Wu XX, Yang HD, Min J, Yuan C, Li LS, Zhang W, Tong Y. Neoadjuvant intra-arterial chemoembolization improves tumor pathological regression and survival in Borrmann type IV gastric cancer. World J Clin Oncol 2026; 17(8): 123351 [DOI: 10.5306/wjco.123351]
Corresponding Author of This Article
Yue Tong, Academic Fellow, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China. natual101@gmail.com
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Wu XX, Yang HD, Min J, Yuan C, Li LS, Zhang W, Tong Y. Neoadjuvant intra-arterial chemoembolization improves tumor pathological regression and survival in Borrmann type IV gastric cancer. World J Clin Oncol 2026; 17(8): 123351 [DOI: 10.5306/wjco.123351]
Xiao-Xing Wu, Hou-Dun Yang, Jiang Min, Chao Yuan, Lian-Shuo Li, Wei Zhang, Yue Tong, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
Author contributions: Wu XX, Yang HD, Min J, Yuan C, Li LS, Zhang W, and Tong Y contributed to the data collection, analysis, and drafting or revision of the manuscript; Wu XX and Yang HD contributed equally to this manuscript as co-first authors; Zhang W and Tong Y contributed equally to this manuscript as co-corresponding authors. All authors have read and approved the final version of the manuscript.
AI contribution statement: During the preparation of this work, the author(s) did not use any generative AI or AI-assisted tools for literature search, data analysis, figure generation, or writing. All content was solely created by the author(s).
Supported by Chongqing Municipal Science and Technology Bureau, No. CSTB2025NSCQ-GPX1134.
Institutional review board statement: This study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (approval No. 2025-560-01).
Informed consent statement: Written informed consent for treatment was obtained from all patients. The institutional review board waived the requirement for additional informed consent for this retrospective analysis of anonymized data.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.
Corresponding author: Yue Tong, Academic Fellow, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China. natual101@gmail.com
Received: May 18, 2026 Revised: July 27, 2026 Accepted: August 20, 2026 Published online: August 24, 2026 Processing time: 101 Days and 6.7 Hours
Abstract
BACKGROUND
Gastric cancer (GC) is a significant global health challenge with high mortality rates. Borrmann type IV GC presents unique challenges owing to its aggressive biological characteristics and lack of specific clinical symptoms in the early stage, thus leading to advanced-stage diagnosis and poor prognosis.
AIM
To explore intra-arterial chemoembolization (IAC) as a novel treatment strategy for Borrmann type IV GC.
METHODS
We retrospectively analyzed 70 patients who underwent IAC followed by gastrectomy. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary outcomes included chemotherapeutic response, toxicities, pathological regression, postoperative morbidity, and mortality. Cox regression analysis was performed to identify independent prognostic factors for Borrmann type IV GC.
RESULTS
Seventy patients received neoadjuvant IAC followed by gastrectomy with a favorable safety profile (grade ≥ 3 adverse events: 8.6%). The objective response rate was 40.0%, with 20.0% of patients achieving pathological complete response (ypT0) and 52.9% achieving lymph node clearance (ypN0). The median OS and DFS were 21.0 months and 19.0 months, respectively, with 3-year OS and DFS rates of 40.3% and 40.0%, respectively. Regional lymph node regression (N-stage regression) was a significant independent protective factor for both OS and DFS regardless of the primary tumor response. Furthermore, objective pathological regression (complete/partial response) showed a potential association with improved survival.
CONCLUSION
Neoadjuvant IAC followed by D2 gastrectomy is a safe and highly effective strategy for the treatment of Borrmann type IV GC.
Core Tip: Borrmann type IV gastric cancer has a poor prognosis because of its diffuse and infiltrative growth pattern. In this retrospective of 70 patients, neoadjuvant intra-arterial chemoembolization followed by gastrectomy achieved an objective response rate of 40.0% with manageable toxicity. Primary-tumor pathological response was associated with better survival in unadjusted analyses, whereas N-stage regression remained independently associated with improved overall survival and disease-free survival after multivariable adjustment. Postoperative complications were associated with worse outcomes. These findings support N-stage regression as a clinically relevant prognostic marker and warrant prospective evaluation of intra-arterial chemoembolization as a therapeutic strategy for Borrmann type IV gastric cancer.
Citation: Wu XX, Yang HD, Min J, Yuan C, Li LS, Zhang W, Tong Y. Neoadjuvant intra-arterial chemoembolization improves tumor pathological regression and survival in Borrmann type IV gastric cancer. World J Clin Oncol 2026; 17(8): 123351
Despite the declining mortality rates in recent years, gastric cancer (GC) remains a formidable malignancy worldwide and ranks as the fourth leading cause of cancer-related death. Studies have revealed an increasing incidence of GC in young adults, accompanied by high mortality[1-3]. Borrmann type IV GC, a distinct classification, is characterized by diffuse infiltration of the stomach wall, thickened gastric folds, and macroscopic presentation without obvious ulceration or elevation. Pathologically, Borrmann type IV GC exhibits marked submucosal fibrosis and hypertrophy of the muscularis and subserosa with extensive vascular, lymphatic, and peritoneal involvement[4]. Cytologically, type IV cancer usually presents as a poorly differentiated adenocarcinoma and signet-ring cell carcinoma[5]. Among all GC types, the incidence of Borrmann type IV GC ranges from 10% to 19%; consequently, its prognosis is remarkably poor. Studies have reported that the overall 5-year survival rate for Borrmann type IV GC is only 13.1%-27.6% after gastrectomy; however, this can be slightly improved when R0 resection is achieved[4,6-8].
Novel therapeutic strategies for Borrmann type IV GC have recently emerged, including neoadjuvant chemotherapy (NAC), immunotherapy, and hyperthermic intraperitoneal chemotherapy[9-12]. However, outcomes remain unsatisfactory. The JCOG0501 trial of the Japan Clinical Oncology Group demonstrated that NAC with S-1 and cisplatin did not significantly improve overall survival (OS) or disease-free survival (DFS) compared with surgery followed by adjuvant chemotherapy. Similarly, studies on the fluorouracil, leucovorin, oxaliplatin, and docetaxel regimen reported low pathological response rates (3%) in patients with Borrmann type IV GC, often without reporting long-term outcomes[13,14]. In addition, phase III trials of nivolumab showed no significant extension of OS and DFS for these patients[12,15]. Given this poor prognosis, there is an urgent need to establish effective therapeutic regimens to improve curative resection rates and prolong OS.
Transcatheter arterial chemoembolization is widely used in the treatment of hepatocellular carcinoma and is a first-line strategy for intermediate-stage liver cancer[16]. Studies have revealed that intra-arterial chemoembolization (IAC) can significantly improve pathological complete response (pCR) and OS rates in locally advanced GC[17]. A phase II study indicated that preoperative intra-arterial infusion chemotherapy could improve the pathological response rate (33.3%) and median survival (27.1 months) of patients with Borrmann type IV GC[9,18-20]. In the present study, we retrospectively evaluated the safety and efficacy of IAC in treating Borrmann type IV GC and analyzed clinicopathological characteristics to identify independent prognostic factors.
MATERIALS AND METHODS
Patients
We retrospectively analyzed the data of eligible patients treated at the Department of Gastrointestinal Surgery of the First Affiliated Hospital of Chongqing Medical University from October 2015 to April 2024. The inclusion criteria were as follows: (1) Histologically proven locally advanced gastric adenocarcinoma; (2) Borrmann type IV classification; (3) Esophageal invasion length ≤ 3 cm; (4) Age > 20 years; (5) Eastern Cooperative Oncology Group performance status of zero or one; (6) No prior chemotherapy or radiotherapy for any malignancy; (7) No prior gastric surgery; (8) Adequate organ function (white blood cell count > 3500/mm3, platelet count > 75000/mm3, aspartate aminotransferase and alanine aminotransferase < 100 IU/L, total bilirubin < 1.5 mg/dL or 25 μmol/L, creatinine clearance > 60 mL/minute); and (9) Completion of at least one cycle of IAC followed by gastrectomy[21]. Informed consent was obtained from the patients upon admission, in accordance with the Declaration of Helsinki.
The exclusion criteria were as follows: (1) Concurrent malignancy at the time of diagnosis; (2) Remnant gastric adenocarcinoma; or (3) Incomplete medical records or inability to cooperate with scheduled follow-up visits. Figure 1 shows the patient selection flow chart for patients with Borrmann type IV GC.
Figure 1 Flow chart of Borrmann type IV gastric cancer patient selection.
IAC: Intra-arterial chemoembolization.
Baseline demographics, disease characteristics, IAC procedural details, adverse events (AEs), perioperative treatment details, and postoperative pathological findings were obtained from electronic medical records. Survival follow-up was conducted through outpatient visits and telephone interviews. Baseline characteristics included age; sex; body mass index (BMI); smoking and drinking history; comorbidities; and hemoglobin, albumin, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 levels. Macroscopic classification was performed by gastroscopy and contrast-enhanced computed tomography of the chest, abdomen, and pelvis. Tumor staging was performed according to the 8th Edition of the Japanese Classification of Gastric Carcinoma[22-24].
Outcomes
The primary endpoints were OS and DFS. OS was defined as the time from the first IAC treatment to death from any cause or the last follow-up, and DFS was defined as the time from the first IAC treatment to tumor recurrence or death. The secondary endpoints included chemotherapeutic response, toxicity, pathological regression, and postoperative morbidity and mortality. Tumor response to chemotherapy was evaluated on the basis of changes in tumor volume, as assessed using contrast-enhanced computed tomography. The objective response rate (ORR) was defined as the proportion of patients achieving complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1. IAC-associated AEs were recorded from the initial dose to 30 days after the final infusion and graded according to the National Cancer Institute Common Terminology Criteria for AEs version 4.0. Postoperative complications were defined as those occurring within 30 days of surgery or during hospitalization and were graded using the Clavien-Dindo classification system[25,26].
IAC protocol
A 5-Fr vascular sheath was inserted through the right femoral artery by using the Seldinger technique and positioned within the celiac axis. Angiography was performed to visualize the celiac trunk and its branches. A 2.9-Fr microcatheter and 2.7-Fr microguidewire were used to superselect the predominant tumor-feeding arteries. The target vessels were selected on the basis of the tumor location: (1) For adenocarcinoma of the cardia and fundus, the left gastric artery and left inferior phrenic artery; (2) For tumors along the lesser curvature, the left and right gastric arteries; (3) For tumors involving the greater curvature, the right gastroepiploic artery and gastroduodenal artery; and (4) For tumors in the gastric antrum, the gastroduodenal and right gastric arteries[27].
The arteries for chemotherapy and embolization were identified on the basis of angiographic findings. From October 2015 to April 2024, 23 patients received intra-arterial oxaliplatin (100 mg/m2) plus docetaxel (50 mg/m2) and 47 patients received intra-arterial oxaliplatin (100 mg/m2) plus nab-paclitaxel (260 mg/m2) following an institutional protocol modification. Docetaxel and nab-paclitaxel were not concurrently administered. Upon the completion of arterial chemotherapy, lipiodol (5 mL) was used to embolize the vasculature, and repeat imaging confirmed the complete occlusion of the tumor blood supply. Following arterial chemoembolization, patients commenced oral administration of S-1 (40 mg/m2) from days 1 to 14.
Surgical procedures
Radiological re-evaluation was performed within 4 weeks of each IAC cycle according to Response Evaluation Criteria in Solid Tumors version 1.1. If significant tumor regression was achieved and the patient was deemed surgically fit by the surgical team, radical D2 gastrectomy was performed. If no significant regression was observed, a second cycle of IAC was administered. The total number of IAC cycles did not exceed three. All patients ultimately underwent gastrectomy, provided that their organ function and performance status remained adequate for surgery. The decision to proceed with surgery was reached by consensus between two gastrointestinal oncological surgeons on the basis of a comprehensive assessment of the post-IAC radiological response, nutritional and performance status, and likelihood of achieving R0 resection.
All patients underwent laparoscopic D2 radical gastrectomy. Surgical approaches included distal gastrectomy with lymph node dissection at stations 1, 3, 4sb, 4d, 5, 6, 7, 8a, 9, 11p, and 12a or total gastrectomy with dissection at stations 1, 2, 3, 4sa, 4sb, 4d, 5, 6, 7, 8a, 9, 11p, 11d, and 12a. Following distal gastrectomy, reconstruction was performed via Billroth I gastroduodenostomy, Billroth II gastrojejunostomy, or Roux-en-Y gastrojejunostomy. Roux-en-Y esophagojejunostomy was performed for total gastrectomy[22,23].
Statistical analysis
Continuous variables were assessed for normality and are presented as mean ± SD or median (interquartile range), as appropriate. Between-group comparisons were performed using Student’s t-test or the Mann-Whitney U test, while paired non-normally distributed data were compared using the Wilcoxon signed-rank test. Categorical variables are presented as n (%) and were compared using the χ2 test or Fisher’s exact test.
Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariable Cox regression was performed to explore prognostic factors. To limit overfitting and directly address the prespecified clinical question, the final multivariable Cox model included four clinically selected covariates: Age (per 10-year increase), T-stage regression, N-stage regression, and postoperative complications. Covariate selection was independent of univariable significance. Tied event times were handled using the Efron method, and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported.
Multicollinearity was assessed using variance inflation factors, and the proportional-hazards assumption was evaluated using covariate-specific and global Schoenfeld residual tests. T-by-N regression interaction and a four-level joint regression variable (neither, T only, N only, or both) were examined as exploratory analyses. Because death was part of the composite DFS endpoint, it was counted as a DFS event. For recurrence-specific analysis, Aalen-Johansen cumulative incidence functions and a Fine-Gray model were used with death before recurrence as the competing event. Internal validation was performed using 2000 bootstrap resamples to obtain optimism-corrected Harrell’s C indices.
Descriptive analyses were performed using SPSS version 26.0, and the revised survival, diagnostic, competing-risk, and bootstrap analyses were conducted using Python version 3.12. All tests were two-sided, and P < 0.05 was considered statistically significant.
RESULTS
Comparison of patients’ clinical characteristics before and after IAC
A total of 70 patients were included in the analysis, and Table 1 summarizes the baseline clinicopathological characteristics. The median age was 66.0 years, and 51 patients (72.9%) were male. Following IAC treatment, significant changes were observed in nutritional and tumor marker parameters. Specifically, the mean hemoglobin level decreased from 113.6 ± 28.3 g/L to 104.6 ± 25.5 g/L (P < 0.001), and the mean albumin level decreased from 37.9 ± 4.3 g/L to 36.2 ± 5.0 g/L (P = 0.003). Additionally, serum CEA levels showed a slight increase from 2.2 ng/L to 3.1 ng/L (P = 0.015). Radiological re-evaluation demonstrated significant tumor regression. Comparisons between pre- and post-IAC imaging revealed a marked regression in the clinical tumor stage, which was characterized by decreased gastric wall thickness and regression of the regional lymph nodes. However, BMI remained stable (P = 0.712), and Eastern Cooperative Oncology Group performance status was maintained at zero or one for all patients, indicating tolerance for subsequent gastrectomy.
Table 1 Comparison of patients’ clinical characteristics between before and after intra-arterial chemoembolization.
Table 2 presents the safety profiles of the neoadjuvant IAC regimen. Generally, this treatment was well-tolerated. All patients experienced mild gastrointestinal reactions during IAC, including nausea (100%), vomiting (92.9%), anorexia (94.3%), and abdominal pain (64.3%). However, these were predominantly grades 1-2. Severe IAC-related AEs (grade ≥ 3) occurred in 6/70 patients (8.6%). Procedural complications were strictly limited to two cases of isolated lower extremity intermuscular vein thrombosis, and severe periprocedural events, such as vascular dissection, gastric perforation, or non-target embolization, were not observed in this cohort. Hematologic toxicity was assessed using routine blood tests and liver and kidney function tests on days 7, 14, and 21 of each treatment cycle. The most frequent hematologic AE was leukocytopenia (62/70, 88.6%). Grade 3 or higher toxicities included leukocytopenia (2/70, 2.9%), anemia (1/70, 1.4%), and neutropenia (3/70, 4.3%). No IAC-related deaths or severe perioperative complications were attributed to the neoadjuvant treatment.
Table 2 Adverse events of intra-arterial chemoembolization plus chemotherapy.
All patients underwent gastrectomy after IAC. Table 3 shows the clinical and postoperative pathological findings. The ORR based on pathological evaluation was 40.0% (28/70). Pathologically, significant regression was achieved: 20.0% (14/70) of the patients achieved a pathological CR (ypT0), and 52.9% (37/70) were confirmed to have no lymph node metastasis (ypN0). There was a significant difference between the clinical and postoperative tumor-node-metastasis stages. Conversely, tumor progression during neoadjuvant therapy was extremely rare and occurred in only two patients, both of whom presented with local peritoneal metastases.
Table 3 Clinical and postoperative pathological findings, n (%).
Comparison of patients’ clinical characteristics between CR/PR and stable disease/PD
Patients were stratified into responder (CR/PR, n = 28) and non-responder (stable disease/PD, n = 42) groups on the basis of tumor regression (Table 4). Baseline clinicopathological characteristics were generally well balanced between the two groups. Regarding demographics and surgical factors, patients in the responder group were significantly older than those in the non-responder group (63.9 ± 13.6 vs 56.3 ± 13.3, P = 0.013) and experienced higher intraoperative blood loss (162.5 ± 147.4 vs 117.9 ± 134.4, P = 0.032). Notably, BMI was significantly higher in the responder group than in the non-responder group [22.2 (17.0-30.0) vs 20.8 (17.0-28.8), P = 0.034]. No significant differences were found in other parameters, including sex, nutritional status (hemoglobin and albumin), tumor markers (CEA and carbohydrate antigen 19-9), number of IAC cycles, or postoperative complications (P > 0.05).
Table 4 Comparison of patients’ clinical characteristics between complete response/partial response and stable disease/progressive disease, n (%)/mean ± SD.
There were no statistically significant differences in tumor burden indicators, including tumor location, degree of differentiation, clinical T stage, N stage, and tumor-node-metastasis stage. The comparable baseline reinforces that the observed survival benefits were likely attributable to the treatment response rather than to the initial disease severity.
Univariable/multivariable Cox regression analysis of OS
In univariable analysis, N-stage regression was associated with better OS (HR = 0.310, 95%CI: 0.153-0.628; P = 0.001), whereas T-stage regression, primary-tumor pathological response, and postoperative complications were not statistically significant (Table 5). The prespecified four-parameter model included age, T-stage regression, N-stage regression, and postoperative complications (32 deaths; events per parameter = 8.0). N-stage regression remained independently protective (adjusted HR = 0.301, 95%CI: 0.138-0.655; P = 0.002), whereas postoperative complications were associated with worse OS (adjusted HR = 3.123, 95%CI: 1.283-7.597; P = 0.012).
Table 5 Univariable and multivariable analysis of overall survival.
In a sensitivity model replacing T-stage regression with primary-tumor pathological response, N-stage regression remained significant, whereas CR/PR did not (Supplementary Table 1). VIFs ranged from 1.083 to 1.125, and Schoenfeld residual tests showed no violation of the proportional-hazards assumption (global P = 0.583; Supplementary Table 2). The bootstrap optimism-corrected Harrell C-index was 0.680 (empirical interval: 0.585-0.778; Supplementary Table 3).
Univariable/multivariable Cox regression analysis of DFS
In univariable analysis, N-stage regression (HR = 0.313, 95%CI: 0.157-0.627; P = 0.001) and primary-tumor pathological response (HR = 0.446, 95%CI: 0.207-0.961; P = 0.039) were associated with better DFS (Table 6). In the four-parameter model (33 events; events per parameter = 8.25), N-stage regression remained independently protective (adjusted HR = 0.314, 95%CI: 0.147-0.669; P = 0.003), whereas postoperative complications were associated with worse DFS (adjusted HR = 3.189, 95%CI: 1.335-7.621; P = 0.009). The sensitivity model produced consistent results, with N-stage regression remaining significant and CR/PR becoming nonsignificant (Supplementary Table 4). No proportional-hazards violation was detected (global P = 0.895; Supplementary Table 2), and the optimism-corrected C-index was 0.679 (empirical interval: 0.585-0.771; Supplementary Tables 3 and 5).
Table 6 Univariable and multivariable analysis of disease-free survival.
All deaths occurred after documented recurrence; therefore, no death-before-recurrence competing event was observed. Accordingly, the Aalen-Johansen estimates equaled one minus the recurrence-free Kaplan-Meier estimates, and the Fine-Gray-equivalent model yielded the same adjusted estimate for N-stage regression (subdistribution HR = 0.314, 95%CI: 0.147-0.669; P = 0.003; Supplementary Table 6, Supplementary Figure 1).
Kaplan-Meier curves of OS and DFS
The observation period at the current data cutoff was 43 months, the median OS for the entire cohort was 21.0 months, and the median DFS was 19.0 months. The 1-, 2-, and 3-year OS rates were 77.8%, 46.8%, and 40.3%, respectively. The 1-, 2-, and 3-year DFS rates were 58.7%, 40.0, and 40.0%, respectively (Figure 2).
Figure 2 Kaplan-Meier curves of survival outcomes for all Borrmann type IV gastric cancer patients.
A: Overall survival; B: Disease-free survival.
Kaplan-Meier curves of OS and DFS in responder vs non-responder group and subgroup analysis
Kaplan-Meier analysis showed that patients with an objective primary-tumor pathological response (CR/PR) had better OS (log-rank P = 0.049) and DFS (log-rank P = 0.034) than those with stable disease/PD (Figure 3). However, this represents an unadjusted association, as CR/PR was not independently associated with OS or DFS in the multivariable sensitivity analyses.
Figure 3 Kaplan-Meier curves of survival outcomes stratified by pathological response.
A: Overall survival in the responder vs non-responder group; B: Disease-free survival in the responder vs non-responder group. OS: Overall survival; DFS: Disease-free survival; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease.
When patients were stratified by N-stage regression, those with N-stage regression had significantly better OS and DFS than those without N-stage regression (both log-rank P < 0.001; Figure 4). Consistent with these findings, N-stage regression remained independently associated with lower hazards of death (adjusted HR = 0.301, 95%CI: 0.138-0.655; P = 0.002) and DFS events (adjusted HR = 0.314, 95%CI: 0.147-0.669; P = 0.003) after adjustment for age, T-stage regression, and postoperative complications. These results support N-stage regression as a robust favorable prognostic factor in this cohort.
Figure 4 Kaplan-Meier curves of overall survival and disease-free survival according to N-stage regression.
A: Overall survival; B: Disease-free survival. Patients with N-stage regression had longer overall survival and disease-free survival than patients without N-stage regression (both log-rank P < 0.001). Vertical plus signs indicate censored observations. OS: Overall survival; DFS: Disease-free survival; N-reg (+): Positive N-stage regression; N-reg (-): Negative N-stage regression.
DISCUSSION
We evaluated the safety and efficacy of neoadjuvant IAC followed by D2 gastrectomy in patients with Borrmann type IV GC. Our cohort demonstrated promising outcomes with an ORR of 40.0% and a pCR rate of 20.0%. The median OS reached 21.0 months, with a 3-year OS rate of 40.3%. Notably, the primary tumor pathological response (CR/PR) was associated with improved OS and DFS in the unadjusted analyses, whereas N-stage regression remained an independent favorable prognostic factor after multivariable adjustment.
Pharmacokinetically, the principal advantage of IAC is its ability to achieve a locoregional drug concentration that is up to 10 times higher than that of conventional intravenous administration[17,28]. This “first-pass” tumor trapping maximizes the cytocidal effect on the primary lesion while significantly reducing systemic drug exposure. Although some studies have suggested that combined intra-arterial and intravenous therapy may present an overall AE profile comparable to that of systemic chemotherapy alone[29], our cohort demonstrated a highly favorable safety profile strictly characterized by “local toxicity and systemic safety”. As anticipated, gastrointestinal symptoms such as nausea and anorexia were almost universal and likely stemmed from localized mucosal irritation induced by regional drug perfusion. Importantly, severe grades 3-4 AEs were remarkably rare and occurred in only 8.6% of patients. Furthermore, although we observed significant post-treatment declines in hemoglobin and albumin levels (Table 1), which were likely secondary to treatment-induced metabolic stress and the aforementioned gastrointestinal symptoms, these nutritional shifts were manageable with rigorous nutritional support during the neoadjuvant phase.
The safety of our IAC protocol is particularly compelling when quantitatively compared with current standard neoadjuvant systemic regimens. The fluorouracil, leucovorin, oxaliplatin, and docetaxel regimen, which is regarded as the standard of care for fit patients, is frequently criticized for its substantial hematologic toxicity, with a 90-day mortality rate of up to 7% and a staggering incidence of grade 3 or higher neutropenia at 52%. Similarly, although a phase III study by Kang et al[30] validated the efficacy of the docetaxel, oxaliplatin, and S-1 regimen in locally advanced GC, it reported two NAC-related deaths and an overall neutropenia rate of 15.1% (36 patients), most of which were grade 3 or above. By contrast, our IAC protocol resulted in grade 3 neutropenia in only 4.3% of patients, with no treatment-related mortality. Crucially, the preoperative nutritional depletion noted in our cohort did not translate into an increased rate of severe postoperative complications, thus firmly validating the safety and feasibility of performing radical D2 gastrectomy following neoadjuvant IAC[13,30-33].
Preoperative chemotherapy is regarded as the standard approach for locally advanced GC, primarily for tumor regression[34,35]. Recent evidence demonstrates that neoadjuvant IAC provides a robust therapeutic advantage by inducing significant tumor downstaging and converting initially unresectable GCs into candidates for radical R0 resection. As demonstrated by Wang et al[29], the localized high-concentration delivery achieved through IAC yielded a significantly higher ORR of 35.5% than the 19.7% in standard systemic chemotherapy cohorts. For patients presenting with obstructive symptoms, Tang et al[28] reported that gastric artery infusion achieved a 75.9% relief rate for digestive obstruction and a remarkable 44.8% conversion rate to surgery. Compared with systemic chemotherapy alone, IAC significantly improved survival in patients with advanced GC, yielding a superior median OS (14 months vs 13 months, P = 0.044) and improved 1- and 2-year survival rates (45.2% vs 40.9% and 9.7% vs 6.1%, respectively)[29]. Crucially, neoadjuvant IAC improved the long-term prognosis, demonstrating a 5-year survival rate of 52.5% compared with 39.8% in the control group (P < 0.05)[36]. Moreover, the application of IAC and transcatheter arterial chemoembolization in patients with GC and synchronous liver metastasis consistently results in superior local disease control and extended survival compared with systemic therapy alone, thus solidifying its role as a versatile and potent bridge to conversion therapy[37,38]. Consequently, we applied this therapeutic strategy to treat Borrmann type IV GC.
In the JCOG0501 trial, pCR was observed in only three patients, and a 51% ORR rate was observed in the group treated with gastrectomy and neoadjuvant S-1 plus cisplatin. However, the 3-year OS rates were similar in the NAC and surgery-only groups, failing to demonstrate a survival benefit for NAC followed by surgery compared with surgery followed by adjuvant chemotherapy for Borrmann type IV or large type III GC. Studies have emphasized that patients with a pathological response (CR/PR) to NAC tend to have better survival outcomes[39-43]. Therefore, pathological response could be a significant prognostic indicator for GC treatment. In our univariable Cox regression analysis, the pathological response (CR/PR) was associated with favorable outcomes. The median OS in the current study was 21.0 months, which exceeds the 14.0 months for palliative IAC for GC, thus confirming the profound survival advantage of surgical conversion[29]. Given the aggressive biological behavior of Borrmann type IV GC, the 40.3% 3-year OS in the current study was shorter than the 52.5% 5-year OS observed in previous studies[36].
The responders were significantly older and had a higher BMI than the non-responders. Although better pathological responses have previously been reported in patients aged ≥ 60 years, this association may reflect age-related tumor heterogeneity and the selection of physiologically fit older patients rather than enhanced chemosensitivity. Higher BMI may indicate better nutritional reserve; however, both median values were within the normal range, the difference was modest, and BMI is an imprecise measure of body composition. As neither age nor BMI was associated with OS or DFS, these findings remain exploratory and may reflect selection bias, residual confounding, or chance.
Furthermore, T-stage and N-stage regression were entered simultaneously into the multivariable model, with low VIFs indicating minimal collinearity. N-stage regression remained independently associated with improved OS (adjusted HR = 0.301, P = 0.002) and DFS (adjusted HR = 0.314, P = 0.003), and these associations persisted in sensitivity models incorporating primary-tumor pathological response. In contrast, the favorable unadjusted associations of CR/PR were attenuated after multivariable adjustment. These findings suggest that regional lymph node regression may be a more robust response-related prognostic marker, potentially informing postoperative risk stratification and individualized surveillance. Nevertheless, validation in larger prospective cohorts is required.
The limited efficacy of traditional systemic chemotherapy for Borrmann type IV GC is largely attributed to abundant desmoplastic stroma and undifferentiated histology, which act as formidable barriers to drug delivery[44]. The findings of the current study suggest that IAC can effectively overcome this barrier. By administering chemotherapeutic agents directly to tumor-feeding arteries, IAC achieves high local drug concentrations while minimizing systemic exposure. Furthermore, concurrent lipiodol embolization induces tumor ischemia and prolongs drug retention. This synergistic mechanism likely contributed to the significant pathological regression observed in our cohort, including a 20.0% (14/70) rate of pCR (ypT0) and a 52.9% (37/70) rate of lymph node clearance (ypN0). Compared with the JCOG0501 trial, which failed to demonstrate a survival benefit with neoadjuvant systemic S-1 plus cisplatin[16,24], the IAC protocol of the current study yielded superior local pathological regression. This highlights that mechanically overcoming the stromal barrier is a critical prerequisite for improving outcomes[45]. Furthermore, the high local drug concentration achieved via regional administration significantly enhanced the probability of regional lymph node regression, thus effectively mitigating the risk of lymphatic metastasis and ultimately translating into a superior long-term prognosis[46,47]. The extensive tumor necrosis and massive neoantigen release induced by IAC could potentially convert immunologically “cold” Borrmann type IV tumors into “hot” tumors (Figure 5). The transition of the tumor microenvironment from “cold” to “hot” following neoadjuvant IAC is primarily driven by the synergistic interplay of immunogenic cell death, hypoxia-induced immunomodulation via the hypoxia-inducible factor 1 alpha/programmed death-ligand 1 axis, and Treg remodeling, ultimately facilitating enhanced cytotoxic T-cell activation[48-50]. Future prospective studies exploring the combination of IAC with immune checkpoint inhibitors (e.g., programmed cell death-1 blockade) are warranted because this approach may further enhance systemic disease control and redefine the standard of care.
Figure 5 Schematic illustration of the tumor microenvironment remodeling induced by neoadjuvant intra-arterial chemoembolization in Borrmann type IV gastric cancer.
A: Pre-treatment immunosuppressive “cold” microenvironment. The tumor is characterized by an abundance of fibroblasts and a dense desmoplastic stroma, which acts as a formidable physical barrier preventing the infiltration of cytotoxic immune cells, such as CD8+ T cells and natural killer cells, restricting them to the tumor periphery; B: Post-treatment inflamed “hot” microenvironment. The localized, high-concentration delivery of oxaliplatin combined with lipiodol-induced embolic ischemia effectively disrupts the stromal barrier. This dual mechanism triggers massive immunogenic cell death and necrosis of the cancer cells, subsequently facilitating the robust, deep infiltration of CD8+ T cells and natural killer cells into the tumor core. NK: Natural killer.
This study has several limitations. First, its retrospective, single-center design and relatively small sample size (n = 70) may limit the generalizability of the findings and introduce inherent selection bias. Second, the lack of a direct control group receiving standard systemic NAC precludes a definitive comparison of efficacy and safety. Third, two taxane-containing regimens were used sequentially during the 9-year study period: Docetaxel, oxaliplatin in 23 patients and nab-P-SOX in 47 patients. Because regimen selection was closely associated with the treatment period and the groups were small and unequal, a reliable comparison between the two regimens was not feasible. Therefore, treatment-era confounding cannot be excluded, and the present study cannot establish the superiority of either regimen. Finally, although the survival outcomes were encouraging, a longer follow-up period is required to confirm the long-term benefits. Well-designed, large-scale, prospective randomized controlled trials are warranted to validate these findings and clarify the optimal treatment regimen.
CONCLUSION
Neoadjuvant IAC followed by D2 gastrectomy was feasible and demonstrated acceptable perioperative safety in selected patients with Borrmann type IV GC. N-stage regression was independently associated with improved OS and DFS, whereas primary-tumor pathological response was associated with favorable outcomes only in unadjusted analyses. Given the retrospective, single-arm design and small sample size, the comparative efficacy of IAC cannot be determined. Larger prospective controlled studies are needed to validate the prognostic value of N-stage regression and clarify the role of IAC relative to standard neoadjuvant therapy or upfront surgery.
ACKNOWLEDGEMENTS
We acknowledge all authors whose publications are referred to in our article.
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