Early vs conventional initiation of adjuvant chemotherapy in advanced gastric cancer: A propensity-matched outcomes study

Abstract

BACKGROUND

Despite emerging evidence from studies on other malignancies that support early adjuvant chemotherapy (AC) initiation, the feasibility and oncologic benefits of this therapy remain underexplored in patients receiving gastric resection.

AIM

To evaluate the feasibility, safety, and oncologic outcomes of early postoperative AC in advanced gastric cancer patients.

METHODS

In this retrospective cohort study, 219 stage II/III gastric adenocarcinoma patients who underwent laparoscopic gastrectomy between 2016 and 2021 were analyzed. Patients were stratified by AC initiation timing: Early (10-13 days, n = 21) vs conventional (4-6 weeks, n = 198). Propensity score matching (1:2) was performed, with balance assessed via standardized mean differences. Recurrence-free survival, overall survival, and safety were compared between the two groups. Sensitivity analyses were conducted to assess the robustness of the findings.

RESULTS

After 1:2 matching (21 patients vs 42 patients), early AC demonstrated comparable 3-year recurrence-free survival (53.7% vs 61.6%, hazard ratio = 0.89, P = 0.562) and overall survival (69.1% vs 66.3%, P = 0.874) rates to conventional timing. Peritoneal recurrence was significantly lower in the early group (4.8% vs 26.2%, P = 0.048), although Cox regression did not confirm a significant difference (hazard ratio = 0.418, P = 0.257). Early initiation correlated with a 2.18-fold greater proportion of patients requiring dose reductions (57.1% vs 26.2%, P = 0.026) but similar grade 3/4 toxicity (42.9% vs 57.1%, P = 0.285).

CONCLUSION

Early AC initiation appears feasible in selected patients but necessitates individualized dose management. Our findings challenge traditional timing paradigms while highlighting the need for molecularly guided treatment sequencing strategies.

Key Words: Gastric cancer; Adjuvant chemotherapy; Postoperative timing; Survival rate; Propensity score; Recurrence pattern

Core Tip: This study pioneers the evaluation of adjuvant chemotherapy initiated within 10-13 days postgastrectomy under enhanced recovery protocols. Early initiation shows comparable survival outcomes to conventional timing but requires tailored dosing to mitigate toxicity. These findings suggest that early chemotherapy is both feasible and safe when carefully managed, and they emphasize the importance of integrating surgical recovery with oncologic treatment, offering a paradigm shift in personalized gastric cancer management.

INTRODUCTION

Gastric cancer (GC) is the fifth most frequently diagnosed malignancy worldwide, with over 1.2 million new cases reported globally in 2023[1]. Despite notable progress in surgical techniques and perioperative care, approximately half of stage II/III patients experience disease recurrence within five years following surgery[2,3], highlighting the critical need for refined adjuvant chemotherapy (AC) strategies. Current guidelines do not have recommendations regarding the timing of initiating AC[4-6], although it generally starts within 4-6 weeks after surgery. However, this treatment window is primarily based on clinical experience regarding postoperative physiological recovery, lacking a thorough consideration of tumor biological behavior and host immune dynamics, which may result in missed opportunities for optimal therapeutic intervention.

Previous investigations have demonstrated the existence of a distinct “immunosuppressive window” occurring 1-7 days postoperatively, during which natural killer cell activity is significantly suppressed[7], whereas the proportion of myeloid-derived suppressor cells markedly increases[8]. Concurrently, the circulating tumor cell count in peripheral blood significantly increases compared with preoperative levels[9]. These cumulative alterations create a microenvironment that facilitates the evasion and colonization of micrometastases, suggesting that early AC intervention may serve as a crucial therapeutic window for interrupting this pathological cascade. Notably, early initiation of AC (within 44 days) was associated with significantly improved 5-year survival in breast cancer patients (92.0% vs 83.3%, P = 0.03)[10]. Emerging evidence across various malignancies similarly demonstrates that reducing the surgery-to-chemotherapy interval confers prognostic benefits by effectively suppressing the proliferation of micrometastatic deposits[11-13]. Nevertheless, GC-specific research regarding this critical issue remains limited and has yet to be thoroughly investigated.

In contrast to breast cancer, the early initiation of AC in GC presents three distinctive clinical challenges: (1) Impaired nutrient absorption secondary to gastrointestinal reconstruction may exacerbate chemotherapy-induced toxicity[14]; (2) Early complications occur in approximately 20% of patients, substantially compromising both tolerance and adherence to oral chemotherapeutic regimens[15]; and (3) Although laparoscopic approaches mitigate surgical stress responses (manifested by a 10%-20% decrease in peak C-reactive protein levels)[16-18] and provide technical support for enhanced recovery after surgery (ERAS) protocols, the dynamic interplay between metabolic reserves and chemotherapeutic tolerance within ERAS paradigms remains to be elucidated.

Building upon this scientific foundation with our study, initiating AC within 10-13 days post-surgery for select patients under ERAS protocols (mean hospitalization: 5.8 ± 3.6 days)[19] is innovatively proposed to possibly confer dual prognostic benefits: First, by targeting the immunosuppressive window to impede micrometastatic progression; second, capitalizing on the metabolic advantages conferred by minimally invasive techniques to increase treatment safety. This hypothesis challenges conventional 4-6-week therapeutic windows and establishes an evidence-based framework for personalized chemotherapy scheduling.

MATERIALS AND METHODS

Study design and patients

Consecutive patients diagnosed with stage II/III GC (American Joint Committee on Cancer 8^th edition) who underwent R0 Laparoscopic gastrectomy with standardized D2 Lymphadenectomy at Zhongshan Hospital of Xiamen University between June 2016 and August 2021 were enrolled in this single-institution retrospective cohort analysis. The inclusion criteria were as follows: (1) Aged 18-80 years; (2) Completed ≥ 3 AC cycles [5-fluorouracil (5-FU) plus calcium folinate plus oxaliplatin/tegafur plus oxaliplatin/capecitabine plus oxaliplatin]; and (3) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients with the following characteristics were excluded from the study: (1) A concurrent or past history of other malignant tumors; (2) Remnant GC; (3) Preoperative chemotherapy or radiotherapy; (4) Distant metastatic disease, encompassing retroperitoneal/supraclavicular lymph node involvement or visceral (hepatic/pulmonary) or skeletal metastases; and (5) Uncontrolled systemic diseases.

Patients were stratified by AC timing: Early (10-13 days) vs conventional (4-6 weeks) groups. The study process is depicted in Figure 1. The follow-up period was 36 months. Overall survival (OS) was defined as the time from the date of surgery to either the end of follow-up or death. Recurrence-free survival (RFS) was defined as the time from surgery to recurrence, metastasis, or the last follow-up. This retrospective cohort study was approved by the Ethics Committee of Zhongshan Hospital of Xiamen University (approval No. 2024-174). The requirement for written informed consent was waived because of the retrospective nature of the study, and the study adhered to the principles outlined in the Declaration of Helsinki.

Figure 1 Flowchart of patient enrollment.

Treatment method

All patients underwent perioperative management according to the ERAS protocol based on ERAS Society guidelines[20]. Three types of chemotherapy regimens were used in this study: (1) 5-FU plus calcium folinate plus oxaliplatin regimen: Oxaliplatin 85 mg/m² intravenous (IV) on day 1 (D1); leucovorin 400 mg/m² IV on D1; and 5-FU 400 mg/m² IV bolus on D1, followed by 5-FU 2400 mg/m² continuous IV infusion over 46 hours, repeated every 2 weeks for 12 cycles; (2) Tegafur plus oxaliplatin regimen: Oxaliplatin 130 mg/m² IV on D1 and oral S-1 (tegafur/gimeracil/oteracil) twice daily (bid) on days 1-14 (D1-14), with dosages based on body surface area (BSA): 40 mg for BSA < 1.25 m², 50 mg for BSA 1.25-1.5 m², and 60 mg for BSA > 1.5 m²; this regimen was repeated every 3 weeks for 8 cycles; and (3) Capecitabine plus oxaliplatin regimen: Oxaliplatin 130 mg/m² IV on D1; capecitabine 1000 mg/m²per os bid on D1-14; repeated every 3 weeks for 8 cycles.

Safety assessment

Treatment adherence was assessed based on chemotherapy completion rate, drug dose reduction rate, chemotherapy schedule modification rate, and relative dose intensity (RDI) in both groups. The RDI was calculated as the proportion of the cumulative delivered dose to the planned dose throughout the entire treatment course. Grade 3 or 4 adverse events were systematically documented from clinical records and assessed via the Common Terminology Criteria for Adverse Events v5.0.

Dose modification

For patients experiencing significant treatment-related toxicity, chemotherapy dose modifications (including delays or reductions) were implemented following the 2024 Chinese Society of Clinical Oncology Guidelines[4]. For hematologic toxicities (e.g., neutrophil count < 1.0 × 10⁹/L or platelet count < 50 × 10⁹/L) and grade ≥ 2 nonhematologic toxicities (e.g., hand-foot syndrome, neuropathy, or gastrointestinal events), treatment was suspended until recovery, and subsequent doses were reduced by 20%-25%. For oxaliplatin (in all regimens), the standard dose was reduced or discontinued in patients with persistent grade ≥ 2 peripheral neuropathy. For S-1 and capecitabine, the oral doses were reduced stepwise (e.g., 120 mg/day → 100 mg/day → 80 mg/day for S-1; 1000 mg/m² → 750 mg/m² bid for capecitabine) based on BSA and tolerance. The 5-FU bolus was omitted or reduced in patients with severe mucositis or myelosuppression. In the early group, AC was initiated upon confirmation of adequate wound healing and gastrointestinal recovery (tolerance of oral intake), with a proactive dose reduction of up to 20% when deemed necessary to improve treatment tolerability.

Statistical analysis

Statistical analyses were performed via SPSS 26.0 and R 4.2.1. Continuous variables were analyzed via the parametric Student’s t test for normally distributed data or the nonparametric Mann-Whitney U test for nonnormally distributed variables. Survival outcomes were assessed via the Kaplan-Meier method, with between-group comparisons performed via log-rank tests. A two-sided α level of 0.05 was established for statistical significance. The Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). Propensity score matching (PSM) was used to minimize baseline disparities between groups, employing a 1:2 nearest neighbor method with a 0.15σ caliper. The matching factors included sex, age, stage, and ECOG performance status. Given the limited sample size, particularly in the early group, we prioritized achieving an adequate matching ratio to preserve statistical power. Therefore, variables such as body mass index (BMI), tumor differentiation, and chemotherapy regimen were not included in the PSM model to avoid excessive case loss. Baseline characteristics between the propensity score-matched groups were assessed via standardized mean differences (SMDs), with an SMD < 0.1 indicating acceptable covariate balance[21]. Sensitivity analysis was performed to ensure the robustness of the results. Additionally, a post hoc power analysis was performed via the ‘powerSurvEpi’ package in R.

RESULTS

Patient characteristics

The study cohort consisted of 219 consecutive patients, with 21 patients (9.6%) allocated to the early group and the remaining 198 patients (90.4%) allocated to the conventional group. Before matching, significant differences were noted in BMI (22.27 kg/m²vs 20.83 kg/m², P = 0.015) and chemotherapy regimen distribution (P = 0.002). Following 1:2 PSM, 63 patients (21 early, 42 conventional) were included in the final analysis. Most baseline characteristics, including age, ECOG grade, and perineural invasion, achieved good balance between groups (SMDs < 0.1), whereas moderate imbalance remained in a few covariates, such as the chemotherapy regimen, BMI, and histology (Table 1).

Table 1 Characteristics of patients before and after propensity score matching, n (%).

Characteristics	Before PSM (n = 219)				After PSM (n = 63)
	Conventional (n = 198)	Early (n = 21)	P value	SMD	Conventional (n = 42)	Early (n = 21)	P value	SMD
Sex			0.854	0.044			0.366	0.246
Male	128 (64.6)	14 (66.7)			23 (54.8)	14 (66.7)
Female	70 (35.4)	7 (33.3)			19 (45.2)	7 (33.3)
Age, years
< 65	136 (68.7)	11 (52.4)			27 (64.3)	12 (57.1)
≥ 65	62 (31.3)	10 (47.6)			15 (35.7)	9 (42.9)
Median, IQR	60.00 (54.00, 65.25)	63.00 (58.50, 70.00)	0.118	0.221	62.50 (57.00, 68.25)	63.00 (58.50, 70.00)	0.890	0.043
BMI, kg/m2
< 23	154 (77.8)	14 (66.7)			30 (71.4)	14 (66.7)
≥ 23	44 (22.2)	7 (33.3)			12 (28.6)	7 (33.3)
Median, IQR	20.83 (18.83, 22.54)	22.27 (20.74, 24.14)	0.015	0.573	21.34 (18.00, 24.16)	22.27 (20.74, 24.14)	0.135	0.448
ECOG grade			0.174	0.305			0.858	0.048
0	65 (32.8)	10 (47.6)			19 (45.2)	10 (47.6)
1-2	133 (67.2)	11 (52.4)			23 (54.8)	11 (52.4)
Stage			0.367	0.220			0.668	0.117
Stage II	56 (28.3)	4 (19.0)			10 (23.8)	4 (19.0)
Stage III	142 (71.7)	17 (81.0)			32 (76.2)	17 (81.0)
PNI			0.819	0.049			1.000	< 0.001
Yes	182 (91.9)	19 (90.5)			38 (90.5)	19 (90.5)
No	16 (8.1)	2 (9.5)			4 (9.5)	2 (9.5)
LVI			0.597	0.128			0.445	0.214
Yes	171 (86.4)	19 (90.5)			35 (83.3)	19 (90.5)
No	27 (13.6)	2 (9.5)			7 (16.7)	2 (9.5)
Histology			0.381	0.105			0.271	0.393
Differentiated	84 (42.4)	11 (47.6)			28 (66.7)	11 (47.6)
Undifferentiated	114 (57.6)	10 (52.4)			14 (33.3)	10 (52.4)
Chemotherapy regimen			0.002				0.136
mFOLFOX-6	14 (7.1)	6 (28.6)		0.858	5 (11.9)	6 (28.6)		0.424
SOX	102 (51.5)	5 (23.8)		0.596	19 (45.2)	5 (23.8)		0.462
XELOX	82 (41.4)	10 (47.6)		0.123	18 (42.9)	10 (47.6)		0.094

PSM: Propensity score matching; SMD: Standardized mean difference; IQR: Interquartile range; BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; PNI: Perineural invasion; LVI: Lymphovascular invasion; mFOLFOX-6: 5-fluorouracil plus calcium folinate plus oxaliplatin; SOX: Tegafur plus oxaliplatin; XELOX: Capecitabine plus oxaliplatin.

Treatment adherence and adverse events

The early group demonstrated significantly higher dose reduction rates (57.1% vs 26.2%, P = 0.026) despite comparable relative dose intensities (median 67.5% vs 73.4%, P = 0.587). The treatment completion rates at 8 cycles (33.3% vs 38.1%) and schedule modification rates (14.3% vs 38.1%, P = 0.08) were not significantly different. Dose reductions occurred primarily during early cycles (1-3) in the early cohort (Table 2). Grade 3/4 neutropenia (47.6% vs 35.7%) and anorexia (42.9% vs 28.6%) predominated in both groups, with no statistically significant differences in severe adverse event rates (P > 0.05). No treatment-related deaths were observed throughout the study duration (Table 2).

Table 2 Grade 3/4 adverse events and adherence/feasibility of each treatment group (n = 63), n (%).

	Conventional (n = 42)	Early (n = 21)	P value
RDI (%), mean ± SD	68.58 ± 27.64	65.34 ± 28.07	0.587
Median (IQR)	73.4 (51.88, 96.25)	67.50 (46.38, 95)
Completion rate
4 cycles	34 (81.0)	17 (81.0)	1.000
8 cycles	16 (38.1)	7 (33.3)	0.786
Dose down rate			0.026
None	31 (73.8)	9 (42.9)
Reduction	11 (26.2)	12 (57.1)
Schedule change rates			0.08
None	26 (61.9)	18 (85.7)
Change	16 (38.1)	3 (14.3)
Adverse event
Overall toxicity	18 (42.9)	12 (57.1)	0.285
Related death	0	0	NA
Leukopenia	4 (9.5)	1 (4.8)	0.657
Neutropenia	15 (35.7)	10 (47.6)	0.363
Thrombocytopenia	8 (19.0)	3 (14.0)	0.639
Anorexia	12 (28.6)	9 (42.9)	0.257
Vomiting	10 (24.4)	4 (19.0)	0.085
Neurotoxicity	1 (2.4)	2 (9.5)	0.219
Diarrhea	3 (7.1)	2 (9.5)	0.742

RDI: Relative dose intensity; IQR: Interquartile range; NA: Not available.

Site of first recurrence

The peritoneum was the primary site for initial recurrence. Peritoneal recurrence occurred in 26.2% (11/42) of patients in the conventional group and 4.8% (1/21) of patients in the early group, indicating a statistically significant difference between the two groups (P = 0.048, Fisher’s exact test). In the conventional group, 3 patients (7.1%) experienced local recurrence and 3 patients (7.1%) experienced lymph node recurrence. In the early group, 3 patients (14.3%) experienced local recurrence and 2 patients (9.5%) experienced lymph node recurrence. Although Cox regression analysis revealed that early intervention was associated with a 58.2% relative reduction in peritoneal recurrence (HR = 0.418, 95%CI: 0.093-1.887; P = 0.257), this finding did not reach statistical significance (Table 3).

Table 3 Site of first recurrence in each treatment group, n (%).

Site	Conventional (n = 42)	Early (n = 21)	HR for recurrence in the early group (95%CI)	P value	P value1
Total number of relapses	16 (38.1)	9 (42.9)
Local	3 (7.1)	3 (14.3)	2.336 (0.470-11.603)	0.299	0.391
Lymph nodes	3 (7.1)	2 (9.5)	1.459 (0.244-8.733)	0.679	1.000
Hematogenous	4 (9.5)	2 (9.5)	1.636 (0.336-7.312)	0.520	0.677
Peritoneum	11 (26.2)	1 (4.8)	0.418 (0.093-1.887)	0.257	0.048

¹Fisher’s exact test.

Some patients experienced recurrence at more than one site. HR: Hazard ratio; CI: Confidence interval.

Survival analyses

The median follow-up was 36.0 months in both the early and conventional groups. After matching, the 3-year RFS rates were 53.7% and 61.6% (P = 0.562), and the 3-year OS rates were 69.1% and 66.3% (P = 0.874) in the early and conventional groups, respectively. Univariate Cox regression analysis revealed that early AC was not associated with improved survival outcomes, with HRs of 1.271 (95%CI: 0.561-2.877, P = 0.566) for RFS and 0.926 (95%CI: 0.356-2.410, P = 0.875) for OS. The Kaplan-Meier survival curves revealed similar survival trends between the early and conventional groups for both RFS and OS, with no statistically significant differences observed (Figure 2).

Figure 2 Recurrence-free survival and overall survival curves for patients in the early and conventional groups. A: Recurrence-free survival curves for patients in the early and conventional groups; B: Overall survival curves for patients in the early and conventional groups.

Sensitivity analyses using the matched cohort

To evaluate the robustness of our primary findings and address the potential confounding effects of variables not included in the initial PSM model, we conducted a sensitivity analysis by adjusting for additional covariates, including BMI, chemotherapy regimen, and tumor differentiation. After adjustment, early AC was still not significantly associated with RFS (HR = 1.199, 95%CI: 0.461-3.121, P = 0.710). No covariates had a statistically significant effect, although undifferentiated tumors showed a nonsignificant trend toward worse RFS (HR = 2.071, 95%CI: 0.929-4.618, P = 0.075) (Table 4).

Table 4 Multivariate Cox regression for recurrence-free survival.

Variable	HR for recurrence	95%CI	P value
Early vs conventional	1.199	0.461-3.121	0.710
Tumor differentiation
Differentiated (reference1)	1
Undifferentiated	2.071	0.929-4.618	0.075
BMI, kg/m2
< 23 (reference1)	1
≥ 23	0.523	0.176-1.554	0.244
Chemotherapy regimen
SOX (reference)	1
XELOX	0.767	0.325-1.809	0.545
mFOLFOX6	0.919	0.144-5.878	0.929

¹The reference category in the Cox model.

HR: Hazard ratio; CI: Confidence interval; BMI: Body mass index; SOX: Tegafur plus oxaliplatin; XELOX: Capecitabine plus oxaliplatin; mFOLFOX-6: 5-fluorouracil plus calcium folinate plus oxaliplatin.

Post hoc power analysis

The post hoc power analysis based on the observed HR (HR = 0.926) for OS, an event rate of 33.3%, and a total sample size of 63 patients yielded a statistical power of approximately 3.6%. This finding indicates a limited ability to detect a statistically significant difference between the early and conventional groups given the current sample size.

DISCUSSION

This study is the first to systematically evaluate the feasibility of early AC (10-13 days) in patients with GC. Despite requiring more frequent dose reductions (57.1% vs 26.2%, P = 0.026), the early group presented rates of severe toxicity (grade 3/4: 42.9% vs 57.1%, P = 0.285) similar to those of patients receiving conventional treatment, suggesting that initiating AC within 10-13 days is clinically safe in carefully selected patients under an ERAS protocol. This finding aligns with the principles of ERAS and may provide a practical basis for challenging the traditional 4-6-week initiation window. However, the early group showed no significant advantage in 3-year RFS (53.7% vs 61.6%, P = 0.562), suggesting that the reduced RDI (RDI = 67.5%) may have partially offset the potential biological benefit of earlier intervention. Notably, the early group had a lower risk of peritoneal recurrence (HR = 0.418, 95%CI: 0.093-1.887), although this difference did not reach statistical significance (P = 0.257). While Fisher’s exact test revealed a nominal difference in peritoneal recurrence between groups (P = 0.048), the small sample size and wide CIs warrant cautious interpretation. This potential trend merits further investigation in larger, prospective cohorts.

These findings align with preclinical evidence. Animal models have shown that primary tumor resection may potentiate the progression of synchronous metastases[22]. However, immediate initiation of AC can effectively suppress cancer metastasis[23,24], providing a biological basis for early intervention. From a clinical perspective, previous studies have focused predominantly on survival benefits within the 4-6-week postoperative window. A Japanese study reported that administering AC within 6 weeks postoperatively significantly reduced recurrence rates (15.7% vs 43.8%, P = 0.05)[25]. Similarly, a Korean cohort study demonstrated that initiating AC within 5 weeks postgastrectomy significantly improved 5-year OS (P = 0.0336)[26]. Kang et al[27] reported that initiating AC within 4 weeks significantly improved the 10-year OS (57.5% vs 38.8%, P = 0.003). However, these studies did not explore ultra-early initiation within ≤ 2 weeks or systematically assess its feasibility, which represents a novel contribution of our study.

Unlike the significant survival benefit observed with AC initiated within 21 days after breast cancer surgery[28], this study did not demonstrate a significant survival benefit for early AC in patients with GC. Sensitivity analyses adjusting for additional clinical variables yielded consistent results, supporting the robustness of our findings. This discrepancy may be attributed to multiple factors. First, the early group had a greater proportion of well-differentiated tumors (47.6% vs 28.6%), which typically demonstrated reduced chemosensitivity[29]. Second, our analysis lacked molecular subtyping (e.g., microsatellite instability-high/Epstein-Barr virus positive status), which significantly influences treatment response[30,31]. Third, the RDI reduction in the early group (67.5% vs 73.4%) might attenuate the biological impact of early intervention[32]. Notably, despite these dose modifications, comparable survival outcomes between groups suggest that personalized dosing strategies may optimize the therapeutic balance in select populations (e.g., elderly or nutritionally compromised patients)[33].

This study has several inherent limitations. First, its retrospective design is subject to potential biases, including unmeasured confounding and selection bias. Additionally, the single-center design and small sample size, particularly the limited number of patients in the early group (n = 21), restricted the ability to detect meaningful survival differences. A post hoc power analysis based on the observed effect size yielded a statistical power of only 3.6%, indicating insufficient power to detect modest survival differences. Future multicenter studies with larger sample sizes are needed to improve the statistical power and generalizability of these findings. Second, the proposed hypothesis of a postoperative “immunosuppressive window” remains speculative, as no immune-related biomarkers (e.g., lymphocyte subsets, myeloid-derived suppressor cells, or circulating tumor DNA) were assessed in this study. Third, owing to limited sample availability, this study did not include molecular biomarker data such as Epstein-Barr virus positive or microsatellite instability-high status, which limits the ability to identify predictors of response to early AC. Future studies should incorporate molecular profiling and serial circulating tumor DNA monitoring to stratify patients better and optimize treatment timing.

Despite these limitations, our study provides the first clinical validation of AC initiation within postoperative days 10-13, establishing an evidence-based framework for the personalized timing of GC adjuvant therapy. The integration of early AC with ERAS protocols and minimally invasive techniques may yield a novel therapeutic strategy for selected patients, particularly those at high risk of peritoneal recurrence. However, definitive confirmation of survival benefits requires large-scale phase III randomized controlled trials, especially within precision medicine paradigms incorporating molecular subtyping.

CONCLUSION

This study demonstrated that initiating AC 10-13 days after surgery is safe and feasible; however, it does not significantly improve survival in patients with stage II/III GC. Clinical decision-making should incorporate tumor biology, patient tolerance, and molecular markers rather than rigidly adhering to specific time points.

ACKNOWLEDGEMENTS

The authors sincerely thank all the participating scholars for their valuable contributions to this study.