Letter to the Editor: Ultra-early adjuvant chemotherapy after gastrectomy: Dose intensity, peritoneal recurrence, and evidence gaps

Abstract

Lin et al published a study in the recent issue of the World Journal of Gastroenterology, which reported a retrospective propensity-matched cohort evaluating ultra-early adjuvant chemotherapy (AC) initiation (10-13 days) after laparoscopic gastrectomy under enhanced recovery pathways. Their study challenges the prevailing practice of initiating AC after postoperative recovery, commonly around 4-6 weeks. While feasibility was demonstrated, interpretation is constrained by very low statistical power, residual confounding, and absent molecular stratification. The early cohort required substantially more dose reductions and had lower median relative dose intensity, raising the key question of whether any theoretical benefit of earlier intervention can persist under compromised dosing. A nominal reduction in peritoneal recurrence is intriguing but not supported by multivariable modeling and is vulnerable to small-sample uncertainty. We provide a structured methodological critique, a pragmatic synthesis of potential benefits and risks, and propose recovery-based selection domains for future trials. Biomarker-stratified, adequately powered randomized trials incorporating circulating tumor DNA and immune monitoring are needed to clarify whether a biologically meaningful postoperative window exists and to identify patients most likely to benefit.

Key Words: Gastric cancer; Adjuvant chemotherapy; Relative dose intensity; Peritoneal recurrence; Postoperative immunosuppression

Core Tip: Ultra-early adjuvant chemotherapy (10-13 days) after gastrectomy is feasible in selected patients but commonly requires dose reduction. Current evidence is underpowered and lacks biomarker stratification, limiting clinical generalization. The peritoneal recurrence signal is hypothesis-generating and should be tested in prospective trials with standardized dosing algorithms, recovery-based eligibility criteria, and molecular/circulating tumor DNA-guided risk stratification.

TO THE EDITOR

Adjuvant chemotherapy (AC) remains central to recurrence prevention after curative-intent resection for stage II/III gastric cancer. Lin et al[1] published a study in the recent issue of World Journal of Gastroenterology, which reported the propensity score-matched outcomes study to systematically evaluate ultra-early AC initiation at 10-13 days after laparoscopic gastrectomy within an enhanced recovery after surgery (ERAS) pathway. Their work is clinically provocative because, as noted by the authors, guidelines do not provide a definitive recommendation on the exact start time of AC, and AC is commonly initiated after adequate recovery, often within approximately 4-6 weeks in real-world practice. For clarity, we use the following practical timing taxonomy: Ultra-early (10-13 days), early (14-21 days), conventional (4-6 weeks), and delayed (> 6-8 weeks)[1-4]. The study pushes timing earlier than most prior clinical datasets and deserves careful contextualization.

Biological rationale: Compelling, but untested in the reported cohort

The hypothesis that earlier systemic therapy might counter a postoperative “immunosuppressive window” is supported by experimental evidence. Surgery can expand myeloid-derived suppressor cells and impair natural killer cell cytotoxicity, promoting metastatic outgrowth[5,6]. Broader translational evidence also supports the concept that perioperative stress perturbs anti-tumor immunity and may increase circulating tumor cells in the early postoperative period[7]. However, Lin et al[1] did not measure immune parameters, circulating tumor cells, or circulating tumor DNA (ctDNA), so the proposed mechanism remains inferential in their cohort. Future studies should incorporate serial immune profiling and minimal residual disease assessment to determine whether ultra-early AC truly targets a measurable biological vulnerability.

Timing and outcomes: What does current evidence support?

Evidence across gastric cancer cohorts consistently warns against substantial delays, yet does not prove that progressively earlier initiation is uniformly superior. A systematic review and meta-analysis associated delays beyond approximately 6-8 weeks with inferior survival in gastrointestinal malignancies including gastric cancer[2]. A large nationwide Korean cohort similarly suggested improved outcomes with earlier starts within standard postoperative windows[3]. In contrast, Western database analyses have sometimes reported limited or no detriment with later initiation, implying that timing effects may be context dependent and influenced by regimen choice, postoperative morbidity, and healthcare delivery factors[4]. Lin et al’s study[1] extends this debate to ultra-early initiation, but its null survival findings should be interpreted as “absence of evidence” rather than evidence of equivalence, given the statistical constraints discussed below.

Dose-intensity paradox: Feasibility achieved at the cost of compromised dosing

A key result is the markedly higher dose reduction rate in the ultra-early group (57.1% vs 26.2%) with a lower median relative dose intensity (67.5% vs 73.4%)[1]. Reduced delivered dose can plausibly offset any advantage of earlier start. In a meta-analysis across solid tumors, lower relative dose intensity was associated with worse survival, although optimal thresholds vary by regimen and setting[8]. In gastric cancer, reduced exposure to S-1 in the adjuvant setting has also been linked to inferior outcomes, particularly when combined with late initiation and inadequate cumulative dosing[9]. Rather than framing this as a binary “timing vs dose” question, future trials should prospectively define dose-modification algorithms and evaluate whether standardized proactive reductions (for example, starting at 75%-80% in ultra-early settings) can preserve tolerability while maintaining cumulative efficacy. This is crucial because clinicians cannot confidently extrapolate feasibility data if feasibility systematically depends on dose compromise.

Peritoneal recurrence: An intriguing but fragile signal

The most notable oncologic signal is the lower observed peritoneal recurrence rate (4.8% vs 26.2% by Fisher’s exact test), while Cox regression did not confirm statistical significance and confidence intervals were wide[1]. Experimental work suggests that immediate perioperative chemotherapy can suppress peritoneal carcinomatosis more effectively than delayed schedules[10,11]. If a true effect exists in humans, it may be most relevant for patients at high risk of peritoneal dissemination, such as diffuse-type histology or advanced T stage. However, given the small matched sample, peritoneal recurrence should be treated as a prioritized hypothesis for prospective testing rather than a basis for clinical adoption.

Missing molecular stratification: A major barrier to clinical translation

Gastric cancer is molecularly heterogeneous, and chemotherapy benefit is not uniform across subtypes. Mismatch repair deficiency/microsatellite instability-high status has been associated with distinct prognostic and treatment-response patterns in gastric cancer cohorts[12]. Epstein-Barr virus (EBV)-associated gastric cancer also demonstrates unique biology and may be associated with different clinical outcomes following systemic therapy[13]. Moreover, histologic differentiation has been associated with in vitro chemosensitivity in gastric cancer[14]. Without microsatellite instability/EBV/Lauren classification or other molecular stratification, any timing effect may be diluted or masked by subtype-specific responsiveness. Future trials should mandate baseline molecular profiling and prespecified subgroup analyses, ideally integrated with ctDNA-guided risk stratification.

Patient selection: Toward pragmatic, recovery-based eligibility domains

Ultra-early AC places substantial demands on postoperative recovery. Even within ERAS pathways and minimally invasive surgery programs, a meaningful minority of patients still experience early complications that can slow recovery and potentially delay readiness for subsequent systemic therapy[15-18]. To improve clinical usability and trial reproducibility, we propose that ultra-early AC eligibility be defined across three recovery domains: (1) Functional status (ECOG 0-1 with independent ambulation); (2) Nutritional adequacy (demonstrated stable oral/enteral intake with acceptable albumin and limited early weight loss); and (3) Absence of clinically significant postoperative complications (no anastomotic leak, uncontrolled infection, or organ dysfunction requiring intervention). These domains should be operationalized with prespecified thresholds and validated prospectively. Nutritional status warrants particular emphasis because gastrectomy commonly leads to postoperative weight loss due to reduced intake and impaired absorption, and chemotherapy may further exacerbate cachexia, which is associated with poorer quality of life and survival[19].

Statistical power and study design: Why structure matters

Lin et al[1] transparently reported extremely low post hoc power (3.6%), highlighting the risk of false-negative conclusions. Residual confounding is also plausible because matching was limited to a small set of variables, while body mass index, regimen distribution, and histology remained imperfectly balanced. Finally, only a small fraction of eligible patients received ultra-early AC, implying substantial clinician-driven selection that may not be captured in routine covariates. To enhance clarity, we summarize key methodological limitations, their implications, and mitigation strategies in Table 1. Large, multicenter randomized trials with biomarker stratification, standardized dose algorithms, and patient-reported outcomes will be required to establish whether ultra-early initiation provides net benefit.

Table 1 Methodological limitations of current evidence: Sources of bias, clinical implications, and mitigation strategies.

Source of bias	Description	Clinical implications	Mitigation strategies
Severe underpowering	Very small ultra-early cohort; wide confidence intervals; post hoc power extremely low in the index study	High risk of false-negative survival conclusions; “no difference” may reflect limited power	Prespecified sample-size calculation; multicenter recruitment; adaptive designs with interim reassessment
Selection bias	Only a small subset receives ultra-early AC; clinician-driven selection; criteria often not explicit	Overestimation of feasibility/safety; limited external validity	Explicit eligibility criteria; screening logs; randomization; intent-to-treat analyses
Residual confounding	Limited matching variables; imbalance may remain in regimen, BMI, histology	Outcomes may reflect baseline differences rather than timing	Randomization; comprehensive baseline capture; multivariable adjustment; sensitivity analyses
Absent biomarker stratification	No MSI/EBV/Lauren or immune/ctDNA assessment	True subgroup effects may be diluted; precision timing not feasible	Mandatory molecular profiling; ctDNA-based MRD stratification; prespecified subgroup analyses
Dose-intensity confounding	More frequent dose reduction; lower median RDI; unclear proactive vs toxicity-driven modifications	Timing effect cannot be separated from dose effect	Prospective dose-finding; standardized dose rules; RDI captured as endpoint with prespecified targets

MSI: Microsatellite instability; EBV: Epstein-Barr virus; BMI: Body mass index; ctDNA: Circulating tumor DNA; RDI: Relative dose intensity.

Implementation considerations: System-level feasibility

Even if efficacy is ultimately demonstrated, ultra-early AC would require redesign of perioperative-oncology workflows. Starting chemotherapy at 10-13 days compresses surgical recovery and oncologic treatment into a tightly coupled pathway, increasing coordination demands across surgery, oncology, anesthesia, nursing, and nutrition teams. In many systems, first-cycle delivery may require inpatient administration or intensified monitoring, with implications for bed capacity and costs. Post-discharge support, including structured symptom monitoring and rapid-access nutritional intervention, would likely be necessary to reduce unplanned visits and maintain adherence. These real-world constraints should be incorporated into trial endpoints through feasibility metrics and cost-effectiveness analyses.

CONCLUSION

Lin et al[1] provide important preliminary evidence that ultra-early AC can be delivered in selected patients within ERAS pathways, but frequent dose reduction and severe underpowering limit inference about oncologic benefit. Table 2 summarizes the potential benefits, challenges, and key research priorities for ultra-early AC. The peritoneal recurrence signal deserves prioritized validation in prospective, adequately powered trials, ideally enriched for patients at high risk of peritoneal dissemination and guided by molecular and ctDNA-defined risk. Ultimately, the goal is not to move chemotherapy earlier for all patients, but to define who benefits, under what dosing strategy, and within what recovery and system constraints.

Table 2 Ultra-early adjuvant chemotherapy in gastric cancer: Balancing opportunities and challenges.

Perspectives	Potential benefits	Risks/challenges	Future research requirements
Biological rationale	Targets a hypothesized postoperative immunosuppressive period; may suppress micrometastatic expansion	Human validation limited; optimal biological timing unknown	Serial immune profiling; CTC/ctDNA monitoring; translational perioperative studies
Oncologic outcomes	Possible reduction in peritoneal recurrence; earlier systemic control	No survival benefit proven; wide confidence intervals; small-sample instability	Adequately powered RCTs; peritoneal recurrence as prespecified endpoint; long-term follow-up
Treatment tolerability	Feasible under ERAS in selected patients; similar grade 3/4 toxicity reported	High dose-reduction rates; lower median RDI; nutrition-related vulnerability	Prospective dose-finding; standardized dose algorithms; patient-reported outcomes
Patient selection	Integration with ERAS and minimally invasive surgery may accelerate recovery	Eligibility criteria often implicit; limited generalizability	Recovery-based criteria (function, nutrition, complications); prediction models; external validation
Implementation	Potential to streamline “surgery-to-systemic therapy” pathway	Increased coordination demands; possible inpatient first-cycle needs; cost and capacity pressures	Feasibility endpoints; implementation science; cost-effectiveness across settings

CTC: Circulating tumor cells; ctDNA: Circulating tumor DNA; RCT: Randomized controlled trial; RDI: Relative dose intensity; ERAS: Enhanced recovery after surgery.