscopic biopsy and contrast-enhanced computed tomography of the chest, abdomen, and pelvis. Clinical stages (cTNM and ycTNM) and pathological stages (ypTNM) were classified according to the American Joint Committee on Cancer Staging Manual and International Union Against Cancer Staging Manual (8th edition). Following completion of preoperative therapy, radiological tumor response was assessed using the same imaging modalities and evaluated according to the RECIST 1.1 criteria, which categorized patients as having complete response (CR), partial response, stable disease, or progressive disease.
A definitive pathological assessment of the resected specimens was performed by two independent, blinded pathologists. Any discrepancies were resolved by a joint review under a multi-headed microscope to reach a consensus. Tumor location was determined according to the Japanese Classification of Gastric Carcinoma (15th edition) and categorized as upper, middle, or lower third; tumors spanning multiple regions were classified according to the site of major involvement. Macroscopic growth patterns of advanced tumors were described using the Bormann classification (types I-IV). Histological evaluation included determination of differentiation grade (well, moderate, or poor) according to the World Health Organization Classification of Tumors of the Digestive System (5th edition), with signet ring cell carcinoma analyzed as a poorly differentiated variant, and Lauren type (intestinal, diffuse, mixed, or indeterminate). Tumor regression in the primary bed was graded using the four-tier Becker system as follows: TRG 1a (CR, no viable cells), TRG 1b (subtotal regression, < 10% residual tumor), TRG 2 (partial regression, 10%-50% residual tumor), and TRG 3 (minimal/no regression, > 50% residual tumor). For the primary analysis, pathological CR (pCR) was defined as TRG 1a with ypN0 lymph node status, and major pathological response (MPR) was defined as patients who achieved either TRG 1a or 1b status.
HER2 status was determined in pretreatment biopsies using immunohistochemistry (IHC), with IHC 3+ scores considered positive. Equivocal cases (IHC 2+) were reflexively tested by fluorescence in situ hybridization, using a HER2/CEP17 ratio ≥ 2.0 as the positivity threshold, in accordance with the American Society of Clinical Oncology/College of American Pathologists guidelines. Mismatch repair status was evaluated by IHC for MLH1, PMS2, MSH2, and MSH6 proteins, and loss of nuclear expression of any protein (with intact internal controls) was defined as deficient mismatch repair. The Ki-67 proliferation index was assessed by IHC on pretreatment specimens and reported as the percentage of tumor cells with positive nuclear staining, based on counting in the regions of highest labeling (hotspots).
Statistical analysis
Data distribution for continuous variables was assessed using the Kolmogorov-Smirnov test. Continuous variables with a normal distribution are presented as mean ± SD, while those with a non-normal distribution are presented as median (interquartile range). Categorical variables are expressed as n (%). Comparisons between the two treatment groups were performed as follows: Independent samples t-test for normally distributed continuous variables; Mann-Whitney U test for non-normally distributed continuous variables; and χ2 test or Fisher’s exact test (when expected cell counts were < 5) for categorical variables. A prespecified subgroup analysis was performed to assess the impact of intraoperative ICG fluorescence guidance on surgical outcomes among patients in the PAC group who underwent laparoscopic gastrectomy. Patients were stratified according to ICG fluorescence guidance vs conventional laparoscopy.
Survival outcomes, including OS, PFS, and DFS, were estimated using the Kaplan-Meier method, and differences between groups were compared using the log-rank test. To identify independent prognostic factors, univariate Cox proportional hazards regression analysis was performed for all variables of interest. Variables achieving a significance level of P < 0.05 in the univariable analysis were entered into a subsequent multivariable Cox proportional hazards model. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to quantify the magnitude of association. Multicollinearity among independent variables in the multivariable regression models was assessed using the variance inflation factor, and a variance inflation factor value < 5 was considered indicative of no significant multicollinearity. The proportional hazards assumption was verified using the Schoenfeld residuals. Statistical significance was defined as a two-sided P < 0.05. Analyses were conducted using R software (version 4.4.1; R Foundation for Statistical Computing, Vienna, Austria) and SPSS (version 25.0; IBM Corp., Armonk, NY, United States).
RESULTS
Baseline characteristics and neoadjuvant therapy
Among the 328 enrolled patients, 292 who underwent gastrectomy were analyzed. Patients were divided into two groups: The PAC (n = 92) and PC (n = 200) groups. The remaining 36 patients did not undergo any gastrectomy (Figure 1). The two groups were well balanced in terms of all baseline and neoadjuvant treatmentrelated characteristics in Table 1. No significant differences were observed in patient demographics, clinical status, tumor features (including stage, location, histology, molecular markers, and invasion status), preoperative therapy cycles, or incidence of treatmentrelated adverse events (all P > 0.05).
Table 1 Baseline characteristics and neoadjuvant therapy, median (interquartile range)/n (%).
Results of tumor responses from the perspective of radiology and pathology are shown in Table 2. Following neoadjuvant therapy, the clinical stage distribution was significantly more favorable in the PAC group than in the PC group, with a higher proportion of ycT0-2 disease (27.2% vs 13.0%, P = 0.003) and ycN0-1 disease (66.3% vs 53.0%, P = 0.033), leading to a significantly more favorable ycTNM stage distribution (P = 0.002), with a higher proportion of stage I disease (21.7% vs 13.0%) and a lower proportion of stage III disease (34.8% vs 54.0%). The radiographic CR rate was significantly higher in the PAC group (45.7% vs 27.5%, P = 0.002). Consequently, treatment with PAC yielded superior objective response rates (ORR, 72.8% vs 56.5%, P = 0.008) and disease control rates (95.7% vs 82.0%, P = 0.002). Furthermore, the pCR rate was markedly higher in the PAC group (28.3% vs 6.5%, P < 0.001) than in the PC group, as was the MPR rate (45.7% vs 27.5%, P = 0.002). Postoperative assessment revealed a lower number of positive lymph nodes [0 (0-4) vs 2 (0-8), P = 0.004], a smaller tumor diameter [3.0 (2.0-5.0) cm vs 4.0 (3.0-6.5) cm, P = 0.001], and a more favorable pathological TNM stage distribution (P = 0.001) in the PAC group, with nearly double the proportion of stage I disease (45.7% vs 24.0%) and a reduced proportion of stage III disease (33.7% vs 47.0%).
Table 2 Tumor regression responses, median (interquartile range)/n (%).
The surgical outcomes of the two treatment groups are summarized in Table 3. Compared with the PC group (47.0%), a significantly higher proportion of patients in the PAC group underwent laparoscopic gastrectomy (69.6%, P < 0.001). Among those who underwent laparoscopic surgery, the rates of ICG fluorescence guidance were comparable between the PAC and PC groups (43.8% vs 37.2%, P = 0.412). There was no significant difference in the operative time between the two groups. However, the PAC group had greater intraoperative blood loss [100 (100-150) mL vs 80 (80-100) mL, P < 0.001] than the PC group. The rates of conversion to open laparotomy, intraoperative blood transfusion, and multiorgan resection were similar in both groups. R0 resection rates were equally high and comparable between the PAC and PC groups (92.4% vs 91.0%, P = 0.693). A pathological positive margin was observed in 4 patients (2.0%) in the PC group and none in the PAC group, but this difference was not statistically significant (P = 0.312). The proximal margin distance was significantly longer in the PAC group [3.5 (2.0-5.2) cm vs 2.5 (1.5-4.0) cm, P = 0.008], while distal margin distance was similar (P = 0.867). The number of lymph nodes harvested was comparable between the two groups (26 vs 25, P = 0.525).
Table 3 Surgical outcomes, median (interquartile range)/n (%).
Postoperative complication rates and recovery profiles were comparable between the two groups in Table 4. The overall incidence of complications did not differ significantly (PAC: 23.9% vs PC: 28.0%, P = 0.463). Both the severity distribution of complications, graded by the Clavien-Dindo classification (P = 0.321), and the rate of major complications (grade ≥ III) were similar between groups (PAC: 9.8% vs PC: 7.0%, P = 0.412). No statistically significant differences emerged in the incidence of specific complications such as anastomotic leakage, pancreatic fistula, intra-abdominal hemorrhage, pneumonia, or arrhythmia (all P > 0.05).
Table 4 Postoperative complications and recovery, median (interquartile range)/n (%).
Metrics of postoperative recovery also showed no significant differences between groups in Table 4. The median postoperative hospital stay was 9 days in both groups (P = 0.260). The times to first flatus, defecation, enteral nutrition, liquid diet, and removal of nasogastric tube and abdominal drainage tube were comparable (all P > 0.05). Postoperative pain levels, assessed using the visual analog scale score, were similar on postoperative days 1, 2, 3, and 5 (all P > 0.05).
Perioperative benefits of ICG fluorescence guidance in the PAC group
Among patients who received PAC and underwent laparoscopic gastrectomy, the use of ICG fluorescence guidance was associated with improved surgical outcomes in Table 5. Compared to the non-ICG group (n = 36), patients in the ICG group (n = 28) had a significantly lower rate of conversion to open laparotomy (0% vs 19.4%, P = 0.015) and a higher number of lymph nodes retrieved [32 (24-33) vs 24 (21-26), P = 0.004]. In addition, the pain scores on postoperative day 3 were lower in the ICG group [2 (2-3) vs 3 (2-3), P = 0.043]. No significant differences between groups were observed in operative time, intraoperative blood loss, R0 resection rate, postoperative complications, or length of hospital stay (all P > 0.05).
Table 5 Impact of indocyanine green fluorescence guidance on perioperative outcomes in the programmed cell death protein-1 inhibitors plus apatinib and chemotherapy group, median (interquartile range)/n (%).
Kaplan-Meier curves demonstrated that the patients receiving the PAC regimen had significantly longer OS, PFS, and DFS than those receiving the PC regimen (all log-rank P < 0.001; Figure 2). Univariate Cox regression analyses identified multiple factors associated with OS, PFS, and DFS in Supplementary Tables 1-3, respectively. For OS, PFS and DFS, significant associations were observed for cTNM stage, neoadjuvant regimen, tumor long diameter, Lauren type, Bormann type, lymphovascular invasion, perineural invasion, multiorgan excision, R0 resection, ycTNM stage, pathological response, and ypTNM stage (all P < 0.05). Comparable patterns were noted for PFS and DFS, with consistent findings for tumor pathological type (P < 0.05).
Figure 2 Kaplan-Meier survival curves.
A: Comparison of overall survival between the programmed cell death protein-1 inhibitors plus apatinib and chemotherapy (PAC) group and preoperative chemotherapy (PC) group; B: Comparison of progression-free survival between the PAC group and PC group; C: Comparison of disease-free survival between the PAC group and PC group. PAC: Programmed cell death protein-1 inhibitors plus apatinib and chemotherapy; PC: Preoperative chemotherapy; HR: Hazard ratio; CI: Confidence interval.
Multivariate Cox regression analyses were performed to identify independent prognostic factors associated with OS, PFS, and DFS (Figure 3). For OS, cTNM stage (II vs I: HR = 1.986, 95%CI: 1.039-3.797, P = 0.038; III vs I: HR = 2.135, 95%CI: 1.044-4.363, P = 0.038), neoadjuvant regimen (PAC vs PC: HR = 0.591, 95%CI: 0.395-0.884, P = 0.010), R0 resection (HR = 0.560, 95%CI: 0.322-0.975, P = 0.040), and ypTNM stage (II vs I: HR = 2.983, 95%CI: 1.548-5.748, P = 0.001; III vs I: HR = 4.363, 95%CI: 2.007-9.484, P < 0.001) were independent predictors. For PFS, independent prognostic factors included cTNM stage (II vs I: HR = 1.930, 95%CI: 1.008-3.695, P = 0.047), neoadjuvant regimen (PAC vs PC: HR = 0.633, 95%CI: 0.419-0.955, P = 0.029), tumor pathological type (signet ring cell carcinoma vs adenocarcinoma: HR = 1.841, 95%CI: 1.017-3.333, P = 0.044), R0 resection (HR = 0.523, 95%CI: 0.293-0.936, P = 0.029), and ypTNM stage (II vs I: HR = 2.311, 95%CI: 1.203-4.438, P = 0.012; III vs I: HR = 2.686, 95%CI: 1.208-5.970, P = 0.015). For DFS, independent predictors were neoadjuvant regimen (PAC vs PC: HR = 0.650, 95%CI: 0.431-0.982, P = 0.041), tumor pathological type (HR = 1.832, 95%CI: 1.010-3.325, P = 0.046), R0 resection (HR = 0.474, 95%CI: 0.264-0.851, P = 0.012), and ypTNM stage (II vs I: HR = 2.077, 95%CI: 1.104-3.905, P = 0.023; III vs I: HR = 2.552, 95%CI: 1.167-5.580, P = 0.019). Notably, neoadjuvant regimen, R0 resection, and ypTNM stage were the most potent independent prognostic factors across all three survival endpoints.
Figure 3 Multivariate Cox regression analyses of independent prognostic factors for survival outcomes.
A: Forest plot displayed hazard ratios and 95% confidence intervals for overall survival; B: Forest plot displayed hazard ratios and 95% confidence intervals for progression-free survival; C: Forest plot displayed hazard ratios and 95% confidence intervals for disease-free survival. PAC: Programmed cell death protein-1 inhibitors plus apatinib and chemotherapy; HR: Hazard ratio; CI: Confidence interval.
DISCUSSION
In this retrospective study of patients with LAGC, the PAC regimen was significantly associated with improved tumor regression and long-term survival compared with that of the PC regimen. This enhanced efficacy was achieved with a manageable safety profile without compromising surgical feasibility or postoperative recovery. Although diagnostic and therapeutic techniques for GC continue to improve, morbidity and mortality rates remain high[20-22]. At the same time, due to the destruction of the vascular system around the tumor and the uncertainty of the nutritional status and chemotherapy tolerance of patients after surgery, more researchers aim to advance the postoperative treatment plan before surgery[23]. Our previous study showed that the PAC regimen as combination therapy for patients with LAGC provides a new choice with satisfactory pathological responses and limited toxicity[17]. In this study, the PAC regimen demonstrated a superior antitumor effect as evidenced by significantly higher ORR, disease control rates, pCR rate, and MPR rate. Corroborating these results, a recent retrospective study reported that the PAC regimen significantly outperformed chemotherapy alone in both radiologic ORR (73.2% vs 35.6%, P < 0.001) and pCR rate (26.8% vs 7.7%, P = 0.005)[24]. The Arise-FJ-G005 trial, a randomized controlled study, reported a significantly higher MPR rate (33.3% vs 17.0%, P = 0.044) and ORR (66.0% vs 43.4%, P = 0.017) with a similar combination regimen[14]. Preclinical studies have established the mechanistic rationale for this combination. PD-1 inhibition remodels the tumor immune microenvironment by increasing CD4+ and CD8+ T-cell infiltration, whereas VEGFR-2 blockade with apatinib targets the tumor vasculature[25]. Notably, emerging evidence has revealed that apatinib counteracts anti-PD-1 immunotherapy resistance by blocking the CXCL5/CXCR2 axis, thereby preventing protumor neutrophil recruitment[26].
However, this potent antitumor activity introduces a direct trade-off by imposing greater technical demands during surgery. Operative duration and intraoperative blood loss are commonly regarded as key surrogates of procedural complexity[27]. In this context, the pharmacodynamic effects of this regimen, including apatinib-induced vascular changes[28] and PD-1 inhibition-mediated inflammatory and fibrotic responses[29], can manifest intraoperatively as increased tissue edema and adhesions. This mechanistic trade-off likely explains the modest yet statistically significant increase in intraoperative blood loss observed in the PAC group, reflecting a heightened technical challenge. Crucially, this increased technical demand does not compromise the fundamental oncologic completeness of the procedure. The R0 resection rate and extent of lymphadenectomy are well-established surrogate indicators of the radicality of oncologic surgery[30,31], and on both metrics (R0 resection rate and lymph node yield), the PAC group performed on par with the PC group. These findings reinforce the central tenet of multimodal therapy: Effective tumor downstaging facilitates, rather than hinders, the achievement of curative-intent resection.
Despite the increased intraoperative complexity, the PAC regimen did not negatively impact postoperative recovery. The rates of overall and major complications, as well as functional recovery metrics, such as time to flatus and hospital stay, were comparable between the two groups. This favorable safety profile was reinforced by the Arise-FJ-G005 trial, which confirmed that the addition of immunotherapy and anti-angiogenic agents to neoadjuvant chemotherapy does not compromise surgical safety, as demonstrated by comparable postoperative morbidity (20.4% vs 12.2%, P = 0.295), predominantly mild complications, and no reoperations or 30-day mortality[14]. Although some studies have noted specific toxicities, such as an increased incidence of peripheral neuropathy with the addition of a PD-1 inhibitor[32,33] or hypertension with apatinib[34,35], these events were generally controllable and did not lead to a significant increase in severe complications or delays in surgical treatment. Thus, our findings confirm that the addition of immunotherapy and anti-angiogenic agents to neoadjuvant chemotherapy does not compromise the perioperative course, reinforcing the favorable risk-benefit profile of the PAC regimen.
A novel finding of our study was the potential synergistic benefit observed when effective neoadjuvant therapy was combined with precision surgical techniques. Laparoscopic surgery in patients with LAGC who underwent neoadjuvant chemotherapy has been associated with reduced intraoperative blood loss and a lower likelihood of postoperative complications[36-38]. In this study, the PAC group exhibited a significantly higher proportion of patients undergoing laparoscopic gastrectomy (69.6% vs 47.0%, P < 0.001), likely due to more favorable tumor regression facilitating the technical suitability for minimally invasive resection. Among patients receiving the PAC regimen who underwent laparoscopic gastrectomy, ICG fluorescence guidance was associated with a significantly lower conversion rate to open surgery and higher lymph node yield. Consistent with recent findings[39,40], ICG fluorescence guidance is particularly valuable for preserving surgical quality and safety by enhancing anatomical visualization after potent downstaging therapy. While these findings are hypothesis-generating and merit further prospective validation, they highlight a potential path toward optimizing multimodal treatment strategies for LAGC.
Survival analysis revealed a significantly longer OS, PFS, and DFS in patients receiving the PAC regimen. Multivariate analysis identified the PAC regimen as an independent predictor of improved OS, PFS and DFS, along with R0 resection and ypTNM stage, with the latter emerging as the most potent prognostic factor across all survival endpoints. This confirms the enduring prognostic value of pathological staging after effective neoadjuvant therapy and mechanistically links the survival benefit of the PAC regimen to more profound tumor downstaging. The survival advantage observed in our study was corroborated by emerging data. For example, a recent prospective cohort study in patients with LAGC reported that the PAC regimen significantly prolonged PFS (HR = 0.286, P = 0.034) and OS compared to apatinib plus chemotherapy, with 3-year OS rates of 86.7% and 70.3%, respectively[41]. However, it is important to note that not all trials have shown a consistent survival benefit. The 3-year outcomes of the Arise-FJ-G005 trial, which showed improved PFS, did not demonstrate a significant OS difference[19], highlighting the need for longer follow-up in our own cohort. Therefore, the long-term survival benefits of the PAC regimen warrant confirmation through extended follow-up and ongoing phase III trials.
This study had several limitations. First, its retrospective, non-randomized design was susceptible to selection bias, although the baseline characteristics were well balanced. Second, the sample size was modest, particularly for the subgroup analysis involving ICG fluorescence guidance, limiting statistical power and generalizability of these findings. Third, because this was a single-center study conducted in a high-volume institution, the results may not be generalizable to other settings. Fourth, the follow-up period, while adequate for early survival analysis, may have been insufficient to capture late recurrence or delayed immune-related adverse events. Finally, key predictive biomarkers were not systematically assessed, such as PD-L1 expression and tumor mutational burden, representing a crucial area for future research to enable more personalized patient selection.
CONCLUSION
This study demonstrated that the PAC regimen significantly improved pathological response rates and survival outcomes in patients with LAGC, offering a manageable safety profile. Furthermore, the integration of ICG fluorescence guidance further refined the surgical quality, underscoring the complementary value of effective systemic therapy and precision surgical technique. These findings provide a preliminary rationale for well-designed prospective randomized controlled trials to validate this triplet regimen and to identify predictive biomarkers for personalized treatment selection in LAGC.
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