Shortening the hiatus: A preliminary challenge to the 4-6 weeks paradigm in adjuvant gastric cancer therapy

Abstract

In this editorial we comment on the article by Lin et al published in the recent issue of the World Journal of Gastroenterology. The conventional 4-6-week interval between gastrectomy and adjuvant chemotherapy (AC), a legacy of open surgery, persists despite advances in minimally invasive techniques and enhanced recovery protocols. Here we show that initiating AC on postoperative days 10-13 is feasible and does not increase surgical or hematologic toxicity. In a propensity-matched cohort of 219 stage II-III gastric cancer patients managed laparoscopically within an enhanced recovery after surgery framework, 21 patients received ultra-early AC. At three years, systemic relapse and overall survival were comparable to the standard-timing group. Although a downward trend in peritoneal metastasis rate was observed in the early chemotherapy group in the univariate analysis (4.8% vs 26%, P = 0.048), the difference was not significant after multivariate correction (hazard ratio = 0.42, 95% confidence interval: 0.09-1.89). This initial signal suggests that there may be potential benefits, but requires verification in larger-scale studies. Dose reductions were more frequent in the early-AC cohort (57% vs 28%), indicating physiological reserves are adequate but finite. These findings challenge the traditional postoperative timeline and suggest the immunosuppressive window (days 7-14) may offer a therapeutic opportunity for micrometastatic control. Our results support further investigation of ultra-early AC while underscoring the need to maintain dose density in future protocols.

Key Words: Gastric cancer; Adjuvant chemotherapy; Peritoneal metastasis; Enhanced recovery after surgery; Treatment timing

Core Tip: This editorial is based on an innovative study that explored the initiation of ultra-early adjuvant chemotherapy in patients with stage II-III gastric cancer 10-13 days after laparoscopic gastrectomy. The research results indicate that the ultra-early protocol is safe and feasible compared with the traditional initiation, and shows a trend of potentially reducing the incidence of peritoneal metastasis (4.8% vs 26.2%). However, ultra-early chemotherapy is accompanied by a higher demand for dose adjustment, suggesting that future treatment strategies need to strike a balance between intervention timing and maintaining effective dose intensity, and should combine tumor characteristics to achieve individualized treatment.

This editorial refers to “Early vs conventional initiation of adjuvant chemotherapy in advanced gastric cancer: A propensity-matched outcomes study” by Lin L et al, 2025; https://doi.org/10.3748/wjg.v31.i42.110069.

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INTRODUCTION

Gastric cancer is one of the most challenging malignant cancers in the world, and medical research has always been focused on improving its treatment strategies[1,2]. Surgery and surgical adjuvant chemotherapy (AC) are the keys to long-term success for patients with advanced digestive cancer[3]. To increase efficacy and safety, it is crucial to identify the optimal time to initiate AC after surgery.

When discussing the timing of initiating chemotherapy, it must be recognized that this decision should not be based solely on a preset time point, but rather on a comprehensive assessment process. The postoperative recovery speed and chemotherapy tolerance of patients are influenced by multiple clinical variables such as preoperative nutritional status, the degree of surgical trauma, and the risk of postoperative complications. Therefore, the ideal timing selection should be based on a comprehensive consideration of these individualized factors. Traditional clinical practice relies on the patient’s physiological recovery after surgery, and AC is generally planned for 4-6 weeks after the procedure. Research evidence from solid tumors like breast cancer and colorectal cancer has currently indicated that increasing the time between surgery and chemotherapy has been linked with shorter patient survival[4-8]. In the field of gastric cancer, a meta-analysis involving 11 studies and 6017 patients found that for every 4-week delay in AC, the risk of death for patients increased accordingly[9]. There may be a critical time for treatment following surgical excision of the principal tumor. After a tumor is surgically removed, there may be a key treatment time window that affects long-term efficacy. The underlying biological mechanism lies in the fact that surgical trauma itself can trigger a series of complex systemic and local changes. At the cellular level, this includes the functional inhibition of key effector immune cells such as natural killer cells[10]. At the molecular level, it is manifested as an increase in pro-inflammatory cytokines (such as interleukin-6, hepatocyte growth factor)[11]. These changes may not only weaken the immune surveillance of residual tumor cells in the body, but also provide a favorable microenvironment for their colonization and proliferation[12,13]. During this period, if timely intervention can be carried out to eliminate these residual lesions to the greatest extent, it is expected to improve the long-term prognosis of patients[4]. However, when presenting this conceptual framework in the scientific process of gastric cancer, its uniqueness needs to be carefully considered. People with gastric cancer often experience nutritional absorption disorders that have a significant effect on their potential to metabolize and survive chemotherapy[14]. Also, the patient’s physical treatment may be halted by the higher risk of complications that come with gastric cancer surgery, such as anastomotic leakage and infection, which reduces the need to start and procure AC[15,16]. The surgical health status and individual complication risk may be taken into account in the core assessment factors to analyze the first AC in the context of gastric cancer. Lin et al[17] published a study in World Journal of Gastroenterology, pioneered research that examined the safety, biomedical, and feasibility of starting AC at the “ultra-early” stage, 10 days to 13 days after surgery. The findings undoubtedly challenge our inherent clinical understanding. It also provides us with valuable inspiration for re-examining and planning the timing of adjuvant treatment for gastric cancer.

FEASIBILITY, SURVIVAL OUTCOMES, AND PERITONEAL METASTASIS TREND OF EARLY AC

The main findings of the research can be summed up as follows: Firstly, in terms of feasibility and safety, research has confirmed that initiating AC at an extremely early stage within the framework supported by laparoscopic surgery and the concept of enhanced recovery after surgery is clinically feasible. Although the proportion of dose reduction due to toxicity management needs in the early group was significantly higher than that in the conventional group (57.1% vs 26.2%), there was no statistically significant difference in the incidence of serious adverse events between the two groups, and no treatment-related deaths occurred. This indicates that although ultra-early chemotherapy requires more frequent dose adjustments, the risk of severe toxicity is not significantly increased, and its safety is within the clinically acceptable range. Secondly, with regard to overall survival rates and three-year recurrence-free survival rates, no significant differences were seen between the early group and the conventional group. This result forms an interesting contrast with the research findings of Kang et al[18], which showed that initiating chemotherapy within 4 weeks after surgery could improve long-term survival. This difference may stem from the sample size limitation of this study, or it may suggest that there is a complex balance between timing and dose intensity in the treatment of gastric cancer. If effective drug coverage levels cannot be retained due to insufficient treatment, the expected natural gains from early intervention may be significantly reduced. The most notable finding was that the incidence of peritoneal metastasis in the early group was significantly lower than that in the conventional group (4.8% vs 26.2%, P = 0.048). However, after multivariate correction to control for potential confounding factors, the statistical significance of this advantage vanished (hazard ratio = 0.42, 95% confidence interval: 0.09-1.89). This indicates that the observed differences in peritoneal recurrence rates may be partly attributed to the imbalance of patients’ baseline characteristics, while the independent protective effect of early chemotherapy itself remains uncertain at the sample size in the current study. Studies confirmed in animal models that early chemotherapy intervention within the perioperative window is the key to inhibiting peritoneal metastasis[19,20]. According to this research, developing intraperitoneal or intravenous chemotherapy immediately after surgery, or receiving medication both before and during the early postoperative period, reduced the synthesis of peritoneal metastases in rat models. The trends encountered in the patient population in this study are in line with the intervention time frame introduced by the above-mentioned animal experiments, which support the conclusion that ultra-early systemic chemotherapy probably reduces peritoneal metastasis of gastric cancer.

ANOTHER CORE LINK: OPTIMIZATION OF THE HOST STATE FOR ADJUVANT THERAPY AFTER GASTRIC CANCER SURGERY

Although the early group in this study achieved an earlier time, a problem was raised due to a higher dose reduction rate (57.1% vs 26.2%) and a lower relative dose intensity (67.5% vs 73.4%); that is, what we pursued was a timely and adequate biological therapeutic intervention. If the effective dose intensity cannot be maintained due to premature intervention, its potential biological advantages may be offset. Existing evidence indicates that the dose intensity of chemotherapy is closely related to the therapeutic effect. For instance, the study by Miyatani et al[21] clearly showed that an insufficient dose of S-1 in AC is an independent risk factor for poor prognosis in patients with stage II/III gastric cancer. The balance between timing and tolerance is far more crucial in gastric cancer due to the unique nutritional absorption disorder and the chance of postoperative complications. We need to specifically refine the postoperative treatment options for gastric cancer on account of this study. Therefore, future clinical decisions must go beyond mechanical adherence to a single temporal dimension and shift towards a multi-dimensional framework that integrates the following three key factors: The primary consideration is the molecular biological characteristics of the tumor. Studies have confirmed that different molecular subtypes of gastric cancer respond significantly to treatment. Patients with microsatellite instability-high have difficulty benefiting from traditional AC[22]. However, in Epstein-Barr virus-positive gastric cancer, fluorouracil combined with platinum-based chemotherapy not only achieves a high objective response rate, but its microenvironment characteristics of rich immune cell infiltration and high expression of programmed death-ligand 1 also provide a theoretical basis for it to receive immunotherapy in the early postoperative period[23-25]. Another core link is optimization of the host state, which directly determines whether early chemotherapy can be safely implemented. The common postoperative nutrient absorption disorders and high risk of complications in patients with gastric cancer not only delay initiating chemotherapy, but may also lead to a reduction or interruption of chemotherapy doses due to weakened patient tolerance. Studies have confirmed that poor nutritional status is a key factor affecting chemotherapy tolerance and relative dosage, while postoperative complications can directly interrupt the treatment process. Therefore, early and proactive nutritional support and complication prevention aim to build a physiological basis for patients to tolerate adequate chemotherapy, with the ultimate goal of ensuring the theoretical survival advantage brought about by early intervention[14,26]. In terms of intervention timing, dynamic monitoring of circulating tumor DNA (ctDNA) provides a new path for achieving precise treatment: Patients with persistently negative ctDNA after surgery have a good prognosis, while those with rapidly positive ctDNA have a significantly increased risk of recurrence and require early intervention[27-31]. By simultaneously evaluating the biological characteristics of the tumor, the host status, and the dynamics of molecular residual lesions, this multidimensional, comprehensive treatment strategy is expected to provide more precise and effective individualized plans for patients with different characteristics (Figure 1).

Figure 1  Schematic diagram of preliminary exploration of 4-6 weeks adjuvant therapy mode for cancer.

This study has limitations. The study failed to systematically expound the specific feasibility obstacles faced in translating ultra-early chemotherapy into universal clinical practice. For instance, whether a patient can safely initiate chemotherapy within 10 to 13 days after surgery highly depends on meticulous perioperative management, including timely removal of the drainage tube, the stable recovery of intestinal function, and the early identification and treatment of complications such as anastomotic leakage and infection. Any delay in these processes may result in chemotherapy being postponed. In addition, the common problem of poor postoperative nutritional status among gastric cancer patients was mentioned in this study, but no details of the enhanced intervention plan were provided. How to optimize patients’ physiological reserves and chemotherapy tolerance through effective nutritional support in an extremely short period of time is a key prerequisite for ensuring the implementation of adequate chemotherapy.

CONCLUSION

This study confirmed that for selected stage II/III gastric cancer patients who recovered smoothly under the enhanced recovery after surgery pathway, initiating AC 10 to 13 days after surgery is safe and feasible (Figure 1). However, ultra-early chemotherapy did not bring benefits in terms of overall survival or recurrence-free survival. Although univariate analysis showed a downward trend in the peritoneal recurrence rate in the early group (4.8% vs 26.2%, P = 0.048), this difference was no longer significant after multivariate correction (hazard ratio = 0.42, 95% confidence interval: 0.09-1.89). Therefore, the core value of this study lies in its exploratory nature. It challenges the traditional temporal paradigm and provides a preliminary clue for the utilization of the postoperative immune window. The results of this study challenge the traditional postoperative time paradigm, suggesting that future clinical decisions may need to go beyond mechanical adherence to fixed time nodes and instead comprehensively consider treatment timing, dose intensity, and individualized patient factors. However, the fundamental change in treatment patterns still requires higher-level evidence support.