Effectiveness of Neoadjuvant Chemotherapy With Docetaxel, Cisplatin, and S‐1 for Locoregionally Advanced Gastric Adenocarcinoma: Findings From a University Hospital in Vietnam

ABSTRACT

Aim

To evaluate treatment results of a neoadjuvant regimen consisting of Docetaxel + Cisplatin + S‐1 (DCS) in patients with locoregionally advanced unresectable gastric adenocarcinoma characterized by tumors with bulky regional lymph nodes (T1–4a, N‐bulky, M0) or T4b tumors (any N, M0)).

Methods

This study included 78 patients with locoregionally advanced gastric adenocarcinoma treated at a university hospital in Vietnam, comprising 47 retrospective and 31 prospective cases. Patients received 2 ‐ 4 cycles of DCS chemotherapy, with each cycle comprising intravenous docetaxel (35 mg/m²) and cisplatin (35 mg/m²) on days 1 and 15, and oral S‐1 (40 mg/m²/twice daily) from days 1 to 14, repeated every 4 weeks. Clinical treatment response was assessed after every three cycles and re‐staging evaluation by using the RECIST criteria and contrast‐enhanced CT scans after 2 ‐ 4 cycles, depending on patient response and tolerability. Patients with a good response and down‐staging were referred for gastrectomy.

Results

The median age was 58 years, and 64.1% were male. Following neoadjuvant chemotherapy, the proportion of T4b tumors decreased from 78.2% to 52.6%, while T4a tumors increased from 20.5% to 43.6%. The rate of N‐bulky decreased from 23.1% to 11.5%. Anemia and neutropenia were the most common hematological toxicities, predominantly grade 1–2. Gastrointestinal toxicity and hair loss were the most frequent clinical adverse events, mostly grade 1–2. Among 65 patients (83.3%) achieving an objective response to neoadjuvant chemotherapy, 42 (53.8%) underwent gastrectomy, with R0 resection achieved in 92.9%.

Conclusion

Neoadjuvant chemotherapy using the DCS regimen every 4 weeks demonstrated high effectiveness and safety in patients with locoregionally advanced unresectable gastric adenocarcinoma characterized by extensive regional metastases, and increased their eligibility for successful gastrectomy (R0 resection).

Trial Registration

This study is a retrospective and prospective cohort study, not a clinical trial.

Abbreviations

CTCAE

Common Terminology Criteria for Adverse Events

DCS

docetaxel + cisplatin + S‐1

ECOG

Eastern Cooperative Oncology Group

Egfr

estimated glomerular filtration rate

HER2

human epidermal growth factor receptor 2

NCI

National Cancer Institute

RECIST

Response Evaluation Criteria in Solid Tumours

TNM

tumor‐node‐metastasis

UMC

University Medical Center at Ho Chi Minh City.

1. Introduction

Gastric cancer is one of the most widespread malignancies and poses significant therapeutic challenges. According to GLOBOCAN (2020), the annual global incidence of gastric cancer exceeds one million, and more than 768,793 people die from gastric cancer [1]. Surgery remains the primary modality for achieving remission of gastric cancer. The risk of recurrence and metastasis remains a major concern. Removal of the primary tumor with margin‐negative R0 resection and thorough lymphadenectomy has become the main treatment [2, 3]. However, patients with gastric cancer presenting with ulcerative infiltrative tumors, diffusely infiltrative tumors, or invading adjacent organs, as well as extensive hematogenous metastases such as bulky lymph nodes (≥3 cm) along the celiac trunk, splenic artery, left gastric artery, or common hepatic artery (N bulky), face an increasing risk of recurrence and have a poor prognosis [4, 5, 6].

The treatment guidelines for gastric cancer provided by the United States [7], Europe [8], and Japan [9] recommend neoadjuvant chemotherapy for gastric cancers with a high risk of recurrence. However, the implementation of neoadjuvant chemotherapy may vary in terms of patient selection, choice of drugs, dosage, and treatment duration across different regions, mainly because of variations in the diagnosis time of gastric cancer through screening programs [10, 11]. Recently, a four‐cycle treatment regimen consisting of Docetaxel + Cisplatin + S‐1 (DCS) has shown promising results, with a high rate of complete response to treatment [12, 13, 14]. However, neoadjuvant chemotherapy with four cycles may have drawbacks, such as a higher rate of adverse events and increased toxicity. Therefore, further research is required to assess and confirm the efficacy of this therapy in various populations.

In 2020, the World Health Organization reported approximately 17,906 new cases of gastric cancer and 14,615 related deaths in Vietnam, out of a total population of 97.58 million [15]. This makes gastric cancer the fifth most common malignant tumor in the country [1]. Unfortunately, Vietnam currently lacks an early screening program for cancer, including gastric cancer. As a result, patients with cancer often receive their diagnosis at a late stage of cancer, making treatments more challenging. Following international guidelines, Vietnam's Ministry of Health has recommended neoadjuvant chemotherapy as one of the effective treatment options. However, further research and insights are needed to ensure the optimal use of chemotherapy. To date, there has been no evaluation of the effectiveness of the DCS regimen in gastric cancer patients and no suggested treatment regimen specifically tailored for this condition. Since 2017, the DCS regimen has been applied at the University Medical Center (UMC) in Ho Chi Minh City for treating metastasis‐stage gastric cancer. From our clinical observations during the initial process, DCS showed positive responses and good tolerance, not only in patients with metastatic stages but also in those with locoregionally advanced unresectable gastric adenocarcinoma [16]. However, no thorough study has assessed the overall effectiveness, side effects, and associated factors.

This study aimed to assess the effectiveness of the DCS regimen as a neoadjuvant therapy for locoregionally advanced unresectable gastric adenocarcinoma, specifically tumors classified as T1–4a with bulky regional lymph nodes (N‐bulky, M0) or T4b (any N, M0). The findings from this research can serve as a valuable reference for suggesting and developing an optimal treatment regimen for this patient population in Vietnam and similar populations worldwide. Furthermore, neoadjuvant chemotherapy has emerged as a critical approach to downstage advanced gastric tumors, increasing the possibility of achieving R0 resection, thus significantly enhancing long‐term patient survival.

2. Materials and Methods

2.1. Setting and Participants

The study was conducted at the UMC in Ho Chi Minh City, Vietnam. From January 2018 to December 2022, a combined retrospective and prospective study was conducted with all patients treated with the DCS regimen at UMC to evaluate treatment efficacy. Patient inclusion criteria were (1) biopsy‐proven, locoregionally advanced gastric adenocarcinoma (T4b‐N any‐M0 or T any‐N Bulky‐M0) treated with the DCS regimen; (2) aged from 18 to 75 years; (3) Eastern Cooperative Oncology Group (ECOG) score of 0–1; (4) human epidermal growth factor receptor 2 (HER2) negative.

We excluded patients if they had any of the following conditions: 1) a history of previous gastric cancer surgery and had been treated with adjuvant chemotherapy or chemoradiotherapy, and immunotherapy; (2) coexisting conditions such as coronary artery disease, unstable angina, heart failure grade III, IV, stroke, central nervous system disorders, infection or sepsis, immune deficiency, active hepatitis B or C; 3) issues related to malabsorption, peripheral neuropathy with a grade ≥ 2 (according to National Cancer Institute (NCI)), bleeding gastric ulcer, gastric outlet obstruction, severe malnutrition; (4) inadequate organ and bone marrow function (hemoglobin < 9.0 g/dL, absolute neutrophil count < 1.5 × 10⁹/L, platelet count < 100 × 10⁹/L, serum bilirubin > 1.5 × upper limit of normal, ALT and AST > 2.5 × upper limit of normal, estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m²).

2.2. Study Procedures

Based on the treatment protocol at the study hospital, eligible patients received chemotherapy with the DCS regimen (2–4 cycles, 4 weeks each). During each cycle, patients received intravenous Docetaxel (35 mg/m²) and Cisplatin (35 mg/m²) on day 1 and day 15 and S‐1 (40 mg/m²/twice daily) orally from day 1 to day 14, repeated every 4 weeks. Before each chemotherapy session, we evaluated the patient's ECOG status, liver function (AST/ALT and bilirubin), kidney function (creatinine, urea, eGFR), hematological parameters (red blood cells, white blood cells, platelets), and gastrointestinal toxicities (nausea, vomiting, diarrhea, constipation, anorexia, gastritis). We also assessed sleep disorders, fatigue, allergic/hypersensitivity reactions, hair loss, hand‐foot syndrome, and chemotherapy‐induced peripheral neuropathy. All grading was performed following Common Terminology Criteria for Adverse Events (CTCAE) criteria (v5.0) [17].

Treatment responses were observed through chest, abdominal, pelvic CT‐scan after every 3 cycles of chemotherapy by a treatment board including a chemotherapy doctor, an oncologist surgeon specializing in gastric cancer surgery, a radiologist, a pathologist, and a palliative care doctor. In cases where gastric cancer progressed, or there was a lack of agreement to continue chemotherapy or drug intolerance, we stopped the DCS regimen and switched to other treatment protocols, such as palliative care or changing the treatment regimen. We evaluated the treatment response using the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria [18]. Patients who showed a positive response to treatment, good drug tolerance with suitable physical conditions, and were eligible for surgical intervention (Figure 1). This study was approved by the Ethics Committee in Biomedical Research at the University of Medicine and Pharmacy at Ho Chi Minh City (37/HĐĐĐ‐ĐHYD). All patients provided written consent to participate in the study and to allow publication of anonymized data and results. No identifiable patient information was included in the manuscript.

FIGURE 1.

Chemotherapy protocols and patients’ follow‐up until surgery.

2.3. Measurements

In addition to demographic characteristics such as age (year), gender (male, female), we recorded other information at the start of DCS therapy, including: ECOG, histological grade, tumor location, carcinoma subtype, endoscopic imaging classification by Bormann, tumor‐node‐metastasis (TNM) stage, and response to treatment according to RECIST [18]. The characteristics and results of the surgery included surgical duration, extent of gastrectomy, lymphadenectomy, histological grade, and TNM stage. We used the ECOG score to assess the overall health status, ranging from 0 to 4 [19]. The histological grade included well‐differentiated adenocarcinoma (grade 1), >95% gland formation, moderately differentiated adenocarcinoma (grade 2), 50%–95% gland formation, poorly differentiated adenocarcinoma (grade 3), <50% gland formation, and undifferentiated (grade 4)—no glandular structures were formed and immunohistochemical staining was required to distinguish it from lymphoma or sarcoma [20]. Tumor location (cardia, corpus, pyloric antrum, esophagogastric junction and whole stomach), adenocarcinoma subtype [21] (tubular adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, poorly cohesive carcinoma and mixed carcinoma) and endoscopic imaging classification according to Borrmann [22] (type I—polypoid or fungating, type II—ulcerative with raised edges, type III—ulcerative with infiltrative margins, type IV—diffusely infiltrative, and type V—unclassifiable) were confirmed by gastric endoscopy.

The TNM stage before treatment was assessed using computed tomography (CT) and confirmed by biopsy. The TNM classification for gastric cancer was based on the Union for International Cancer Control [23] and the American Joint Committee on Cancer eighth edition (2017) [24].

Treatment response was assessed using the RECIST 1.1 criteria [18], including complete response, partial response, stable disease, and progressive disease. For potential adverse effects monitoring and assessment, we used the CTCAE 5.0 scale [17]. Hematological toxicity was assessed at each cycle on the basis of biochemical and hematological tests. Clinical toxicities were recorded through examinations during each treatment session. The characteristics and results of the surgery consisted of the duration of surgery, the extent of gastrectomy (total gastrectomy, distal gastrectomy, proximal gastrectomy, pylorus preserving gastrectomy), lymphadenectomy (no lymphadenectomy, only lymph node removal, D1 lymphadenectomy, D2 lymphadenectomy), resection margin (R0: no residual cancer cells on microscopic examination, R1: residual cancer cells on microscopic examination, R2: residual cancer cells on macroscopic examination), histologic grade, and the TNM staging. The post‐neoadjuvant chemotherapy TNM classification was reassessed using the same methodology as the initial evaluation.

2.4. Data Analysis

We analyzed the data using Stata version 17. Because of the descriptive nature of the study, only descriptive statistics were used. For qualitative data such as treatment response and TNM subgroups, we used frequencies and percentages. For quantitative data such as age and surgical duration, we used mean and standard deviation (SD) or median and interquartile range (IQR) when appropriate. In addition to reporting the highest grade of each toxicity, we also assessed the timing of adverse events by estimating the time from treatment initiation to the onset of the first sign of toxicity (hematological, biochemical, or clinical) using the Kaplan–Meier method. Overall survival was estimated within 3 years from treatment initiation. Survival curves were compared using the log‐rank test between patients with and without treatment response, as well as between those with and without resection. A p‐value <0.05 was considered statistically significant for all analyses.

3. Results

3.1. Demographic Characteristics and Effectiveness of Neoadjuvant Chemotherapy

During the study period, approximately 1000 gastrectomies were performed at the study hospital. Of these, 78 patients (47 retrospective and 31 prospective) met the eligibility criteria and were included in the analysis. Most patients were male (64.1%) with a median age of 58 (IQR = 50–66) years. More than two‐thirds of the patients (67.9%) had normal overall health conditions (ECOG = 0). Nearly half of the patients (48.7%) had tumors located in the pyloric antrum, and 30.8% had tumors located in the corpus. Poorly differentiated adenocarcinoma was the most common histological subtype, accounting for 59.0%. Many patients (69.2%) had diffuse‐type carcinoma, and 17.9% had tubular carcinoma. Endoscopic imaging evaluation according to the Borrmann classification indicated that types II and III were the predominant types, accounting for 42.3% and 35.9%, respectively (Table 1).

TABLE 1.

Baseline demographic and clinicopathological characteristics of patients with locoregionally advanced gastric adenocarcinoma.

	Characteristics	Frequency	Percentage
Gender	Female	28	35.9
	Male	50	64.1
Age (years)	Median (IQR)	58	50–66
Age group (years)	≤50	17	21.8
	51–60	23	29.5
	61–70	25	32.1
	>70	13	16.7
Eastern Cooperative Oncology Group (ECOG)	Normal	53	67.9
	Restrict	25	32.1
Tumor location	Cardia	8	10.3
	Corpus	24	30.8
	Cardia—Corpus	2	2.6
	Pylorus	38	48.7
	Esophagogastric junction	6	7.7
Histological grade	Poorly differentiated	46	59.0
	Moderately differentiated	29	37.2
	Well differentiated	3	3.8
Adenocarcinoma subtype	Tubular adenocarcinoma	14	17.9
	Papillary adenocarcinoma	1	1.3
	Mucinous adenocarcinoma	6	7.7
	Poorly cohesive carcinoma	54	69.2
	Mixed carcinoma	3	3.8
Borrmann endoscopic classification	Type I	14	17.9
	Type II	33	42.3
	Type III	28	35.9
	Type IV	2	2.6
	Indeterminate	1	1.3

The number of chemotherapy cycles completed by patients was as follows: 1 patient (1.3%) completed 1 cycle, 7 (9.0%) completed 2 cycles, 25 (32.1%) completed 3 cycles, and 45 (57.7%) completed all 4 planned cycles. However, because this study included both retrospective and prospective cohorts, data on relative dose intensity (RDI) were not systematically recorded for the retrospective cases and therefore could not be accurately reported. The treatment response assessment showed that approximately 16.7% of patients had disease progression or metastasis after the treatment, and the overall response rate was 83.3% (n = 65). The results of TNM staging before and after chemotherapy are also presented in Table 2. Regarding the primary tumor (T), the proportion of T4b decreased from 78.2% before chemotherapy to 52.6% after chemotherapy, and T4a increased from 20.5% before chemotherapy to 43.6% after chemotherapy. Regarding regional lymph nodes (N), the proportion of N‐Bulky decreased from 23.1% before chemotherapy to 11.5% after chemotherapy, resulting in an increase in N2 from 38.5% before chemotherapy to 46.2% after chemotherapy. After neoadjuvant chemotherapy, 5.1% of patients (n = 4) had new metastases.

TABLE 2.

Tumor staging and treatment response before and after neoadjuvant chemotherapy.

	Stage/Characteristics	Frequency (n)	Percentage (%)
Primary tumor (T)	Before chemotherapy
	T3	1	1.3
	T4a	16	20.5
	T4b	61	78.2
	After chemotherapy
	T3	3	3.8
	T4a	34	43.6
	T4b	41	52.6
Regional lymph nodes (N)	Before chemotherapy
	N1	10	12.8
	N2	30	38.5
	N3	20	25.6
	N‐Bulky	18	23.1
	After chemotherapy
	N0	1	1.3
	N1	11	14.1
	N2	36	46.2
	N3	21	26.9
	N‐Bulky	9	11.5
Distant metastasis (M)	Before chemotherapy
	M0	69	88.5
	Indeterminate	9	11.5
	After chemotherapy
	M0	74	94.9
	M1	4	5.1
Treatment response (RECIST)	Complete response	1	1.3
	Partial response	41	52.6
	Stable disease	23	29.5
	Progressive disease	13	16.7

3.2. Neoadjuvant Chemotherapy Toxicity Assessment

The results of hematological toxicity (Figure 2A) showed that anemia appeared early in over 50% of patients after the first treatment cycle and accumulated in up to four treatment cycles in about 95% of patients. Neutropenia was a hematological toxicity that did not appear quickly but had the second‐highest accumulation rate, approximately 73% of patients. Most hematological toxicities were grade 1–2, with a low incidence of grade 3–4 toxicity (7/78 patients, accounting for 9.0%), including anemia (n = 1), decreased white blood cell count (n = 1), decreased neutrophil count (n = 4), and increased liver enzymes (n = 1). In terms of clinical toxicity (Figure 2B), hair loss occurred earliest, right after the first treatment cycle, in about 44% of patients, and the highest cumulative incidence with nearly all patients experiencing hair loss. Gastrointestinal toxicity also appeared very early and had the second‐highest cumulative incidence, with about 49% of patients reporting this symptom. Clinical toxicity was mainly grade 1–2, with a low incidence of grade 3–4 toxicity, which was only seen in hair loss toxicity (9/78 patients, accounting for 11.5%).

FIGURE 2.

Toxicity during the treatment.

3.3. Surgical Outcome After Neoadjuvant Chemotherapy

Among 65 patients who showed good response to neoadjuvant chemotherapy and were evaluated for surgical eligibility by the multimodal treatment board, 42 patients underwent gastrectomy, accounting for 53.8% of the total treated patients (Figure 1). Among the nongastrectomy patients, ten individuals were considered to have stable disease after neoadjuvant chemotherapy but remained unsuitable for radical surgery due to persistent locally advanced or unresectable tumors; these patients were subsequently switched to maintenance chemotherapy with S‐1. Seven patients demonstrated a treatment response but ultimately refused surgery, either personally or at the request of their families. Additionally, six patients exhibited a partial response to treatment based on the RECIST but were suspected of having distant metastases at the time of surgical evaluation. These patients underwent exploratory laparotomy, during which peritoneal metastases were confirmed, and gastrectomy was therefore not performed.

The TNM stage of all patients was first assessed by contrast‐enhanced CT scan prior to neoadjuvant chemotherapy. Following completion of chemotherapy, posttreatment TNM staging was re‐evaluated using the same imaging modality. In patients who underwent gastrectomy, the final TNM stage was determined by pathological examination of the resected specimen. Among the 42 patients eligible for gastrectomy, 50% underwent distal gastrectomy. R0 resection was achieved in 92.9% of cases, and 95.2% of patients received D2 lymphadenectomy. For the three patients with R1 resection, the causes were multiorgan invasion (liver and diaphragm (n = 1), pancreas (n = 1), and pancreas with transverse mesocolon (n = 1)).

Before neoadjuvant chemotherapy, based on TNM staging using CT‐scan, only one patient had T3 disease, and none had T0 or T1 (Table 3). After surgery, based on TNM staging using pathological examination, nearly 40% achieved T0, T1, or T3 on pathological staging. For regional lymph nodes, N0 was observed in 33.3% and N1 in 28.6% after surgery, compared with 14.3% N1 and no N0 prechemotherapy. However, two patients were found to have peritoneal metastases after surgery, despite achieving R0 resection. During the 3‐year follow‐up, overall survival progressively declined among all participants (Figure 3A). Patients who responded to neoadjuvant chemotherapy or underwent gastrectomy had significantly better survival compared with their counterparts (Figure 3B, C; log‐rank test p < 0.001).

TABLE 3.

Surgical characteristics and pathological outcomes in resected patients after neoadjuvant chemotherapy.

	Resection (R)
Characteristics	Total (n = 42) n (%)	R0 (n = 39) n (%)	R1 (n = 3) n (%)
Surgery duration (h) (mean ± SD)	3.8 ± 1.3	3.8 ± 1.3	3.7 ± 1.5
Extent of gastrectomy
Total	14 (33.3)	13 (33.3)	1 (33.3)
Distal	21 (50.0)	20 (51.3)	1 (33.3)
Proximal	6 (14.3)	5 (12.8)	1 (33.3)
Preserving pylorus	1 (2.4)	1 (2.6)	0 (0.0)
Lymphadenectomy
D2	40 (95.2)	37 (94.9)	3 (100.0)
No lymphadenectomy	1 (2.4)	1 (2.6)	0 (0.0)
Only lymph nodes	1 (2.4)	1 (2.6)	0 (0.0)
Histological grade
Poor	25 (59.5)	24 (61.5)	1 (33.3)
Moderate	17 (40.5)	15 (38.5)	2 (66.7)
Primary tumor (T)
Before chemotherapy
cT0	0 (0.0)	—	—
cT1	0 (0.0)	—	—
cT2	0 (0.0)	—	—
cT3	1 (2.4)	—	—
cT4a	9 (21.4)	—	—
cT4b	32 (76.2)	—	—
After chemotherapy
ycT0	0 (0.0)	—	—
ycT1	0 (0.0)	—	—
ycT2	0 (0.0)	—	—
ycT3	3 (7.1)	—	—
ycT4a	26 (61.9)	—	—
ycT4b	13 (31)	—	—
After surgery
ypT0	7 (16.7)	7 (17.9)	0 (0.0)
ypT1	2 (4.8)	2 (5.1)	0 (0.0)
ypT2	0 (0.0)	0 (0.0)	0 (0.0)
ypT3	7 (16.7)	7 (17.9)	0 (0.0)
ypT4a	24 (57.1)	22 (56.4)	2 (66.7)
ypT4b	2 (4.8)	1 (2.6)	1 (33.3)
Regional lymph nodes (N)
Before chemotherapy (clinical)
cN0	0 (0.0)	—	—
cN1	6 (14.3)	—	—
cN2	13 (31.0)	—	—
cN3	12 (28.6)	—	—
cN‐Bulky	11 (26.2)	—	—
After chemotherapy (clinical)
ycN0	1 (2.4)	—	—
ycN1	7 (16.7)	—	—
ycN2	17 (40.5)	—	—
ycN3	13 (30.9)	—	—
ycN‐Bulky	4 (9.5)	—	—
After surgery (pathology)
y pN0	14 (33.3)	14 (35.9)	0 (0.0)
ypN1	12 (28.6)	10 (25.6)	2 (66.7)
ypN2	9 (21.4)	8 (20.5)	1 (33.3)
ypN3	7 (16.7)	7 (17.9)	0 (0.0)
ypN‐Bulky	0 (0.0)	0 (0.0)	0 (0.0)
Distant metastasis (M)
Before chemotherapy (clinical)
M0	40 (95.2)	—	—
Indeterminate	2 (4.8)	—	—
After chemotherapy (clinical)
M0	42 (100)	—	—
M1	0 (0.0)	—	—
After surgery (pathology)
M0	40 (95.2)	37 (94.9)	3 (100.0)
M1	2 (4.8)	2 (5.1)	0 (0.0)

FIGURE 3.

Overall survival within 3 years from treatment initiation, stratified by response to neoadjuvant chemotherapy and gastrectomy status.

4. Discussion

In search of an optimal neoadjuvant chemotherapy regimen, our study has yielded promising results with the DCS regimen in patients with locoregionally advanced gastric cancer. Administering the four‐cycle DCS regimen has shown high effectiveness and safety. The high level of effectiveness of the treatment regimen was demonstrated by a high response rate assessed through RECIST (42/78 = 53.8%) and R0 resection (39/42 = 92.9% among patients who underwent surgery and 39/78 = 50% in the overall cohort), as well as a significant reduction in TNM staging. Safety was demonstrated by the relatively low toxicity associated with DCS neoadjuvant chemotherapy, which was typically grade 1–2 and commonly included toxicities seen with other adjuvant chemotherapy regimens.

Previous studies on the effectiveness of the DCS regimen in advanced‐stage gastric cancer have shown a relatively large range of response rates, from 54% to 88% [13, 25, 26, 27]. The rate of patients who had downstaging and converted to radical surgery after DCS chemotherapy also varied from 23.5% to 86.7% [13, 25, 26, 27]. A possible reason for the wide range of these figures and the difference between previous studies and ours is the patient inclusion criteria. According to Kinoshita et al. [28], besides 42 patients who were initially classified as unresectable, 15 of 57 patients were also evaluated as having potential for surgery, including para‐aortic lymph node metastasis (16a2b1 PAN) or fewer than three distant peripheral liver metastases, leading to a greater prognosis. Similarly, Fushida et al. [12] only evaluated the effectiveness of the DCS regimen in patients with para‐aortic lymph node metastasis in general. Therefore, the response rate of the DCS regimens in the above studies (ranging from 73.7% to 76.9%) [12, 28] is lower than ours (83.4%). In a study by Nam et al. [16] evaluating the outcomes of advanced gastric cancer chemotherapy with the same DCS regimen dosage as ours, with 90% of patients having distant metastasis, the response rate was low (34.2%). However, that study revealed that patients with T4b and N‐bulky might have the most benefit from this regimen, with 15.9% converted from unresectable to resectable.

Another reason for this difference is the specification of the treatment protocol. Dosage and treatment schedule are the main issues in studies aiming to balance high response rates and acceptable toxicity. Studies using high‐dose DCS regimen every 3 weeks with Docetaxel at 60–80 mg/m² and Cisplatin at 60 mg/m² achieved relatively high response rates (74.4%–88%). However, this was accompanied by increased toxicity, especially hematological toxicity with grade 3 or higher neutropenia (66.7%–79.1%), which was much higher than our results (5.1%) [12, 26]. Recent reports with a 4‐week cycle using Docetaxel at 40 mg/m² and Cisplatin at 60 mg/m² showed improved toxicity, but the response rates also decreased accordingly (over 50%) [14, 25, 27, 28]. The dose splitting DCS protocol with Docetaxel and Cisplatin every 4 weeks, as used in our study, has proven to be effective with high tolerability and compliance, suitable for outpatient treatment, especially among those with tumors invading other organs and bulky lymph nodes that cannot be removed at the beginning.

Regarding the resection rate after neoadjuvant chemotherapy with DCS, our study revealed a resection rate twice as high as in previous studies. Fukuchi et al. [29] reported that 40 of 151 patients (26.5%) with stage IV gastric cancer underwent surgery after chemotherapy with S1 + Cisplatin or Paclitaxel. Similarly, in the study by Sato et al. [26], among 27 patients who responded to chemotherapy, 7 (22.6%) underwent gastric resection. The R0 resection rate in our study (over 90%) is also higher than that in similar studies, such as JCOG0210 (73%) [30] or JCOG0501 (74.2%) [31]. However, the resection rate in our study might have been even higher if patients and their families had not refused surgery. In a study by Tsuchida et al. [27], using the high‐dose DCS regimen every 4 weeks, the reported R0 resection rate was 93.5%. However, the incidence of adverse effects during chemotherapy was also high.

In terms of postoperative staging of the disease, in our study, T4 was the most common, with T4a being the predominant subtype, while the T1 stage accounted for a small proportion. Regarding lymph node involvement, the rate of lymph node metastasis in our study is consistent with the findings of Tsuchida et al. [27], with a lymph node metastasis rate of 66.7%. In our study, 7 of 42 (16.7%) patients achieved a complete pathological response after surgery. This rate is five times higher than that reported by Tsuchida et al. [27], where only 1 of 30 patients (3.3%) achieved a complete response. Along with the relatively low toxicity rate, these results demonstrate the potential of the DCS regimen in the neoadjuvant treatment of locoregionally advanced gastric adenocarcinoma.

Although our study is among the first of its kind in Vietnam, many clinical implications can be learned. First, the DCS regimen is effective but requires patient selection, particularly among patients with locoregionally advanced‐stage gastric adenocarcinoma. This approach balances the benefits and potential toxicities for patients. Second, to ensure high effectiveness, the DCS regimen requires close patient surveillance during treatment, with special attention to critical toxicities such as granulocytopenia. Third, during our study, we observed that some patients responded well to treatment very early, while others did not respond until the last dose, despite these patients having a similar stage. Therefore, individualized dosing can optimize the DCS regimen's outcomes for these patients.

However, our study has certain limitations. First, our study was conducted at a single hospital with a relatively small sample size, and thus, the findings may not be highly representative. Furthermore, interpretation of the R0 resection rate requires caution. The 92.9% figure in our study was calculated only among patients who underwent surgery and was thus vulnerable to selection bias; on an intention‐to‐treat basis across the entire cohort (n = 78), the R0 rate was 50%. This discrepancy likely reflected nonefficacy factors such as COVID‐19‐related service disruptions during the study period, patient/family refusal, perioperative comorbidities or risk, logistical/financial barriers, and disease progression, which prevented some patients from proceeding to surgery. Different clinical settings with varying contextual influencing factors and disease severity may yield different outcomes. Therefore, further studies are needed to confirm our findings. Second, some techniques used in the study may not have been optimized. For instance, preoperative peritoneal metastasis assessment should employ diagnostic laparoscopy for more accurate results or positron emission tomography (PET) and CT to evaluate suspected metastatic lesions. Third, our study was limited to short‐term postoperative outcomes and did not assess surgical complications as a measure of safety or evaluate the long‐term effectiveness of DCS. Additional research with extended follow‐up is warranted to clarify its overall safety profile and the long‐term impact of the DCS regimen.

5. Conclusion

Neoadjuvant chemotherapy using the DCS regimen every 4 weeks showed high effectiveness and safety in patients with locoregionally advanced unresectable gastric adenocarcinoma and increased their eligibility for successful radical surgery. Despite our study supporting the use of DCS, these are only short‐term results. Further research is needed, especially focusing on the final treatment results and the long‐term effectiveness of the entire treatment process.

Author Contributions

Tho Vinh Tran designed the study, collected, analyzed data, and wrote the manuscript. Truc Thanh Thai designed the study, analyzed data, visualized results, and validated the results. Loi Ngoc La collected data. Ngon Van Dinh analyzed data and visualized results. Long Duy Vo designed the study and collected data. Bac Hoang Nguyen designed the study and supervised all study activities. All authors drafted, revised, and approved the final manuscript.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to restrictions.