Comparison of Neoadjuvant Chemotherapy Followed by Surgery vs. Surgery Alone for Locally Advanced Gastric Cancer: A Meta-Analysis

Locally advanced gastric cancer (LAGC) remains a significant global health challenge, with over one million new cases and 768,800 deaths reported worldwide in 2020. Despite advancements in surgical techniques and adjuvant therapies, the prognosis for LAGC remains poor, as 40–50% of patients fail to achieve radical resection (R0 resection), and over half experience recurrence after surgery. The debate over the efficacy of neoadjuvant chemotherapy followed by surgery (NACS) compared to surgery alone (SA) continues, with conflicting evidence on survival benefits and perioperative safety. This meta-analysis, encompassing 20 studies (6 randomized controlled trials and 14 retrospective cohort studies) and 3,362 patients (1,420 in NACS, 1,942 in SA), systematically evaluates the oncological and surgical outcomes of these two approaches.

Study Design and Methodology

The meta-analysis included studies published between January 2000 and January 2021 from databases such as PubMed, Embase, and Cochrane Library. Eligible studies compared NACS (using regimens like cisplatin/fluorouracil, oxaliplatin-based therapies, or docetaxel combinations) with SA in LAGC patients. Primary outcomes focused on overall survival (OS), while secondary outcomes included perioperative indicators (operation time, harvested lymph nodes, R0 resection rate) and postoperative complications (Clavien-Dindo classification, anastomotic leakage, mortality). Study quality was assessed using the modified Jadad scale for RCTs and the Newcastle-Ottawa scale for cohort studies. Statistical analyses were performed using Review Manager 5.3, with hazard ratios (HRs), risk ratios (RRs), and weighted mean differences (WMDs) calculated for outcomes.

Key Findings on Survival and Surgical Outcomes

Overall Survival

Pooled data from eight studies (1,085 NACS vs. 1,576 SA patients) revealed no significant difference in OS between NACS and SA (HR = 0.86, 95% CI: 0.67–1.11, P = 0.240). This aligns with trials like the JCOG0501 study, which reported comparable survival rates despite improved R0 resection in the NACS group. However, subgroup analyses from the MAGIC trial and FNCLCC/FFCD studies suggested survival benefits in specific populations, highlighting heterogeneity in patient selection and chemotherapy regimens.

R0 Resection and Operative Metrics

NACS significantly improved R0 resection rates (RR = 1.08, 95% CI: 1.03–1.14, P = 0.003), a critical determinant of long-term outcomes. For instance, the FNCLCC trial reported a 12% increase in R0 rates with preoperative chemotherapy. However, NACS prolonged operation time by an average of 14.27 minutes (P < 0.0001), likely due to chemotherapy-induced tissue fibrosis complicating dissection. The number of harvested lymph nodes, a proxy for surgical quality, showed no difference between groups (WMD = −1.60, P = 0.200), indicating comparable lymphadenectomy completeness.

Postoperative Complications and Safety

Morbidity and Mortality

Total postoperative complications (RR = 0.91, P = 0.140) and 30-day mortality (RR = 0.80, P = 0.490) were similar between NACS and SA. However, NACS reduced reoperation rates by 48% (RR = 0.52, P = 0.030) and anastomotic leakage by 47% (RR = 0.53, P = 0.007). These benefits may stem from tumor downstaging, which facilitates safer resections. Intra-abdominal abscesses, ileus, and wound infections showed no significant differences, underscoring the safety of NACS in experienced centers.

Chemotherapy-Related Toxicity

Grade II–IV complications (Clavien-Dindo classification) were comparable, with Grade III events trending lower in NACS (RR = 0.79, P = 0.080). Notably, studies using triplet regimens (e.g., docetaxel/cisplatin/fluorouracil) reported higher hematologic toxicity but did not increase surgical morbidity, suggesting manageable side effects with proper patient selection.

Clinical Implications and Limitations

The absence of OS benefit contradicts earlier meta-analyses by Hu et al. (2019) and Xiong et al. (2014), which reported survival advantages for NACS. This discrepancy may arise from variations in chemotherapy protocols, staging accuracy, and regional treatment practices. For example, Asian trials often use S-1-based regimens, while Western studies favor platinum/taxane combinations. Moreover, preoperative staging inaccuracies (e.g., overestimation of T3/T4 tumors in 12.3% of JCOG1302A cases) may dilute treatment effects.

The improved R0 resection and reduced reoperation rates support NACS as a feasible strategy for borderline resectable tumors, particularly in high-volume centers. However, the lack of standardized protocols—ranging from 2–4 cycles of chemotherapy and variable drug combinations—limits generalizability. Additionally, most included studies lacked long-term quality-of-life data, a critical factor in treatment decision-making.

Future Directions

Ongoing trials evaluating immunotherapy (e.g., pembrolizumab in KEYNOTE-585) and targeted therapies (e.g., trastuzumab for HER2+ tumors) in neoadjuvant settings may redefine LAGC management. Molecular profiling to identify biomarkers for chemotherapy response could further personalize treatment. Meanwhile, consensus on optimal regimens and staging criteria is urgently needed to harmonize global practices.

Conclusion

This meta-analysis confirms that NACS enhances R0 resection rates and reduces specific surgical complications without compromising short-term safety. However, the lack of OS benefit underscores the need for refined patient stratification and novel therapeutic approaches. While NACS is a viable option for locally advanced disease, its role in improving long-term survival remains to be elucidated through rigorously designed trials integrating modern oncologic therapies.

doi.org/10.1097/CM9.0000000000001603

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